Renal Flashcards
I /Causes of renal artery stenosis
Atherosclerotic disease 60-80%
Fibromuscular dysplasia 10-20%
Other:
- Renal artery embolism
- Dissection/Thrombosis
- Post traumatic injury
- Occlusion from aortic stent graft
- External compression
- Systemic vasculitis
Fibromuscular dysplasia (FMD)
Non-atheromatous, non-inflammatory vascular condition
- F>M 3:1
- Age 30-50
-
Factors affecting renin level
Oestrogen, pregnancy, cortisol excess, intra-renal parenchymal dx
Postural changes, sympathetic tone, sodium intake
Most common cause of overall graft loss in Australia
Early (1st year):
- Cardiovascular (36%)
- Infection (27%)
- Cancer (3%)
Later (>1yr)
- Cancer
- CVD
- infection
Death-censored graft loss: most common cause?
Early: Graft thormbosis (38%)
Rejection 24%
GN (4%)
Late:
Chronic allograft nephropathy (72%)
GN (7%)
Acute rejection 4%, non adherence 4%
Which chromosome is PKD1 located
16
Which chromosome is PKD2 located
chromosome 4
Extra-renal manifestation of ADPKD?
pancreatic/hepatic cysts, mitral valve prolapse, aortic regurgitation and intracranial aneurysms (a cause of haemorrhagic stroke)
Cystinuria
Cystinuria is an autosomal recessive disorder characterised by the formation of recurrent renal stones. It is due to a defect in the membrane transport of cystine, ornithine, lysine, arginine (mnemonic = COLA)
Genetics
chromosome 2: SLC3A1 gene, chromosome 19: SLC7A9
Features
recurrent renal stones
are classically yellow and crystalline, appearing semi-opaque on x-ray
Diagnosis
cyanide-nitroprusside test
Management
hydration
D-penicillamine
urinary alkalinization
What one of the following is the most common type of SLE associated renal disease?
Diffuse proliferative glomerulonephritis
Inheritance pattern of Alport sx
X-linked dominant
What is a nephrotic range proteinuria in a 24hr collection?
> 3/5g/24h
What is partial lipodystrophy associated with?
membranoproliferative glomerulonephritis type II
What does crescent formation signify?
Parietal epithelial cell proliferation and mononuclear cell infiltration form crescent-shape in Bowman’s space - hallmark of inflammatory GN
RPGN Type 1
Anti GBM mediated
LINEAR immunofluorescence pattern due to IgG and C3 deposition along capillary loops
If there is lung haemorrhage - Goodpasture’s
RPGN Type 2
Immune complex mediated
GRANULAR pattern due to subendothelial or subepithelial deposition of IgG and C3
C3 Normal:
- IgA Nephropathy
- HSP
Decreased C3:
- Membroproliferative GN
- SLE
- IE
- Post-infectious GN
- Cryoglobulinemia
RPGN Type 3
Non-immune mediated
No immune staining
ANCA +ve
c-ANCA: GPA
p-ANCA: EGPA, Microscopic polyangiitis
alport syndrome
- X-linked dominant
- defect in the gene which codes for type IV collagen
Alport’s syndrome usually presents in childhood. The following features may be seen: - microscopic haematuria
- progressive renal failure
- bilateral sensorineural deafness
- enticonus: protrusion of the lens surface into the anterior chamber
- retinitis pigmentosa
- renal biopsy: splitting of lamina densa seen on electron microscopy.
electron microscopy: characteristic finding is of the longitudinal splitting of the lamina densa of the glomerular basement membrane, resulting in a ‘basket-weave’ appearance
Which renal disease is
associated with partial
Lipodystrophy
Mesangioglomerulonephritis with C3 nephritic factor
low C3 and normal C4
PResents as nephrotic syndrome
What causes hypokalaemia
hypertension with low renin
and aldosterone?
cushings, liddle’s, 11 beta hydroxylase deficiency, 17 alpha hydroxylase deficiency
Aminoglycoside inducd nephrotoxicity
- 5-7 days
- ATN (distal tubular damage)
- inability to concentrate urine
- Can see hypo of elements
RF:
- duration of therapy
- age
- comorbid disease
- reduced affective arterial vol
- Sepsis
- frequency of dosing
Mild proteinuria
hyaline and granular cast
FeNa >1%
ATN
FeNA >1%
Urine Na >40mmol/L
Urine osmolality <350mOsm/kg
Urea:creatinine ratio normal
FeUrea >35%
Brown granular cast
In ADPKD, what predicts progression to ESKD?
Size of cyst
htTKV as a prognostic biomarker in ADPKD.
AIN
Features
* fever, rash, arthralgia
* eosinophilia
* mild renal impairment
* hypertension
Pathophysiology
histology: marked interstitial oedema and interstitial infiltrate in the connective tissue between renal tubules
Causes
drugs: the most common cause, particularly antibiotics
penicillins and cephalosporins, rifampicin, antimicrobial sulfonamides, ciprofloxacin and other quinolones
NSAIDs
allopurinol
furosemide
PPI
systemic disease: SLE, sarcoidosis, and Sjögren’s syndrome
infection: Hanta virus , staphylococci
Urine:
- sterile pyuria
- White cell cast
Acute interstitial nephritis, most commonly:
Drug induced (NSAIDs, COX-2i, antibiotics+++, PPI) 70-75% - also not dose dependent.
Autoimmune (SLE, sjorgrens, sarcoid) 10-20%
Infections (eg legionella, CMV, streptococcus)
Presentation non-specific – nausea, vomiting, malaise, rash, fever, eosinophilia. But many are asymptomatic. May be oliguric.
Labs:
↑creatinine, eosinophilia, eosinophiluria (25-35%).
Urine sediment typically shows white cells and white cell casts.
May have red cells, gross haematuria only in ~5%.
Variable proteinuria but usually not significant and nephrotic syndrome in <1%.
Definitive diagnosis only on biopsy/histology.
RTA
Type 1 (distal), defect in H+ secretion in DT
Urine pH >5.5
Hypokalaemia
Urine: calcium is high
Causes:
Hereditary
Collagen vascular dx
Cirrhosis
Nephrocalcinosis
MM
Type 2: Proximal, defect in HCO3 reabsorption in PCT
urine pH <5.5
Hypokalaemia
Causes:
Sulfanomides
Acetazolamide (Carbonic anhydrase inhibitors)
Fanconi sx
MM
Type IV, Inadequate aldosterone –> reduced sodium reabsorption and K secretion
Urine ph<5.5
Hyperkalaemia, hyperchloraemia
Causes:
- hyporeninemic hypoaldosteronism
- HTN
- DM
- Chronic interstitial nephritis
- Aldosterone resistance
FMD
- non atheromatous, non-inflammatory vascular condition
- Women, 30-50
- Renal arteries in 60%, bilateral in 35%
- mid to distal artery, string of beads appearance
- RF: smoking, pregnancy
Common dx to recur post transplant
MPGN, aHUS
FSGS and IgA
least likely: anti-GBM
BK virus nephropathy
Histologically is similar to graft rejection
Serum PCR is a specific and sensitive test for diagnosis
Clinical outcome is good if detected earlier
Presents as **patchy interstitial (plasma cells and Lt) nephritis
presence of viral inclusions +SV40 **
BK lives in the medulla
Decoy cells in urine (characteristic, but not patho)
RF:
- degree of immunosuppression, donor age, ureteral stent, viral co-infection
Tx: is reduction of immunosuppression
IgA nephropathy
§ Most common cause of primary GN
§ Peak 20s/30s
Male:F 2:1
§ Presentation: □ 40-50% Macroscopic haematuria +/- flank pain, low grade fever □ 30-40%: microscopic haematuria + mild proteinuria □ 10%: NS or RPGN ® Nephrotic sx is suggestive of advanced dx RARE: malignant HTN or AKI
IgA nephropathy
Associated disease
HIV
Cirrhosis/CLD - etoh, HBV, HCV
Coeliac (1/3 of pts)
GPA in remission
IgA nephropathy
Biopsy indication
Proteinuria >1g/day *The need for dialysis and death increased in those presenting with protein excretion >1g/day *
New onset HTN
Elevated serum creatinine
Degree of renal injury and HTN at presentation correlates with progression of dx to ESRD
IgA nephropathy
Treatment
Goal: reduce rate of decline
BP control
RAAS blockade
SGLT2i
> 1g/day –> consider immunosuppression
IS or dialysis: □ IS should NOT be considered in those with severe irreversible kidney damage
eGFR <30 for >3mo , small echogenic kidneys, any evidence of severe interstitial fibrosis, tubular atrophy or glonerularsclerosis
IgA nephropathy
prognostic factors
HTN
Proteinuria (rather than microalbuminuria)
Poor prognostic factors:
- MALE
- Proteinuria >1-2g/day
- HTN
- Smoking
- Hyperlipidemia
- ACE genotype DD
25% will develop ESRF
dialysis disequilibrium syndrome (DDS)
neurologic symptoms related to cerebral edema. New patients who are just being started on intermittent hemodialysis are at greatest risk for DDS, particularly if the BUN is markedly elevated (>175 mg/dL or 60 mmol/L).
Clinical utility of PLA2R antibodies
80% association with primary membranous nephropathy
- specificity 99%, sensitivity 78%
- good response to rituximab
No correlation to secondary MN
What is another antibody that specific to podocyte mb antigen?
IgG4 ab for THSD7A
Smaller number of primary MN
Membranous GN
Nephrotic sx
Antibody and complement induced cytotoxicity on podocytes –> non exudative, non-proliferative capillary wall lesion
(granular deposits of IgG and C3 at the basement mb Thickened basement mb
Spike and dome
- Subepithelial immune complex:
> IgG ab binding tp foot processes on podocytes ( PLA2R, THSDA antigens)
>** correlates with disease activity ** in primary MN - Complement activation via lectin pathway
> syblytic effect
> stimulates GEC-GBM degrading protease and TGF-beta > matrix production
> **no inflammatory cells **
Associated with:
Solid tumour malignancies: prostate, lung, lymphoma, leukaemia
HBV, malaria, syphilis
SLE (Class V), thyroiditis, RA
NSAIDs/gold
When do you start immunosuppresive therapy in Primary Mb GN
PLA2R or TSHD7A positive in serum and proteinuria >3.5g/day
What are the treatment options for PMN?
ACEi/ARB - improve proteinuria and improve prognosis
Severe cases need IST:
- - Rituximab
- Cyclophosphamide + steroid
- CNI +/- pred
1/3 will develop ESRF
Steroids alone won’t be effective
consider anticoagulation for high-risk patients
What does low urinary chloride indicate in the context of hypokalaemia/metabolic alkalosis?
GI losses/dehydration
Risk with EPO use
- HTN
- VTE
- Seizures
- Pure red cell aplasia
Side-effects of erythropoietin
- accelerated hypertension potentially leading to - encephalopathy and seizures (blood pressure increases in 25% of patients)
-bone aches
-flu-like symptoms
-skin rashes, urticaria
-pure red cell aplasia* (due to antibodies against erythropoietin)
raised PCV increases risk of thrombosis (e.g. Fistula)*
- iron deficiency 2nd to increased erythropoiesis
Membranoproliferative GN
MPGN/MCGN
Can be** nephritic or nephrotic**
Poor prognosis
3 types:
- type 1 (90%):
> Hep C, cryoglobulinemia **
> > other: SLE, Hep B, Subacute endocarditis
> Renal biopsy:
EM: “tram tracks**” due to subendothelial and mesangial immune deposits
> Low C3 and C4
Type 2: dense deposit disease (DDD)
- causes: **partial lipodystrophy **(patients classically have a loss of subcutaneous tissue from their face), factor H deficiency
- caused by persistent activation of the alternative complement pathway
- LOW serum C3
- C3b nephritic factor is found in 70%
> an antibody to alternative-pathway C3 convertase (C3bBb)
> stabilizes C3 convertase
> renal biopsy
electron microscopy: intramembranous immune complex deposits with ‘dense deposit
LM:
- thickening of BM due to C3 deposition
- mesangial cytoplasm between GBM and endothelial cells
- Hypercellularity (mesangial cells and monocytes)
Membranous nephropathy
Good prognostic factors
Female
Young
Asymp. proteinuria (modest)
Risk factors for urothelial (transitional cell) carcinoma of the bladder
Smoking
- most important risk factor in western countries
- hazard ratio is around 4
Exposure to aniline dyes
- for example working in the printing and textile industry
-examples are 2-naphthylamine and benzidine
Rubber manufacture
Cyclophosphamide
Risk factors for squamous cell carcinoma of the bladder include
Schistosomiasis
Smoking
Anti-glomerular basement membrane (GBM) disease (Goodpasture’s syndrome)
- rare type of small-vessel vasculitis associated with both pulmonary haemorrhage and rapidly progressive glomerulonephritis
- Ab againt Type 4 collagen
- M 2x >F
- Bimodal distribution (20s, 60s)
- HLA DR2
renal biopsy: linear IgG deposits along the basement membrane
raised transfer factor secondary to pulmonary haemorrhages ( rasied DLCO)
Tx:
- PLEX
- Steroids
- Cyclophosphamide
Time course difference between infection induced IgA nephropathy and PSGN?
IgA is days and PSGN is weeks
PSGN
Nephritic syndrome
Associated with GA beta haemolytic strep
Usually infection 2-6 weeks prior
Oliguria, oedema, HTN, tea/cola coloured urine
Lab: low C3 (norm 6-8 wks after presentation), increased ASO and Anti DNase titre
EM: Hump-shaped subepithelial deposits
Endocapillary diffuse proliferation and exudative glomerulonephritis on light microscopy
**immunofluorescence: **granular or ‘starry sky’ appearanc
What level of stenosis in the renal artery causes symptomatic HTN?
> 80%
Acyclovir and AKI? mechanism
Acute kidney injury (AKI) due to intratubular crystal precipitation is observed in association with many medications. Patients are generally asymptomatic, although occasionally present with flank pain. Urinalysis may show hematuria, pyuria, and crystals with a characteristic morphology
—** Acyclovir is rapidly excreted in the urine (being both filtered and secreted) and has a relatively low solubility**. Thus, bolus intravenous (IV) therapy, especially if the patient is volume depleted, may lead to the deposition of acyclovir crystals in the tubules, resulting in intratubular obstruction and foci of interstitial inflammation
Membranous nephropathy
Risk of progression
This patient has membranous nephropathy - depending on certain risk factors, patients with this disease are stratified to either low, moderate or high risk
Low risk of progression – Protein excretion remains less than 4 g/day and creatinine clearance remains normal for a six-month follow-up period.
●Moderate risk of progression – Protein excretion is between 4 and 8 g/day and persists for more than six months, and creatinine clearance is normal or near normal and remains stable over 6 to 12 months of observation.
●High risk of progression – Protein excretion is greater** than 8 g/day** and persists for three months and/or creatinine clearance is reduced (and considered due to MN) or declines over three months of observation
All patients with proteinuria are commenced on an ACE/ARB. For patients that are low risk, observation is recommended. For patients that are moderate and high risk - immunosupression is recommended, of which cyclophosphamide + corticosteroid combination is recommended
Urine anion gap
GI cause: negative
Renal cause: positive (i.e. in RTA)
Renal cell cancer
basics
- RCC accounts for 85% of primary renal neoplasm
- arises from proximal renal tubular epithelium
- most common: clear cell
- Men
- middle age
- vHL sx
- TS
- slight increase with ADPKD
fx:
- haematuria, loin pain, abdominal mass
- PUO
- Endocrine: EPO, PTHrp, renin, ACTH
- 25% will have mets at presentation
- paraneoplastic hepatic dysfunction sx
- Veriocele
Stauffer syndrome
a paraneoplastic disorder associated with renal cell cancer
typically presents as cholestasis/hepatosplenomegaly
it is thought to be secondary to increased levels of IL-6
Management:
- for confined disease a partial or total nephrectomy depending on the tumour size
patients with a T1 tumour (i.e. < 7cm in size) are typically offered a partial nephrectomy
- alpha-interferon and interleukin-2 have been used to reduce tumour size and also treat patients with metatases
- receptor tyrosine kinase inhibitors (e.g. sorafenib, sunitinib) have been shown to have superior efficacy compared to interferon-alpha
Crescenteric/RPGN
- a rapid loss of renal function associated with the formation of epithelial crescents in the majority of glomeruli.
Causes
- Goodpasture’s syndrome (linear glomerular IF staining)
- Wegener’s granulomatosis (pauci immune)
- others: SLE, microscopic polyarteritis
Features
-nephritic syndrome: haematuria with red cell casts, proteinuria, hypertension, oliguria
- features specific to underlying cause (e.g. haemoptysis with Goodpasture’s, vasculitic rash or sinusitis with Wegener’s)
- Anti-GBM/ANCA GN: fibrinoid necrosis and little/no endocapillary hypercellularity in the non-necrotic area. more disruption to Bowman’s capsule
- Immune complex crescenteric GN: more glomerular endocapillary hypercellularity, thickening of capillary wall, more diffuse process, less crescents
Most common cause of HTN
Essential HTN (80-95%)
RF:
- salt
- obesity
- Alcohol
- angiotensin excess
- sympathetic excess
- FHx
HTN
DBP >95mmHg, steep increase in cardiovascular mortality
Increase IHD and stroke risk with both increasing systolic and diastolic BP
Clinical evidence showes treating HTN –> reduces stroke (35-40%), MI (20-25%), HF (50%)
There is evidence for intensive BP control to <120mmHg systolic
**Half dose drug combination is better than full dose monotherapy **
Night time dosing improves mortality
Causes of secondary HTN
Common:
- intrinsic renal disease
- renovascular disease
- Mineralocorticoid excess
- OSA
- Meds: OCP, NSAIDS
Uncommon:
- Pheochromocytoma
- Glucocorticoid excess/cushing’s
- Coarctation of Aorta
- Hyper/Hypothyroidism
Primary aldosteronism
Morning PAC and PRA
- PAC >416, PRA <1.0
- AND: PAC/PRA >555 per hour (increases)
- then investigate for primary aldosteron excess
Confirmatory tests:
1. oral salt loading
2. IV salt loading
3. Fludrocortisone suppression
Tx:
Adrenal CT
- unilateral hypodense nodule >1cm <2cm
> under 40 - consider APA or PAH
> over 40: Adrenal venous sampling - if lateralisation -> APA or PAH
otherwise: bilateral idiopathic hyperplasia - medical tx
Renal artery stenosis
- Angiogram is gold standard
- CT angio: most sensitive
- resistive indices >0.8: predicts poor outcome with angioplasty
- treatment with stent doesn’t work
Tx:
Unilateral RAS:
- ACEi/ARB +/- thiazide
- Angioplasty for FMD
Bilateral
- Avoid ACEi/ARB
- no evidence for stenting
Creatinine
- metabolism of creatine in muscle and meat
- Variable based on age, body size, and sex
- Freely filtered, not reabsorbed, but secreted by PT
- GFR 125ml/min
Osmolality
2 x NA + gluc + urea
ADH production
- osmoreceptors in the hypothalamus sense osmolality
- ParaVN and SON express gen coding for VP
- posterior pituitary
- V2 receptors in thick ascending LoH, DCT, and CD
- cAMP pathway –> increases AQP2 gene transcription and phosphorylates already made AQP2 vesicles –> fusion to mb –> increases AQP2
- water entry into cell
Tolvaptan: blocks V2 receptors in distal nephrons and CD. Reduces cyst formation in PCKD
V2 is released if there is a fall in arterial blood **volume **
- V1 receptor increase vascular resistance
Regulators of effective arterial blood volume
RAAS
Carotid sinus and aortic arch: baroreceptors –> medulla oblongata –> increase sympathetic activity
Cardiac receptors: regular release of ANP and BNP
Stimuli for renin release
- sympathetic nerve activation (acting through β1-adrenoceptors)
- reduced Na delivery to distal tubules
- renal artery hypotension (caused by systemic hypotension or renal artery stenosis)
Euvolemic hypotonic hyponatraemia
SIADH, psychogenic, renal failure (adv), Thiazide
Low serum Na, low serum osmolality, high urine osmolality >100
High urine Na, normal serum K and pH
Causes of SIADH
- ADH secreation from Small CLC
- CNS disorder
- Drugs: SSRI, carbamazepine, cipro, amiodarone, immunosuppression
-** Recent surgery - mediated by pain afferents** - Pulm. disease
- Hormone def: hypopituitarism and low TSH
- Idopathic: occult tumour or GCA
Causes of SIADH
- ADH secreation from Small CLC
- CNS disorder
- Drugs: SSRI, carbamazepine, cipro, amiodarone, immunosuppression
-** Recent surgery - mediated by pain afferents** - Pulm. disease
- Hormone def: hypopituitarism and low TSH
- Idopathic: occult tumour or GCA
Hypovol. hyponatraemia
- Renal fluid loss: high urine Na and chloride
- GI loss:
> diarrhoea or sequ in 3rd space -> low urine Na
> vomiting: high urine Na , due to metabolic alkalosis –> Na excretion with loss of urinary bicarb, and low urine chloride
Hypervolemic hyponatraemia
HFrEF, reduced tissue perfusion, arterial vasodilatation
Hypertonic hyponatraemia (serum osmolality is high)
HYperglycaemia
IVIG infusion
Sorbitol or mannitol irrigation in uro or gynae procedures
which diuretic causes hypercalcaemia?
thiazide
AR syndromes that resemble actions fo diuretics
Bartter = loop diuretic
- high levels of prostaglandin production –> stimulates renin
- hypokalaemia and metabolic alkalosis
- will also have low Ca and Mg level in serum
Gitelman: thiazide
- high serum Ca, and low serum Mg
cramps in limbs, polyuria and fatigue
Tx:
- electrolytes
- NSAIDS to block PGE2
What do the macula densa sense?
stimulated by decrease in chloride
What happens to renin with ACEi/ARB?
Renin level increase
RAAS
- angiotensinogen produced by the liver (others)
- ACE: vascular endothelial cells in the lung (others)
>Converts AT1 to AT2
> breaks down bradykinin - AT2:
> arterial vasoconstriction –> increase BP (early)
> Hypothalamys: increase thirst, increase ADH –> increase CO
> Renal: low levels: vasoconstrict efferent (increase GFR). High levels: vasoconstrict afferent and efferent: dec. GFR
> Adrenal (late) via AT1R: zona glomerulosa to increase aldosterone –> R. on CD principal cells of CD–> cGMP –> N/K atpase and increase ENaC –> Na retension
AT2 receptor 1: vasoconstricts, inflammatory mediator, proliferation of vascular smooth muscle
recep 2: opposite, but less in the kidneys
Intrarenal RAS:
- AT2 in renal interstitial fluid is 1000x more than systemic system
- very sensitive to sodium intake
ACE2: produced by endothelium of coronary and intrarenal vessels have opposing action to ACE1
Affect of aldosterone outside of the kidneys
- activation of inflammatory cascade and production of proinflammatory cytokines
- insulin resistance
- ## promates cardiac fibrosis
what increases potassium uptake into the cells?
Insulin
Aldosterone
Catecholamines, GH
Alkalosis
Increased potassium secretion during daylight hours
K+ and acidosis
Hyperkalaemia –> increase K+ into cells, thus H+ out of cells –> acidosis in plasma
Bicarbonate and kidneys
- No bicarb in the urine
- 90% reabsorbed in PCT
- 10% in distal nephrons
Normal anion gap
Loss of bicarb
compensated by increase in Cl-
- Severe diarrhoea
- Renal failure
- Proximal Type 2 RTA
Impaired acid secretion:
- mod renal impairment
- RTA - Typw 1 and 4
High Anion gap acidosis
Methanol
Ureamia
DKA
Paraldehyde
Isoniazid/iron
Lactic acidosis
Ethylene glycol, ethanol
Salicylates
CAT
Carbon monoxide
Aminoglycoside
Theopyllines
type 1 RTA
Distal defect in H-ATPase
Normal anion gap/metabolic acidosis
urine pH increased >5.5
Causes:
- autoimmune disease
- Sjogrens, RA
-* Hypercalciuria as a primary defect*
Urine:
- increased calcium
- reduced citrates
- high urine pH
= increased risk of nephrolithiasis
Hypokalaemia:
- lack of H+ excretion for Na, means K+ has to exchange for Na+
- Metabolic acidosis at PCT –> reduced Na reabsorption –> aldosterone activation –> increased Na reabsorption in CD exchange for K+
Hypokalaemia reversed with Nabicarb (alkali) therapy
Type 2 RTA
Proximal
Loss of bicarb reabsorption secondary to Na/H+ pump in PCT
- increased bicarb distally, overwhelms pump
- increased excretion of bicarb
- fall in serum bicarb 12-20
- metabolic acidosiss
Causes:
Myeloma
Fanconi
- global PCT dysfunction (so you lose phosphate, glucose, AA, Na, bicarb). Genetic: associated with wilson’s. Acquired: cisplatin, heavy metals
Drugs
Urine pH <5.5, rapid rise in pH when serum bicarb is corrected
Urine calcium is low
Hypercalcaemia
Hypokalaemia
Treatment with bicarb requires higher dose cf type 1. increased bicrb diuresis stimulates potassium secretion –> hypokalaemia
Type 4 RTA
Hyperkalaemia
Mild normal anion gap metabolic acidosis
Causes:
- hyporeninemic hypoaldosteronism
>NSAIDs, CNI, chronic interstitial nephritis, DM, acute GN
>ARBs or K+ sparing diuretics
>Heparin (toxin to zona glomerulosa cells)
>Primary adrenal insufficiency (addison’s)
Polycystic kidney diseae
ADPKD (commonest inherited renal disease)
PKD1 on Chr16, PKD2 (Chr 4)
OTher: GANB, DNAJB11
PKD1/PKD2: polycystin 1/2 –> ciliopathy
100% penetrance
mostly monoallelic, most mutations are point mutations. nontruncating mutations (33%)
15% don’t have family history - de novo, mosaicism, mild disease
PKD1 is more severe thatn PKD2
Kidney function is usually intact till 4th decade
50% reach ESKD by 60 (ESKD is 55 for PKD1 and 75 for PKD2)
PCKD
RF for progressive renal disease
- PKD1, truncting mutation
- MALE
- Early onset of sx
- FHx of early ESKD
- Kidney size
- HTN
- Proteinuria (usually absent in PCKD)
PCKD
Clinical presentation
PKD1 have more cysts than PKD2
Cysts can occur in other organs
not associated with RCC
HTN
Haematuria
Proteinuria (less common)
Renal failure
Flank pain:
>cyst haemorrhage
>Cyst infection (quinolone are good for cyst penetration
>Calculi
>UTI
Chronic pain sx
PCKD
Extra-renal manifestation
Cerebral aneurysm 5% in young 20% in >60
- usually have MCA involved
- Avoid smoking and BP control is important
- Screen high risk pt: MRI without gad or CTA
Hepatic cysts:
- mod- sev PLD in 15% of ADPKD
- More severe in post-menopausal females (avoid estrogen replacement)
- hepatomegaly –> early satiety, reflux, abdo bloating/pain, dypnoea,backpain, ascites, oedema
- IVC obstruction/ cholangitis
Pancreatic cysts (a/w IPMN)
Seminal vesicle cysts
Cardiac:
-MVP and AR
- less frequent MR/TR
- CM, LVH, diastolic dysfucntion, AF, coronary aneurysm/dissection, asymptomatic pericardial effusion
- consider beta blockers
Aortic aneurysm/dissection
Colonic and duodenal diverticulae
Abdominal wall/inguinal hernia
PCKD
Diagnosis
- enlarged kidneys and bilateral diffuse cysts
- MRI is more sensitive
-
if no FHx:
> more than 10 cysts and bilateral enlargement
no Cyst on MRI by 18 excludes dx
If Fhx positive:
- <40: >3 cysts total involving both kidneys
-if <5 cysts on MRI by 40 = exclude dx
- 40-59: 2 cyst in each kidney on USS
- >60: >4 cysts in each kidneys
PCKD
DDx
- multiple benign simple cysts
- Acquired renal cystic dx: dialysis pt
- ADTKD (dilation of Med. CD, prog fibrosis, not enlarged, cortex spared, bland urine sediment
- ARPKD (PKHD1 gene mutation), more severe disease
- TS: can coexist (PKD1 + TSC2 = early ESKD)
> angiomyolipoma, skin angiofibromoas, cortical tubers, astrocytoma, seizrues, LAM (lymphangioleiomyomatosis), cardiac rhambo, sclerotic bone disease
PCKD
Treatment
- HTN: contributes to GFR decline and CV morbidity.
- BP control reduced TKV and GFR decline
- improves CV mortality cf non-PCKD CKD
- ACEi/ARB - Reduce salt intake (2.3-3 g/day)
- Increase fluid intake >3L/day
- maintain urine osmolality <280
- hypotonic urine: helps reduce cyst growth and GFR decline - Lipid control
Drugs:
1. Tolvaptan: V2-R antagonist
- earlier tx is more beneficial
- reduce rate of TKV growth, GFR decline, kidney pain
- Effects of eGFR is sustained and cumulative
4 yrs of tx delays dialysis by 1 year
indication: eGFR <90, and deciline >5ml/min/year or 2.5 for 5 years or more
Dose: 45mg mane, then 15mg 8hrs later
Max: 90mg mane, 30mg afternoon
if hypernatraemic: hydrate or reduce dose
if hyponatraemia: reduce hydration or increase dose
low osmolar diet
Often need to drink 5L/day
ADR:
- 6-8% decline in eGFR (is ok)
- polydipsia, polyuria, nocturia
- abnormal LFTs
- Hypernatraemia
Contraindication for Tolvaptan:
- baseline hypernatraemia
- inability to sense or respond to thirst
- Hypovolemia
- Concomitant diuretic use
- interacts with CYP3A4
Amyloidosis and brief info on tx
AL: Daratumumab (CD38), CyBorDex or BMD
AA: TNF alpha blocker
Hereditary ATTR: Liver transplant
WT ATTR: tafamidis - prevents misfolding
BK nephropathy
Polyomavirus
DNA
Decoy cells in urine is characteristic
Biopsy:
- interstitial nephritis, and tubular injury
- Viral inclusions in epithelial cells
- DCT and CD mostly involved
Occurs 2-60 month post transplant
present with progressive graft dysfunction with no symptoms
Graft failure in 45% of affected pts
RISK
Tac or MMF
Recccurent episode of rejection
HLA mismatch
Men
Tx:
reduce IS
Management of acute rejection
- tissue
- Methylpred for 3 days
- Failure to respond:
> OKT3 or Antithymocyte depleting ab - +/- increase CNI
- PLEX/IVIG/Ritux if antibody mediated
- REfractory or recurrent: High dose Tac or MMF
What renal tx immunosuppression is ok in Pregnancy?
cyclosporin or azathiopurine
Benefits of renal transplant
Improves QoL
Increases life expectancy
Return to employment
Ability to travel
Improves fertility and pregnanct outcome
Where as, dialysis has reduced life expectancy, reduced QoL
Renal transplant
Random facts
- For deceased donor transplant: high mortality in the first 100 days
- Live donor is better: graft survival and pt survival; attenuates early mortality risk in elderly pts - younger pt, greater mortality cf. to gen popn
- pre-empttive transplant is associated with best long term outcomes
- HLA sensitised patients are difficult to match
-CDC>flow>virtual XM (risk of rejection/graft loss)
- Single kidney: probable increase in BP, increased risk of ESKD but absolute risk ~0.5%
ABO incompatible donors:
- higher AR and AMR
- comparable outcomes to matched living donors in the long term.
Duration of dialysis pre-tx –> reduced survival post
- ## death with graft function is the most common cause of graft loss in older people
Renal Transplant
Criteria for living donors
- low perioperative risk
- Acceptable lifetime risk of ESKD (rememeber that accumulative risk for young people are greater)
- pre donation risk –> post donation risk
> age, HTN, DM (absolute contraindication), BMI, GFR, albuminuria, smoking
Renal transplant
Treatment overview
Belatacept: Target CD80/86 ligand (preventing signal two) - it’s a CTLA4 attached to IgG Fc)
Induction with Basiliximab or ATG:
Basiliximab - Anti CD 25 (IL-2R ab): inhibit T-cell proliferation
Maintenance:
Prednisone
CNI: TAC/cyclosporin
Mycophenolate (95%) vs Aza (anti metabolite)
Renal Transplant
Low dose tac + MMF + Pred + Anti CD25
Better survival, GFR at 3yrs, low rate of rejection
Renal Transplant
Basiliximab vs ATG
- B has less acute rejection and minimal SE
- ATG: less acute rejection high immunological risk group
- Increased risk of infection and malignancty
> EBV D+/R- has high risk of PTLD
> can use in steroid resistance rejection
Renal Transplant
What do you use for maintenance IS?
- Steroids
- CNI
- Antimetabolite
Renal Transplant
CNI
- rate limiting enzyme in T-cell proliferation
- Inhibit IL2 mediated T-cell proliferation
- inherently nephrotoxic with long term use
- Causes HTN, lipids, Thrombotic microangiopathy
- (without CNI –> high rate of rejection and poor graft survival
Remembers ther is NO bone marrow suppression
- can use in pregnancy
Renal Transplant
CNI
TAC is stronger so less rejection and de novo DSA (results is chronic rejection)
If they have risk of T2DM –> use cyclosporin
If they have immunological risk –> tacrolimus
Tac: More hypomg/phos, more neurotoxic and tremor
Cyclo: more hum hypertrophy, more hirsutism, interaction with drugs ie statin
Renal Transplant
Antimetabolites
Inhibits T-cell proliferation in the cell cycle (G1-S)
- MMF results in less early rejection
MMF/MPA:
- inhibits IMPDH involved in purine synthesis
- levels lowered by cyclosporin (not Tac)
- AE: Bone marrow suppression
* worsened with the use of valgangciclovir +/- bactrim
Myco vs Aza:
- less rejection
- more diarrhoea
-** MMF CI in pregnancy **–> switch to AZA
What’s beneficial about mTORi?
Less viral infection
Less renal toxicity
Less malignancy
Less neutropenia and diarrhoea
More rejection and discontinuation rate
Renal transplant
Graft loss - death with graft function
What are early and late causes?
Early: CVD, Infection, Cancer
Late: Cancer, CVD, infection
Renal transplant
Death censored graft loss
Early and late causes
Early (<1yr): graft thrombosis, rejection, GN
Late:
Chronic allograft nephropathy
> Chronic antibody mediated rejection
- Early unresolved rejection
- Non adherence
- De novo DSA (esp class 2 DQ)
GN
Renal transplant
Immediate allograft dysfunction
DGF
- delayed graft function
- mostly due to ischaemic ATN
>RF: deceased donor, donor AKI, Donor age, DCD, cold ischaemia time >24h, mode of dialysis
Other causes other than ATN:
- Thrombosis - not salvageable, USS /MAG-3 scan
- Obstruction/urine leak
- Rejection (biopsy 1 week after)
- Early recurrence
Causes of immediate graft loss
DGF
Rejection
Vascular- thrombosis
Obstruction
Causes of graft loss 1-12 weeks
Rejection
Drugs (CNI toxicity)
Obstruction
Infection
Recurrence of underlying GN
Acute graft loss >3months
Volume depletion
Drugs
Rejection
Obstruction
Recurrence
- earluy: FSGS, aHUS, MPGN, ANCA
- Late: IgAN, MbN, MPGN
RAS
De novo
Acute rejection
- either cell mediated (T-cell) or Ab mediated or mixed
- Rising creatinine - rejection until proven otherwise (BIOPSY)
RF:
Prev. HLA sensitisation
Pre-tx ab against donor
- ABO, HLA, non-HLA
- Younger pt, older donor
- Ischaemia time, DGF
- HLA mismatch (More MM, the worse graft survival, DQ MM is important)
Treatment:
1. TCMR:
- methylpred
- ATG if steroid resistant
- AbMR
- PLEX
- IVIG
- +/- Rituximab
Prophylaxis:
PJP
CMV
Rejection without return baseline –> affects survival
CMV
most common opportunistic infection
- associated with increased mortality
- increased risk with D+, R- status and degree of IS
Proph vs pre-emptive:
- D+/R-: prophylaxis for 6 months
- D-/R+ or D+/R+: 3 months
- D-/R-: no proph unless ATG used for induction
Tx:
- Valgang is good for both prophylaxis and tx (2x)
- Gang for severe or poor GI absorption
- if resistant: UL97 mutation
- –> Foscarnet or cidofovir
foscarnet inhibits viral specific DNA polymerase
Common cancers in IS renal transplant
NHL, Kidney, Melanoma
Cancer death in tx pt:
NHL, lung, colorectal
Skin cancers are very common in tx patients
Met. SCC - common cancer related death in post tx
Avoid AZA
HLA importance in renal tx
HLA is coded on chr 6
DR>B>A
Post tx complication: random facts
- RR of kaposi sarcoma is very high (400-500)
- post tx lymphoproliferative dx - Bcell monoclonal, EBV associated, relflects over IS.
- **diabetes **: 10-15% at 1 year
> increased graft failure and increased mortality
> infrequently develops nephropathy
> More potent pred. of graft failure than AR
Smoking 2x risk of graft loss and 50% overall survival
BP affects graft survival
Obesity: surgical complication, DGF, increased mortality and poor graft survival
common cause of early graft loss is non-adherence
Post-transplant erythrocytosis
it’s angiotension mediated
so tx with ACEi or ARBs
Electrolyte disturbance post tx
- hypomagnesemia: CNI renal wasting
- hypophosphataemia: diuresis, increased PTH or FGF 23, which increases phosphate excretion
MAG3 scan
- ATN: normal perfusion, slow wash out and persistent isotope accumulation
- Hyperacute rejection: no perfusion
- Cyclosporin toxicity: prolonged clearance
RF for renal stones
Urinary factors:
High urine calcium
High urine oxalate
Low urine citrate
Low pH – e.g. chronic diarrhoea with HCO3 loss
Dietary:
Low calcium intake
High oxalate intake
High animal protein intake
Low potassium intake
High sodium intake
Lower fluid intake
Other: previous hx of stones, FHx, those with increased enteric oxalate absorption (malabsorption post-bariatric surgery), drugs (acyclovir), diabetes/obesity/gout/HTN
Lupus nephritis
Renal involvement is common
Proteinuria>haematuria
Female and black people
WHO classification
class I: normal kidney
class II: mesangial glomerulonephritis
class III: focal (and segmental) proliferative glomerulonephritis
class IV: diffuse proliferative glomerulonephritis
class V: diffuse membranous glomerulonephritis
class VI: sclerosing glomerulonephritis
Class IV (diffuse proliferative glomerulonephritis) is the most common and severe form. Renal biopsy characteristically shows the following findings:
- glomeruli shows endothelial and mesangial proliferation, ‘wire-loop’ appearance
- if severe, the capillary wall may be thickened secondary to immune complex deposition
- electron microscopy shows subendothelial immune complex deposits
- granular appearance on immunofluorescence
Lupus nephritis
Treatmentt
Everyone should be on HCQ
IS for active III/IV
- Steroid + MMF or CYC
- Maintenance: MMF or AZA
V:
- RAAS blockade, HCQ, BP optimise
- IS if nephrotic range proteinuria
Lupus nephritis
Treatmentt
Everyone should be on HCQ
IS for active III/IV
- Steroid + MMF or CYC
- Maintenance: MMF or AZA
V:
- RAAS blockade, HCQ, BP optimise
- IS if nephrotic range proteinuria
aHUS
- Mutation in factor H predom. C-terminal
- autoantibody bind to C terminal epitope
- C3 mutation prevents factor H binding
> 50% have an underlying mutation, then get an environmental second hit
Tx:
Eculizumab - high risk of meningococcal infection
thus vax and abx for first 2 weeks of treatment
PLEX
Avacopan is a complement** 5a receptor (C5aR) antagonist** that blocks C5a-induced upregulation of C11b (integrin alpha M) on neutrophils and inhibits C5a-mediated neutrophil activation and migration. - used in ANCA +ve vasculitis
REnal bone disease
abnormality in Ca, PO4, PTH, FGF23, Klotho and Vit d metabolism
Ab bone turnover, mineralisation and linear growth or strength
Each biochemial abnormality is associated with high mortality rate due to CVS
MBD develops as early as Stage 2 CKD
Klotho is lost, FGF23 is raised (associated with mortality) bone formation is reduced and vascular calcification develops
Phosphate:
- doesn’t rise til later on as FGF23 and PTH maintain PO4 excretion
**
Pattern of Bone dx:**
- Osteitis fibrosa cystica - high turnover mediated by PTH
- Adynamic bone disease - low turnover
- higher # risk and ectopic calcification cf high turnover dx
- Osteomalacia: low turnover with abnormal mineralisation
- Mixed
treatment:
- Control phosphate
- Maintain calcium
- lower PTH (once >2x ULN):
> - Calcitriol usually given when PTH >50, aiming to turn off the PTH production. no effect on outcome
> Calcimimetics (cinacalcit) - once started need to continue forever. Cinacalcet directly lowers parathyroid hormone levels by increasing the sensitivity of the calcium sensing receptors to activation by extracellular calcium, resulting in the inhibition of PTH secretion. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.
> Surgery:
- complication post op: hungry bone: hypocalcemia, hypophosphataemia, hypomg,
- K+ may go up
CKD
- increases all cause mortality
- lower GFR and albuminuria are independent RF for **CVD and mortality **
- non-traditional RF for CVD in CKD:
> Vascular calficification due to bone mineral metabolism abnormality
> Uraemia
> Inflammation
RF:
age, DM, HTN, ethinicity, F - CKD, M- ESKD, FHx, obesity, episodes of AKI
SGLT2:
CKD
improvement in decline in RF, ESKD and renal or CV death
Improvement in all cause mortality and CVD and hosp. from HF
Independent of DM status
What should we not use alpha blockers early on for BP control
Excess mortality
Proteinuria
Most potent predictor of ESKD
*not in PCKD
ACEi/ARB similar affect
MRA added to RAS blockade improves proteinuria
Reduction in proteinuria slow GFR decline
Independent RF for CVD
Dialysis
Wouldn’t start statin on pt on HD - no change in mortality
- high PO4, low calcium, high PTH and high FGF23 are all independently associated with increased mortality
Diet
Salt intake <2.5g, 100mmol/day
What is the action of PTH?
- reduce renal reabsorption of PO4, increase bone turnover, increase FGF23, increase 1,25 Vit-D
VitD and PO4
increases renal reabsorption of PO4 and gut absorption, increase FGF23 production, and reduced PTH release
FGF23 and phosphate
reduce renal reabsorption, reduce 1,25 VitD, reduce PTH
FGF23
produced by osteoclast and osteoblasts in response to increase PO4, increase PTH, increase Vit D
less in response to high calcium
FGFR/Kloth co-receptor: in PCT and, DCT, PTH gland
- In the PCT: inhibits Na/Phosphate –> phosphaturia
- inhibit 1,25 Vit D by inibiting alpha 1 hydroxylase and stimulating 24 hydroxylase (catabolic)
- directly inhibits PTH secretion
Klotho is produced in the kidney, this in CKD, FGF23 is unable to inhibit PTH production due t lack of klotho
Osteoporosis and CKD
- DEXA not validated
- difficult to diagnose
- Treat CKD-MBD first
- anti-resorptive therapy may increase risk of # (in animal model)
FSGS
Causes
* idiopathic
* secondary to other renal pathology e.g. IgA nephropathy, reflux nephropathy
* HIV
* heroin
* Alport’s syndrome
* sickle-cell
renal biopsy:
focal and segmental sclerosis and hyalinosis on light microscopy
effacement of foot processes on electron microscopy
Which CD4 T cell is most implicated in the pathogenesis of GN?
Th17
Congential nephrotic syndrome
NPHS1 – nephrin
Familial FSGS
NPHS2 – podocin
TRPC6
Do not respond to steroids
Whst’s the difference between primary and secondary FSGS on EM?
Primary shows diffuse foot process effacement, where as secondary shows focal/segmental
serum soluble urokinase‐type plasminogen activator receptor
(suPAR).
Up to two thirds patients with **FSGS **have elevated levels of
Renal disease only occurs when sufficient circulating suPAR
activates podocyte β3 integrin causing foot process
effacement, proteinuria and FSGS like glomerulopathy
Immature myeloid cells produce suPAR
