Cardio/Resp/Renal Flashcards

Question

Hypoxaemia - causes (broad)

Answer 1

Hypoventilation Diffusion limitation Shunt (R->L) VQ mismatch

Answer 2

Hypoventilation | VQ mismatch

Answer 3

Reduction in functional lung volume - TLC < 80%

Answer 4

``` K = ketoacidosis U = uraemia (renal failure) L = lactic acidosis (ischaemia) T = toxins (ethylene glycol, methanol, aspirin (salicyclates), metformin) ```

Answer 5

``` C = chloride excess (eg. NaCl) A = acetazolamide, Addison’s G = GIT causes – diarrhoea, vomiting, fistula (pancreatic, ureters, biliary, small bowel, ileostomy) E = extra – RTA ```

Answer 6

Reflects the metabolic component of an acid-base disorder Normal value is 0 If BE <0, have less HCO3- than normal, therefore have metabolic acidosis If BE >0, have more HCO3- than normal, therefore have metabolic alkalosis

Answer 7

Irreversible abnormal dilatation and anatomic distortion of the bronchial tree and represents a common end stage of many non-specific and unrelated antecedent events Common thread in the pathogenesis of bronchiectasis consists of difficulty clearing secretions and recurrent infections with a ‘vicious cycle’ of infection and inflammation -> injury + remodelling

Answer 8

clinical syndrome in children with symptoms and/or signs of bronchiectasis but who lack a radiographic diagnosis of bronchiectasis

Answer 9

CF, followed by primary immunodeficiency

Answer 10

PCD is an inherited disorder characterised by impaired ciliary function Includes = ciliary akinesia, dyskinesia and aplasia Common consequence is impaired mucociliary clearance Key features - Chronic sinuopulmonary disease - Persistent middle ear effusions - Laterality defects - Infertility The common defect in PCD is the absence of dynein arms, the structures necessary for the generation of movement of cilia and sperm tails Typically autosomal recessive

Answer 11

Parainfluenza viruses (1,2,3) account for 75%

Answer 12

1. Larygomalacia 2. Congenital subglottic stenosis 3. Vocal cord paralysis

Answer 13

Aberrant innominate artery (AKA brachiocephalic artery) ii. May be asymptomatic and discovered incidentally, OR cause severe symptoms iii. Expiratory wheezing and cough occur, and rarely, reflex apnoea or ‘dying spells’ iv. Surgical intervention rarely necessary v. Infants are treated expectantly as the problem is self-limited

Answer 14

Dilated (60% of childhood cardiomyopathy) Dilatation -> impaired contraction -> systolic dysfunction Cause: idiopathic, myocarditis (infective, viral), genetic Intracavitatory thrombus is common -> PE and systemic emboli 90% present with heart failure In infants, anomalous coronary origin from a pulmonary artery must be excluded (ALCAPA) Recent review – 1/3 die, 1/3 recover completely, 1/3 improve with some residual cardiac dysfunction

Answer 15

a. Becoming one of the most common causes of chronic CHF in children b. Non-linearly dose related – occurring in 2-5% of patients who have received a cumulative dose of 400-500 mg/m2 and up to 50% of patients who have received more than 1000 mg/m2 of doxorubicin Patients have a history of receiving doxorubicin, with the onset of symptoms 2-4 months, and rarely years after completion of therapy ii. Usually asymptomatic until signs of CHF – tachypnoea, and exertional dyspnoea i. NO effective treatment a. Symptomatic patients have a high mortality rate b. 2 year survival rate is about 20% c. Almost all patients die by 9 years after the onset of illness

Answer 16

Hypertrophic cardiomyopathy 30% of childhood cardiomyopathy e. 10-20% of infants of diabetic mothers develop a transient form of HCM with or without LVOT obstruction >13mm is abnormal for LVH Inherited in 30-60% of cases - autosomal dominant Syndromes (Noonan, Beckwith Weidemann, LEOPARD, Friedreichs ataxia) Metabolic ii. Thickening of LV -> reduced diastolic filling -> LA enlargement and pulmonary venous congestion 1. This results congestive symptoms (exertional dyspnoea, orthopnoea, PND)

Answer 17

a. Extremely rare – 5% of cases in children b. Basic defect unknown c. Diastolic dysfunction with normal wall thickness and systolic dysfunction d. Relentless downhill course – the worst type of cardiomyopathy (contrasting HOCM which is very variable) i. Typically require transplantation within years Mostly idiopathic b. The ventricles are normal in size and systolic function c. Only the atria are markedly dilated (biatrial enlargement) – characteristic finding a. Poor prognosis – not improved by medical management b. SCD is common c. High risk of atrial tachycardias and thromboemboli d. 2 year survival 50%

Answer 18

i. First or second degree AV block ii. Profound sinus bradycardia or sinoatrial block iii. SVT (atrial or junctional ectopic beats and tachycardias), rarely ventricular arrythmias iv. Shortening of QTc and reduced amplitude of T wave are signs of digitalis effect

Answer 19

i. Primary post-transplant malignancy ii. Usually polymorphic: B cell origin, EBV driven iii. 9% within 7 years, 3 year 70% survival iv. Management 1. Reduction/ cessation of therapy 2. IV acyclovir 3. Chemotherapy 4. Rituximab has shown some benefit

Answer 20

``` Secundum defect (50-70%) Primum defect (15-30%) Sinus venosus defect (10%) Coronary sinus ASD (rare) ```

Answer 21

ECG: • RAD (+90 to +180) with mild RVH or RBB (rsr’ in V1) • The dilated RV prolongs repolarisation of the RV because of its longer pathway – producing either complete or incomplete RBB (rsr’ in V1) [BBB NOT due to actual block in right bundle) • Mild RVH may be present CXR: • Cardiomegaly with enlargement of the RA and RV, increased PBF if large shunt • Cardiomegaly with enlargement of the RA and RV may be present • Prominent pulmonary artery segment and increased pulmonary vascular markings – if shunt significant

Answer 22

i. ASD <3mm diagnosed <3 months of age – spontaneous closure in 100% ii. Spontaneous closure occurs >80% of the time with defects 3-8mm by age 1.5 years iii. Defect >8mm rarely occurs spontaneously; and is not likely to occur after 4 years of age

Answer 23

Perimembranous - Membranous defect involves varying amounts of muscular tissue adjacent to membranous septum (Perimembranous VSD)

Answer 24

i. Perimembranous + muscular = spontaneous closure can occur 1. Occurs most frequently with small defects during the first 6 months of life 2. 60% of small to moderate muscular VSDs close spontaneously; NOT after 8 years of age 3. 35% of small perimembranous VSDs close spontaneously; NOT after 5 years of age 4. VSDs do not become bigger with age, they decrease in size ii. Inlet defects and outlet (infundinbular) = defects do NOT become smaller or close spontaneously

Answer 25

i. Small shunt 1. At < 5mm, the shunt tends to be restrictive (negligible shunting) as there is anatomical to flow ii. Large shunt 1. >10 mm, minimal anatomical resistance to flow 2. May be called dependent/ non-restrictive, as shunting dependent on level of PVR 3. When PVR drops at ~ 2 months, features of shunting appears

Answer 26

ECG: • Small VSD = normal • Moderate VSD = LVH and occasional LAH • Large VSD = BVH with or without LAH • If pulmonary obstructive disease = only RVH CXR: • Degree of cardiomegaly and the increase in pulmonary vascular markings directly relate to the magnitude of the L to R shunt • Small = pulmonary vascular congestion, no chamber enlargement • Medium = enlargement of LA, LV and PV, with increased pulmonary markings • Large = significant cardiomegaly, biventricular enlargement, LA enlargement, greatly increased pulmonary vascularity; also have dilatation/ prominence of main pulmonary artery • Eisenmenger = the main PA and hilar PAs enlarge, but the peripheral lung fields are ischaemic and heart size normal

Answer 27

Trisomy 21 - 70% patients with AVSD have Downs

Answer 28

i. Complete form of ECD = VSD + ostium primum type of ASD + clefts in the mitral and tricuspid valve (Single valve orifice connecting the atrial and ventricle chambers – usually has 5 leaflets) ii. Partial form of ECD = ostium primum type of ASD + cleft in the mitral valve (-> mitral regurg) a. Balanced (the majority): AV orifice equally committed to RV/ LV b. Unbalanced: orifices committed primarily to one ventricle -> single ventricle physiology (may require Fontan

Answer 29

Superior axis = AVSD (pink) or tricuspid atresia (blue) ECG: • Superior QRS axis with QRS axis between -40 and -150 degrees characteristic o Different to secundum ASD o Occurs due to abnormality in development of bundle of His • RVH or RBBB (rsR’ in V1) as in secundum ASD • 50% of the patients have a prolonged PR interval (1st degree block) CXR: • As for secundum ASD – except enlargement of the LA and LV when MR is significant • Characteristic ‘goose neck’ deformity is seen on a left ventriculogram

Answer 30

Does not occur

Answer 31

ECG: • Superior QRS axis with QRS axis between -40 and -150 degrees characteristic • Prolonged PR interval • RVH or RBB present in all cases, may have LVH too • Q waves in lead I and aVL CXR: • Biatrial and biventricular hypertrophy o Volume overload of the LA and LV, as in VSD and partially due to MR o Volume overload of the RA and RV, as in ASD • Pulmonary vascular markings increased, main PA segment prominent

Answer 32

Characteristic of PDA (not present if small)

Answer 33

Characteristic of PDA | Loudest LUSE/infraclavicular

Answer 34

Hallmark of stenosis at the semilunar valves/valvular stenosis o Pulmonary stenosis  prominent PA segment visible on CXR o Aortic stenosis  dilated aorta may look like a bulge on the right upper mediastinum, or a prominence of the aortic knob on the left upper mediastinum and chest film • Post-stenotic dilation is NOT seen with sub-valvular stenosis; it is only MILD or not seen with Supravalvular stenosis

Answer 35

ECG: • RAD, RVH in moderate PS • RAH and RVH ‘strain’ may be seen in severe PS (T wave inversion on praecordial leads) • Neonates with critical PS may show LVH because of a hypoplastic RV and relatively large LV CXR: • Heart size usually normal on CXR • Dilatation of the main pulmonary artery may be seen (post stenotic dilatation) • Pulmonary vascular markings are usually normal but may decrease if severe • Cardiomegaly only if CHF develops • In neonates with severe PS – lung fields oligaemic with varying degrees of cardiomegaly

Answer 36

i. Congenital rubella = pulmonary stenosis AND peripheral pulmonary stenosis ii. Alagille = peripheral pulmonary stenosis iii. Williams = peripheral pulmonary stenosis iv. Noonan = pulmonary stenosis (valvular) with dysplastic pulmonary valves

Answer 37

Bicuspid aortic valve - most common cause valvular aortic stenosis (valvular is most common type of AS) 2nd is VSD

Answer 38

Dyspnoea/fatiguability Exertional syncope Chest pain

Answer 39

ECG: • LVH with moderate to severe stenosis; may have strain pattern in severe stenosis (poor correlation between ECG and severity) CXR: • Heart size usually normal in children – can have a dilated ascending aorta or a prominent aortic knob with valvular AS resulting from post-stenotic dilatation • Significant cardiomegaly does not develop unless CHF occurs later in life or AR becomes substantial • Newborns with critical AS show generalised cardiomegaly with pulmonary venous congestion

Answer 40

Mitral valve (regurgitation) - note, still rare - followed by aortic valve

Answer 41

Tetralogy of Fallot

Answer 42

Tetralogy of Fallot (10% of cyanotic lesions)

Answer 43

ECG: • RAD (+120 to +150), RVH, RAH • Acyanotic – may be normal QRS and RVH CXR: • Heart size is normal or smaller than normal • Pulmonary vascular markings a decreased – ‘black’ lung fields may be seen in TOF with pulmonary atresia • Boot shaped heart = concave main PA segment (small pulmonary artery) + upturned apex due to RVH • RA enlargement (25%) and right aortic ring (25%) may be present

Answer 44

ECG: • LAD/Superior QRS axis (between 0 and -90) – appears in most patients without TGA (only 50% with TGA) • LVH is usually present • RAH or bi-atrial hypertrophy is common CXR: • Normal or mildly enlarged cardiac silhouette – enlargement of RA and LV • Pulmonary vascularity decreases in most patients • Occasionally concave PA segment may produce boot shape heart similar to TOF

Answer 45

DiGeorge in 30% of cases Key features: a. Common pulmonary artery/ aorta b. VSD always present c. Cyanosis is MILD due to high pulmonary blood flow d. Eventually leads to increased pulmonary resistance + Eisenmenger’s

Answer 46

Hypoplastic left heart syndrome - Hypoplasia of the LV – completely nonfunctional a. Unwell in the newborn period b. Acidosis out of proportion of CO2 c. Complications = inadequate systemic circulation, pulmonary venous hypertension OR pulmonary over circulation c. Association = Turner, Trisomy 18, Jacobsen’s syndrome d. Also a prevalence of associated brain anomalies a. ABG = decreased PO2 and normal PCO2, severe metabolic acidosis out of proportion to the PCO2 (caused by markedly decreased output) characteristic of the condition

Answer 47

Think about referring your patient to an allergist/immunologist when there is the presence of > 2 of the following warning signs: 1. > 8 ear infections in one year 2. > 2 severe sinus infections in one year 3. > 2 months treatment of antibiotics with little effect 4. > 2 pneumonias per year 5. Insufficient weight gain or growth delay 6. Recurrent deep skin or organ abcesses (ex. :liver, lungs) 7. Persistent thrush in mouth or fungal infection on skin 8. Need for intravenous antibiotics to clear infections 9. > 2 deep seated infections (ex. : septicemia, meningitis) 10. Family history of a primary immunodeficiency

Answer 48

6-8 resp infections/yr first 10 years 6 otitis media/year first 2-3 years 2 gastroenteritis/yr first 2-3 years May exceed these in day care or with older siblings

Answer 49

Altered facies (flattened nose, prominent infraorbital creases, micrognathia, large low set ears) Aberrant limb positioning Late growth deficiency Pulmonary hypoplasia

Answer 50

Blood from torn emissary veins accumulates within loose connective tissue between galea aponeurotica and periosteum Subgaleal space extends from orbits to nape of neck and laterally above ears Can accumulate a large amount of total blood volume Crosses sutures and covers fontanelles Shifts to dependent part of head May push ears forward

Answer 51

Collection of blood under periosteum | Does not cross sutures, distinct borders

Answer 52

``` Brachial plexus injury RFs: macrosomia, shoulder dystocia Injury to C5 and C6 nerve roots +/- C7 Limp arm with internal rotation of forearm and flexion of wrist DDx: clavicular fracture Complete recovery occurs in most cases ```

Answer 53

Hand is paralysed but infant has full function of elbow and shoulder

Answer 54

a. Congenital pulmonary airway malformation (CPAM) = hamartomatous (noncancerous tumor made of an abnormal mixture of normal tissues and cells from the area in which it grows) or dysplastic lung tissue mixed with more normal lung b. Due to embryologic abnormalities of branching morphogenesis c. Connection with tracheobronchial tree d. Blood supply= pulmonary circulation e. Prognosis dependent on size f. Generally confined to one lobe g. 1-4/100,000 births Type 1 most common 75% asymptomatic Surgery (resolve symptoms, malignancy risk)

Answer 55

a. Aberrant formation of segmental lung tissue that has NO connection with the bronchial tree or pulmonary arteries b. Non-functioning c. Receives its arterial supply from systemic arteries (commonly off the aorta) d. Classified by how blood returns to the right side of the heart i. Inferior vena cava = extra-lobar ii. Pulmonary veins = intra-lobar (75-85%) e. Sequestration functions as a space-occupying lesion within the chest; does NOT participate in gas exchange i. Does NOT lead to left to right shunt or alveolar dead space f. Communication with the airway can occur as a result of a rupture of infected material into an adjacent airway g. Collateral ventilation within intrapulmonary lesions via pores of Kohn can occur h. Gastric or pancreatic tissue ay be found within the sequestration i. Cysts may also be present Rx: surgical resection

Answer 56

a. Developmental anomaly of the lower respiratory tract characterised by hyperinflation of one or more of the pulmonary lobes 🡪 progressive, massive, uniform dilatation of a lobe b. Results in compression of the remaining lung tissue and herniation of the affected lobe across the anterior mediastinum into the opposite chest 🡪 displacement of the mediastinum i. Affected lobe is essentially non-functional due to overdistension - LUL most common ii. Atelectasis of the ipsilateral normal lung can occur Almost all present by 1 year of age Rx: Surgery

Answer 57

Congenital heart disease (1/3 all anomalies) 1% of live births 25% "critical" i.e. needing surgery first year of life

Answer 58

Congenital heart disease

Answer 59

24 hours to 2 weeks Duct dependent PBF -> cyanosis Duct dependent systemic BF -> shock/hypoperfusion

Answer 60

1. Occurs in: a. CHD i. Critical CoA ii. Interrupted aortic arch iii. Critical AS b. PPHN 2. Deoxygenated blood flow through the ductus arteriosus supplies the lower half of the body’s circulation 3. Oxygenated blood from the left heart supplies the upper body via the vessels proximal to the site of arch obstruction 4. Difference of >3% in oxygen saturations measured on the right and (preductal) and either foot (post ductal) identifies differential

Answer 61

1. Hypoplastic left heart syndrome 2. Critical AS 3. Critical CoA 4. Interrupted aortic arch

Answer 62

R) heart lesions: critical PS, pulmonary atresia with intact ventricular septum, Ebstein anomaly, (TOF and TA depending on RVOT obstruction) L) heart lesions: HLHS, critical AS

Answer 63

a. Spleen absent b. Bilateral R sidedness characterised malformations of the major organs i. Bilateral, three lobed lungs with bilateral eparterial bronchi ii. Various gastrointestinal malformations iii. Symmetrical midline liver iv. Malrotation of the intestine c. Complex cardiac malformations i. Normal IVC ii. TGA with pulmonary atresia (85%) iii. Single ventricle and common AV valve iv. TAPVR to Extracardiac structures occurs in >75% >95% die within first year

Answer 64

Usually female (70%) a. Multiple splenic tissue b. Tendency for bilateral left sidedness i. Bilateral, bilobed lungs (ie two left lungs) ii. Bilateral, hyperartrial bronchi iii. Symmetrical liver iv. Occasional absence of gallbladder v. Intestinal malrotation c. Cardiovascular abnormality iii. Key features 1. Absence of the hepatic segment of IVC with azygous (right side) or hemiazygous (left side) continuation is seen in 85% 2. Two ventricles are usually present 3. TGA, PS or pulmonary atresia, TAPVR occur less often 4. ECG shows superiorly oriented P axis (ectopica atrial rhythm) resulting from absence of the sinus node 5. Occurs more often in females First year mortality 60%

Answer 65

Complete = abnormal vascular structures or their remnants form a COMPLETE circle around the trachea and esophagus 1. Includes: a. Double aortic arch (most common, 40%, presents in early infancy with respiratory distress and feeding problems) b. Tight aortic arch Incomplete = do not form a complete circle, but do compress the trachea and esophagus 1. Includes a. Anomalous innominate artery b. Aberrant right subclavian artery (asymptomatic) c. Anomalous left PA (vascular sling/ pulmonary sling) Barium swallow diagnostic (EXCEPT for in innominate artery)

Answer 66

``` Common causes = HAT SAND • HOCM • AVSD • Tricuspid atresia • Single ventricle • ASD primum • Noonan’s (especially HCM) • DORV ```

Answer 67

* Normal amplitude < 3mm * Normal duration <0.07 infants, <0.09 children, <0.12 adults * Amplitude changes with hypertrophy RAH - tall >3mm LAH - wide >100msec (2.5 small squares)

Answer 68

o Pathological = if deep (> 25% R wave amplitude), wide, or unusual location  Appear in the right precordial leads ie V1 (eg severe RVH)  Are absent in the left precordial leads (e.g. LBBB)  Are abnormally deep (ventricular hypertrophy of the volume overload type)  Are abnormally deep and wide (myocardial infarction or fibrosis)

Answer 69

o For the first 8 days - T waves are upright throughout the precordial leads. o >8 days the T waves become inverted in V1-3 [right precordium] (= the “juvenile T-wave pattern”)  T wave inversion up to V4 permitted o Progressive change to upright T waves across precordial leads from L to R with growth o Juvenile T-wave pattern can persist into adolescence and early adulthood (= “persistent juvenile T waves”)  Particularly common in V1

Answer 70

• Extra positive deflection at the end of the T wave • Common causes o Hypokalaemia o Normal finding at slower heart rates (sinus bradycardia)

Answer 71

PR <200msec QRS <120msec QTc <490msec if <6mo or <440 if >6mo

Answer 72

Summary: upright T waves V1, tall R V1, deep S V6, RAD for age (Parks) 1. RAD for patients age 2. Increased right sided QRS voltages a. Large R wave in V1 (also III, aVR and V2) b. Large S wave in V6 (also I, V4 and V6) c. Abnormal R/ S ratio – generally big R waves in R leads, big S waves in L leads 3. Upright T wave in V1 > 3 days of life if < 7 years (also V3R , V4R) 4. Abnormal Q waves in V1 suggestive 5. ‘Strain pattern a. Features more consistent with ‘pressure overload’ – Tall R waves, upright T waves b. Features more consistent with ‘volume overload’ - rsR’ pattern, prolonged QRS

Answer 73

Important for determining ventricular hypertrophy RVH (543, 321) - cm R in V1: <1mo 5, 1mo-1yr 4, >1yr 3 S in V6: <1mo 3, 1mo-1yr 2, >1yr 1 LVH (123, 345) - squares R in V6: <1mo 3, 1mo-1yr 4, >1yr 5 S in V1: <1mo 1, 1mo-1yr 2, >1yr 3

Answer 74

Summary: Tall R V6, deep S V1, T wave inversion V5/V6 Park’s 1. (LAD) 2. Increase in L sided QRS voltages a. R wave in V6 b. S wave in V1 c. T axis change = strain d. R in V5/6 + S in V1 > 30 mm under 1 year, >40 mm after 1 year, > 60mm (?age – Andrew Davies’ lecture/ Harrison) e. S in V1 > 2x R in V5 3. Deep Q waves in L praecordial leads suggestive 4. Strain pattern ( ?T waves inverted in lead 1 or aVF) 5. Diastolic vs systolic a. Systolic overload: T wave inversion over L praecordial leads b. Diastolic overload: Q waves with normal T waves

Answer 75

* +ve criteria for LVH + RVH * +ve for LVH OR RVH and big voltages in other ventricle (> 50th percentile) * Large equiphasic QRS complexes in > 2 limb leads mid praecordial leads (V2-5)

Answer 76

QRS up in V1 o Diagnostic criteria  Broad QRS >120ms  RSR’ pattern in V1 (+/- V2-3) (M shaped QRS complex) = M  Wide, slurred S wave in lateral leads (I, AVL, V5-6) = W o Associated features  ST depression and T wave inversion in right precordial leads (V1-3) o Variations  Sometimes rather than RSR’ pattern, there may be a broad monophasic R wave or qR complex

Answer 77

o Post-operatively – particularly TOF (90% of repaired TOF have RBBB) o CHD = AVSD, Ebstein’s anomaly, COA, PAPVR o Right ventricular hypertrophy / cor pulmonale o Pulmonary embolus o Ischaemic heart disease o Rheumatic heart disease o Myocarditis or cardiomyopathy o Degenerative disease of the conduction system o Congenital heart disease (e.g. atrial septal defect)

Answer 78

• RSR’ in V1 (R waves the same size) • QRS normal/ mildly prolonged • Causes: normal variant, secundum ASD (with RAD), primum ASD (with LAD), Ebstein’s anomaly (with RAH + delta waves) -> differentials: ASD, Ebsteins anomaly

Answer 79

QRS down in V1 o Diagnostic criteria  Broad QRS >120ms  Absence of Q waves in lateral leads (I, V5-6)  QRS down or mostly down in V1 (dominant S wave in V1)  Broad monophasic R wave in lateral leads (I, avL, V5-6)  Prolonged R wave peak time >60ms in left precordial leads (V5-6) o Associated features  Appropriate discordance: the ST segments and T waves always go in the opposite direction to the main vector of the QRS complex  Poor R wave progression in the chest leads  LAD

Answer 80

``` o RARE IN CHILDREN o Cardiac surgery/disease o AV replacement o LVH Other (adults) – aortic stenosis, IHD, HTN, dilated cardiomyopathy, anterior MI, primary degenerative disease (fibrosis) of the conducting system (Lenegre disease), hyperkalaemia, digitoxin toxicity ```

Answer 81

``` • Based on K+ o 5.5-6.5 = tall peaked T waves o 5.5-7.5 = loss of P waves o 7.0-8.0 = widened QRS o 8.0-10.0 = sine wave, ventricular arrythmias, asystole ``` • Summary of abnormalities o Tall peaked T waves, best seen in precordial leads o Prolongation of QRS duration o Prolongation of PR interval o Disappearance of P wave o Wide bizarre biphasic QRS complexes (sine waves). o Eventual asystole

Answer 82

• K+ <2.5 o Prominent U waves develop with apparent prolongation of the QTc (prolonged “QU” interval) o Flat or biphasic T waves o ST segment depression • K+ falls further o PR interval prolongs o Sinoatrial block may occur

Answer 83

Hypercalcaemia • Shortens the ST segment and QTc Hypocalcaemia • Prolongs the ST segment with resultant prolongation of the QTc

Answer 84

* Initial widespread concave ST segment elevation and PR segment depression. * ST segment returns to normal within 1-3 weeks, along with flattening of the T waves. * T wave inversion (with isoelectric ST segment) occurs from 2-4 weeks after the onset of pericarditis.

Answer 85

o –ve P wave in I, and +ve in AVF | o V5 and V6 have no wave form – no electrical activity in this part of the chest

Answer 86

P axis is between 0 and +90 degrees (= upright P waves in lead II and inverted P waves in aVR)

Answer 87

Supraventricular tachycardia Key points a. Rapid regular, usually narrow (< 80 ms) complex tachy of 220-320bpm (infants) and 150-250 (older children) b. The P wave is usually invisible, or if visible is abnormal in axis and may precede or follow the QRS (“retrograde P waves”) c. 90% of paediatric dysrhythmias are SVT; 90% of SVT are of re-entrant type d. Half of patients with SVT will have no underlying heart disease e. Almost 1⁄4 will have congenital heart disease and 1⁄4 will have WPW f. Consider fever or drug exposure (particularly sympathomimetics) g. SVT may be well tolerated in infants for 12-24 hours  congestive heart failure later manifests with irritability, poor perfusion, pallor, poor feeding and then rapid deterioration. h. Note that > 95% of wide complex tachycardias in paediatrics are NOT VT, but SVT with aberrancy, SVT with BBB (in pre-existing congenital heart disease) or a type of accessory pathway re-entrant SVT

Answer 88

Antidromic accessory RAVT

Answer 89

a. No heart disease in 50% of patients b. WPW pre-excitation present in 10-20% of cases, which is evident only after conversion to sinus rhythm c. Some CHDs more prone to this arrythmia  Ebstein anomaly, hamartoma (eg. in TS), HCM/ DCM, single ventricle, L-TGA (/ congenitally corrected TGA) d. SVT may occur following cardiac surgeries

Answer 90

features in sinus rhythm a. Short PR (<120ms) b. Delta wave – slurring slow rise of initial portion of QRS c. QRS prolongation >110 ms d. ST segment and T wave discordant changes – ie in the opposite direction to the major component of the QRS complex e. Absent Q wave in V6 i. Q wave in V6 is due to septal activation L  R ii. There is no Q wave in V6 due to WPW iii. Absence is a sign of pre-excitation

Answer 91

Arrythmias related to exercise are significant. Induction or exacerbation with exercise may be an indication of underlying heart disease In children PVCs characteristically are reduced or eliminated by exercise All children with symptomatic ventricular arrhythmias and those with complex PVCs (multiform PVCs, ventricular couplets, unsustained ventricular tachycardia) should be treated i. Beta blockers – effective for cardiomyopathy and occasionally for RV dysplasia ii. Other antiarrhythmic drugs iii. Anti-arrythmic agents that prolong the QT interval (class IA quinidine + procainamide; class IC encainide + flecainide; class III amiodarone) should be AVOIDED a. Children with otherwise normal hearts, occasional isolated uniform PVCs that are suppressed by exercise do not require extensive Ix b. Asymptomatic children with multiform PVCs and ventricular couplets should have 24 hour Holter monitoring, even if they have structurally normal hearts, to detect the severity and extent of ventricular arrythmias c. Children with uniform PVCs, including bigeminy and trigeminy, do not need to be treated if exercise stress test and echo are normal e. For patients with symptomatic ventricular arrhythmias or sustained VT and seemingly normal hearts, MRI (preferable) or cardiac cath may be indicated to Ix for RV dysplasia i. Occasionally invasive EPS or Endomyocardial biopsy indicated f. Children with multiform PVCs and runs of PVCs (VT) with or without symptoms need to be evaluated by an electrophysiologist

Answer 92

7-20 Polyhydramnios (1-2%): AFI>24 or single deepest pocket >8 - 1/3 associated anomalies Oligohydramnios (10%): AFI<5 or single pocket <2

Answer 93

i. Severe hypoxia in FiO2 100% ii. Evidence of R to L shunt iii. TTE confirmation structurally normal heart 4. Risk factors a. MAS (41%) b. Pneumonia (14%), RDS (13%), mixed (14%) c. CDH (10%) d. Pulmonary hypoplasia (4%) e. Idiopathic (17%)

Answer 94

Pulmonary haemorrhage Key points a. Relatively uncommon b. Occurs in 10% of extremely preterm infants c. Massive pulmonary haemorrhage can be fatal d. Pulmonary haemorrhage is the only severe complication whose rate is increased with surfactant treatment i. Seen with all surfactants; incidence ranges from 1-5% of treated infants ii. Incidence higher with natural surfactant

Answer 95

a. 70% of neonatal encephalopathy associated with events prior to onset of labour b. Antenatal i. Maternal factors = unemployment, family history of seizures or neurological disorder, infertility treatment, thyroid disease ii. Placental conditions = severe pre-eclampsia, post-dates, abnormal placenta iii. Fetal problems = IUGR -> strongest risk factor c. Intrapartum i. Persistent occipitoposterior position ii. Shoulder dystocia iii. Emergency cesarean delivery iv. Operative vaginal delivery v. Acute intrapartum events or sentinel events – uterine rupture, placental abruption, cord prolapse vi. Inflammatory events – maternal fever, chorioamnionitis d. NOTE i. Perinatal stroke is a separate recognized entity in term newborns with encephalopathy ii. Metabolic and neurodegenerative disorders may underlie neonatal encephalopathy

Answer 96

a. Neonatal encephalopathy = heterogenous, clinically defined syndrome characterised by disturbed neurologic function in infant born >35 weeks gestation b. Key features i. Reduced level of consciousness ii. Difficulty with initiating + maintaining respiration iii. Depression of tone and reflexes

Answer 97

i. Maintained at 72 hours form 33-35 degrees ii. Started within 6 hours off delivery iii. Reduces cerebral metabolic rate, reduces apoptosis, lowers production of nitric oxide and free radicals iv. Must be < 6 hours post birth, and > 35/40 v. Followed by 12 hours of active gradual rewarming after 72 hours of cooling. vi. Only neuroprotective therapy vii. Indicated if suspected HIE viii. Improved survival and outcome at 18 months in infants who meet criteria for HIE ix. Side effects = thrombocytopenia, reduced HR, SC fat necrosis (can be associated with hypercalcaemia)

Answer 98

1. Key points a. Rare, but 30% of paediatric vascular malformations 2. Pathogenesis a. Multiple AV shunts draining into a dilated median prosencephalic vein of Markowski (embryonic vein not present in adults) b. Medial prosencephalic vein usually regresses to form the great cerebral vein (Galen) with formation of vertebral veins c. If persistently high blood flow, the median prosencephalic vein of Markowski progressively enlarges to form an aneurismal VGM 3. Clinical features a. Neonates = high output cardiac failure b. Infants = hydrocephalus + neurological c. Older children/adults = headache, seizures, SAH 50% mortality

Answer 99

a. Very common, differs from childhood stroke b. Defined as acute neurological syndrome with chronic sequelae due to cerebral injury of vascular origin occurring between 20 weeks gestation + 28 days postnatal life c. Focal cerebral injury due to i. Arterial ischaemic stroke (majority MCA distribution) ii. Cerebral venous thrombosis iii. Primary intracerebral haemorrhage d. Common cause of neonatal encephalopathy e. Seizures are most common manifestation 7. Outcome a. Poor outcome b. Most children have lifelong disability c. Perinatal stroke accounts for most cases of Hemiparetic CP d. Additional morbidity seen in 25% - disorders of language, learning, cognition and behaviour, long-term epilepsy e. Stroke recurrence for both the child and subsequent pregnancies are extremely low

Answer 100

Congenital anomalies (20-25%)

Answer 101

Subdural haemorrhage (subarachnoid second most common) a. Most common type of intracranial hemorrhage b. Venous bleed between dural and arachnoid c. Clinical manifestations i. 24-48 hrs of life, apnea, respiratory depression & seizures ii. Irritability, altered GCS iii. Rarely, increased ICP with increase HC, tense fontanelle, apnea, bradycardia, coma d. Investigations i. CT best for diagnosis – blood not bound to suture lines, crescent e. Treatment i. Most managed conservatively, surgery in ↑ICP ii. Serial FBE for ?blood loss and replacement if concern iii. Think about coagulopathy if birth history not suggestive iv. Treat seizures with phenobarbitone

Answer 102

Clavicle Humerus is most common long bone fracture Multiple fractures are rare - suspect osteogenesis imperfecta

Answer 103

Erb’s palsy i. 90% brachial plexus injury ii. Risk factors – macrosomia, BW >4kg, shoulder dystocia iii. Injury to C5/6 +/- C7 iv. Excessive traction on upper cords of plexus during delivery v. Presentation 1. Limp arm in “waiter’s tip” position – arm held in adduction, elbow extended and forearm pronated with wrist flexed 2. Absent biceps jerk 3. +/- phrenic nerve involvement with diaphragmatic palsy in 5% vi. Prognosis – most resolve spontaneously by 4 months vii. Management 1. Nothing 2. Physiotherapy (after 1-2weeks) 3. Splinting to prevent contracture if at risk 4. Surgical repair if absent biceps or shoulder function at 6-12weeks (3 months is cut off for intervention) – nerve grafting Klumpke’s palsy i. Rare = seen in breech delivery (difficult head extraction) ii. Injury to C8/T1 iii. Presentation 1. Claw hand deformity 2. Wrist drop 3. Absent grasp reflex 4. May have associated Horner’s 5. May have accompanying bony fracture iv. Management – as above

Answer 104

Sarcoidosis is a multisystem disorder of unknown aetiology characterized by the accumulation of T lymphocytes, mononuclear phagocytes, and noncaseating granulomas in involved tissues. Key points a. Idiopathic inflammatory disease involving multiple organ systems b. Diagnosis of exclusion from other diseases with granuloma formation c. African American females disproportionately affected d. Rarely found in children <8 years of age Clinical manifestations a. Skin rash, iridocyclitis, and arthritis seen most often WITHOUT pulmonary symptoms in children b. Pulmonary disease less progressive compared with adults – rarely progresses to fibrosis c. Ocular disease more likely to be progressive than in adults d. African American children more likely have LN involvement, nonspecific elevations of gamma globulin, erythema nodosum and hypercalcaemia e. Usually unremarkable examination Most common laboratory findings i. Hypergammaglobulinemia ii. Hypercalciuria + hypercalcaemia iii. Elevated ALP when liver disease present iv. Anaemia of chronic disease v. Serum ACE elevated in 75% - false positives can occur (diagnostic of sarcoid) Treatment a. Pulmonary sarcoidosis spontaneously resolves in 75% of patients without therapy b. Corticosteroids are mainstay of treatment – usually not started when stage I or II is present without symptoms c. Absolute indications include stage III disease with symptoms d. When pulmonary disease is progressive, GCS therapy is aimed at prevention of fibrosis, honey-combing and irreversible lung disease e. Alternative immunosuppressants are sometimes used

Answer 105

a. Typically caused by alveolar rupture during acute or chronic pulmonary disease b. LRTI is a common aetiology for pneumomediastinum in children < 7 years of age c. Acute asthma is more common in older children and adolescents d. Other causes = following vomiting, dental extractions, T+As, HFNP, normal menses, obstetric delivery, diabetes with ketoacidosis, acupuncture, anorexia and inhalation e. Can also result from oesophageal perforation (Boerhaave syndrome), penetrating chest trauma or inhaled FB

Answer 106

a. TG in the form of chylomicrons b. T lymphocytes c. Electrolyte concentration similar to plasma d. Immunoglobulins and fat soluble vitamins

Answer 107

a. Thoracic duct injury as a complication of cardiac surgery = most common in children b. Chest injury c. ECMO d. Primary or metastatic intrathoracic malignancy – particularly lymphoma e. Newborns – during delivery f. LESS COMMON = lymphangiomatosis, restrictive pulmonary disease, thrombosis of the duct, superior vena cava or subclavian vein, TB or histoplasmosis, congenital anomalies of lymphatic system i. Refractory chylothorax in fetus associated with missense mutation in integrin alaph9 gene

Answer 108

3. Etiology a. Primary = essential HTN b. Secondary i. Renal (75%) 1. Renal parenchymal disease = post-infectious GN, chronic GN, obstructive uropathy, reflux nephropathy, haemolytic uraemic syndrome, PCKD 2. Renovascular disease = renal artery disorders (stenosis, polyarteritis), renal vein thrombosis ii. Cardiovascular (15%) = coarctation iii. Endocrine (5%) = phaeochromocytoma, hyperthyroidism, congenital adrenal hyperplasia, primary hyperaldosteronism, Cushing syndrome iv. Other (5%) = neuroblastoma, neurofibromatosis, steroid therapy, raised ICP 4. Most common etiology by age a. Newborns = renal artery thrombosis or stenosis, congenital renal malformation, CoA, bronchopulmonary dysplasia b. <6 years = renal parenchymal disease, coarctation, renal artery stenosis c. 6-10 years = renal artery stenosis, renal parenchymal disease, primary hypertension d. >10 years = primary hypertension, renal parenchymal disease

Answer 109

Haemophilus, Actinobacillus, Cardiobacterium, Eikenella and Kingella i. Gram Negative bacilli + part of normal oral flora ii. Often require 5 days to grow

Answer 110

Tender, pea-size red nodes at the ends of the fingers or toes (rare in children) - infective endocarditis

Answer 111

Small, painless, haemorrhagic areas on the palms or soles (rare) - infective endocarditis

Answer 112

Oval, retinal hemorrhages with pale centers located near optic disc - infective endocarditis

Answer 113

For infective endocarditis. Definite IE A. Pathological criteria 1. Microorganisms demonstrated on culture or histology of a vegetation, a vegetation that has embolised, or intra-cardiac abscess, OR 2. Pathological lesions; vegetation or intracardiac abscess confirmed by histologic examination showing active endocarditis B. Clinical criteria 3 major criteria, OR 1 major criteria AND 3 minor criteria, OR 5 minor criteria Possible IE 1 major criteria AND 1 minor criteria, OR 3 minor criteria Rejected Firm alternative diagnosis explaining evidence of IE Resolution of IE syndrome with antibiotic therapy for <4 days No pathological evidence of IE at surgery or autopsy, with antibiotics <4 days Does not meet criteria for IE Major A. Blood culture positive for IE 1. Typical microorganism from 2 separate blood cultures: Viridans strep, Strep bovis, HACEK, Staph aureus, community-acquired enterococci 2. Microorganism consistent with IE from persistently positive blood cultures defined as follows: at least 2 positive cultures from blood samples drawn > 12 hours apart; or all of 3 or a majority of >=4 separate cultures of blood (with first and last sample drawn at least 1 hour apart) 3. Single positive blood culture for Coxiella burnetii or anti-phase 1 IgG Ab titre >1:800 B. Evidence of endocardial involvement 1. Oscillating intra-cardiac mass on valve or supporting structure, in the path of regurgitation jets or on implanted material 2. Abscesses 3. New partial dehiscence of prosthetic valve 4. New valvular regurgitation Minor 1. Predisposition, predisposing heart condition, or IVDU 2. Fever 3. Vascular phenomena = major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial haemorrhage, conjunctival hemorrhages, Janeway lesion 4. Immunologic phenomena – GN, Osler nodes, Roth spots, and rheumatoid factor 5. Microbiologic evidence: positive blood culture but does not meet criteria above, or serological evidence of active infection with organism consistent with IE

Answer 114

a. Infections i. Viruses = adenovirus, coxsackieviruses, echoviruses and many others  MOST COMMON ii. Chagas disease (Trypanosoma cruzi) = more common in South America iii. Rarely bacteria, rickettsia, fungi, protozoa and parasites b. Immune-mediated = acute rheumatic fever, Kawasaki disease c. Collagen vascular diseases d. Toxic myocarditis = drug ingestion, diphtheria exotoxin, anoxic agents

Answer 115

a. Viral infection = most common cause, especially in infancy b. Acute rheumatic fever = common cause in older children c. Bacterial infection (PURULENT PERICARDITIS) = S. aureus, H influenzae, N meningiditis, Streptococci d. Tuberculosis = an occasional cause of constrictive pericarditis with insidious onset e. Heart surgery = postpericardiotomy syndrome f. Collagen disease such as RA g. A complication of oncologic disease or its therapy, including radiation h. Uremia (uremic) pericarditis

Answer 116

1. Key points a. Result of scarring and consequent loss of the normal elasticity of the pericardial sac b. Pericardial constriction is typically chronic – but can be subacute, transient or occult 2. Causes a. Earlier viral pericarditis b. Post cardiac surgery c. Tuberculosis d. Incomplete drainage of purulent pericarditis e. Haemopericardium f. Mediastinal irradiation g. Neoplastic infiltration h. Connective tissue disorders 4. Clinical presentation a. History i. Symptoms related to fluid overload – peripheral edema, anasarca ii. Symptoms related to diminished CO – fatigability, dyspnoea on exertion b. Examination i. Distended jugular veins ii. Hepatomegaly with ascites iii. Systemic edema iv. Diastolic pericardial knock (resembles opening snap), heard along the left sternal border v. Absence of heart murmur vi. Pulsus paradoxus 6. Management a. Complete resection of pericardium b. Symptomatic improvement occurs in 75% of patients

Answer 117

1. Background a. Second most common vasculitis in childhood after HSP – unknown aetiology b. Most common cause of acquired heart disease in children in developed countries; causes coronary artery aneurysms (CAA) c. 85% of cases occur under 5 years of age; peak 18-24 months d. KD in children <6 months and >5 years less common, but MORE likely to develop CAA e. Genetic link – more common in Japanese population

Answer 118

Major: ACHES ; Minor: TAPE Major - Arthritis - Chorea - Heart: carditis/valvulitis - Erythema marginatum - Subcutaneous nodules Minor - Temperature - Arthralgia - PR prolongation - Elevated acute phase reactants

Answer 119

1. Key points a. ARF is caused by an immunological reaction to infection with group A streptococcus b. Acute, generalised inflammatory response affecting hearts, joints, brain and skin i. ARF leaves no lasting damage to brain, joints and skin ii. Damage to the heart (mitral +/- aortic valve) may remain once acute episodes has resolved = RHD iii. Recurrences are likely in the absence of preventative measures c. Upper respiratory tract infection (increasing evidence for skin) Peak age 5-15, mostly ATSI population

Answer 120

?Revised Jones criteria Initial episode of ARF Two major, OR One major + two minor PLUS evidence of preceding GAS infection Recurrent attack of ARF (past ARF or RHD) Two major, OR One major + two minor, OR Three minor PLUS evidence of preceding GAS infection Major manifestations High risk group Carditis = including subclinical evidence of rheumatic valve disease on echo Polyarthritis or aseptic mono-arthritis or polyarthralgias (THIS is the main difference in major criteria) Sydenham chorea** Erythema marginatum Subcutaneous nodules ``` All other groups Carditis = including subclinical evidence of rheumatic valve disease on echo Polyarthritis Sydenham chorea Erythema marginatum Subcutaneous nodules ``` Minor manifestations High risk group Fever ESR >= 30 or CRP >=30 Prolonged PR interval on ECG ``` All other groups Fever Polyarthralgias or aseptic mono-arthritis ESR >= 30 or CRP >=30 Prolonged PR interval on ECG ``` High risk = ATSI living in rural or remote areas, or in disadvantage suburban areas ** Note: Sydenham chorea is present in 25% of Aboriginal Australians (particularly female adolescents) with ARF; as part of the major manifestations, Sydenham chorea is sufficient to diagnose ARF without evidence of previous S. pyogenes infection if other causes of chorea have been excluded b. Evidence of preceding infection = ASOT, anti-DNAseB

Answer 121

RSV (>50% of cases)

Answer 122

1. Parasympathetic nervous system 🡪 bronchoconstriction (M3 receptors) 2. Sympathetic nervous system 🡪 bronchodilation (B2 receptors)

Answer 123

Improvement of FEV1 by 12% or more

Answer 124

1. Key points a. Rare condition characterised by recurrent episodes of airway obstruction secondary to large proteinaceous branching casts – take the shape of and obstruct the tracheobronchial tree b. Most frequently encountered in the setting of underlying respiratory or congenital cardiac disease 2. Associated conditions a. Lymphangitic disorders b. Pulmonary infections c. Acute chest syndrome of sickle cell disease d. Congenital cardiac disease – Fontan 🡪 occurs in 14% 3. Pathogenesis a. Unknown b. In the setting of structural heart disease, may result from alterations in pulmonary blood flow or from alterations in lymphatic drainage, either congenital or secondary to the protein-losing enteropathy 4. Clinical manifestations a. Present with cough, dyspnoea, wheeze, or pleuritic chest pain b. Depending on the degree of airway obstruction patients may be hypoxaemic or in severe respiratory distress c. Expectoration of large, branched casts pathognomonic 5. Investigations a. CXR = may show collapse of the involved area of the lung, or areas of bronchiectasis distal to sites of long-standing obstruction b. Bronchoscopy 6. Treatment a. Correct underlying condition b. Rigid or flexible cystoscopy for cast removal 7. Complications and prognosis a. Related to underlying disease b. Those with congenital heart disease are at high risk for plastic bronchitis-related mortality

Answer 125

1. Protracted bacterial bronchitis (most common 0-2 years) - wet cough 2. Asthma 3. Bronchiectasis

Answer 126

a. Most common cause of chronic cough in children <5 years– 40% b. Persistent infection of conducting airways c. More common in boys than girls d. Most common in children age 1-3 years e. Common organisms i. H influenzae ii. Streptococcus pneumoniae iii. Moraxella catarrhalis 2. Definition a. Cough lasting >4 weeks b. Response to 2 weeks of antibiotic therapy c. Absence of specific pointers indicating an alternative cause 4. Investigations a. CXR = bilateral peribronchial accentuation 5. Treatment a. Prolonged antibiotics – 2 week course of augmentin i. May require longer course ii. Resolution suggests PBB b. If still coughing at 2 weeks – additional 2 weeks c. If still coughing at 4 weeks – FB +/- CT chest d. If persisting after antibiotics consider bronchiectasis 6. Prognosis a. Duration of chronic cough proportional to adulthood lung function – detrimental long-term

Answer 127

High-pitched, monophonic sound made when breathing best heard over anterior neck i. Results from oscillation of a narrowed airway ii. Presence suggests significant obstruction of the large airways

Answer 128

Liver | Converted to angiotensin 1 by renin

Answer 129

Juxtaglomerula cells/apparatus

Answer 130

Lungs | Converts angiotensin 1 to angiotensin 2

Answer 131

i. Systemic – vasoconstriction (increase MAP) ii. Thirst iii. Posterior pituitary ADH release – promotes water reabsorption iv. Adrenal aldosterone secretion – sodium and water retention in DCT/CD v. Renal 1. Constriction of efferent > afferent arterioles – increases GFR a. In higher doses – afferent and efferent constriction 2. Strongly promote NaCl and water reabsorption in PCT

Answer 132

a. Secreted by zona glomerulosa of the adrenal cortex b. Acts on the principal cells of cortical collecting tubule c. Stimulates Na/K/ATPase pump on basolateral side of cortical collecting tubule AND increases sodium permeability on luminal side of the membrane (activates ENAC) d. Stimulated = ↑ extracellular potassium levels, AngII e. Net effects = retention of sodium, secretion of K+ and H+

Answer 133

a. Synthesized in SON (supraoptic nucleus)/PVN (paraventricular nucleus) of the hypothalamus b. Release triggered by hyperosmolarity and hypotension c. Increase water permeability of distal collecting tubule + collecting duct d. Binds to V2 receptors at distal tubules: increases cAMP formation, stimulates movement of aquaporin to luminal side of the cell membranes

Answer 134

Specialised epithelial cells at the distal collecting tubule Detects volume and salt delivery to distal collecting tubule, communicates with juxtaglomerular apparatus to regular secretion of renin.

Answer 135

Smooth muscle cells found in afferent arteriole that constrict + dilate arteriole under communication from macula densa and secrete renin

Answer 136

* ACE-I = Dilates the efferent arteriole reducing the GFR * NSAID = Prevents PG mediated vasodilation of the afferent arteriole to maintain GFR; thereby further reducing GFR * Diuretics = reduce plasma volume and GFR

Answer 137

= the bulk of reabsorption i. Highly coiled, cuboidal epithelium with lots of microvilli for reabsorption ii. 60-65% sodium reabsorbed iii. Bicarbonate/ chloride/ amino acid/ glucose and solute reabsorbed - phosphate entirely reabsorbed in PCT iv. Secretion of H+, organic anions (urate, ketoacid anions, penicillins, cephalosporins) and cations (citrate, cimetidine) - secretion of H+ at this point allows resorption of bicarb (combines to make H20 and CO2) c. Osmolality = stays the SAME (water resorbed with sodium) d. Metabolic functions = vitamin D activation, release of EPO, renin, site of gluconeogenesis Very permeable to water

Answer 138

= creates concentration differences i. Thin = squamous epithelium with high water permeability - minimal mitochondria - diffusion ii. Thick = cuboidal epithelium  lots of mitochondria for active transport, no water permeability - active iii. 25-30% of sodium absorption (NKCC2 co transporter - Na/K/2Cl) iv. Sodium absorption important in making the countercurrent system with hyperosmotic medulla Loop diuretics

Answer 139

``` = fine tuning i. Reabsorbs 5% of Na Cl ii. Mg and Ca reabsorption (site of effect of PTH) iii. 5% of bicarbonate Secrete K/H/urea Thiazides Macula densa ```

Answer 140

i. Goes into medulla, merges to form minor calyces/major calyces ii. Concentrates urine via ADH creating aquaporins allowing H2O reabsorption Principle cells – site of aldosterone action (Na/K transport - regulates ENAC (epithelial sodium channel)) Intercalated cells – site of acid base balance - type A: secrete H and absorb HCO3 in acidosis - type B: secrete HCO3 and absorb H in alkalosis ``` Potassium sparing diuretics (cortical) ADH antagonists (medullary) ```

Answer 141

Co transport INTO the cell (from lumen across apical membrane in nephron) of sodium with glucose

Answer 142

Exchange sodium INTO the cell for excretion of H+ (across apical membrane in nephron, from lumen into cell)

Answer 143

a. K shifted IN to cells by insulin, aldosterone, beta adrenergic stimulation, alkalosis b. K shifted OUT of cells by acidosis, cell lysis, increased ECF osmolarity

Answer 144

a. Mechanisms to INCREASE sodium (ie. decrease excretion) i. RAAS 1. Angiotensin = increases sodium reabsorption in the proximal tubule 2. Aldosterone = increases sodium reabsorption in the distal tubule ii. Noradrenaline = increases in response to volume depletion 1. Decreases renal blood flow  reducing filtered load of sodium 2. Stimulates renin release iii. ADH = released if severe volume depletion b. Mechanisms to DECREASE sodium (ie. increase excretion) i. ANP = promotes excretion of sodium and suppression of renin

Answer 145

2. Renal a. All filtered potassium is reabsorbed b. Further excretion of K dependent on principal cells of the collecting duct c. Proximal tubule – 65% resorbed d. Loop of Henle – 25-30% resorbed e. Collecting ducts = variable reabsorption by the principle cells i. Secretion requires aldosterone and adequate sodium delivery ii. Na/K/ATPase at basolateral membrane imports K into tubular cells iii. K then diffuses OUT down luminal membrane via ROMK / Maxi K 3. Regulatory factors a. Aldosterone i. Stimulates Na/K/ATpase pump on late distal tubules + collecting ducts ii. Also increases number of potassium channels in luminal membrane b. Inhibited by acidosis i. ↑ H concentration in inhibits Na/K/ ATPase 4. Summary a. Factors that INCREASE potassium secretion include (ie. lower potassium) i. Aldosterone ii. Increased sodium delivery to the distal nephron iii. Increased urine flow rate

Answer 146

1. Renal a. Filtered and reabsorbed by kidneys, NO secretion b. Proximal tubule reabsorption = 60-70% i. Most paracellular (dissolved in water, carried via solvent drag) ii. 20% is transcellular = Ca-ATPase and sodium counter transport c. Loop of Henle = 20% i. Restricted to thick ascending limb ii. 50% paracellular – passive diffusion iii. 50% transcellular – stimulated by PTH iv. ?CaSR affects claudin – paracellular tight junctions d. Distal tubule = 5-10% - active transport i. Diffusion across luminal membrane through calcium channels ii. Requires active transport across basolateral membrane by Ca-ATPase pump iii. Stimulated by PTH, 1,25-vit D and NCC e. CD = 5% 2. Regulation a. PTH = ↑ calcium reabsorption in thick ascending loop of Henle and distal tubules b. Metabolic alkalosis = stimulates Ca reabsorption c. Local effects = prescribed by calcium sensing receptor d. Sodium levels = volume depletion/ decreased sodium delivery increases urinary calcium

Answer 147

• Proximal tubule = 10-25% resorption (passive) • Loop of Henle = 65-70% o passive paracellular reabsorption o driven by NKCC2 electrochemical gradient o Tight junctions claudin 16+ 19 proteins mediate transport o Inhibition by TALLOH cell and CaSR activation • Distal collecting tubule = active resorption 10% o Mediated by TRPM6 o Increased by NCC activity

Answer 148

* Most is resorbed, secretion depends on intake – if resorption transporters overwhelmed, excess will be excreted. * With ‘normal intake, 85-90% filtered PO4 reabsorbed, 10-15% fractional excretion 1. Renal a. Proximal tubule = 75-80% of resorption i. Mainly transcellular ii. Sodium – phosphate cotransport across luminal membrane (Npt2a, Npt2c ,Pit-2) iii. Unclear mechanism on basolateral membrane b. Loop of Henle c. Distal tubule = 10% 2. Regulation a. PTH = decreases transport maximum for phosphate (reduces resorption) b. FGF23 = inhibits sodium-dependent phosphate reabsorption (works with coreceptor Klotho) c. 1,25-D = increases phosphate reabsorption

Answer 149

a. Hypovolemia and appropriate ADH levels i. Volume loss leads to release of ADH ii. When hypotonic fluids ingested, free water is retained in excess of solutes  decrease and sodium concentration iii. Includes 1. GI losses a. Eg diarrhoea, rehydration with free fluids 2. Diuretic induced hyponatremia a. Diuretics  volume loss  ADH release b. Diuretics enhance sodium and potassium excretion c. Water comparatively retained due to ADH release 3. Renal salt wasting a. Cerebral salt wasting: hyponatremia and ECF depletion due to inappropriate renal sodium wasting, usually post CNS surgery / head injury b. Bartter/ Gitelman syndromes c. 21 hydroxylase deficiency, hypoaldosteronism d. Skin losses: eg CF e. Intense exercise b. Normovolaemia and inappropriate ADH levels i. Failure of ADH to be suppressed in the setting of excess water intake ii. Includes 1. Central a. pulmonary / CNS disease b. Endocrine: hypothyroidism, cortisol deficiency 2. Nephrogenic: a. AVPR2 mutations 3. Medications – increase sensitivity of vasopressin receptors: cyclophosphamide, vincristine, valproate, carbamazepine, oxcarbazepine c. Hypervolaemic conditions i. Decreased effective circulating volume  nephrotic syndrome, cirrhosis, heart failure  hypervolemia with excess water retention and drop in plasma sodium

Answer 150

a. Common i. Water loss in excess of sodium 1. Diarrhoea – especially with hyperosmolar feeding/hydration 2. Severe burns ii. Inability to obtain/ swallow adequate water (+/- impaired concentrating ability) – including neonates b. Less common i. Water deficit from 1. Impaired thirst drive eg. hypothalamic lesion 2. Diabetes insipidus 3. Osmotic diuresis ii. Gain of sodium iii. Ingestion of large concentration of sodium – inappropriate formula, high osmolarity rehydration iv. Iatrogenic sodium administration

Answer 151

a. Normal GFR = 80-140 ml/min/1.73m2 b. Classified as early, established or irreversible c. RIFLE criteria used in research – creatinine + urine output used d. Two key features i. Sudden loss of GFR (renal function) 1. Increased urea/creatinine – creatinine more reliable 2. UO variable – high/normal/low 3. Oliguria = <250 ml/m2/day (<0.5 ml/kg/hour) ii. Inability to excrete solute load 1. Nutrition leads to solutes for renal excretion 2. Kidneys have limited concentrating capacity 3. Definition oliguria assumes a standard solute load (sodium, chloride, urea) e. Oliguria vs polyuria i. UO variable – high / normal / low 1. Polyuric if tubulointerstitial pathology – no reabsorption 2. Anuria/oliguria - glomerular pathology – no filtration ii. Oliguria - <250mL/m2/day (<0.5mL/kg/hour)

Answer 152

``` Prerenal • Dehydration • Haemorrhage • Sepsis • Hypoalbuminaemia • Sepsis ``` ``` Intrarenal Vascular [technically pre-renal] • Renal arterial thrombosis • Renal vein thrombosis • TMA/HUS Glomerular • TMA/HUS • GN Tubular • Ischaemic ATN • Drug/toxic ATN • Tubular obstruction eg. tumour lysis Interstitial • Acute interstitial nephritis • Pyelonephritis ``` ``` Postrenal = obstruction • Posterior urethral valves • Ureteropelvic junction obstruction • Uterovesicular junction obstruction • Ureterocele • Tumour • Urolithiasis • Haemorrhagic cystitis • Neurogenic bladder ```

Answer 153

b. Most AKI is associated with increased RENIN – except post-strep GN (infiltration of GN prevents renin release)

Answer 154

1. Key points a. Intrinsic (not pre/post) AKI not due to primary vasculitis, interstitial disease 2. Etiology o Ischaemic 60% - all causes of pre-renal AKI can lead to ischaemic ATN a. Nephrotoxic 40% - NSAIDS, aminoglycosides, contrast nephropathy, chemotherapy 3. Pathogenesis a. Triggered by reduction in blood flow b. Autoregulation → constriction of efferent artery + dilation of afferent arteriole (maintains GFR) c. Further ↓ RBF leads to activation of RAAS system: angiotensin causes vasoconstriction of all vessels esp efferent arteriole d. If RBF drops further, massive release of renin causes nonspecific afferent + efferent constriction, leading to tubular necrosis 4. Investigations a. Urine = muddy brown, epithelial cells (sloughed tubular epithelium) b. UEC = salt wasting 5. Treatment a. No interventions shown to improve outcome of ATN b. Supportive treatment only c. Recovery phase – likely distal tubule (sodium, potassium bicarbonate) loss therefore replace 1-2mmol/kg

Answer 155

1. Key points a. Diagnosed on USS by renal tract dilatation BUT can be missed if severe dehydration OR retroperitoneal fibrosis b. Can ONLY cause AKI if there is a single kidney / kidney impairment / bilateral obstruction 2. Etiology a. Stones/ clot, ureteric obstruction/ PUV b. Neurogenic bladder (chronic obstruction) 3. Pathophysiology a. Collecting duct dysfunction → loss of water, sodium, retention of K and H b. Severe dehydration → RAAS activation, reduction of GFR, pre-renal insult c. Obstruction + ATN + sepsis = whole nephron injury 4. Treatment a. Relieve obstruction b. Post obstructive diuresis: i. Need to replace all urine output + insensible losses ii. 15 mL/kg/ day + urine output hourly iii. Use 5% dextrose + half normal saline +/- KCl iv. Likely will need sodium + potassium + bicarb (1-2 mmol/kg/ day) v. Consider Mg/ Phosphate

Answer 156

``` <5 years • Congenital anomalies – renal hypoplasia, dysplasia, obstructive uropathy • Congenital nephrotic syndrome • Prune belly syndrome • Cortical necrosis • FSGS • ARPCKD • Renal vein thrombosis • HUS ``` >5 years • Acquired disease – GN including SLE • Inherited disorders – familial juvenile nephronopthisis, Alport syndrome

Answer 157

Stages a. Use Schwarz formula for eGFR – 0.413 x (height (cm)/ create (mg/dL)) b. Stage 1 = GFR > 90 with kidney damage c. Stage 2 = 60-90 d. Stage 3 = 30-60 e. Stage IV = 15-30 f. Stage V = < 15  plan for RRT

Answer 158

a. Hyperfiltration i. Important final common pathway of glomerular destruction ii. As nephrons are lost, the remaining nephrons undergo structural and functional hypertrophy characterized by an increase in glomerular blood flow iii. The driving force for glomerular filtration is increased in the surviving nephrons iv. Compensatory hyperfiltration temporarily preserves total renal function  progressive damage to surviving glomeruli b. Proteinuria i. Proteins that traverse the glomerular capillary wall can exert a direct toxic effect on tubular cells and recruit monocytes and macrophages enhancing the process of glomerular sclerosis and tubulointerstitial fibrosis c. HTN = uncontrolled HTN can exacerbate the disease progression by causing arteriolar nephrosclerosis and by increasing the hyperfiltration injury d. Hyperphosphataemia = calcium deposition in the renal interstitium and blood vessels

Answer 159

a. Bones - reduced vitamin D activation -> reduced calcium absorption -> hypocalcaemia -> inc PTH - retention of phosphate -> hyperphosphataemia -> inc PTH - bone resorption - osteitis fibrosis cystica - treat with low phosphate diet / phosphate binders, vitamin D b. Blood vessels c. Anaemia - inadequate EPO - treat with iron, B12, folate, EPO d. BP - volume overload, overproduction of renin - treat: weight reduction, exercise, low salt diet, ACE-i e. Acid base balance / acidosis - reduced excretion of H (late, CKD4) - supplement bicarb f. Fluid/electrolyte management - sodium high/low - hyperK with GFR<10% - treat: dietary restriction, loop diuretic, correct acidosis (H/K exchanged in kidney) g. Growth impairment h. Malnutrition i. Proteinuria - treat: ACE-i, AT1 receptor antagonist

Answer 160

The 2012 KDIGO guidelines suggest that dialysis be initiated when there are signs or symptoms attributable to kidney failure (such as serositis, acid-base or electrolyte disorders not easily corrected medically, pruritus), an inability to control volume status or blood pressure, a progressive deterioration in nutritional status that is refractory to dietary interventions, or cognitive impairment. The KDIGO guidelines state that such signs and symptoms often but not invariably occur when the eGFR is between 5 and 10 mL/min/1.73 m2. The 2014 Canadian Society of Nephrology guidelines recommend monitoring and actively treating symptoms when the eGFR declines below 15 mL/min/1.73 m2. The guidelines recommend commencing dialysis in asymptomatic patients when the eGFR declines to below 6 mL/min/1.73 m2 or when symptoms occur. European guidelines suggest that, in patients with a GFR <15 mL/min/1.73 m2, dialysis should be considered when symptoms are present, while recognizing that the majority of patients will be symptomatic and need to start dialysis with GFR in the range of 6 to 9 mL/min/1.73 m2. The 2015 KDOQI guidelines suggest that the decision to start dialysis should be based on uremic signs and symptoms, evidence of protein-energy wasting, and the ability to medically manage metabolic abnormalities and volume overload and not based upon the level of kidney function

Answer 161

Haemodialysis • Primarily removes solute by DIFFUSION • Dialysate fluid is used • During hemodialysis, urea, creatinine, and potassium move from blood to dialysate, while other solutes, such as calcium and bicarbonate, move from dialysate to blood. Haemofiltration • Uses HYDROSTATIC PRESSURE to induce the filtration of plasma water across the haemofilter membrane • Solutes are removed by CONVECTION • Dialysate fluid is NOT used • The frictional forces between water and solutes (called solvent drag) result in the convective transport of small and middle molecular weight solutes (<5000 Daltons) in the same direction as water. Doesn't alter CONCENTRATION of these solutes. Hence... • Substitution fluid is usually required to prevent excessive fluid removal, and to dilute solutes (urea, creatinine).

Answer 162

1. Key points a. Employs patients own peritoneal membrane as a dialyzer b. Access to peritoneal cavity achieved by surgically inserted Tenckhoff catheter c. Cycle = inflow, dwell, outflow 2. Physiology a. Peritoneal dialysis solution primarily consists of water, osmotic agents, electrolytes + minerals i. Osmotic agents allow net water removal by altering the osmotic pressure gradient between the peritoneal dialysis solution + plasma water ii. Dextrose is most commonly used osmotic agent b. Solute moves down concentration gradient across peritoneal membrane by diffusion (dialysis) c. Water moves across peritoneal membrane by osmosis (ultrafiltration) d. Ultrafiltration causes movement of solutes by drag forces even without concentration gradient

Answer 163

a. Absolute i. Omphalocele ii. Gastroschisis iii. Bladder exstropy iv. Diaphragmatic hernia v. Obliterated peritoneal cavity and peritoneal membrane failure b. Relative i. Impending abdominal surgery ii. Impending (<3 months) liver donor kidney transplantation iii. Lack of appropriate caregiver

Answer 164

``` Catheter malfunction Infection e.g. peritonitis Sclerosing peritonitis Reduced appetite Negative body image Caregiver burnout Bleeding Failure of peritoneal membrane - with time membrane thickens and becomes fibrotic due to glucose break down products and lactate ```

Answer 165

1. Key points a. Infection is one of the most significant complications of paediatric PD b. Contributes to major morbidity due to loss of peritoneal membrane function + technique failure c. Fungal peritonitis is an infrequent complication in paediatric patients 2. Cause a. Peritoneal-dialysis related i. Contamination with pathogenic skin bacteria during exchanges ii. Exit site or tunnel infection b. Secondary peritonitis i. Underlying pathology of GIT eg. appendicitis 4. Etiology a. Bacteria – CONS > Streptococci > Staphylococcus i. also gram negs and fungi 5. Clinical presentation a. Abdominal pain b. Fever c. N+V d. Cloudy effluent e. Hypotension 6. Investigations a. Peritoneal fluid analysis i. Cell count > 100 cells/mm3 ii. >50% PMN b. Culture of exit site c. Blood cultures + FBE 7. Treatment b. Antimicrobial i. Coverage for GP and GN organisms – IV vancomycin + ceftazadime ii. Intraperitoneal administration of antibiotics is preferred to intravenous administration, unless the patient appears septic c. Indications for catheter removal i. Refractory peritonitis – does not respond within 5 days ii. Relapsing peritonitis iii. Fungal or mycobacterial peritonitis iv. Peritonitis occurring with intra-abdominal pathology eg. abscess 8. Complications a. Catheter loss b. Transfer to haemodialysis c. Death

Answer 166

1. Key points a. Peritoneum becomes thickened and fibrosed, affecting gut peristalsis and leading to gut obstruction and malnutrition 2. Etiology a. Prolonged period on PD b. Recurrent peritonitis c. Prolonged use of PD with high glucose concentration 3. Clinical manifestations a. Episodes of sterile peritonitis, fever, abdominal pain, ascites, increased CRP b. Poor UF and decreasing small solute clearance c. Adhesions with gut obstruction d. Adhesions with migration of catheter resulting poor drainage 4. Investigations a. US – thickened bowel loops b. Peritoneal calcification c. Diagnosis – biopsy of peritoneum 5. Treatment a. Transfer to HD (although process may continue) b. Surgery if GIT obstruction occurs c. Nutritional support – TPN d. No evidence for immunosuppression 6. Prognosis a. High mortality due to complications of surgery and malnutrition b. Intra-peritoneal transplantation is difficult if necessary

Answer 167

2. Etiology (decreasing order) a. Aplasia, hypoplasia, dysplasia b. Obstructive uropathy c. FSGS

Answer 168

3. Indications a. 8-10 kg for adult sized kidney b. RRT required i. Start planning when GFR < 30 (stage IV) ii. Pre-emptive transplant may be considered if GFR < 10-15 c. Must be on dialysis to be listed for deceased donor Tx in Australia d. Quiescence of underlying disease if autoimmune e. Contraindications i. Relative contra-indications = pre-existing metastatic malignancy, HIV, severe neurological disease ii. Patients with autoimmune diseases resulting in ESRD are candidates for transplants after a period of immunologic quiescence of the primary disease for a period of at least 1 year

Answer 169

ii. Cardiac death

Answer 170

Chronic rejection Acute rejection Vascular thrombosis

Answer 171

a. Hyperacute rejection i. Occurs in the first minutes following transplantation ii. Results from pre-formed HLA antibodies that bind to vascular endothelial cells of the graft  complement activation  endothelial injury ‘ iii. Rare iv. Only treatment is graft removal b. AKI i. Influenced by age and condition of donor, specific recovery time, technique of organ preservation, adequacy of volume replacement time during and after surgery, and the cold and warm ischaemia time ii. Tubular damage aggravated by cyclosporine or tacrolimus c. Vascular thrombosis i. Third most common cause of graft failure in children ii. Risk factors = extremely young donor or recipient (main), hypercoagulability (chronic nephrotic syndrome) and venous malformation in recipient, pre-transplant peritoneal dialysis, hypotensive episode, multiple arteries d. Urological complications i. Early complications include 1. Urine leak due to ureteral necrosis, bladder injury or obstruction a. Clinical manifestations = abdominal pain, collection on USS, rising Cr due to reabsorption, hyperkalaemia, oliguria b. Diagnosis = aspiration + biochemical analysis or DTPA c. Treatment = IDC 2. Urinary tract obstruction a. Acute = clot or lymphocele b. Later = VUJ obstruction, ureteric stenosis (due to BK virus infection) c. Diagnosis = USS/DTPA/MAG3 d. Treatment = dilation or surgical

Answer 172

Hyperacute i. Occurs in the first minutes following transplantation ii. Results from pre-formed HLA antibodies that bind to vascular endothelial cells of the graft  complement activation  endothelial injury ‘ iii. Rare iv. Only treatment is graft removal b. Acute i. Elevation of serum creatinine may be a late sign, particularly in children ii. Frequent complication of paediatric renal transplants iii. Definition = decline in allograft function (elevated serum creatinine) + histopathological changes iv. Two forms of rejection = acute cellular rejection and acute antibody-mediated rejection v. Early and sensitive sign of rejection = hypertension + low-grade fever vi. Differentials 1. Urinary tract obstruction = exclude with USS 2. Calcineurin inhibitor nephrotoxicity = identified on biopsy 3. CMV and BK virus 4. Renal artery stenosis 5. Pyelonephritis c. Chronic i. Leading cause of graft loss and primarily results from immune and non-immune injuries such as HTN, diabetes and hyperlipidaemia ii. Results in elevated serum creatinine + increasing proteinuria + worsening hypertension iii. Children often have a gradual decline in their renal function and often have fixed proteinuria and HTN

Answer 173

4. Recurrence of primary disease a. Renal allograft failure in 12% of the primary diagnoses of children b. Risk of recurrence of nephrotic syndrome is 30% c. FSGS – 20-30% i. FSGS is the most frequent cause of graft loss due to recurrent disease ii. More likely if disease begins >6 years and there is rapid progression to ESRD d. HUS e. Alport syndrome 3-4% f. MPGN – type 1 20-70%, type 2 – up to 100%, graft loss in 50% g. IgA nephropathy – 50%

Answer 174

a. Pneumonia and UTI are the most common post-transplant bacterial infections b. UTI i. Commonest infection post-transplant ii. <1 month – immunosuppression high iii. Similar organisms; also candida in patients with stent iv. UTI can rapidly progress to urosepsis and can be confused with acute rejection v. TMP-SMX used for prophylaxis in the first 6 months post-transplant c. Fungal infection i. Recurrent fungal growth on urine culture ii. Organisms – Candida, aspergillus iii. Can be invasive iv. Treatment – nilstat, fluconazole (will increase immunosuppression levels CYP3A + can impact renal function), liposomal amphotericin d. PJP i. <6months post-transplant ii. Cough, fever, hypoxia with exercise, diffuse interstitial infiltrates on CXR iii. Diagnosis – BAL iv. Treatment – bactrim prophylaxis, IV bactrim e. Herpesviruses (CMV, HSV, VZV, EBV) i. Many young children have not been exposed to these viruses and lack protective immunity ii. Antiviral prophylaxis with ganciclovir and valganciclovir for 3-12 months has reduced the incidence of clinical CMV disease iii. Serial surveillance done f. Polyomavirus nephropathy (BK nephropathy) i. Important cause of allograft dysfunction ii. 30% of children have BK viruria – although allograft dysfunction is observed in a lower number iii. Primary or secondary (reactivation) iv. Primary infection = asymptomatic or fever, malaise, vomiting, respiratory illness, pericarditis, transient hepatic dysfunction v. Remains latent in urinary tract and kidney and can be reactivated or cause nephropathy (1-10% all Tx), haemorrhagic cystitis, ureteric stenosis, other. vi. Diagnosis = BKV PCR blood/urine, nephropathy biopsy vii. Treatment = screening, reduction in immunosuppression

Answer 175

a. Majority lymphoproliferative disease b. Routine screen for lymphadenopathy, hepatosplenomegaly and EBV screen c. Others = cervical cancer + skin cancer d. EBV associated PTLD i. Most common malignancy post-transplant ii. 1-2% usually EBV associated iii. Usually <12 months post-transplant iv. Clinical presentation = sore throat, tonsillar enlargement, lymphadenopathy, hepatosplenomegaly, fever, weight loss, night sweats, malaise, abdominal/neurological/respiratory symptoms v. Diagnosis = histological oligo/monoclonal proliferation of B cells in lymphoid tissue vi. Treatment = screening, reduction in immunosuppression

Answer 176

Associated with single umbilical artery, external ear anomalies, imperforate anus and scoliosis

Answer 177

a. ABSENT kidney on single side – in true agenesis the ureter and the ipsilateral bladder hemitrigone are absent i. Note different from aplasia, in which a nubbin of non-functioning tissue is seen capping a normal or abnormal ureter b. Contralateral kidney undergoes hypertrophy (primarily after birth)

Answer 178

a. Often associated with other congenital anomalies – eg VATER syndrome b. Increased in newborns with a single umbilical artery c. Most have an ipsilateral absent vas deferens (as the Wolffian duct is absent) d. Reduced nephron number, renal enlargement, risk of trauma to larger kidney a. Contralateral vesicoureteric reflux = 15% b. PUJ and or VUJ obstruction = 20%

Answer 179

1. Key points a. 1/3000 births, male > female (70%) 2. Clinical manifestations a. Incompatible with extra-uterine life  death occurs shortly after birth i. Death occurs due to pulmonary insufficiency due to pulmonary hypoplasia (NOT renal failure) b. Potters syndrome – Potter facies (eyes widely separated with epicanthic folds, the ears are low set, the nose is broad and compressed flat, the chin is receding, and there are limb anomalies) i. Accounts for 20% of newborns with potter phenotype 3. Diagnosis a. Maternal USS showing oligohydramnios b. Non-visualisation of the bladder, and absent kidneys

Answer 180

1. Cystic renal dysplasia 2. Obstructive uropathy 3. ARPCKD 4. Renal hypoplasia 5. Medullary hypoplasia

Answer 181

1. Key points a. Kidney is replaced by cysts and does NOT function (by definition); can result from ureteral atresia b. Kidney size is highly variable c. Usually unilateral (L>R) and generally not inherited d. Bilateral MCKDs are incompatible with life e. Most common cause of an abdominal mass in the newborn – however most not palpable f. Incidence 1/2000 - 1/4000, slight male preponderance 3. Clinical manifestations a. Most antenatally diagnosed – cysts may be identified prenatally, but the cysts regress in utero and no kidney is identified on imaging at birth b. 15% present as unilateral flank mass c. 4% present as UTI d. Haematuria/ proteinuria 4. Associated anomalies a. 1/3 have abnormal contralateral kidney – VUR/ obstruction/ ectopic ureter b. VUR = 20% contralateral kidney, 15% ipsilateral into atretic ureter c. Obstruction = PUJ obstruction, ureteric stenosis, ectopic ureter d. Contralateral hydronephrosis = 5-10% have contralateral hydronephrosis 7. Prognosis a. Complete involution in 60% by age 10 years – most disappearance/involution occurs in first 5 years of life b. Hypertension 0.2-1.2% c. Wilms tumour 0.3% (‘debunked’ as per Lil)

Answer 182

Renal dysplasia

Answer 183

a. Horseshoe kidneys i. Lower poles of the kidneys can fuse in the midline creating a horseshoe kidney ii. Fused portion is termed the isthmus and may be thick functioning parenchyma or a thin fibrous band d. Associations i. Turner syndrome (7% of Turner’s have horseshoe kidneys) ii. T13, T18, T21 iii. VACTERL f. Complications i. Wilms tumour 4 x more common than general population ii. Stone disease iii. Ureteropelvic junction obstruction = stone disease

Answer 184

PUJ - pelvoureteric junction obstruction

Answer 185

Ureter duplication

Answer 186

``` • Balloon like dilatation of the distal ureter due to pinpoint ureteric orifice • Usually upper half of duplex system • F>M • Leads to proximal dilatation • Consequences o Decreased functional bladder capacity, obstruction to emptying o Associated with VUR/ UTIS • May require surgical opening ```

Answer 187

a. A ureter that drains outside the bladder is referred to as an ectopic ureter d. The ectopic ureter typically drains the upper pole of a duplex collecting system (2 ureters) e. Ureteral orifice site i. Found along the pathway of the developing mesonephric system ii. Male = posterior urethra (50%), prostatic utricle (10%), seminal vesicle (33%), ejaculatory duct (5%), vas deferens (5%) iii. Females = bladder neck (35%), urethrovaginal septum (35%), vagina (25%), cervix, uterus etc 1. Often the terminal aspect of the ureter is narrowed, causing hydroureteronephrosis

Answer 188

a. Up to 65% normal healthy infants have VUR up to 6 months of life b. Decreases with age to 1-2 % c. More common in males d. Present in 15% of infants with antenatal hydronephrosis e. May be associated with congenital dysplasia (this group more susceptible to CKD)

Answer 189

a. I = Reflux fills the ureter without dilation b. II = Reflux fills the ureter and collecting system without dilation c. III = Reflux fills and mildly dilates the ureter + collecting system with mild blunting of the calices d. IV = Reflux fills and grossly dilates the ureter with blunting of calices and tortuosity of the ureter e. V = Massive reflux grossly dilates the collecting system; blunting of calyces with loss of papillary impression f. IV + V = result in reduced renal parenchyma

Answer 190

a. Recurrent/atypical UTI b. Often develop pyelonephritis – fever, dysuria, frequency, loin pain, sepsis c. Reflux nephropathy – HTN, renal impairment, occasional ESRF d. Bladder dysfunction e. Prenatal hydronephrosis – 80% male

Answer 191

a. 50% of grade 1-3 will resolve with growth alone b. Renal impairment = relatively uncommon i. 20% of children with ESRF have reflux nephropathy/ CAKUT (now improving) ii. 5-10% of adults with ESRF have reflux nephropathy iii. Scarring correlates with grade of reflux  reflux rarely causes injury in the absence of infection UNLESS it is high pressure c. Hypertension = common i. Most common cause of HTN in children d. Good prognostic factors i. Grade I/II = likely to resolve with time ii. Grade III = younger age at diagnosis, unilateral reflux e. Mean age of resolution is 6 weeks

Answer 192

Vesicoureteric reflux

Answer 193

a. UTI i. Antibiotic prophylaxis controversial ii. Options = trimethoprim, bactrim, nitrofurantoin (NOT: cephalexin, amoxicillin, augmentin) iii. Reasonable to give 6/ 12 months/ until toilet trained OR monitor urine samples iv. Circumcision 1. If boys < 12 months have an atypical infection  offer circumcision 2. Beyond 12 months there is less evidence to support this b. Monitoring i. Consider surveillance for UTI – FWT for leukocytes and nitrites ii. MCUG/ upper tract imaging every 12 months c. Surgical therapy i. Deflux 1. Endoscopic procedure, bulking agent inserted through a cystoscope beneath the ureteral office 2. 70-80% success rate + 10% recurrence rate ii. Reimplantation of ureters iii. Nephrectomy = if renal function is poor

Answer 194

a. Membranous valve in the proximal part of the urethra (just below the bladder neck) which causes obstruction b. Considered in any male with renal outflow tract obstruction c. 1/5000-8000 pregnancies d. Usually dx between birth – 5 years

Answer 195

a. Antenatal hydronephrosis (50% cases detected) b. Respiratory distress secondary to lung hypoplasia c. Weak urinary stream d. UTI in boy e. Delayed daytime continence

Answer 196

a. Incontinence – due to urethral sphincter distortion, hypertonic bladder with incomplete emptying b. VUR – occurs in 30-50% of patients secondary to increased intravesical pressure c. 30% develop CKD d. UTI – due to VUR e. “VURD” valves, unilateral reflux and dysplasia

Answer 197

a. Poor prognostic factors i. Oligohydramnios ii. Hydronephrosis evident < 24 /40 iii. Bilateral cortical renal cysts iv. Persistent Cr elevation after decompression b. Good prognostic factors i. Normal USS between 18-24 weeks gestation ii. Visible corticomedullary junction on renal USS

Answer 198

1. Key points a. Male>female 2. Clinical manifestations a. Bladder open i. Lower anterior abdominal wall absent ii. Bladder visible through ‘hole’ 1. May turn inside out 2. Small bladder 3. Detrusor, bladder neck, ext sphincter abnormal b. Associated abnormalities i. Symphysis pubis widely separated ii. Perineum usually short – anus more anterior, occasional anal stenosis iii. Male = undescended testes + short penis iv. Female = usually normal uterus, ovaries 1. Can have Short vagina, uterine prolapse c. Consequences i. Long-term continence issues 3. Treatment a. Genital reconstruction

Answer 199

1. Key points a. Commonly diagnosed on antenatal USS – as early as 12th week gestation b. Most often transient or clinically insignificant c. Aim to identify cases of CAKUT as underlying cause d. Most obstructed kidneys will not cause damage until increased urine production at 5-9 weeks - the exception to this is posterior urethral valves, which require intervention ASAP 4. DDx a. No ureteric dilatation i. Transient hydronephrosis ii. Pelviureteric obstruction iii. VUR b. Ureteric dilatation i. Ureteric obstruction ii. VUR moderate- severe iii. Abnormal bladder iv. Posterior urethral valves c. High risk features i. Bilateral hydronephrosis >SFU grade 3, APD > 10 mm ii. Unilateral dilatation APD > 15 mm iii. Single kidney iv. Duplex system v. Ureteric dilatation vi. Ureterocele d. Low risk features i. Unilateral hydronephrosis SFU 1-3 APD < 15 mm ii. Bilateral hydronephrosis SFU 1-2 APD < 10 mm iii. NO ureteric dilatation iv. Normal bladder v. No renal abnormality aside from hydronephrosis 5. Postnatal management a. Antibiotic prophylaxis b. Assess for palpable kidney or bladder  urgent referral to urology + USS c. Investigations i. USS = timing depends on whether unilateral or bilateral involvement 1. Bilateral fetal hydronephrosis or single hydronephrotic kidney – day 2 of life 2. Unilateral fetal hydronephrosis – at the timing of regaining birth weight ii. MCUG = if persistent postnatal hydronephrosis d. Circumcision = male infants with severe hydronephrosis

Answer 200

a. Divides renal cystic masses into five categories based on imaging on contrast-enhanced CT – based on cyst wall, septae, calcification, enhancement b. Predicts risk of malignancy (1-5, 5 being mostly malignant)

Answer 201

1. Key features a. 1/20,000 live births b. Carrier rate 1/70 c. Results in dual-organ disease  should be considered ARPKD/congenital hepatic fibrosis 2. Genetics a. Mutation in PKHD1 gene; encodes fibrocystin b. Most patients are compound heterozygotes, carrying two different mutant alleles 4. Clinical manifestations a. Presentation i. Frequently diagnosed perinatally - cause of FDIU + pulmonary hypoplasia/ Potter phenotype ii. Cause of antenatal bright kidneys iii. Typical child presents with bilateral flank masses during neonatal period or in early infancy iv. Occasionally present later with mixed renal-hepatic clinical picture – often more pronounced hepatic presentation 5. Diagnosis a. Renal imaging findings + 1 or more of i. Clinical/lab/imaging signs of hepatic fibrosis ii. Hepatic pathology with ductal plate abnormality iii. Absence of renal cysts in both parents iv. Parental consanguinity – AR inheritance v. Confirmed sibling with ARPKD 7. DDx – other causes of bilateral renal enlargement a. Multicystic dysplasia b. Hydronephrosis c. Wilm’s tumour d. Bilateral renal vein thrombosis 8. Treatment a. Supportive b. Treatment of hypertension c. Feeding – high calories to ensure weight gain, may need NGT d. Work up for dialysis/ transplantation (liver-kidney transplantation) i. May require nephrectomy e. Liver – management of cholangitis +/- prophylactic antibiotics, + portal HTN (BB +/- banding +/- TIPS +/- transplant) f. Genetic counselling 9. Prognosis a. Severe renal impairment  may die in the neonatal period (30%) b. 15 year survival 70-80% c. Survivors: develop CRF by 15 years (> 50%) d. Concomitant liver disease  poor prognosis i. 45% liver involvement = Caroli disease

Answer 202

1. Key features a. 1/400-1/1,000 people affected  most common hereditary human kidney disease b. Accounts for >5% of CKD c. Rare in children, usually presents later – cannot be excluded until 30 years of age 2. Genetics a. Autosomal dominant b. Most mutations unique to a given family c. Mutations i. PKD1 Chr 16 (85%) = polcystin  membrane protein involved in cell-cell and cell-matrix interactions ii. PKD2 Ch 4 (10-15%) = polcystin 2  non-selective cation channel 4. Clinical manifestations a. Wide spectrum of severity – intrauterine death with Potter sequence to mild CKD in adulthood b. Presentation i. Prenatal diagnosis in some cases enlarged kidneys with or without cysts on USS in families with known ADPKD; prenatal DNA testing for identified mutations available ii. Usually present 4th or 5th decade of life iii. Presenting symptoms = gross or microscopic haematuria, bilateral flank pain, abdominal masses, HTN, UTI iv. Cysts in multiple systems (kidney, liver, pancreas, spleen) 5. Investigations a. Diagnosis – enlarged kidneys with bilateral macrocysts in a patient with an affected 1st degree relative i. NOTE: diagnosis may be made in children BEFORE the affected parents b. If patients have genetically defined ADPKD – screening USS are usually done i. Normal in <=20% by age 20, and <5% by age 30 c. USS = multiple bilateral macrocysts in enlarged kidneys i. Normal kidney size and unilateral disease often in children 6. Treatment a. Supportive b. Annual review = BP, early morning protein c. Hypertension = ACE-I first line d. Avoid trauma e. Avoid NSAIDs f. High fluid intake g. Avoid protein load h. Screening for Berry aneurysms in older patients 7. Prognosis a. ADPKD that occurs initially in older childhood has good prognosis, normal renal function during childhood in >80% b. Neonatal ADPKD has worse prognosis c. Most develop CKD by 60s d. Disease progression correlates to degree of HTN

Answer 203

1. Key points a. Commonest inherited etiology in a newly presenting child with ESRF b. 1/50,000 c. Usually few preceding symptoms other than longstanding polydipsia and polyuria d. Extra-renal manifestations in 20% - retinitis pigmentosa, hepatic fibrosis, skeletal defects e. Resultant chronic tubulointerstitial nephropathy and progression to ESRD f. Extra-renal manifestations consistent with ciliary pathology in 20% 2. Genetics a. AR b. >10 genes identified c. Most common mutation (20%) – homozygous deletion of NPHP1  results in juvenile form d. 6 genes – NPHP1-NPHP6 e. Genes encode cytosolic proteins involved in function of primary cilia, basal bodies, centrosome (nephrocystins) 3. Pathogenesis a. Ciliary dysfunction (ciliopathy) = renal tubular cells unable to perceive luminal flow, leading to dysregulated tissue growth and cyst development 4. Classification a. Infantile - ESRF by 3 years b. Juvenile - most common - ESRF by 13 c. Late onset/adult - ESRF by 19-20 (universal by 20) 5. Key features - Polyuria/polydipsia - Progressive CKD with normal BP - Bland urinalysis - Normal/slightly reduced kidney size - Extra-renal manifestations e.g. retinitis pigmentosa 6. Many associated syndromes 8. DDX - most common is tubulointerstitial nephritis 9. Management a. No specific management b. Replace water to prevent hypovolaemia c. Adequate salt intake d. EPO + Fe supplements e. Vitamin D analogues and supplementation + phosphate binders – those with evidence of secondary hyperparathyroidism

Answer 204

a. RENAL i. Progression to ESRF is universal by 20 years of age ii. Reduced urinary concentrating ability with bland urinary sediment iii. Chronic tubulointerstitial nephritis iv. Cysts at corticomedullary junction (from both ducts and tubules) v. Normal or decreased kidney size vi. Histology 1. Renal tubular (and glomerular) cysts 2. Tubular membrane disruption – thickening and wrinkling 3. Tubulointerstitial cell infiltrates with interstitial fibrosis + tubular atrophy b. EYE i. Retinal dysplasia retinitis pigmentosa [Senior-Loken syndrome + Leber congenital amaurosis] ii. Occulomotor apraxia [Cogan syndrome] c. SKELETON i. Thoracic deformity ii. Cone-shaped epiphysis [Mainzer-Saldino syndrome] iii. Skeletal dysplasia iv. Shortening of limbs and ribs v. Polydactyly, brachydactyly vi. Craniosynostosis d. HEART i. Situs invertus (infantile nephronopthisis) ii. Cardiac malformations – septal and valve defects e. BRAIN i. Cerebellar vermis aplasia ii. Encephalocele iii. Cerebral ataxia iv. Hypotonia v. Severe developmental delay f. LIVER i. Ductal plate malformation ii. Hepatosplenomegaly and portal fibrosis

Answer 205

* TC is an autosomal dominant mutation caused by mutations in TSC1 (9q34) and TCS2 (16p13.3) genes * TSC2 lies adjacent to PKD1 * A high proportion of patients with renal cystic diseases have contiguous deletions of TSC2 and PKD1 * Neurological features predominate, although there are a number of significant renal manifestations * 75% develop angiomyolipomata * 20% develop simple cysts * PCKD develops in <5%

Answer 206

i. Microscopic haematuria = >3-5 RBC per high power field on freshly voided and centrifuged urine 1. Often benign, usually transient ii. Gross haematuria 1. Child may have serious disease 2. Painful – dysuria (UTI), renal colic (stone), loin (PUJ, IgA nephropathy) 3. Painless – nephritis (often tea/cola coloured)

Answer 207

SHIRT (stone, haematologic/hereditary, infection/iatrogenic, renal, tumour/trauma) Factitious • Non-pathological = urate crystals in infants, ingested foods, medications, dyes • Pathologic = haemoglobinuria from haemolytic anaemia, myoglobuinuria from rhabdomyolysis Glomerular • Immunological = glomerulonephritis (eg. PSGN, IgA nephropathy, MPGN, systemic diseases) • Structural disease = Alport syndrome, thin basement membrane disease • Toxin-mediated injury = HUS Tubulointerstitial/ parenchymal • Inflammation = interstitial nephritis, pyelonephritis • Vascular = sickle cell trait/disease, Nutcracker syndrome • Structural = cyst rupture, Wilms tumour, urinary tract obstruction, renal trauma Lower urinary tract • Inflammation = cystitis, haemorrhagic cystitis, urethritis • Injury = trauma, kidney stone • Tumour, polyp, malformation ``` Other • Infection = TB, schistosomiasis, bacteria/viral cystitis • Coagulopathy • Sickle cell disease • Renal vein thrombosis • Hypercalciuria (microscopic) ```

Answer 208

Nephrotic syndrome Nephrotic syndrome is a condition involving the loss of significant volumes of protein via the kidneys (proteinuria) which results in hypoalbuminaemia. The definition of nephrotic syndrome includes both massive proteinuria (≥3.5 g/day) and hypoalbuminaemia (serum albumin ≤30 g/L). 1 Clinical features As a result of hypoalbuminaemia, nephrotic syndrome is associated with oedema (due to reduced oncotic pressure), hyperlipidaemia and hypercoagulability. Urinalysis Typical findings on urinalysis in the context of nephrotic syndrome include: Proteinuria (protein ++++) Frothy appearance Nephritic syndrome Nephritic syndrome is a condition involving haematuria, mild to moderate proteinuria (typically less than 3.5g/L/day), hypertension, oliguria and red cell casts in the urine. Urinalysis Typical findings on urinalysis in the context of nephritic syndrome include: Haematuria (blood +++) Proteinuria (mild – protein ++) Red cell casts – distinguishing feature of nephritic syndrome, form in nephrons and indicate glomerular damage

Answer 209

a. Glomerulonephritis/ nephritic syndrome i. Post-infectious GN ii. IgA nephropathy/ HSP nephritis iii. MPGN – primary, secondary iv. SLE v. RPGN – Goodpasture’s vi. ANCA vasculitis vii. Anti-GBM nephritis b. Haemolytic uraemic syndrome i. Oliguric/anuric ii. MAHA iii. Thrombocytopaenia c. Inherited collagen GBM diseases i. Alport ii. Thin Membrane disease d. Nephrotic diseases i. Immunologic vs genetic

Answer 210

Renal - acute post infectious (post strep) - membranoproliferative GN Systemic - lupus nephritis - subacute bacterial endocarditis - shunt nephritis - essential mixed cryoglobulinaemia - visceral abscess

Answer 211

Renal - IgA nephropathy - idiopathic rapidly progressive GN Systemic - polyarteritis nodosa - hypersensitivity vasculitis - Wegeners granulomatosis - HSP - Goodpastures syndrome

Answer 212

IgA nephropathy • Begins days after the onset of an URTI • Inciting illness may be an URTI, gastroenteritis, or UTI • C3 levels usually normal • IF = mesangial IgA deposits • Hypertension initially treated with ACE-I/ARB APSGN • Begins weeks after an antecedent streptococcal infection • Inciting illness may be a pharyngitis or skin infection • C3 and CH50 levels are reduced • Biochemical evidence of streptococcal infection • Hypertension initially treated with frusemide

Answer 213

a. 6 key presentations i. Macroscopic haematuria = most common 1. Often with renal angle pain 2. May have associated oliguria 3. DDX – acute nephritis; BP must be measured ii. Asymptomatic microscopic haematuria +/- proteinuria iii. Acute nephritis = haematuria, proteinuria, renal insufficiency, HTN iv. RPGN = uncommon v. Nephrotic syndrome (rare, <10%) vi. Mixed nephrotic/nephritic b. Commonly occurs in the context of URTI = Synpharyngitic i. Time interval between infection and haematuria = 1-2 DAYS (by definition <5/7 days) ii. VS. postinfectious GN = 10-14 days post pharyngitis, or 3-6 weeks post skin infection

Answer 214

7. Management a. Key = BP control and management of significant proteinuria i. ACE-I and ARB – effective in BP and reducing proteinuria b. Immunosuppression – no good evidence i. Corticosteroids = ? reduce proteinuria and improve renal function in those with low eGFR ii. Steroid sparing agents have also been used (AZA, CPA, CyA) 8. Outcome a. Most IgA nephropathy does not lead to significant kidney damage in children b. Complete remission more likely in children i. 20-30% of children will develop ESKD in 15-20 years after disease onset ii. Rate of progression slow c. Adults develop ESKD at a rate of 1.5% per year (where present with proteinuria) d. Features associated with ESKD i. Proteinuria ii. HTN iii. Baseline GFR iv. Biopsy findings = glomerulosclerosis, tubular atrophy, interstitial fibrosis e. No effect on prognosis = persistence/ frequency of haematuria

Answer 215

2. Genetics a. AS and TBMN are due to structural abnormalities of the GBM i. Key component of BM is type IV collagen – composed of alpha chains ii. 6 genes encoding the alpha chains – COL4A1 to COL4A6 – trimer x2  type IV collagen iii. Chains have specific assembly partners, as well as tissue and developmental expression iv. Mutations in three of these chains are associated with AS b. 85% of patients = X-linked inheritance  mutation in COL4A5 gene located on X chromosome i. Affected individuals almost exclusively male c. Other AD and AR mutations in other genes encoding chains of type IV collagen i. AR – COL4A3 or COL4A4 – 10-20% ii. AD - COL4A3 or COL4A4 – rare, less severe iii. Females carrying COL4A5 mutations can have broad spectrum of severity, presumably due to random inactivation d. NOTE: MYH9 gene causes phenotypically similar + biopsy similar condition but also affects platelets + WBC

Answer 216

a. Renal i. Microscopic haematuria - all patients have asymptomatic microscopic haematuria ii. Gross haematuria - single or recurrent episodes of gross haematuria – seen in 50% of patients iii. Proteinuria – often seen in boys, may be absent, mild or intermittent in girls iv. Progressive proteinuria – can become severe enough to cause nephrotic syndrome b. Bilateral sensorineural hearing loss i. Never congenital; deficit begins in the high-frequency range, but progresses to involve hearing associated with normal speech  hearing aids ii. 90% of hemizygous males with X-linked AS iii. 10% of heterozygous females with X-linked AS iv. 67% of patients with autosomal recessive AS c. Ocular abnormalities i. Occur in 30-40% of patients with X-linked AS ii. Abnormalities include: anterior lenticonus (conical protrusion of lens), macular flecks and corneal abrasions d. Leiomyomatosis = of the esophagus, tracheobronchial tree and female genitals, in association with platelet abnormalities is rare

Answer 217

Pathognomonic for Alport Syndrome

Answer 218

Alport Syndrome

Answer 219

5. Natural history a. Often progress b. Persistent microhaematuria  intermittent macrohaematuria (with URTI)  proteinuria  renal failure 6. Prognosis and treatment a. Risk of ESRD highest in hemizygotes and autosomal recessive homozygotes i. Hemizygotes with X-linked AS = occurs <30 years in 75% of individuals ii. X-linked heterozygotes = 12% by age 40, 30% by age 60 years b. Risk factors for progression = gross haematuria during childhood, nephrotic syndrome, prominent GBM thickening c. Intra-familial variation differences in the age of ESRD among family members d. No specific therapy – ACE-I or ARB slow rate of progression e. Careful management of renal failure complications f. Approximately 5% of kidney transplants develop anti-GBM nephritis – occurs primarily in males with X-linked AS who develop ESRD before 30 years

Answer 220

1. Key points a. Presence of persistent microscopic haematuria AND isolated thinning of FBM on EM b. Overlap with AS; some patients with AS initially have a picture of TBMN c. Diagnosis of exclusion

Answer 221

a. Sporadic or inherited b. AD c. Heterozygous mutations in COL4A3 and COL4A4 – alpha3 and alpha4 chains of type IV collagen of GBM d. In half of cases of TBMN genetic etiology unclear

Answer 222

a. Microscopic haematuria is often initially observed during childhood and may be intermittent b. Episodic gross haematuria can also be present – particularly after respiratory illness c. Isolated haematuria in multiple family members WITHOUT renal dysfunction referred to has benign familial haematuria  most patients will not undergo renal biopsy – presumed TBMD d. No family history of abnormal renal function, eye problems, deafness

Answer 223

4. Natural history a. Rare cases of TBMD progress  [proteinuria, HTN, or renal insufficiency 5. Prognosis a. “Benign familial haematuria” – not associated with other signs of renal disease (proteinuria, renal impairment) b. Can be overlap with AS c. Female ‘carriers’ can be affected to variable degrees (random X inactivation) d. Annual BP an urine PCR screening warranted e. Very rare progression to ESRF

Answer 224

a. Post GAS infection (nephritogenic strep A) i. 1-2 weeks post throat infection – typically colder months ii. 3-6 weeks after skin infection (typically with eczema) [streptococcal pyoderma] – typically warmer months Resolution - gross haematuria 2 weeks - HTN 4 weeks - low C3 8 weeks - persistent proteinuria 6 months - intermittent proteinuria 12 months - microhaematuria 2 years

Answer 225

d. Most common in children ages 2-12 years; uncommon < 3 years e. Spectrum = microscopic haematuria, acute nephritis, nephrotic syndrome a. Post GAS infection (nephritogenic strep A) i. 1-2 weeks post throat infection – typically colder months ii. 3-6 weeks after skin infection (typically with eczema) [streptococcal pyoderma] – typically warmer months b. Sudden onset haematuria (urine tea or coca cola coloured), oliguria, HTN, edema c. Nephrotic syndrome develops in minority (<5%) d. Non-specific symptoms = malaise, abdo pain, flank pain e. Varies asymptomatic microscopic haematuria with normal renal function to gross haematuria with acute kidney failure f. NOTE: other infectious can also cause GN (EBV, CMV, hep B, endocarditis)

Answer 226

a. Mediated by immune complexes – circulating immune complex formation with streptococcal Ag and subsequent glomerular deposition  become trapped in the glomerulus b. Group A strep possess M proteins, and nephritogenic strains are related to the M protein serotype (molecular mimicry, cross react with glomerula components)

Answer 227

a. Urine = RBC, often RBC casts, proteinuria, PMN b. FBE = mild normochromic anaemia from haemodilution or low grade haemolysis c. Evidence of prior GAS infection i. Positive throat swab ii. ASOT raised in majority of pharyngeal infections, but may not be post-skin infection 1. Can be positive in normal children (approx 20%) 2. Rises 3-4 weeks post infection iii. Anti-DNAse B = positive 1. Rises in 6-8 weeks d. Complement i. Low C3  returns to normal by 6-8 weeks (if low level persists consider MPGN or SLE) ii. C4 normal (unlike MPGN, SLE, endocarditis) e. Renal biopsy i. Indications 1. RPGN 2. Atypical course = prolonged macrohaematuria (especially if no evidence of strep), prolonged proteinuria, no recovery of C’ by 8 weeks ii. Histology 1. Glomeruli enlarged and relatively bloodless 2. Diffuse mesangial cell proliferation with increase in mesangial matrix 3. PMN infiltration 4. Crescents and interstitial inflammation in severe cases 5. Immunofluoresnce = lumpy-bumpy depots of IG and C’ (sub-epithelial humps) 6. EM = electron dense humps observed on epithelial side of GBM (‘starry sky’)

Answer 228

a. Manage complications of acute renal insufficiency and HTN b. 10 day course of oral penicillin – does not alter course of APSGN – reduces spread of nephritogenic organism c. Oliguria – aim urine output >1mL/kg/hour d. Oedema – fluid and salt restrict, diuretics if required (usually frusemide) e. Hypertension – management with ACEI if required (or CCB) f. AKI – monitor Cr and urine output, treat hyperkalaemia (resonium), sodium bicarbonate g. Methylpred sometimes considered – little evidence

Answer 229

6. Natural History a. Acute phase resolves within 6-8 weeks i. Hypertension + macrohaematuria resolve within 1 week ii. Urinary protein excretion + microhaematuria usually normalize by 4-6 weeks iii. Complement normalizes by 6-8 weeks b. Persistent microscopic haematuria can persist for 1-2 years c. Unlikely to have recurrence 7. Prevention a. Early systemic antibiotic therapy for streptococcal infections does NOT eliminate risk b. Family members of patients with acute GN, especially young children – cultured and treated if GAS +ve 8. Prognosis + complications a. Posterior reversible encephalopathy syndrome b. If severe hypertension or hypervolaemia  encephalopathy and/or HF c. 95% resolve spontaneously, 5%  RPGN or slowly progressive d. <2%  glomerulosclerosis and chronic renal disease

Answer 230

1. Key points a. SLE = fever, weight loss, dermatitis, haematological abnormalities, arthritis b. GN is the most important cause of morbidity and mortality in SLE 2. Epidemiology a. Renal disease in childhood SLE is present in up to 80% of children (>adults) b. Commonest presentation of SLE – occurs in 30-70% c. Most children with SLE are adolescent females d. Particularly occur in Indian, Maori or Pacific Islanders 3. Risk factors a. Deficiency of C1q is rare but the strongest single genetic factor for SLE b. Ethnicity and socioeconomic factors do NOT predict development of lupus nephritis in children 4. Pathogenesis and pathology a. Clinical manifestations of SLE are mediated by immune complexes b. Autoantigens are directed predominantly at nuclear antigens which act as immunogens c. Binding of autoantibodies to GN components rather than passive ‘trapping’ of circulating immune complexes is central to the development of GN i. Mesangial/ subendothelial deposits = large complexes, negatively charged, proliferative (nephritis) ii. Subepithelial deposits = native Ag-immune complexes, less inflammatory, result in membranous nephropathy with nephrotic features

Answer 231

6. Clinical manifestations a. Mild lupus nephritis (class I-II, some class III) = haematuria, normal renal function, proteinuria <1 g/24 hours b. Class III (some) and ALL patients with class IV nephritis = haematuria, proteinuria, hypertension, reduced renal function, nephrotic syndrome, or acute renal failure c. class V nephritis = nephrotic syndrome 7. Investigations a. FBE = lymphopenia b. Serology + markers of active disease i. ANA = positive in 85% with lupus (but high prevalence in healthy population) ii. dsDNA = positive in 60% with lupus (more specific) iii. Disease activity / nephritis similar = ↑ dsDNA ↓ C3/C4 [low C3 during flare, low C4 pre-flare] iv. Cutaneous lupus, photosensitivity = anti Ro v. Sjogrens = anti La vi. Neonatal lupus = maternal Anti Ro vii. Thrombosis, miscarriage, livedo reticularis = anticardiolipin, B2 microglobulin, lupus anticoagulant c. Urine = haematuria, proteinuria d. Renal biopsy = any haematuria/proteinuria/renal dysfunction MUST have biopsy

Answer 232

8. Treatment a. Regular urine screen for evidence of nephritis b. Class I + II - no specific treatment; good prognosis c. Class III-V - require treatment d. Immunosuppression – goal: i. Clinical remission = normalization of renal function and proteinuria ii. Serological remission = normalization of anti-DNA antibody, C3 and C4 levels e. Treatment i. Initiation = combination of prednisolone, pulse IV methylprednisolone, cyclophosphamide ii. Maintenance = combination of MMF, AZA, cyclophosphamide, rituximab iii. Other treatment options = plasmapheresis – only considered if accompany TTP or ANCA disease iv. Relapsing/resistant disease = consider MMF, cyclophosphamide, rituximab f. Adjunctive i. ACE-I ii. Statin g. Other immunomodulators = hydroxychloroquine (joint, skin, relapse prevention) 9. Prognosis a. Renal survival (CKD without RRT) 80% 10 years after diagnosis b. High risk for progression to ESKD = diffuse proliferative WHO grade IV nephritis

Answer 233

1. Key points a. HSP is the most common small vessel vasculitis in childhood b. Triad = purpuric rash, arthritis, abdominal pain c. 50% of patients with HSP develop renal manifestations i. Asymptomatic microscopic haematuria ii. Severe, progressive GN 2. Epidemiology a. Most common in younger children b. Male: female 2:1 3. Pathogenesis a. Deposition of polymeric IgA in glomeruli b. Glomerular findings can be indistinguishable from IgA nephropathy (? Larger complexes) 4. Clinical manifestations a. Classically follows onset of the rash, often presenting weeks or months after initial presentation b. Nephritis can be manifest at the initial presentation, but rarely before onset of the rash c. Severe combined acute nephritis and nephrotic picture i. Haematuria + hypertension + AKI ii. Proteinuria + nephrotic syndrome d. Most patients have mild renal manifestations – isolated microscopic haematuria w/o significant proteinuria e. Mild renal involvement can occasionally progress to more severe nephritis f. Severity of systemic manifestations does NOT correlate with severity of nephritis g. Timing of renal disease i. Most patients who develop nephritis have urinary abnormalities by 1 month, and nearly all by 3 months after onset of HSP (rare beyond this) ii. Urinalysis should be done weekly in patients with HSP during the period of active clinical disease iii. Thereafter should be done monthly for 6 months h. RCH guidelines = if the initial urinalysis is normal or only reveals microscopic haematuria, review clinically and check BP/early morning urinalysis at these recommended time intervals i. Weekly for the first month after disease onset ii. Fortnightly from weeks 5-12 iii. Single reviews at 6 and 12 months iv. Return to 1 if there is a clinical disease flare

Answer 234

6. Natural history a. 1/3 symptoms <14 days b. 1/3 symptoms 2-4 weeks c. 1/3 symptoms > 4 weeks d. 1/3 recurrence – usually within 4/12 7. Treatment a. Steroids do NOT impact development of nephritis b. Efficacy of treatment for moderate to severe HSP nephritis have shown no benefit c. Various immunosuppressants often used – steroids/AZA d. If RPGN = cyclophosphamide/ TPE 8. Prognosis a. Excellent prognosis for most patients – spontaneous and complete resolution of the nephritis typically occurs in majority of patients with mild initial manifestations (isolated haematuria with insignificant proteinuria) b. Poor prognosis i. Nephritic/nephrotic at presentation ii. Persistent/ progressive proteinuria iii. Older age iv. Recurrence v. Necrosis or crescentic changes c. Untreated – risk of renal failure is 2-5% in patients with HSP, but 50% in those with severe early renal clinical and histological disease

Answer 235

1. Key points a. Nephritic syndrome with rapidly deteriorating renal function – commonly dialysis requirement b. Crescents on biopsy 2. Etiology a. Primary i. IgA nephropathy ii. MPGN iii. Anti-GBM b. Secondary i. ANCA-mediated ii. SLE nephritis iii. Post-streptococcal GN – note rarely proceeds to CGN but as it is the most common cause of GN in childhood accounts for significant percentage of patients with CGN iv. IgAV/HSP nephritis 3. Pathology + pathogenesis a. Hallmark = crescents in glomeruli b. Crescent formation = proliferation of parietal epithelial cells in Bowman’s space = final common pathway of any severe inflammatory glomerular injury c. Fibrous crescents = late finding 4. Clinical manifestation a. Acute nephritis = haematuria, some degree of renal insufficiency + HTN b. Often concomitant proteinuria, often with nephrotic syndrome c. Occasionally late presentation with oliguric renal failure 5. Investigations a. Diagnosis = biopsy 6. Prognosis + management a. Children with crescentic post-infectious GN can spontaneously recover b. Natural course of other forms of RPGN = ESRF in weeks to months c. Poor prognosis = fibrous crescents (irreversible) d. Management = little evidence i. High dose corticosteroids + cyclophosphamide + rituximab ii. Plasmapheresis – may be beneficial for Goodpasture disease or ANCA-associated RPGN

Answer 236

1. Key points a. Pulmonary-renal syndrome = pulmonary haemorrhage + crescentic GN b. Rare in childhood c. Does not recur 2. Pathogenesis a. Antibodies directed against type IV collagen  GBM and alveolar basement membrane 3. Clinical manifestations a. Haemoptysis + acute GN with rapid course to ESRF b. No other symptoms involved 4. Investigations a. Anti-GBM Ab present b. ANCA can be present  more severe prognosis 5. DDx – other pulmonary-renal syndrome a. SLE b. HSP c. Granulomatosis with polyangiitis 6. Treatment a. High dose IV methylpred + cyclophosphamide + plasmapheresis b. Rituximab has previously been used 7. Prognosis a. Very poor b. High risk of ESKD – 1 year kidney survival 16%

Answer 237

1. Key points a. Ab directed against neutrophil cytoplasmic Ag b. cANCA = PR3 ANCA = granulomatosis with polyangiitis (GPA or Wegners) c. pANCA = MPO ANCA = microscopic polyangiitis (MPA/renal limited vasculitis) 2. Clinical manifestations a. Can present with slow progressive symptoms/ sudden acuity b. Focal segmental necrotising PAUCI-IMMUNE crescentic GN c. Fevers/malaise/weight loss d. Joints/eyes/ skin/nervous system/ heart can also be involve 3. Investigations a. Immunofluorescence b. ELISA – confirm positive IF, detect specific antigen Ab directed against i. MPO = myeloperoxidase ii. PR 3 = proteinase 3 4. ANCA associated Small Vessel Vasculitis a. GPA = Wegners i. cANCA positive 90% ii. Granuloma upper + lower respiratory tract (80% lung involvement) + kidneys (rarely seen) iii. 20-30% will relapse over 5 years – monitor with cANCA b. MPA i. pANCA positive 70% ii. No granuloma iii. Can have respiratory involvement (pulmonary capillaritis – can haemorrhage), interstitial lung disease; not usually chronic rhinosinusitis of GPA 5. Renal manifestations a. RPGN b. Proteinuria c. Heamaturia d. Acute nephritis 6. Other features of vasculitis a. ENT = GPA > MPA b. Pulmonary = GPA + EGPA > MPA c. Skin = vasculitis – purpura, urticaria, erythema nodosum, livedo reticularis 7. Treatment a. Immunosuppression = steroids, cyclophosphamide, rituximab b. Severe necrotising GN and pulmonary haemorrhage – indications for PLEX c. Maintenance = AZA, glucocorticoids, ? Rituximab 8. Prognosis a. >80% mortality if untreated – 10% over 10-20 years with treatment

Answer 238

a. Overall i. Microvascular injury with endothelial damage is characteristic in ALL Forms of HUS ii. Capillary and arteriolar endothelial injury in the kidney lead to localised thrombosis  impaired glomerular filtration  AKI iii. Progressive platelet aggregation in areas of microvascular injury  consumptive thrombocytopenia iv. Thrombotic microvasculature  mechanical damage to RBC  microangiopathic anaemia b. Diarrhoea-associated i. Shiga toxin or Shiga-like verotoxin  endothelial activation ii. Shiga toxin can directly activate platelets to promote their aggregation c. Pneumococcal-associated HUS i. Neuraminidase cleaves sialic acid on membranes of endothelial cells, RBC and platelets to reveal the underlying cryptic Thomson-Friedenreich (T) antigen  endogenous IgM recognizes Ag  microvascular angiopathy d. Genetic i. Deficiencies of ADAMTS13 and regulators of the C’ cascade predispose patients to develop HUS ii. ADAMTS13 deficiency  impaired cleavage of vWF multimers  enhanced platelet aggregation iii. Factor H arrests amplification and propagation of C’ activity

Answer 239

2. Clinical manifestations a. Diarrhoea associated i. Occurs a few days after gastroenteritis – prodromal intestinal symptoms can range from mild to moderate – diarrhoea is often bloody but not always ii. Following the prodromal illness  sudden onset pallor, irritability, weakness and lethargy iii. Oliguria may be present in early stages but often masked by diarrhoea b. Pneumococci i. Unwell with pneumonia, empyema and bacteraemia when they develop HUS 3. Complications a. CNS involvement = majority of patients with HUS have some CNS involvement i. Most have mild manifestations – irritability, lethargy or non-specific encephalopathic features ii. Severe CNS involvement occurs in 30% - seizures, encephalopathy 1. Results from focal ischaemia secondary to microvascular CNS thrombosis 2. Small infarctions common b. Hypertension = may produce encephalopathy c. GIT = severe inflammatory colitis, ischaemic enteritis, bowel perforation, intussusception, pancreatitis d. Note despite thrombocytopaenia bleeding in HUS rare

Answer 240

4. Treatment a. Supportive care – fluid and electrolyte management, early institution of dialysis, RBC i. If fluids provided early can help the initial pre-renal phase where dehydration from gastroenteritis contributes ii. Note in pneumococci associated HUS RBC must be washed before transfusion – endogenous IgM directed against the revealed T antigen plays a role in accelerating disease iii. Platelets generally not administered as rapidly consumed b. Up to 50% require dialysis c. No evidence that direct therapy against pathogenic organism in diarrhoea-associated HUS improves outcome i. Antibiotics to enteric toxicogenic organisms (STEC) can increase toxin release – NOT recommended d. Prompt treatment of pneumococcal infection important 5. Prognosis a. Mortality <5% with early and appropriate supportive care b. 5% remain dependent on dialysis, 30% left with some degree of CKD c. Risk factors i. High WCC ii. Prolonged oligoanuria iii. Shigella dysentery iv. CNS and gut involvement d. Pneumococci associated HUS has mortality as high as 20% e. Negligible risk of recurrence post Tx unless uncover aHUS f. Require long-term monitoring for HTN, proteinuria, CKD

Answer 241

1. Key points a. <10% of HUS b. Any age including newborns c. Often present during/after acute illness d. Alternative C’ pathway constantly being activated – C3 constantly being hydrolysed – inhibitors are required to prevent over-activation 2. Clinical manifestations a. Major feature = absence of diarrhoea b. Other features = can be indolent and unremitting once they manifest OR can have relapsing pattern precipitated by an infectious illness c. Recurrent episodes of haemolysis and renal failure with high risk of ESRF 3. Etiology a. Complement-mediated i. Mutations in genes for C3, CD46, and complement factors H, B and I ii. Acquired C’ dysregulation due to Ab to complement factors B and H b. Mutations in non-complement genes i. Coagulation pathway 1. DGKE gene 2. PLG mutation 3. Thrombomodulin mutation ii. Cobalamin 4. Treatment a. Plasma infusion or plasmapheresis – experimental treatment i. Plasma therapy can be helpful in patients with ADAMTS13 or factor H ii. Also considered for patients with other genetic forms of HUS b. Eclizumab – C5 inhibitor – approved for treatment of atypical HUS in USA i. Great promise in treatment of atypical HUS, including HUS occurring following renal transplantation ii. Note increased risk of Neisseria meningitidis – require prophylaxis c. NOT helpful = antibiotics, toxin binders, anti-motility agents, NSAIDs, anti-platelet, anticoagulation, fibrinolytics, immunosuppression, plasma exchange including PLEX d. Transplant i. MCP less recurrence as replace the defective protein (in kidney) ii. Decline live donor if no gene identified 5. Prognosis a. Prognosis for HUS not associated with diarrhoea more severe due to recurrence risk b. Familial, genetic forms have variable prognosis

Answer 242

a. Microangiopathic haemolytic anaemia (MAHA) = non-immune haemolysis resulting from intravascular RBC fragmentation that produces schistocytes on peripheral blood smear b. Thrombotic microangiopathy (TMA) = specific pathological lesion in which abnormalities in the vessel wall of arterioles and capillaries lead to microvascular thrombosis i. Not all MAHA is caused by TMA, but nearly all TMAs cause MAHA and thrombocytopaenia 2. Etiology a. Thrombotic thrombocytopenic purpura (TTP) b. Shiga-toxin mediated HUS c. Drug induced TMA d. Complement induced TMA e. Rare hereditary disorders of B12 metabolism

Answer 243

Due to infective endocarditis or infected shunt 1. Key points a. Types of renal disease in patients with IE i. Bacterial infection related immune complex mediated GN ii. Renal infarction from septic emboli iii. Renal cortical necrosis b. In addition i. Drug-induced AIN ii. AKI secondary to nephrotoxic antibiotics – aminoglycosides 2. IE associated GN a. Etiology i. Staph aureus 55% ii. Streptococcus iii. Less common = Bartonella hensalae, Coxiella burnetii b. Clinical manifestations i. AKI ii. Haematuria c. Investigations i. C3 = low ii. C4 = low in some (20%) iii. ANCA = positive in some (33%) 3. Shunt nephritis a. Complication of infected ventricular shunts used for treatment of hydrocephalus b. Frequency declined since ventricuovascular shunts have replaced ventriculoperitoneal shunts

Answer 244

1. Key points a. Occurs in 2 distinct clinical settings i. Newborns and infants – associated with asphyxia, dehydration, shock, sepsis, congenital hypercoagulable states, maternal diabetes ii. Older children – nephrotic syndrome, cyanotic heart disease, inherited hypercoagulable states, sepsis, following kidney transplantation 2. Clinical manifestations a. Typical = sudden onset gross haematuria and unilateral or bilateral flank masses b. Other features i. Hypertension ii. Microscopic haematuria iii. Microangiopathic haemolytic anaemia with thrombocytopenia iv. Oliguria 3. Investigations a. USS – shows marked renal enlargement b. Doppler – confirms diagnosis c. Thrombophilia screen 4. DDx a. Other conditions with haematuria associated with rapid development of microangiopathic haemolytic anaemia or enlargement of the kidney(s) i. HUS ii. Hydronephrosis iii. PCKD iv. Wims tumour v. Intra-renal abscess or haematoma 5. Treatment a. Supportive care – correct fluid and electrolyte imbalance, treatment of renal insufficiency b. Anticoagulation c. Thrombolysis sometimes required if bilateral 6. Prognosis a. Partial or complete renal atrophy can occur following RVT in neonate  increased risk of CKD, renal tubular dysfunction and systemic hypertension b. Older children often have recovery of renal function

Answer 245

1. Key points a. Usually AD disorder b. Can be associate with other conditions resulting in hypercalcaemia i. Hyperparathyroidism ii. Vitamin D intoxication iii. Immobilisation iv. Sarcoidosis c. Cause of haematuria 2. Clinical manifestations a. Variable clinical presentation i. Recurrent gross haematuria ii. Persistent microscopic haematuria iii. Dysuria or abdominal pain in the absence of stone formation 3. Investigations a. 24 hour urinary calcium excretion = > 4 mg/kg  diagnostic 4. Consequences a. If untreated hypercalciuria  nephrolithiasis in 15% of cases b. Increased risk for i. Development of low bone mineral density ii. Urinary tract infections iii. Kidney stones 5. Treatment a. Oral thiazide diuretics – normalize urinary calcium excretion by stimulating calcium reabsorption in the proximal and distal tubules i. This can lead to resolution of haematuria and prevent nephrolithiasis ii. Dose can be up-titrated iii. Usually ceased after 1 year, but resumed if gross haematuria, nephrolithiasis or dysuria recurs iv. Monitoring of electrolytes important due to risk of hypokalaemia b. Potassium citrate – helpful in patients with low urinary citrate excretion and symptomatic dysuria c. Sodium restriction i. Urinary calcium excretion parallels sodium excretion d. Dietary calcium restriction is NOT recommended (unless >250% of recommended dietary allowance)

Answer 246

1. Spectrum of disease a. Gross or microscopic haematuria seen in children with sickle cell disease or sickle trait i. Tends to resolve spontaneously in most children b. Polyuria caused by urinary concentrating defect, renal tubular acidosis, and proteinuria associated with glomerular lesions c. 20-30% of patients with sickle cell disease develop proteinuria i. Nephrotic range proteinuria with or without clinically apparent nephrotic syndrome occurs in 30% - usually heralds CKD 2. Etiology a. Microthrombosis secondary to sickling in the relatively hypoxic, acidic, hypertonic renal medulla where vascular stasis is present b. Contributing factors = analgesia, volume depletion with prerenal failure, infection, iron-related hepatic disease c. Glomerular hyperfiltration mediated by intra-renal production of PG and synthesis of NO is involved in the pathogenesis of proteinuria and kidney failure 3. Treatment a. Tubular manifestations have no treatment other than usual recommendations for sickle cell disease b. ACE-I or ARB can be used to affect a significant reduction in urine protein excretion c. Gross haematuria secondary to papillary necrosis may require treatment with aminocaproic acid or desmopressin acetate d. Hydroxyurea and newer treatments for sickle cell disease have decreased the manifestations of SSN 4. Prognosis a. SSN can eventually lead to hypertension, renal insufficiency, and progressive kidney failure

Answer 247

1. Epidemiology a. 5-20% for adults b. 1% of children c. M > F d. FHx in 20-40% e. 60% have metabolic risk factor = ALL must be considered to have metabolic cause 4. Stone composition a. Calcium oxalate = 60-90% b. Calcium phosphate = 10% c. Struvite = 1-14% d. Uric acid = 5-10% e. Cystine = 1-5% f. Mixed/other = 4% 6. Metabolic disorders causing stones a. Hypercalciuria = most common b. Hyperoxaluria c. Cystinuria d. Disorders of purine metabolism 2. Risk factors a. Geography = hot climate b. Race c. Metabolic eg. hypercalciuria, hyperoxaluria d. Infection (esp urease producing spp, e.g. Proteus) e. Urinary stasis due to congenital/structural problem f. Dietary factors i. Developed = high protein  upper tract  calcium oxalate/phosphate stones ii. Developing = high cereal  bladder  NH4/UA/infection stone iii. Na (reduced Ca resorption) = biggest risk factor 1. Salt reabsorption creates solvent drag for calcium to be reabsorbed 2. ↑salt intake leads to ↓ salt reabsorption, ↓ calcium reabsorption 3. ↑ calcium in the tubules predisposes to precipitation iv. Protractive = citrate, potassium, Mg v. Calcium = important increased risk with low intake vi. High GI CHO and obesity – metabolic syndrome g. Drugs = melamine, indinavir, ceftriaxone d. Inhibitors of stone formation = citrate, diphosphonate, magnesium, glycosaminoglycans, glycoproteins

Answer 248

a. All children with stones should be Ix for underlying metabolic condition b. Confirmation of calculi i. Renal USS 1. Specific >1.5mm 2. Detects radio lucent calculi (uric acid) 3. Associated obstruction 4. May miss small/ureteric calculi – if severe pain likely in ureter 5. DDx – THP kidney ii. AXR – especially if USS negative 1. 90% of stones are calcified to some degree = radio-opaque 2. If small can be difficult to see 3. Struvite = radio-opaque 4. Cystine, xanthine and uric acid calculi = radiolucent but often slightly opacified iii. CT/spiral CT (unenhanced) 1. Most sensitive; all stones 2. Stones in any location c. Complications – obstruction/infection i. UTI – urine MCS ii. Obstruction – renal USS, or DTPA/MAG3 d. Find a cause i. Stone analysis ii. Urine 1. Urine pH, microscopy and culture 2. Urine metabolite excretion – 24 hour OR Cr ratios a. Cystine, calcium, oxalate, uric acid, citrate (protective), Mg b. NOTE: i. Full assessment x3 times ii. Spot urine with calcium, oxalate, urate and cystine – most important iii. Blood = CMP, uric acid, acid-base, PTH, vitamin D

Answer 249

a. Dietary i. High fluid intake – often effective in preventing further stones - daily intake of 2-2.5L ii. Low salt intake (to reduce urinary Ca) – high Na increases urinary excretion of Ca b. Medical i. Alpha-adrenergic blockers – can help facilitate stone passage c. Metabolic defects i. Potassium supplements – to reduce urinary Ca excretion ii. Citrate forms soluble complexes with Ca; supplemental potassium citrate - prevents calcium stones iii. Bicarbonate supplementation increases urinary citrate iv. Allopurinol – prevents uric acid stones v. Cystinuria/oxalosis = surveillance USS, urine 3-6/12 vi. Monitor bloods on penicillamine d. Assess likelihood of spontaneous passage i. <7mm = wait and repeat USS 3/12 ii. >7mm = surgical referral e. Surgical i. Percutaneous nephrostomy OR stent – if acute obstruction

Answer 250

1. Age = median 2 years, 75% <5 year 2. Sex = 80% male (although often seen in females with recurrent infection) 3. Etiology a. Often urease producing organism (eg proteus, klebsiella, E coli, pseudomonas) (PKEP) b. Urinary alkalinsation  excessive production of ammonia  leads to precipitation of Mg ammonium phosphate + calcium phosphate 4. Clinical manifestations a. Infection i. 90% at diagnosis ii. Resistant to therapy iii. Proteus – urease  alkaline urine b. FTT common 5. Site a. Left 66% b. Upper tract 85%  staghorn c. Bilateral 15% 6. Composition a. Struvite = MgNH4PO4-6H2O  triple phosphate b. Carbonate apatite = Ca10[PO4]6CO3 7. Urologic abnormalities a. 33% VUR – later 11% b. 33% other abnormality c. Ureteric dilatation d. Calcium excretion - often transiently raised acutely 8. Treatment a. Removal essential b. ? Acidify the urine (acid phosphate) 9. Complications a. Xanthogranulomatous pyelonephritis b. Pyonephrosis c. Renal scarring d. Nephrectomy

Answer 251

1. Key points a. Commonest metabolic cause of stones is hypercalciuria 2. Physiology a. Calcium excretion is affected by Na intake b. Ca reabsorption in the proximal tubule parallels Na reabsorption  changes that lead to an expansion of extracellular volume (eg. high Na intake) will decrease Na and thus Ca reabsorption in PT 3. Urine calcium excretion a. 99% filtered calcium is resorbed – proximal tubule + thick ascending loop of Henle i. Paracellular gradient via solvent drag b. Hypercalciuria i. 24 hour urine Ca excretion > 0.1 mmol/kg/day ii. 2 hour fasting Uca/Ucr ratio >0.7 in children over 2 years (up to 2 for infants due to low creatinine)

Answer 252

a. Hypercalcaemia i. Hyperparathyroidism ii. Vitamin D excess iii. Immobilsation iv. Hypophosphatasia v. Hypophosphataemia b. Normocalcaemia i. Idiopathic hypercalciuria ii. Immobilsation iii. Medullary sponge kidney iv. Drugs = topiramate, frusemide, steroids v. Ketogenic diet vi. Glycogen storage disease type 1A vii. Dent Disease viii. Bartter syndrome ix. Wilson’s disease x. FHHNC = familial hypoMg with hypercalciuria + nephrocalcinosis xi. Distal RTA = increase UCa, reduced UCa, elevated urine pH

Answer 253

a. Polygenic – some AD b. Reduced dietary calcium  increased oxalate absorption + reduced BMD i. Elevated oxalate can result in oxalate stone formation c. Clinical manifestations i. Haematuria/ leukocyturia ii. Nephrocalcinosis iii. Calculi iv. Reduced BMD d. Treatment i. Increase fluid – 1.5-2x normal fluid intake ii. Dietary 1. Reduce dietary SODIUM (NOT calcium) 2. Increase dietary potassium iii. Citrate Ca chelation + alkalinsation (potassium citrate) iv. Thiazides – reduce calcium excretion v. ? BMD – bisphosphonates

Answer 254

1. Key points a. Radiolucent stones b. Result from uric acid overproduction 2. Etiology a. Idiopathic b. Tumour lysis syndrome c. Lesch-Nyan syndrome i. AR disorder due to deficiency of hypoxanthine-guanine phosphoribosyl transferase ii. Key features = choreoathetosis, self-mutilation, uric acid calculi and CKD d. Primary gout e. Glycogen storage disease type 1 – may increase uric acid excretion f. Ketogenic diet or high protein g. Drugs – salicyclates h. Dihydroxyadeninuria i. Familial juvenile hyperuicaemic nephropathy j. Xanthinuria i. AR disorder due to deficiency of xanthine oxidase - converts xanthine to uric acid  hypouricaemia and xanthine stones ii. Low selenium + urinary uric acid iii. Orange nappies 3. Treatment a. Alkalinise urine – EXTREMELY sensitive b. Allopurinol (xanthine stones in LNS) c. Uricase

Answer 255

1. Key points a. 1-3% nephrolithiasis b. 6-8% of all nephrolithiasis in children c. Age of presentation = 50% <10 y, 90% <20y d. Stone free interval 3-6 months e. UNRELATED to cystinosis f. Often presents with bladder stones 2. Genetics + pathogenesis a. AR - Heterozygotes usually do not form stones b. Gene mutations i. SLC3A1 (rBAT – necessary transport subunit) ii. SCLA7A9 (encoding actual transporter) c. Defective re-absorption of dibasic amino acids (cystine, ornithine, lysine and arginine) – cystine crystallises f. Classification i. A = recessive mutations in SCL3A1 (45% of patients; heterozygotes unaffected) ii. B = recessive mutations in SCL7A9 (>50% of patients; heterozygotes have moderately increased cysteine excretion iii. AB = heterozygote mutations of both (2%) 4. Specific treatment c. Alkalinise urine – sodium bicarbonate or sodium citrate (NOTE uric acid stones more soluble) d. Reduce dietary sodium e. Solubilize/ chelate cystine = penicillamine i. Cysteine + cysteine – NOT soluble ii. Cysteine + penicillamine – SOLUBLE iii. Note penicillamine has many side effects including membranous nephropathy 5. Monitoring a. Urinary cystine <100 um/mmol Cr b. SG <1.010; U pH >7 c. Renal USS

Answer 256

1. Key points a. Important cause of calcium stones = oxalate increases the solubility product of calcium oxalate crystallization  increases the likelihood of calcium oxalate precipitation b. Always think of hyperoxaluria with severe nephrocalcinosis 2. Etiology a. Primary i. Inherited metabolic disorders ii. Rare iii. Primary types 1 and 2 (association of nephrocalcinosis and renal ureteric calculi is highly suggestive of primary hyperoxaluria type 1) = PH1, PH2, PH3 b. Secondary i. Increased enteric oxalate absorption 1. Oxalate absorption is increased if there is not enough Ca to bind oxalate in the gut 2. Fatty acids usually bind calcium in GIT - ↓ fatty acids = ↓calcium = less binding with oxalate in the GIT and increased absorption 3. Conditions a. Malabsorption syndromes – IBD, cystic fibrosis b. Low Ca diets

Answer 257

1. Key points a. Usually infantile onset – 50% by 5 years 2. Genetics a. AGXT 2q37.3 b. Consanguinity – homozygotes c. Many compound heterozygotes 3. Clinical manifestations a. Renal stones b. ESKD = 20% by 15 years, 50% by 25 years, infantile 80% at 3 years c. Recurrent nephrolithiasis – nephrocalcinosis, progressive loss of renal function d. Occasionally presents in adulthood e. Systemic oxalosis i. Occurs when saturation pot reached = plasma oxalate >30 uM in early renal insufficiency ii. Deposition in all tissue except liver 1. Retinal, media of vessels, PNS, myocardium (AV block), thyroid, skin livedo reticularis 2. Bones a. X-ray = radiodense metaphyseal bands b. Diffuse demineralisation + replacement of marrow  pain, fractures iii. EPO resistant anaemia 4. Treatment a. Aim = reduce oxalate production + increase urinary solubility b. Pyridoxine = 10-30% pyridoxine responsive c. Solubility = fluid 2-3L/m2/day, citrate/Pi/Mg e. ESKD treatment i. Dialysis – extensive HDx required to reduce calcium load ii. Kidney transplant iii. Liver/kidney

Answer 258

a. Definition = increase in the Ca content of the cortex or medulla b. Due to any cause of hypercalcaemia, hypercalciuria, or hyperoxaluria c. USS = hyperechoic medullae, which can be graded according to severity d. Classified as medullary or cortical e. Common causes i. Frusemide – particularly in premature infants ii. Distal RTA iii. Hyperparathyroidism iv. Medullary sponge kidney v. Hypophosphatemic rickets vi. Sarcoidosis vii. Cortical necrosis viii. Hyperoxaluria ix. Prolonged immobilisation x. Cushing syndrome xi. Hyperuricosuria

Answer 259

1. Key points a. Breakdown of striated muscle resulting in release of myoglobin, which is nephrotoxic i. Accounts for up to 20% AKI b. Characteristic - elevated CK levels with TRIAD i. Muscle pain ii. Weakness iii. Myoglobinuria (red-brown urine) 2. Etiology a. Hereditary myopathies and inflammatory muscle diseases b. Traumatic muscle injury c. Increased voluntary or involuntary muscle activity (seizures, severe asthma, heat stroke) d. Toxins: alcohol and drugs (neuroleptic malignant syndrome, malignant hyperthermia) 3. Clinical manifestations a. Proximal muscle pain, weakness b. Malaise, fever, tachycardia c. Nausea, vomiting abdominal pain d. Myoglobinuria – red/brown urine 4. Investigations a. CK =usually >5x upper limit of normal (1500 to >100,000 IU/L) i. Predominantly all skeletal muscle fraction (MM) with small amount of myocardial fraction (MB) ii. Rises 2-12hrs, peaks within 24-72hrs iii. CK half-life 1.5 days, should see reduction within 3-5 days c. AST and ALT often elevated d. UEC = hyperkalemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia e. Urine i. Myoglobin (haeme-containing respiratory protein released from damaged muscle in parallel with CK) ii. Myoglobin detected as ‘blood’ on urine dipstick, but no RBC on microscopy iii. Proteinuria – due to release of myoglobin and other proteins released by damaged myocytes 6. Prevention and treatment of AKI a. Volume replacement b. Dialysis i. No evidence for removal of myoglobin, haemoglobin or uric acid by dialysis ii. May be necessary to control volume overload, hyperkalaemia, acidaemia and uraemia in established AKI c. Allopurinol = hyperuricaemia

Answer 260

a. Fluid + electrolyte imbalance i. Hypovolaemia – ‘third-spacing’ of ECF into damaged muscles ii. Hyperkalaemia and hyperphosphataemia – release from muscles iii. Hypocalcaemia- deposition of calcium phosphate in damaged muscle and decreased bone responsiveness to PTH iv. Elevated uric acid – increased release of purine from damaged muscle and reduced clearance in ARF v. Metabolic acidosis b. Acute kidney injury i. Affects 15-50% ii. Risk factors: sepsis, dehydration, acidosis iii. Volume depletion results in renal ischaemia, tubular obstruction due to haeme pigment cases and tubular injury from free chelatable iron c. Compartment syndrome = post fluid resuscitation d. DIC = rare

Answer 261

1. Epidemiology a. 2nd most common bacterial infection to otitis media b. Accounts for 7% in febrile infants and young children c. 0.3-1.3% of all infants have a UTI at some stage, F>M 2-4:1 (1-3% girls, 1% boys) d. <3 months M > F e. < 12 months M = F f. > 12 months F > M (2-4x higher) g. Symptomatic UTI before puberty occurs in 3-5% of girls and 1-2% of boys h. Recurrence in 50% of girls and uncommon in boys 2. Risk factors a. Female > 12 months / uncircumcised male b. VUR c. Obstructive uropathy/ anatomical abnormality d. Neuropathic bladder e. Constipation/ pinworm infestation 3. Microbiology a. E. coli = 75-90% b. Klebsiella c. Proteus (much more common in males) d. Enterococcus e. Adenovirus and other viral infections

Answer 262

a. Barriers to infection i. Unidirectional urinary flow ii. Uroepitheliium iii. Local proteins that inhibit bacterial attachment – eg Tamm Horsfall protein (uromodulin) = prevents UPEC colonization, impedes fimbrial attachment, activates innate and adaptive immunity b. Innate + adaptive immune response i. Uroepithelial cell activation and transmembrane signaling  production of distinct inflammatory markers ii. Production of distinct inflammatory mediators, and inflammatory cell recruitment iii. Cell and bacterial destruction iv. Toll like receptors 1. Toll like 2: lipoproteins from gram positive bacteria 2. Toll like 4 lipopolysaccharide signaling receptor 3. Toll like 11: recognises uropathogenic E.coli c. Bacterial properties i. Fimbriae allow bacteria to attach and become internalized in transitional epithelial cells ii. Usually fimbriae are inhibited by mannose, but many strains of E. coli are mannose-resistant

Answer 263

a. Cystitis i. Bladder symptoms = dysuria, frequency, urgency and abdominal pain ii. Does NOT cause fever/ renal injury b. Pyelonephritis i. Abdominal/ back/ flank pain ii. Systemic features = fever, malaise, vomiting c. Asymptomatic bacteriuria i. +ve urine culture without symptoms – no renal injury ii. < 1% in girls > 5, rare in boys d. Variants i. Acute haemorrhagic cystitis = E. coli, adenovirus ii. Eosinophilic cystitis = treated with antihistamines and NSAIDs iii. Interstitial nephritis = negative culture, ulceration on cystoscopy

Answer 264

b. Ultrasound i. Identifies = kidney size, hydronephrosis, ureteral dilatation, duplicated urinary tract, bladder anatomy c. DMSA i. Radioisotope injected IV taken up by normal tubular epithelium in the distal tubule (NOT secreted) ii. Areas of poor uptake = tubular atrophy + interstitial fibrosis iii. Suggests scarring secondary to tubular damage (eg reflux nephropathy) d. DTPA/ MAG3 i. Functional study - radioisotopes are taken up by renal parenchyma with some secretion ii. Provides differential of kidney function between two sides iii. Does NOT show scarring iv. MAG 3 – better if low GFR (neonates, CKD) v. DPTA – estimates GFR e. Indirect MCU i. Child voids when MAG3 hits bladder ii. Helps exclude/ confirm bladder neck obstruction + PUV but does not pick up all cases of reflux f. MCUG/VCUG i. Child is catheterized, radioisotopes injected into the bladder ii. XRS performed during filling and voiding iii. Only tolerated < 12 months iv. Should be performed 2-6 weeks after infection to allow inflammation to resolve v. Can be done on table with cystoscopy  allows deflux at the same time vi. Antibiotic cover required

Answer 265

a. Urine MCS i. Leukocytes – suggestive but not diagnostic ii. Growth of single organism >108 CFU/L = infection iii. Growth of single organism at lower count of 106-8 CFU/L from catheter or SPA urine suggests infection iv. Collection of urine 1. Older children = mid-stream urine 2. Younger children a. Clean catch = contamination rate 25% b. IDC = contamination rate 10% c. SPA = gold standard, contamination rate 1% v. Dipstick 1. Screening test 2. Nitrates most sensitive component

Answer 266

1. Atypical UTI a. Clinical symptoms = poor stream/ palpable kidneys/ bladder b. Unusual organism = proteus, enterococcus c. Bacteremia/ septicaemia d. Prolonged clinical course e. Known antenatal abnormalities f. Raised Cr g. Failure to respond to treatment within 48 hours 2. Recurrent UTI a. 2 or more episodes of pyelonephritis b. One episode of pyelo + 1 cystitis/ LUTI c. Three or more cystitis

Answer 267

7. Treatment a. Oral antibiotics are usually appropriate b. Children who are seriously unwell, and most infants under 3 months, should be admitted c. Most frequent cause of UTI – E coli  80% resistance to amoxicillin, cotrimoxazole 40-50% resistance d. Cystitis = 3-7 days e. Pyelonephritis = 7-10 days f. Oral treatment = trimethoprim, bactrim, cephalexin g. IV treatment = gentamicin + benzylpenicillin 8. Adjunctive treatment a. Hiprex b. D-mannose – sugar impedes attachment of E coli to epithelium c. Cranberry i. Some evidence to suggest may decrease risk of symptomatic UTIs over a 12 month period, particularly for women with recurrent UTIs ii. Effectiveness for other groups is less certain

Answer 268

a. Goal of imaging = identify i. Renal damage ii. VUR = 30% iii. Obstruction = 1% b. RCH i. Unwell children, those with renal impairment, and boys <3 months should have renal USS prior to discharge ii. Older children do not require an USS iii. Summary from lecture 1. Children of all ages with atypical UTI – perform US during the acute infection to identify structural abnormalities of urinary tract (often require repeat when well) 2. Infants <6 months with 1st UTI that is responsive to treatment  US within 6 weeks of infection 3. Children <3 years with atypical and/or recurrent UTI, do a DMSA scan 4-6 months after the acute infection to detect renal parenchyma defects

Answer 269

Involuntary wetting at an inappropriate time and place in a child 5 years and older. RCH: Urinary incontinence is defined as day wetting in a child over 5 years of age that occurs more than once per month for ≥ 3 months. Daytime urinary continence is usually achieved by 4 years of age. Day wetting occurs in around 10 percent of 5-6 year olds, decreasing with age.

Answer 270

1. Monosymptomatic night time wetting or enuresis = WITHOUT daytime symptoms 2. Nonmonosymptomatic night time wetting or enuresis = WITH daytime symptoms a. Includes – urgency, incontinence, increased/decreased voiding frequency, voiding post-ponement, holding manoeuvres, interrupted flow

Answer 271

a. Urine culture and analysis b. Renal US c. Bladder US = pre and post micturition volumes i. Residual volume<20ml ii. Or <10% of CBC iii. Expected bladder capacity (mL) = 30 x (2 + age to max of 12 years) d. Bladder diary (frequency volume chart) e. Uroflow i. Measurement of urine flow during voiding – rate, pattern ii. Least invasive iii. Age > 4 years, 3 curves prior to interpretation iv. Useful for follow up of bladder training + biofeedback training v. Facilitates selection for UD f. Urodynamics i. Measure pressure/ volume relationship of the bladder ii. Continuous study of filling and emptying iii. Requires transurethral or suprapubic approach + rectal probe for abdominal pressure iv. Combine with fluoroscopy – provides anatomical information (bladder shape, VUR, configuration + behaviour of bladder neck and pelvic floor) v. Indications 1. Neuropathic bladder eg. CP, spina bifida 2. Bladder outlet / urethral anomalies (concern re pressure) 3. Obstructive flow patterns 4. Suspected functional bladder problems refractory to treatment a. Dysfunctional voiding ?? fail to respond to treatment b. Underactive bladder c. Overactive bladder – failure to respond to traditional treatment?? d. Guide to treatment – pharmacotherapy or urotherapy e. Recurrent UTI vi. Measures 1. Abdominal pressure (via transducer in rectum) 2. Intravesical pressure (pressure transducer at urethral valve) 3. Detrusor pressure (difference between abdominal + intravesical pressure 4. Normal bladder functional residual capacity 5. Residual volume

Answer 272

a. Conservative therapy i. Timed voiding schedules ii. Minimize fluid intake > 5 pm iii. Manage constipations b. Pharmacologic therapy i. Anticholinergic agents = oxybutynin 1. Decrease frequency of detrusor contractions during the filling phase of the bladder 2. Good for overactive bladders / small bladder capacity 3. AE = constipation, dry mouth, flushing , heat intolerance  should NOT be used in patients with underactive bladder, fractionated voiding pattern, hx of urinary retention ii. Alpha antagonists = tamsulosin 1. Relax smooth muscle at the bladder neck and proximal urethra c. Other i. Biofeedback and pelvic muscle floor training ii. Less used in children – neurostimulation, botox iii. Urotherapy: for dysfunctional voiding: voiding frequency, bladder emptying,

Answer 273

1. Key points a. Rare syndrome that refers to urine leakage occurring only with laughter b. Condition exclusively of girls c. Unclear aetiology - ?CNS disorder 2. Management a. Not well studied b. Methylphenidate effective in small case studies c. Biofeedback successful in a small case series d. NOTE: past MCQ answer oxybutynin

Answer 274

1. Key points a. At five years of age, 15% of children are incontinent – usually isolated nocturnal enuresis, 20% have significant daytime symptoms (bladder dysfunction) b. M>F c. 15% resolve spontaneously per year d. FHx – 60% if family member 2. Etiology a. Nocturnal polyuria b. Detrusor overactivity c. Disturbed sleep d. ?Abnormal secretion of ADH – does not form normal circadian pattern e. Genetic tendency – concordance among monozygotic twins 2x that of dizygotic twins 3. Treatment a. Lifestyle i. Drink with meals and void post ii. Motivational therapy b. Alarm i. Most effective long-term therapy – best for motivated children ii. Body and matt alarm – child is only one allowed to turn alarm off iii. Lots of children wet in first 90 minutes of sleep, second wet at midnight iv. Takes 8-10 weeks v. Can challenge with 500ml of water at bed time c. Pharmacological i. Desmopressin 1. Risk of hyponatraemic seizures – particularly IN as most effective 2. Do not give to families who are not trustworthy 3. Spray 10 mcg/squirt 4. Talbet 200 mcg 5. Transmucosal 120 mcg – max dose 240 mcg  most commonly use by Lil ii. Oxybutynin – if OAB component

Answer 275

a. Protein > 40 mg/m2/hour | b. UrPr/Cr >2.0

Answer 276

a. Benign proteinuria i. Transient proteinuria 1. Typically, after vigorous exercise, fever, dehydration, seizures and adrenergic agonist therapy 2. Usually mild, glomerular in origin, and always resolves within a few days 3. Does NOT indicate renal disease 4. ALWAYS follow up with early morning urine when well/rested ii. Postural (orthostatic) proteinuria 1. Benign condition defined by normal protein excretion while recumbent but significant proteinuria when upright 2. Glomerular in nature, more common in adolescents and tall, thin individuals 3. NOT associated with progressive renal disease 4. Many children with orthostatic proteinuria continue to have this to adulthood – most commonly adolescent boys b. Pathological i. Glomerular = disruption of normal glomerular barrier to protein filtration 1. Increased filtration of macromolecules eg. albumin, Ig heavy chains 2. Usually associated with other manifestations of glomerular disease (haematuria, RBC casts, HTN, renal insufficiency) 3. Sensitive marker for presence of glomerular disease but also seen in benign states – fever, exercise, orthostatic 4. Check urine ACR and urine A:P ratio >0.4 5. ACE-inhibitors used to treat – slows glomerulosclerosis ii. Tubular = increased filtration, impaired reabsorption or secretion of protein 1. LMW proteins eg. RBP, beta-2 microglobulin, Ig light chains 2. Smaller proteins that are normally filtered across the glomerulus then almost completely resorbed by the proximal tubule 3. Occasionally result in uPCR > 200 4. Compared ACR and PCR, urine electrophoresis, measure urine RBP, B2 microglobulin 5. Etiology = Fanconi syndrome, Dent’s disease (hypercalciuria, stones), ATN, pyelonephritis, structural renal disorders, tubular toxins (antibiotics, chemotherapy) 6. Combination of tubular proteinuria with evidence of tubular electrolyte wasting and glycosuria = Faconi syndrome

Answer 277

2. Key triad/definition a. Proteinuria (mainly albuminuria) b. Hypoalbuminaemia (<25 g/L) c. Edema d. Hypercholesterolaemia (>250 dg/dL) (d. Hypoproteinaemia  hepatic lipoprotein synthesis + reduced lipoprotein metabolism  elevation in serum lipids (cholesterol, TG) + lipoproteins)

Answer 278

a. Idiopathic nephrotic syndrome i. Nephrotic syndrome in the absence of other glomerular pathology mediated by systemic disease (eg. SLE), structural glomerular changes (eg. Alport syndrome), vasculitis, immune complex deposition (eg. post-infectious GN)  90% of children ii. Minimal change disease (MCD) = 85% of children iii. FSGS = 10-15% of children b. Non-idiopathic nephrotic syndrome i. Membranous nephropathy (hep B) ii. Secondary 1. SLE 2. HSP 3. Membranoproliferative GN (MPGN) iii. Congenital nephrotic syndrome = presentation of nephrotic syndrome during the first 3 months of life (often present before or at birth) c. Syndromic i. Denys Drash (WT mutation; AD) = ambiguous genitals, infant onset SRNS, Wilm’s tumour ii. Pierson (LAMB2 mutation) = nephrotic syndrome (mesangial sclerosis), eye problems including microcoria iii. Nail Patella iv. Frasier v. Other = Alport syndrome, Alagille, CMT, Fabry, SCD, alpha-1 AT

Answer 279

i. Age <1 year or >12 years ii. Systemic symptoms – fever, rash, joint pains (SLE) iii. Persistent HTN – can have mild HTN first 1-2 days

Answer 280

a. Renal vein thrombosis – nephrotic + haematuria b. Protein malnutrition c. Liver failure d. Protein losing enteropathy e. Acute or chronic GN f. Heart failure

Answer 281

i. Steroid resistant NS (4-6 weeks refer) ii. Red flags at initial presentation 1. Age <12 months or >12 years 2. Hypertension 3. Gross haematuria 4. Persistent renal insufficiency

Answer 282

a. Infection – due to loss Ig, impaired opsonization/lymphocyte function i. Can present as primary peritonitis b. Thrombosis – prophylactic anticoagulation not recommended, low dose aspirin c. Hypothyroidism – low TBG d. Hypertriglyceridemia e. Poor growth/nutrition/hypovolemia

Answer 283

a. Manage edematous state i. No added salt diet ii. Daily weights, daily urine dipstick iii. Strict FBC iv. IV 20% albumin (with frusemide) 1. Given if: a. Intravascular deplete b. Severe/symptomatic edema 2. N. saline NOT given due to high salt load resulting in worsening edema b. Prophylaxis against complication i. Oral penicillin V (phenoxymethylpenicillin) (NB. If profoundly septic IV ceftriaxone) ii. Ranitidine – prophylaxis against gastric ulcers iii. NOTE: given that presenting episode is generally short-lived, systemic anticoagulation is NOT indicated c. Prednisolone = to induce remission i. Mainstay of treatment ii. 60 mg/m2 per day as single dose (max 60 mg/day) for 4 weeks then slow tapering (usually 3/12) 1. Meta-analysis has shown longer duration of steroids (12 weeks or more) reduces the subsequent rate of relapse 2. If no response – admit for IV methylprednisolone iii. Clinical diagnosis of steroid sensitive nephrotic syndrome is used in children who enter remission during first 28 days of therapy iv. 80-90% of INS will respond to initial steroid therapy (= steroid sensitive nephrotic syndrome ie. SSNS) v. Children with SSNS have an 80% chance of having one or more relapses; 50% of these children will have frequent relapses

Answer 284

13. Relapses a. Urine protein should be checked and documented (daily for at least 1-2 years) to identify relapse (= 3+ or 4+ protein for 3 consecutive days)  aim start prednisolone PRIOR to onset of edema b. Weight should be checked when oedematous c. Most common trigger is intercurrent infection d. Management of relapse i. 60 mg/m2/day until remission ii. 40 mg/m2day until 28 days then stop e. Second line agents i. FRNS/SDNS – alternative prednisolone, cyclophosphamide, calcineurin inhibitor, MMF, rituximab ii. SRNS – calcineurin inhibitor, rituximab 14. Additional issues for relapsing or steroid dependent a. Increased infection - qualify for additional booster Prevenar (pneumococcal conjugate vaccine), and the pneumovax (23 valent pneumococcal) b. Vitamin D deficiency – loss in urine c. Hyperlipidaemia d. Hypothyroidism – loss in urine e. Steroid complications – bone density, cataracts (posterior sub-capsular)

Answer 285

a. SSNS i. 2.5% mortality ii. Usually MCD – normal glomerulus on LM/podocyte effacement on EM iii. At first presentation 1. 25% no relapse 2. 25% infrequent relapse 3. 50% become FR/SD/SR iv. Most relapses eventually cease in childhood/early adulthood v. Younger onset – longer course vi. Iatrogenic sequelae 1. Steroids 2. Cyclophosphamide vii. Transformation to SR/FSGS b. Idiopathic/primary FSGS i. 1/3 improve ii. 13 persistent heavy proteinuria iii. 1/3 ESRF by 5 years iv. Worse outcome 1. Genetic 2. Onset <1 year 3. Tubular atrophy on biopsy v. Recurrent disease in transplant 1. 33% idiopathic FSGS – if exclude genetic cause likely higher 2. More likely if rapid initial course (<2 years to ESKD)

Answer 286

1. Key points a. Most common histological form of primary NS in children b. ABSENCE of gross haematuria, renal insufficiency, hypertension and hypocomplementaemia c. 100% present as nephrotic syndrome 2. Epidemiology a. Median age 2-3 years b. >80% of children with NS have MCNS c. Male: female 2:1 3. Clinical manifestations a. Mild oedema, eyes, extremities b. Then generalized – as cities, pleural effusion, genital c. 10% HTN, microscopic haematuria d. Absence of significant HTN and AKI, macroscopic haematuria, >12years

Answer 287

a. Urinalysis 3+ or 4+ protein and microscopic haematuria in 20% b. Spot Pr:Cr >2 early morning sample i. Urinary protein excretion >40mg/m2/hour c. Urine MCS (rule out infection) d. Serum Cr – usually normal e. Albumin – low f. Serum cholesterol and triglycerides – elevated g. NORMAL complement h. +/- nephritis screen if atypical presentation or older i. Biopsy = not usually required; normal LM and IF i. EM = effacement of epithelial foot processes

Answer 288

5. Management a. Treatment with steroids initiated WITHOUT renal biopsy if child has typical NS b. 2 mg/kg/day (60 mg/m2/24 hour, maximum 60 mg/day); provided once per day c. >90% of children who respond to steroids to so within 4 weeks d. Responders should receive steroids for 12 weeks e. Renal biopsy indicated for non-responders because steroid resistance decreases the chance that MCNS is underlying f. Frequent relapses or steroid resistance may necessitate immunosuppressants 6. Steroid responsiveness a. >90% respond to steroids b. 80% relapse – defined as heavy proteinuria that persists for 3 or more consecutive days i. Steroids usually effective for relapse c. 80% will enter long-term remission during childhood; the remainder continue have relapses into adulthood, although the frequency tends to decrease 7. Management of relapses a. >70% of children with SSNS will develop relapses b. ISKDC relapse regimen: prednisolone 60 mg/m2/day (max 80 mg) daily until urinary remission (3 days of zero or trace proteinuria), followed by 40 mg/m2/day (maximum dose 60 mg) on alternate days for 14 doses over a 28 day period c. Management of frequently relapsing steroid dependent NS i. At least 50% of patients will follow a frequently relapsing nephrotic syndrome (FRNS) or steroid dependent nephrotic syndrome (SDNS) course ii. > 2 relapses in the first 6 months after initial steroid response predicts for high risk FRNS or SDNS iii. Alternative medications = levimasole, cyclophosphamide, ciclosporin, MMF, tacrolimus, rituximab

Answer 289

a. Steroid responsiveness = MOST important factor in determining prognosis i. Steroid responsive patients have little risk of chronic renal failure b. Mortality rate of 1-7.2% (sepsis, vascular thrombosis) in published studies – however current rate thought to be much lower c. 5% of children develop secondary steroid resistance (ie. previously were steroid sensitive)

Answer 290

1. Definition = failure of proteinuria to resolve at least 28 days of prednisolone at 60 mg/m2/day 2. Key points a. Renal biopsy mandatory – histology may alter treatment i. Majority = FSGS, diffuse mesangial proliferation, or MCD ii. Repeat biopsy may show apparent ‘transformation’ from MCD to FSGS b. Genetic analysis mandatory i. Mutations in NPHS2 (Podocin) 1. First reported in cases of familial SNRS 2. Over 50 mutations described 3. DDx a. FSGS b. MCD c. Diffuse mesangial proliferation d. Membranoproliferative GN e. Membranous nephropathy f. Causes of congenital and infantile nephrotic syndrome 4. Management a. Poor data b. Immunosuppression i. Alkylating agents – cyclophosphamide ii. Corticosteroids iii. Ciclosporin, tacrolimus iv. Mycophenolate mofetil v. Rituximab c. Non-immunosuppressive agents/ supportive management 5. Outcomes a. Poor outcome in SRNS that does not subsequently respond to immunosuppressive therapy b. High rate of development of CKD5 c. With MCD histology – steroid resistance at 8 weeks results in CKD5 in around 20% i. Majority will develop FSGS on histology d. Of children with FSGS who fail to respond to steroids – 1/3 progress to CKD5 during 11 year follow-up i. Subset of patient with malignant form of FSGS with rapid progression to CKD5

Answer 291

1. Key points a. FSGS describes the histological lesion 2. Epidemiology a. 10-20% of children with primary NS b. More common in children >6 years 3. Clinical manifestations a. May present like MCNS or with less impressive proteinuria 4. Investigations a. Biopsy i. LM = Focal sclerotic lesions ii. IF = stain IgM and C3 positive iii. EM = foot process effacement 5. Pathophysiology a. Circulating factor increases glomerular permeability is found in some patients with FSGS 6. Management + prognosis a. No clear effective therapy b. Steroids i. Approximately 35% respond ii. May initially respond to steroids then develop resistance c. Immunosuppressants d. Renal transplant i. >35% of children with FSGS progress to renal failure ii. Recurrence of FSGS occurs in 30% who undergo renal transplant

Answer 292

1. Key points a. Characterised by hypocomplementaemia with signs of glomerular renal disease b. 5-15% of children with primary NS c. Typically persistent d. High likelihood of progression to renal failure e. Rare; predominantly disease of older children and young adults [second decade of life] f. M:F equal g. Type 1 MPGN most common h. Key feature = ‘tram-tracking’ i. Crescents may appear in 10-15% of cases 2. Etiology a. Primary MPGN = majority; uncertain etiology b. Secondary MGN i. Infections = streptococcal, staphylococcal, hep B, hep C, HIV ii. SLE iii. Cryoglobulinaemia type II iv. Ventricularoatrial shunts (shunt nephritis) 3. Classification a. Immunofluoroscence - immune complex mediated - complement mediated - neither b. Electron microscopy - type 1 (most common), d/t circulating immune complexes (infection, autoimmune, gammopathies, idiopathic) - type 2, not d/t immune complexes, d/t deranged complement regulation - type 3

Answer 293

6. Clinical presentation a. Haematuria (macro or micro) and proteinuria (moderate to nephrotic syndrome) b. HTN c. Impaired renal function d. Anaemia e. Diagnosis may be made in a child previously thought on clinical grounds to have acute nephritic syndrome to post infectious GN, where the clinical situation fails to improve and the C3 fails to rise after 6-8 weeks 7. Investigations a. Biopsy diagnostic b. Investigations – CH 50/AH 50, Factors I/H, C3 nephritic factor, Factor H mutation c. C3 - low in most cases (+/- C4 low in some cases) d. C3 nephritic factor – may be present if C3 low (auto-Ab that combines with C3 converting enzyme and prevents its breakdown by factor H)

Answer 294

8. Management a. Poor evidence b. Children with mild disease (no impaired renal function, HTN or nephrotic range proteinuria) can be observed c. Use of cyclophosphamide, azathioprine and other agents have been used – no evidence d. Long term steroids – alternate day e. Other therapies – ACE-I, treatment of underlying infections in secondary MPGN f. C3 nephropathy/ dense deposit disease – FFP/plasma exchange/ C inhibitors 9. Outcome a. Without treatment – over 50% develop ESKD by 10 years following onset; 90% by 20 years b. Factors associated with poor outcome i. Nephrotic syndrome at presentation ii. Low GFR at 12 months post diagnosis iii. Chronic damage (interstitial fibrosis, tubular atrophy, glomerular sclerosis) on initial biopsy iv. Type II MPGN 10. Transplant = high change of recurrence in all types of MPGN (particularly C’ mediated)

Answer 295

1. Overview a. Most common cause of nephrotic syndrome in adults; rare in children b. <5% of children with primary NS i. In children most common in 2nd decade of life c. Seen most commonly in adolescents and children with systemic infections or associated with medications d. M:F equal 2. Etiology a. Primary = idiopathic; no identifiable i. Primary far more common in children b. Secondary = up to half of cases (higher in adults) i. Infection = hepatitis B, malaria, congenital and secondary syphilis, leprosy, schistosomiasis 1. Incidence of secondary MN higher in areas where hepatitis B is more common ii. Multisystem disease = SLE, diabetes mellitus, IBD, sarcoidosis iii. Drugs = penicillamine, gold, captopril, NSAIDs, factor replacement in haemophilia iv. Malignancy 3. Pathogenesis a. In situ immune complex formation b. Idiopathic disease may result from molecular mimicry – M-type phospholipase A2 receptor may act as an antigen (protein present on normal podocytes) - PLA2R antibodies demonstrated in 70-80% of adult membranous disease and 60% of children c. Immune complexes  complement activation i. Podocyte changes  loss of slit diaphragm integrity  proteinuria ii. Changes in collagen production  GBM thickening d. Changes in collagen production = GBM thickening

Answer 296

4. Clinical presentation a. Nephrotic syndrome (70%) b. Microscopic haematuria (70%) c. Asymptomatic proteinuria (30%) d. Hypertension (20%) e. Macroscopic haematuria (2%) f. Renal impairment at presentation (<5%) g. Major vein thrombosis – commonly renal vein thrombosis (particularly common in membranous nephropathy) 5. Investigations a. C3 and C5 levels normal in idiopathic MN [Depressed in MN secondary to SLE or hep B] b. Biopsy

Answer 297

6. Management a. Treat causes of secondary MN eg. infection, malignancy i. Hepatitis B associated MN has high rate of spontaneous remission; if not treatment with interferon A b. No evidence for the management of idiopathic childhood MN c. Immunosuppressive therapy = generally if renal impairment or HTN at present i. Corticosteroids = extended course can be helpful in prompting complete resolution ii. Alkylating agents, ciclosporin iii. Rituximab = evidence of benefit in adults d. Supportive treatments i. HTN – ACE-I or ARB ii. Treatment of dyslipidaemia iii. Anti-thrombotic prophylaxis (eg. aspirin) If persistently nephrotic iv. Pneumococcal vaccine or penicillin V prophylaxis v. Thyroxin replacement due to loss of binding protein in the urine (monitor TSH) e. Management if asymptomatic proteinuria alone (ie. no nephrotic syndrome, renal impairment or HTN) i. Low rate of progression to CKD and may enter spontaneous remission ii. ACE-I +/- ARB to reduce proteinuria iii. AE of immunosuppression probably outweigh benefit 7. Outcome a. Children presenting with asymptomatic, low grade proteinuria can enter remission spontaneously b. 20% progress to CKD i. More common in those with heavy proteinuria + HTN at presentation c. 40% continue with active disease d. 40% achieve complete remission

Answer 298

1. Key points a. Congenital = presenting during the first 3 months of life (often present before or at birth) b. Infantile = presenting between 3 to 12 months of age 2. Classification a. Primary i. Finnish type ii. Heterogenous group of abnormalities 1. Includes diffuse mesangial sclerosis and conditions associated with drugs or infections b. Secondary i. Infectious = congenital CMV, hep B and C, HIV, syphilis, congenital toxoplasmosis, congenital rubella, malaria ii. Syndrome-associated 1. Denys-Drash syndrome (DDS) 2. Nail-patella syndrome 3. Lowe syndrome 4. Galoway-Mowatt syndrome 5. Frasier syndrome 6. Pierson syndrome (microria and CNS) 3. Diagnosis a. Prenatal onset is supported by elevated levels of maternal alpha-fetoprotein 4. Management [OTHER than Finnish] a. If secondary to congenital infection – treatment of specific infection b. Children with MCD or FSGS in infancy  steroids similar to older children c. No specific therapies for DMS or FSGS associated with Frasier syndrome

Answer 299

1. Overview a. Commonest form of CNS b. Occurs worldwide – increased incidence in Finland (1/8200) – rare in other races 2. Genetics a. AR b. NPHS1 gene mutation – encodes nephrin i. Forms part of slit diaphragm ii. Interacts with podocin c. >70 mutations detected 3. Clinical manifestations a. Raised AFP in pregnancy in blood and amniotic fluid (secondary to proteinuria) b. Low BW c. Large placenta (>25% mass of newborn) d. Widely spaced fontanelles and cranial sutures e. Postural elbow and knee deformities f. Heavy proteinuria with rapidly developing hypoalbuminaemia and edema 4. Diagnosis a. Genetic testing b. Renal biopsy iii. Progressive glomerular sclerosis and interstitial fibrosis develops by 6-12 months of age 5. Management a. Nephrectomy + peritoneal dialysis b. Medical/ supportive therapy i. ACE-I + PG to reduce protein loss ii. Albumin infusions until bilateral nephrectomy performed iii. High protein and calorie diet iv. Antibiotics +/- IVIG for infection v. Thyroxine (low TBG) c. Transplant i. Only definitive therapy ii. Note risk of thrombosis – major abdominal vessels need to be assessed pre-transplant for patency iii. Recurrent nephrotic syndrome can occur in up to 25% of children with Finnish type CNS 6. Outcome a. Almost always results in development of CKD 5

Answer 300

(LITFL) OVERVIEW Anion Gap = Na+ – (Cl- + HCO3-) The Anion Gap (AG) is a derived variable primarily used for the evaluation of metabolic acidosis to determine the presence of unmeasured anions The normal anion gap depends on serum phosphate and serum albumin concentrations An elevated anion gap strongly suggests the presence of a metabolic acidosis BOAST e. Metabolic acidosis i. NORMAL anion gap = bicarbonate deficiency - renal acidification defects (RTA, renal failure) - bicarb loss (diarrhoea, small bowel losses, CF) ii. WIDE anion gap = acid load - endogenous acid load (lactic/keto/uraemia/organic acidaemia) - exogenous load (toxic alcohols, salicylates)

Answer 301

b. Usually caused by i. Low serum chloride ii. Low circulating volume (contraction alkalosis) 1. Includes reduced effective arterial circulating volume (CCF, cirrhosis) iii. Acid loss – vomiting, high RAAS activity iv. Primary hyperaldosteronism v. Hypokalaemia ``` Chloride responsive • Low ECFV • Low urine chloride (<25 mEQ/L) • Alkalosis likely to improve fairly easily with chloride supplementation (ie. non-renal chloride loss) EG: • Vomiting • Diuretic • Non-absorbable anion eg. imipenem • Stool chloride loss – laxative abuse • Post-hypercapnoea ``` ``` Chloride resistant • High ECFV • High urine chloride (>40 mEQ/L) • Alkalosis likely to persist despite chloride supplementation (ie. likely renal chloride/ hydrogen loss) EG • Hyperaldosteronism o Primary o Secondary  Hypertension  Increased RAAS activity • Bartter’s/ Gitelman’s syndrome • Milk-alkali syndrome ```

Answer 302

1. Key points a. All types of tubular acidosis = metabolic acidosis due to failure of renal tubules to maintain acid base b. Key feature = normal anion gap (hyperchloraemic) metabolic acidosis (ie are due to retention of HCL/ salt that is metabolized to HCl or loss of sodium bicarbonate) c. Treatment is with bicarbonate replacement and supplementing other losses d. Major complication is rickets – can be due to loss of phosphate or due to Ca buffering acid 2. Classification a. Proximal (type II) renal tubular acidosis b. Distal (type I) renal tubular acidosis c. Combined proximal and distal (type III) - very rare i. Due to inherited carbonic anhydrase deficiency ii. Causes mixed renal tubular acidosis, osteopetrosis, cerebral calcification and mental retardation d. Hyperkalemic (Type IV) renal tubular acidosis

Answer 303

a. Potassium i. True hyperkalaemic acidosis = type IV RTA ii. Normal or low potassium = type I or II b. Urinary pH i. <5.5 = proximal RTA (type II) ii. >6.0 = distal RTA (type I) c. Urine anion gap i. Positive gap suggests a deficiency of ammoniagenesis and the possibility of distal RTA ii. Negative gap consistent with proximal tubule bicarbonate wasting (gastrointestinal bicarbonate wasting) d. Urinalysis i. Glycosuria, proteinuria, or haematuria  suggest more global tubular dysfunction or damage ii. 24 hour urine calcium and creatinine = to identify hypercalciuria e. Renal USS i. Detect underlying structural abnormalities ii. Identify presence of nephrocalcinosis – distal RTA

Answer 304

a. Mainstay is bicarbonate replacement i. Often require large quantities of bicarbonate – up to 20 mEq/kg/24 hour – in the form of sodium bicarbonate or sodium citrate solution ii. Base requirement for distal RTAs generally 2-4 mEq/kg/24 hour b. Correction of other electrolyte abnormalities i. Faconi syndrome – require phosphate supplementation ii. Distal RTAs – monitor for development of hypercalciuria 1. Symptomatic hypercalciuria (recurrent episodes of gross haematuria), nephrocalcinosis, or nephrolithiasis – thiazide diuretics decreases urine calcium excretion iii. Type IV RTA – require treatment for hyperkalaemia with sodium-potassium exchange resin (Kayexalate)

Answer 305

1. Key points a. Impaired ability of the proximal tubule to reclaim filtered bicarbonate b. Inherited or persistent from birth (or transient during infancy) c. Proximal RTA usually occurs as a component of global proximal tubular dysfunction (aka Faconi syndrome) 2. Classification a. Proximal RTA i. Idiopathic ii. Sjogren iii. Carbonic anhydrase inhibitor b. Proximal renal tubular failure = Renal Fanconi syndrome i. Cystinosis – most common ii. As below – Lowe’s, Wilsons, Tyrosinemia, Hereditary Fructose intolerance, MMA, drugs 5. Clinical manifestations a. Growth failure in the 1st year of life b. Additional symptoms i. Polyuria + Dehydration (from sodium loss) ii. Anorexia, vomiting and constipation iii. Hypotonia c. Primary Faconi syndrome – additional symptoms secondary to phosphate wasting including rickets d. Systemic diseases present with additional symptoms related to underlying disease 6. Investigations a. Blood i. Non-anion gap (hyperchloraemic) metabolic acidosis ii. Hypokalaemia iii. Low bicarbonate b. Urine i. pH acidic (<5.5) due to acidosis ii. Varying degrees of phosphaturia, aminoaciduria, glycosuria, uricosuria and elevated urinary Na/K

Answer 306

a. Caused by mutations in the gene encoding the sodium bicarbonate cotransporter NBC1 b. Features i. Ocular (band keratopathy, cataracts, glaucoma)  blindness ii. Short stature iii. Enamel defects of the teeth iv. Intellectual impairment v. Occasionally BG calcification

Answer 307

a. Systemic disease caused by a defect in the metabolism of cysteine that results in accumulation of cysteine crystals in the major organs of the body c. 3 clinical patterns have been described i. Young children = infantile/nephropathic cystinosis 1. Present in the first 2 years of life with severe tubular dysfunction and growth failure 2. If not treated, ESRF develops by the age 10 ii. Adolescents = benign milder form characterised by less-severe tubular abnormalities and slower progression to renal failure iii. Adults = benign adult form with no renal involvement d. Genetics + pathogenesis i. AR mutation in CTNS gene e. Clinical manifestations i. Polyuria and polydipsia ii. Growth failure iii. Rickets iv. Fever – caused by dehydration or diminished sweat production v. Patients typically fair skinned and blond due to diminished pigmentation vi. Ocular presentations – photophobia, retinopathy, impaired visual acuity vii. Other – hypothyroidism, hepatosplenomegaly, delayed sexual maturation viii. With progressive tubulointerstitial fibrosis  renal fibrosis f. Diagnosis i. Cystine crystals in the cornea ii. Leukocyte cysteine content = elevated; confirms diagnosis iii. Prenatal testing available g. Treatment i. Aimed at correcting metabolic abnormalities associated with Faconi syndrome or chronic renal failure ii. Cysteamine – which binds to cystine and converts it to cysteine 1. Oral = facilitates lysosomal transport and decreases tissue cysteine 2. Eye drops = oral cysteamine does not achieve adequate levels in ocular tissue 3. Early initiation of the drug can prevent or delay deterioration in renal function iii. GH – patients with growth failure that does not improve with cysteamine may benefit from GH iv. Kidney transplant – option for patients in renal failure v. BMTx

Answer 308

1. Key points a. Impaired hydrogen secretion in the distal nephron 2. Etiology a. Primary i. Idiopathic (sporadic) ii. Familial (type 1a-1c, carbonic anhydrase deficiency) b. Secondary i. Autoimmune disorders = Sjogren’s syndrome, AIH/PBC, SLE, RA ii. Nephrocalcinosis iii. Drugs = ifosfamide, amphotericin B, lithium, ibuprofen, foscarnet iv. Hypercalciuric conditions = hyperPTH, vitamin D intoxication, idiopathic hypercalciuria v. Other = medullary sponge kidney, obstructive uropathy, renal Tx rejection, vi. Syndromic = Marfan’s, Wilsons, EDS 5. Clinical manifestations a. Recessive form presents in infancy b. Growth failure c. Distinguishing features = nephrocalcinosis and hypercalciuria d. Phosphate and massive bicarbonate wasting of pRTA is generally absent e. Bone disease + nephrocalcinosis i. Results from mobilization of organic components from bone to serve as buffers to chronic acidosis ii. High urine pH without citrate promotes crystallization of Ca and PO 6. Investigations a. Blood i. Non-anion gap (hyperchloraemic) metabolic acidosis ii. Hypokalaemia (due to hyperaldosteronism) iii. Hyperammonaemia b. Urine i. Alkaline urine (pH >5.5) ii. HIGH urinary calcium iii. LOW urinary citrate

Answer 309

3. Pathogenesis a. Reduced ability to secrete H+, can be due to i. Decreased net activity of the proton pump - H-ATPase pump in type A intercalated cells ii. Increased hydrogen ion permeability of the luminal membrane (inc reabsorption) iii. Urine cannot be acidified to less than 5.5 iv. H+ ion retention leads to normal anion gap metabolic acidosis b. HCO3- can fall below 10 c. Hypokalemia occurs due to renal potassium wasting i. Na reabsorption needs to be exchanged for H/ K 1. If H secretion is impaired, K is secreted instead ii. H+ can be secreted by H-ATPase pumps or H-K-ATPase pumps 1. If H-ATPase pump impaired, H-K-ATPase pump is more active, wasting potassium iii. Metabolic acidosis also inhibits proximal tubule sodium reabsorption: this delivers more sodium to distal tubule salts where aldosterone acts iv. This can be REVERSED by alkali therapy 1. Increased bicarbonate delivery to the distal nephron allows more H+ to be secreted, reducing aldosterone secretion and therefore sodium reabsorption/ potassium secretion d. Other important biochemical features i. Increased chloride absorption to compensate for loss of bicarbonate ii. Chronic metabolic acidosis can impair citrate excretion, can predispose to renal stones 4. SUMMARY a. Alkaline urine = due to impaired hydrogen ion excretion, urine pH cannot be reduced to <5.5, despite the presence of severe metabolic acidosis b. Hyperchloraemia = loss of sodium bicarbonate distally, owing to lac of H+ to bind to in the tubular lumen, results in increased chloride absorption and hyperchloraemia c. Hypokalaemia = inability to secrete H+ is compensated by increased K+ secretion distally, leading to hypokalaemia d. Hypercalciuria = usually present and can lead to nephrocalcinosis or nephrolithiasis e. Hypocitraturia = chronic metabolic acidosis impaired urinary citrate excretion; further increases the risk of calcium deposition in the tubules

Answer 310

1. Urine pH <5.5 in prox/type 2 (able to resorb bicarb distally) 2. Bicarb higher in type 2 3. Hypokalaemia in both - improves with therapy in distal, worsens in proximal 4. Nephrocalcinosis is a feature of distal/type 1 5. Fanconi is a feature of proximal/type 2

Answer 311

1. Etiology a. Aldosterone deficiency b. RAAS blockage c. Drugs – spironolactone, amiloride, lithium, calcineurin inhibitors d. Pseudohypoaldosteronism (collecting duct resistance to aldosteronism) e. NOTE: In children, aldosterone unresponsiveness is a more common cause of type IV RRTA i. Transiently = during an episode of acute pyelonephritis or urinary obstruction ii. Chronically = particularly in infants and children with a history of obstructive uropathy 3. Clinical manifestations a. Growth failure in the first year of life b. Polyuria + dehydration from salt wasting common c. Rarely, patients present with life-threatening hyperkalaemia (especially those with pseudohypoaldosteronism type 1) d. Patients with obstructive uropathies can present acutely with signs and symptoms of pyelonephritis 4. Investigations a. Features of hypoaldosteronism i. Hyperkalaemic non-anion gap metabolic acidosis ii. May have hyponatraemia b. Urine may be alkaline or acidic c. Elevated urinary Na levels with inappropriately low K level reflect the absence of aldosterone effect 5. Treatment a. Depends on underlying cause i. Reduce potassium ii. Sodium chloride supplementation (PHA type 1) iii. Thiazides (PHA type 2) b. Urology referral if due to obstructive uropathy

Answer 312

2. Pathogenesis a. Either i. Impaired aldosterone production (hypoaldosteronism) ii. Impaired renal responsiveness to aldosterone (pseudohypoaldosteronism) b. Normal function of aldosterone i. Direct effect on the H+/ATPase responsible for hydrogen secretion ii. Potent stimulator for potassium secretion in the collecting tubule 1. This further affects acid-base status by inhibiting ammoniagenesis and thus H+ excretion c. Consequences i. Hypoaldosteronism/ reduced aldosterone synthesis leads to reduced sodium reabsorption ii. Na reabsorption usually creates a charge difference which is offset by secretion of H+ or K+ secretion iii. ↓ aldosterone action = ↓ sodium reabsorption = ↓ H+ and K + secretion = acidosis

Answer 313

1. Key points a. Present in primary RTA – particularly type II or pRTA b. Hypophosphataemia + phosphaturia are common in renal tubular acidosis, which are also characterised by hyperchloraemic metabolic acidosis, various degrees of Bicarbonaturia, and often hypercalciuria and hyperkaluria c. Bone demineralization without overt rickets is usually detected in type I and distal RTA i. Characterised by bone pain, growth retardation, osteopenia, and occasionally pathological fractures ii. If patients with RTA have chronic renal insufficiency, vitamin D levels are reduced in relation to the degree of renal impairment iii. Bone demineralisation probably relates to dissolution of bone because calcium carbonate in bone serves as a buffer against the metabolic acidosis due to the hydrogen ions retained by patients with RTA 2. Treatment a. Administration of sufficient bicarbonate to reverse acidosis reverses bone dissolution and the hypercalciuria that is common in distal RTA b. Proximal RTA is treated with both bicarbonate + oral phosphate i. Doses of phosphate similar to those used in familial hypophosphataemia or Fanconi syndrome ii. Vitamin D is required to offset the secondary hyperPTH that complicates oral phosphate therapy iii. Following therapy, growth in patients with pRTA is greater than in patients with primary Fanconi syndrome

Answer 314

1. Key points a. Rare congenital or more commonly acquired disorder of water metabolism b. Inability to concentrate urine even in the presence of ADH 2. Etiology a. Congenital i. X-linked recessive disorder 1. Most common pattern of inheritance of inheritance ii. Autosomal dominant or recessive – 10% of cases b. Secondary i. Not uncommon – seen in many disorders affecting renal tubular function 1. Examples = obstructive uropathies, acute or chronic renal failure, renal cystic diseases, interstitial nephritis, nephrocalcinosis, or toxic nephropathy caused by hypokalaemia, hypercalcaemia, lithium or amphotericin B ii. Defective aquaporin expression eg. Lithium intoxication iii. Secondary ADH resistance – loss of the hypertonic medullary gradient as a result of solute diuresis or tubular damage resulting in inability to absorb sodium or urea 4. Clinical manifestations a. Congenital DI i. Present in newborn period with massive polyuria, volume depletion, hypernatraemia + hyperthermia ii. Irritability and crying common features iii. Constipation and poor weight gain iv. Developmental delay and mental retardation – due to episodes of hypernatraemic dehydration v. Diminished appetite and poor oral intake – due to need to consume large amounts of water 1. Even with adequate caloric supplementation – growth abnormalities persist vi. Behavioral problems – hyperactivity and ST memory problems b. Secondary DI i. Present later in life ii. Usually present with polyuria and hypernatraemia iii. Associated symptoms such as dev delay and behavioral abnormalities less common

Answer 315

5. Investigations + diagnosis a. Paired serum + urine osmolality = serum osmolality >290 mOsm/kg with urine of <290 mOsm/kg diagnostic b. Challenge with ADH = serial urine and osmolality hourly for 4/24 c. Water deprivation test d. Investigation of secondary DI i. Detailed history to assess possible toxin exposures ii. Renal function iii. Renal USS to identify obstructive uropathies or cystic disease - note that due to the massive urine output patients with congenital DI can have non-obstructive hydronephrosis 6. Treatment a. Congenital NDI i. Maintenance of adequate fluid intake and access to free water ii. Minimize urine output by minimizing solute load with low-osmolar, low-sodium diet 1. For infants human milk or low-solute formula (similar PM 60/40) 2. Most infants with congenital DI require gastrostomy or NG feeds to ensure adequate fluids during the day and overnight 3. Sodium intake in older patients should be <0.7 mEq/kg/242 hours iii. Administering medications to reduce urine output 1. Thiazide diuretics effectively induce Na loss and stimulate proximal tubule reabsorption of water 2. Potassium-sparing diuretics (Amiloride) often indicated 3. Indomethacin – if patients have inadequate response to diuretics alone – additive effect on reducing water excretion a. Renal function needs to be closely monitored as can cause deterioration in renal function over time b. Secondary NDI i. Access to free water ii. Monitoring of serum electrolytes and volume status 7. Prognosis a. Prevention of recurrent dehydration and hypernatraemia in patients with congenital NDI has significantly improved Neurodevleopmental outcomes b. However behavioral issues ongoing issue

Answer 316

Definition = Inflammatory infiltrate in the kidney interstitium, usually caused by drugs, with inflammation of the tubules (sparing of the glomeruli and blood vessels)

Answer 317

1. Etiology a. Drugs i. Antimicrobials = penicillin derivatives, cephalosporins, sulfonamides, TMP-SMX etc. ii. Anticonvulsants = carbamazepine, phenobarbital, phenytoin, valproate iii. Other drugs = allopurinol, diuretics, NSAIDs, PPIs etc. b. Infections = adenovirus, BK virus, CMV, EBV, HBV, HIV etc c. Disease-associated = GN (eg. SLE), acute allograft rejection, tubulointerstitial nephritis and uveitis (TINU) syndrome d. Idiopathic 2. Pathogenesis + pathology a. Hallmarks i. Lymphocytic infiltration of the tubulointerstitium - T cell mediated disease ii. Tubular edema iii. Varying degrees of tubular damage b. Eosinophils may be present particularly in drug induced TIN 3. Clinical manifestations a. 1-2 weeks post drug exposure if drug-induced TIN b. Classic presentation = fever, rash and arthralgia in the setting of rising creatinine i. Rash – maculopapular to urticarial and is often transient c. Constitutional symptoms = nausea, vomiting, fatigue wand weight loss d. Flank pain (stretching of renal capsule from inflammation) e. Features of underlying disease eg. SLE f. 30-40% of patients with acute TIN are non-oliguric and HTN is less common 4. Investigations a. Peripheral eosinophilia may be present – especially with drug-induced TIN b. Urinalysis i. Microscopic haematuria – often present ii. Significant haematuria and proteinuria is common – unless caused by NSAID  can present with nephrotic syndrome iii. WBC, granular or hyaline casts iv. RBC casts are absent (sign of glomerular disease) c. Biopsy = establish the correct diagnosis in cases where the etiology or clinical course confounds the diagnosis d. USS = not diagnostic but can demonstrate enlarged, echogenic kidneys e. Removal of suspected offending agent followed by spontaneous improvement in renal function is highly suggestive of the diagnosis 5. Treatment a. Supportive care b. Corticosteroid = within 2 weeks of discontinuation of the certain agent ?? improved recovery + prognosis 6. Prognosis a. For patients with prolonged renal insufficiency, the prognosis remains guarded, and severe acute TIN from any cause can progress to chronic TIN

Answer 318

1. Key points a. In children, most commonly occurs in the context of i. An underlying congenital urological renal disease eg. obstructive uropathy or vesicoureteral reflux ii. An underlying metabolic disease affecting the kidneys b. Can be idiopathic however this is less common in children c. Chronic TIN is seen in all forms of progressive renal disease, regardless of underlying cause, and the severity of interstitial disease is the single most important factor for predicting progression to ESRF 2. Etiology a. Drugs and toxins = analgesics, cyclosporin, lithium, heavy metals b. Infections c. Disease associated = metabolic and hereditary, cystinosis, oxalosis, Fabry disease, Wilson disease, sickle cell, Alport, juvenile nephronophthisis, medullary cystic disease d. Immunologic = SLE, Crohn’s disease, chronic allograft rejection, TINU syndrome, anti-tubular BM disease e. Urologic = PUV, Eagle-Barrett syndrome, ureteropelvic junction obstruction, vesicoureteric reflux f. Miscellaneous = Balkan nephropathy, radiation, sarcoidosis, neoplasm g. Idiopathic h. TIN with uveitis = Rare autoimmune syndrome of chronic TIN with anterior uveitis and bone marrow granulomas that occurs primarily in adolescent girls 4. Clinical manifestations a. Non-specific and reflect signs and symptoms of chronic renal insufficiency b. Fatigue, growth failure, polyuria, polydipsia and enuresis c. Anaemia d. Tubular damage  renal salt wasting, therefore significant HTN is unusual e. Faconi syndrome, proximal renal tubular acidosis, distal renal tubular acidosis, and hyperkalaemic distal renal tubular acidosis can occur 5. Investigations a. USS = additional evidence of chronicity, such as small, echogenic kidneys, corticomedullary microcysts suggestive of JN, or findings of obstructive uropathy b. VCUG = vesicoureteral reflux or bladder abnormalities c. Biopsy = to determine underlying etiology 6. Treatment a. Supportive b. Obstructive uropathy – salt supplementation c. Antibiotic prophylaxis 7. Prognosis a. Depends on underlying cause b. ESRD can develop over months to years c. Patients with JN uniformly progress to ESRD by adolescence