Renal Flashcards
Calculate Anion gap
NA+K - HC03+Cl
ddx for NAGMA metabolic acidosis
- Renal tubular acidosis (RTA) 2. Excessive HCO3 loss from GIT
What is reabsorbed in the proximal tubule?
Glucose, amino acids, protein, vitamins, lactate, urea, uric acid, Na, K, Ca, Mg, , HC03, H20
not Cl
What disorders cause Fanconi’s syndrome?
hint) there are three causes and only 2 are disorders
Inherited tubular disorders : cystinosis, Dents, Lowes
Metabolic disorders: wilsons, tyrosinaemia, hereditary fructose intolerance, galactosemia, type 1 glycogen storage disease,
drugs: aminoglycosides, valproate, cisplatin, ifosfamide
heavy metal toxicity
What is Fanconi’s syndrome?
Generalised impairment of procimal tubule function.
Bicarbonate loss (Type 2 RTA)
Glycosuria
Hypophosphatemia
aminoaciduria
LMW proteinuria
What are the types of RTA?
Type 1: distal RTA (impaired secretion of H+ in distal nephron)
Type 2: proximal RTA
Type 4: Hyperaldosteronism
describe what happens in distal RTA
Distal (type 1) renal tubular acidosis (RTA) is characterized by impaired hydrogen ion secretion in the distal nephron, which reduces the kidney’s ability to excrete the daily acid load (50 to 100 mEq on a typical Western diet). This results in progressive hydrogen ion retention and a normal anion gap (or hyperchloremic) metabolic acidosis. If untreated, the plasma bicarbonate concentration can fall below 10 mEq/L.
Inability to excrete daily acid load
Progressive loss of buffer
Serum HCO3- < 10mmol/L
UpH >5.6
Hypokalaemia and sodium wasting
Hypercalciuria with risk of stones and nephrocalcinosis
Positive urinary anion gap (Na + K - Cl)
Describe what happens in proximal RTA
RTA is caused by defects that reduce the capacity to reclaim filtered bicarbonate in the proximal tubule, there are 3 processes by which bicarbonate is reclaimed by the body. Abnormalities of one or more of the multiple proximal tubule transporters, pumps, or enzymes can impair sodium bicarbonate reabsorption and cause the bicarbonate wasting found in proximal RTA
Distal reabsorption modifies HCO3- loss Serum HCO3- usually 12-20mmol/L Bicarb wasting only occurs when plasma HCO3- is > renal threshold.
HCO3- infusion causes alkaline urine (pH>7.5)
Describe what happens in type 4 Renal Tubular acidosis
reduced aldosterone effect (aldosterone maintains proper water balance by enhancing Na+ reabsorption and K+ secretion from extracellular fluid of the cells in kidney tubules.)
plasma bicarb >17mmol/L, urine pH <5.3, hyperkalemia, normal urinary calcium
describe the 3 clin presentations of Bartter’s Syndrome
what diuretic (chronic ingestion) does this mimic?
Hypokalaemia, hypochloraemia, metabolic alkalosis
normotensive, hyperreninaemia
Increased urinary excretion of K, Cl and Na
UrinaryCl>10mmol/L
Hypercalciuria
Polyuria, polydipsia, vomiting, constipation, salt craving,
tendency to dehydration, FTT Fatigue, weakness and cramps Developmental delay Nephrocalcinosis
various genetic defects that cause Bartter syndrome directly or indirectly reduce the activity of one of several electrolyte transporters in the thick ascending limb.
Loop diuretic
describe the pathophysiology of Bartter’s syndrome
Hereditary tubulopathy (group of) Can be considered as impaired Na+ and Cl- reabsorption in thick ascending limb (TAL) of Loop of Henle (LoH)
◦ Similar to action of frusemide
Increased K+ secretion distally
Decreased Ca++ reabsorption in LoH (coupled to Na-K-2Cl)
Bartter’s: Differential Diagnosis?
Diuretic use (no increase in urinary PGE2 and no improvement with indomethacin). Laxative abuse, vomiting or bulimia (extra renal states of chloride depletion)-exclude by measuring urinary chloride. Mineralocorticoid excess (hypertension). Mitochondrial cytopathies with proximal tubular dysfunction (Kearns Sayre and Fanconi Syndrome can both mimic Bartter in infancy).
Gitelman’s Syndrome; describe the major features and genetics
Hypokalaemia & hypomagnesaemia
Transient episodes of weakness and tetany
May have alkalosis
Urinary calcium low
Autosomal recessive ◦ NCCT gene (SLC12A3)
Diminished NaCl transport in distal CT
Like chronic thiazide use
Treat with magnesium
describe the features of Diabetes insipidus
Diagnosis
◦ Polyuria in a dehydrated child + hypernatraemia
◦ Normal maximal urinary osmolality 800-1200 mmol/l decreased to 350-600 mmol/l.
◦ Lack of response to DDAVP distinguishes from central DI
treatment of DI
Treatment
◦ Water
◦ Thiazides + amiloride (or indomethacin)
◦ Growth failure & developmental delay are both less likely with early treatment
Where is sodium maximally reabsorbed in the kidney
- Proximal tubule 60% (reg. by angiotensin)
- Thick Ascending limb of LoH 30% (reg. by aldosterone)
- Distal Convoluted tubule 5-8% (reg. by aldosterone)
- Collecting Duct 2% (reg. by aldosterone)
Define nephritis
Acute nephritic syndrome, characterized by red to brown urine, proteinuria (which can reach the nephrotic range), edema, hypertension, and an elevation in serum creatinine, which demonstrates inflammation In contrast to the protein losing Nephrosis. Often only C3 will be decreased as the
Ddx for Nephritis and major defining fx?
- C3 glomerulopathy (hematuria, hypertension, proteinuria, and hypocomplementemia, which may follow an upper respiratory infection in some patients. However, patients with C3 glomerulopathy continue to have persistent urinary abnormalities and hypocomplementemia beyond four to six week)
- IgA nephropathy − Patients with IgA nephropathy often present after an upper respiratory infection, similar to the presentation of patients with PSGN. Potential distinguishing features from PSGN include a shorter time between the antecedent illness and hematuria (less than 5 versus more than 10 days in PSGN) and a history of prior episodes of gross hematuria since recurrence is rare in PSGN.
- Secondary causes of glomerulonephritis − Lupus nephritis and IgA vasculitis (IgAV; Henoch-Schönlein purpura [HSP]) nephritis share similar features to PSGN. However, extrarenal manifestations of the underlying systemic diseases and laboratory testing should differentiate them from PSGN.
Which pathway of the complement cascade is activated in PSGN, Atypical hemolytic uremic syndrome, C3 glomerulopathy
these glomerular diseases share uncontrolled activation of the alternative pathway as the defining pathophysiology
what is the difference between osmolarity and osmololality
osmolarity is the molar concentration of solute particles per litre of solution, whereas osmolality is the molar concentration of solute particles per kg of solvent (water) (1 mole of solute for how much water?)
Normal body fluids osmolality: 285mOsmol/kg H20, urine osmolality may vary between 60 and 1400mOsmol/kg H20
What cells respond to vasopressin and where are they in the nephron?
Principle (p) cells in the distal tubule respond to ADH
intercalated I cells that contain lots of mitochondria and secrete hydrogen ions
Renin: where is it produced and what does it do?
Produced by the kidney, renin acts on angiotensin I, which is converted to angiotensin II, which is a potent vasoconstrictor affecitng blood pressure, tubular absorption of Na+, and aldosterone secretion from the adrenal glands. Renin release is stimulated by sympathetic filtration of the granular cells or a decrease in filtrate (Na+) concentration. The latter can occur following a fall in plasma volume, vasodilation of the afferent arterioles and renal ischaemia.
Describe the pathway of Vitamin D
- steroid hormone produced in food and synthesised in the skin in the presence of sunlight.
- hydroxylated in the proximal tubules
- regulated by PTH, phosphate and negative feedback. Active Vit D is essential for the mineralisation of bone, and promotes absorption of calcium ions and phosphate from the gut.
What can pass through the glomerulus?
anything under the molecular weight of 70kDa (glucose, amino acids, Na, K, urea), and must be positively charged - due to the anions on the glomerular surface. protein bound molecules evven if positively charged cannot pass through.
what are the main mechanisms that govern glomerular filtration?
- tubuloglomerular feedback: responding to a change in tubular fluid flow rate
- Myogenic mechanism: this responds to changes in arterial pressure
Where is water mostly rebasorbed?
70% of water is reabsorbed in the proximal tubule - driven by a transtubular osmotic gradient, created by osmosis through the basement membrane into the peritubular capillary. this movement is also driven by the high oncotic pressure in the peritubular capillary.
Where and how is chloride reabsorbed?
over 60% of chloride is reabsorbed in the middle and late tubule. chloride ions enter the cells by passive reabsorption, however intercellular potential prevents the entry into cells in the early part of the proximal tubule. the reabsorption of glucose, amino acids, and HC03 with Na+ in the initial part of the proximal tubule creates a filtrate that is concentrated with Cl-. This produces a diffusion gradient which allows movement of the ions into the intercellular space.
reabsorption of glucose?
normal plasma glucose is 2.5-5.5mmol/L. usually 0.2-0.5 mmol of glucose is filtered every minute. and increase in the plasma glucose concentration results in a proportional amounf of glucose filtered. Virtually all filtered glucose is reabsorbed in the proximal tubule, unless the amount of filtered glucose exceeds the absorptive capacity of the cells.
definition of an AKI?
stage 1: seru creatinine 1.5-1.9 above baseline; <0.5mL/kg/hour urine for 6-12 hours.
2. 2.0-2.9 x baseline ; <0.5mL/Kg/hr for >12 hours
Stage 3 serum creatinine 3 x baseline or decrease in egfr to <35mL/Min/1.732m2 or initialtion of renal replacement therapy; <3.0mL/Kg or anuria for >12 hours
What are the indications for RRT (renal replacement therapy)?
In children, the indications to initiate maintenance dialysis are in many ways similar to those in adults and consist of a combination of clinical (eg, uncontrolled hypertension, edema, and inability to provide adequate nutrition) and biochemical (eg, hyperkalemia, hyperphosphatemia, and acidosis) characteristics;
AKI
◦ Volume overload not responsive to diuretics
◦ Hyperkalaemia and oliguria
◦ Maximise nutrition in oliguria
◦ Metabolic acidosis not responsive to other therapy ◦ Uraemic encephalopathy or pericarditis
◦ Tumor lysis syndrome
◦ Severe organic acidaemia or hyperammonaemia
◦ Specific toxins
starting dialysis when eGFR is 10 to 15 mL/min/1.73 m2
aetiology of AKI?
Prerenal: volume depletion (haemorrhage, GIT losses, DI, salt wasting); Redristibution: sepsis, nephrotic syndrome; capillary leak; inadequate effectiv volume (hepatorenal, CCF)
Intrinsic Acute tubular necrosis (evolved from pre rena, drugs and toxins)
Interstitial nephritis (drugs, idiopathic), glomerulonephritis
vascular (HUS, renal artery or vein thrombosis, cortical necrosis)
Obstruction
hydronephrosis, myoglobinuria, lumour lysis
What is the aetiology of acute tubular necrosis?
decreased renal perfusion with decreased gfr, resulting in loss of tubular function.
Urine osmolality <350mosm/kg), urinary sodium >40mmol/L FeNa (functional excretion of sodium) >2% (should be less than 1%)
What are the three diagnostics criteria for HUS?
- Microangiopathic haemolytic anaemia
- Thrombocytopaenia
- Acute nephropathy
Extrarenal manifestations: GIT necrosis, Brain infarction, cerebral oedema, prancreatic necrosis, myocardial.
Long term complications of HUS?
30-50% D+ (post diarrhoeal) have hypertension or renal abnormalities
what is the aetiology and pathophysiology of HUS
- post diarrhoea (90%) (verocytotoxin prodicing E coli - 0157:H7; 0111:H7)
oliguria 4-7 days after - other infections, drugs, bone marrow, SLE, antiphospholipid syndrome, inherited defects in compliment proteins
Genetic forms: low levels of C3; mutations in gene encoding factor H (negative regulator of C3) and other complement regulatory proteins.
Treatment for atypical HUS?
Dialysis
genetic forms: replace factor H with FFP/cryoprecipitate
evolving role of eculizumab
Most common atetiology for End Stage Kidney Disese
Glomerulonephritis (30%) FSGS, reflux nephropathy (10-20%), Hypoplasia/dysplasia (15%), Posteror urethral valves (7-10%), nephronopthisis, HUS (3%), familial glomerulonephritis, cystinosis. AR polycystic kidney disease, other 15%
FSGS
FSGS is characterized by the presence of sclerosis in parts (segmental) of at least one glomerulus (focal) in the entire kidney biopsy specimen, when examined by light microscopy (LM), immunofluorescence (IF), or electron microscopy (EM). histologic lesion, rather than a specific disease entity, that is commonly found to underlie the nephrotic syndrome in adults and children. In primary FSGS, a putative circulating factor that is toxic to the podocyte causes generalized podocyte dysfunction manifested by widespread foot process effacement. Primary FSGS is often responsive to immunosuppressive therapy, including glucocorticoids, cyclosporine, and other immunosuppressive agents. By contrast, immunosuppression is not indicated in secondary FSGS.
Reflux nephropathy
We believe the latter and will present convincing evidence supported by large scale prospective randomized controlled trials that VUR is not the ogre it was thought to be and is not important to find following a UTI (with some exceptions)
nephronopthisis
Patients with NPHP have gene mutations that encode components of the ciliary apparatus. Although mutations in NPHP1 gene account for 20 percent of cases, at least 20 different genes have been associated with NPHP. All the genes encode proteins that are localized to the primary cilia, basal bodies, and centrosomes.
These gene defects result in the characteristic findings of NPHP:
- Autosomal recessive inheritance
- Impaired urinary concentrating ability and sodium reabsorption
- Bland urinalysis (absence of proteinuria, hematuria and cellular elements)
- Chronic tubulointerstitial nephritis and progression to end-stage kidney disease (ESKD) generally before the age of 20 years
Nephronopthisis clinical picture?
Nephronophthisis (NPHP) is a clinical condition caused by a group of autosomal recessive cystic kidney disorders
NPHP is characterized by the insidious onset of end-stage kidney disease (ESKD). Extrarenal manifestations are present in 20 percent of patients, including retinitis pigmentosa, hepatic fibrosis, and skeletal defects
What syndromes are associated with renal dysplasia?
renal hypodysplasia is associated with mutations in genes expressed during kidney development, including EYA1 and SIX1 (branchio-oto-renal syndrome), FRAS1 (Fraser syndrome), PAX2 (renal-coloboma syndrome), SALL1 (Townes-Brocks syndrome), TCF2 (renal cysts and diabetes mellitus), TRAP1 (VACTERL syndrome) and DSTYK (renal hypodysplasia, ureteropelvic junction obstructions, and vesicoureteral reflux) [13,26-28]. Mutations in the PBX homeobox 1 gene (PBX1), which is involved in renal development, were detected by targeted exome sequencing in 5 of 204 unrelated patients with CAKUT
What are the major mutations associated with nephronopthisis?
Juvenile NPHP is associated with mutations in all the NPHP genes except NPHP2, including NPHP1, the most commonly affected gene.
●Mutations in NPHP2 and NPHP3 result in infantile and adolescent NPHP, respectively [17,25].
●Mutations in NPHP5 are associated with retinitis pigmentosa (also referred to as tapetoretinal degeneration) and the Senior-Loken syndrome.Mutations in NPHP6 and NPHP8 are associated with retinal degeneration and cerebellar vermis aplasia in the Joubert syndrome or Meckel-Gruber syndrome.
What are the major mutations associated with nephronopthisis?
- Juvenile NPHP is associated with mutations in all the NPHP genes except NPHP2, including NPHP1, the most commonly affected gene.
- Mutations in NPHP2 and NPHP3 result in infantile and adolescent NPHP, respectively [17,25].
- Mutations in NPHP5 are associated with retinitis pigmentosa (also referred to as tapetoretinal degeneration) and the Senior-Loken syndrome.Mutations in NPHP6 and NPHP8 are associated with retinal degeneration and cerebellar vermis aplasia in the Joubert syndrome or Meckel-Gruber syndrome.
infantile is the worst, and leads to CKF in the first year.
posterior urethral valves
Posterior urethral valves (PUV) are obstructing membranous folds within the lumen of the posterior urethra that are the most common etiology of urinary tract obstruction in the newborn male. obstructing persistent urogenital membrane. bilateral hydronephrosis, dilated bladder, and a dilated posterior urethra (keyhole sign) in a male fetus is suggestive of PUV. Associated renal dysplasia is often seen in patients with PUV.
