Renal Flashcards
What does utility based allocation of transplant organ mean?
Places the survival of the graft as the priority.
Action of angiotensin II
- Constricts vascular smooth muscle
- Release of NA/Adrenaline from post ganglionic sympathetic fibres
- Increased sympathetic outflow
- Release of ADH
- Increased aldosterone secretion from zona glomerulosa
Normal anion gap value?
Causes of normal anion gap metabolic acidosis
8-16
Think HARD:
Hyperchloraemia
Acetazolamide, Addison’s disease
Renal tubular acidosis
Diarrhoea, ileostomies, fistulae
Diseases with highest risk of recurrence after renal transplantation
Atypical HUS and MPGN - roughly 50%
30% - IgA nephropathy and FSGS
Risk of recurrence with anti-GBM disease is extremely uncommon, estimated around 5%.
How would you assess metabolic alkalosis?
Divide according to urine chloride level
If Urine Cl <20 - chloride responsive alkaloses, majority caused by loss of HCL rich GI secretion due to NG suction or vomiting.
Urine Cl >20 - chloride unresponsive. Further divide into hypertensive or normotensive.
Normo/hypotension with metabolic alkalosis would suggest Bartters or Gitelmans or active diuretic use.
Hypertensive cases - further divided into:
- High renin activity (renin secreting tumour or RAS)
- Low renin activity (primary hyperaldosteronism)
- Low renin AND aldosterone activity (exogenous glucocorticoids, Cushings syndrome, 11/17 hydroxylase deficiency, liddle syndrome, or licorice ingestion.
Difference between KDIGO and older KDOQI guideline on CKD
Probably the biggest change is that although the glomerular filtration rate (GFR) classification scheme has remained with stages 1 through 5 (stage 3 is now split into 3A and 3B), there are now also albuminuria stages A1, A2, and A3. This new guideline recommends eliminating the term “microalbuminuria.” Instead, the guideline uses stages A1, A2, and A3 for the degree of albuminuria.
3 stimulus for ADH release
- Osmolarity >280 mOSM
- Decreased atrial stretch secondary to low blood volume
- Decreased blood pressure
Factors responsible for formation of renal casts
RBC casts WBC casts Tubular epithelial cell casts Granular cast Hyaline cast
Casts are cylindrical structures that are formed in the tubular lumen; several factors favor cast formation: urine stasis, low pH, and greater urinary concentration [2]. Casts will assume the shape and size of the renal tubule in which they are formed. All casts have an organic matrix composed primarily of Tamm-Horsfall mucoprotein, which comprises the basic architecture for any cast. Casts are defined by the nature of the cells or other elements that are embedded in the cast matrix.
RBC casts - glomerular disease, AIN
WBC casts - glomerular or interstitial inflammation
Tubular epithelial cell casts - desquamation of the tubular epithelium, including acute tubular necrosis (ATN), acute interstitial nephritis, and proliferative glomerulonephritis
Granular cast - ATN
Hyaline cast - non specific
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 alkaliniza
Kidney’s role in acid-base balance
PCT and CD are involved.
- Reclamation of HCO3 - 90% by PCT, 10% by CD (primarily via hydrogen secretion by a proton pump (H-ATPase)
- Acid excretion by alpha intercalated cells. H+ secreted are buffered by phosphate and ammonium ions. Ammonium production increases in response to intracellular acidosis.
Describe the renal potassium handling
Almost all of the potassium filtered by glomerulus is reabsorbed by PCT and LoH.
Any potassium which is present in the final urine is actively secreted by cells in the distal nephron, particularly the connecting tubule and the principal cells in the cortical collecting tubule.
Distal potassium secretion is primarily influenced by:
- Aldosterone
- Distal delivery of sodium and water
Distal tubule reabsorption of sodium is more rapid than that of chloride, resulting in a relatively electronegative lumen that provides a favorable gradient for passive potassium secretion from the tubular cell into the lumen through potassium channels in the luminal membrane
Type 1 RTA
Disease association?
Can be due to:
- Diminished activity of H ATPase pump in the collecting tubule or to a lesser degree decreased activity of luminal H/K ATPase which secretes H and reabsorbs K
- Increased membrane permeability
Results in inability to acidify urine below pH <5.5, hypokalaemia
Kidney stones and nephrocalcinosis because chronic acidosis causes bone resorption and renal tubular resorption of calcium.
Associated with Sjogren’s syndrome (complete absence of proton pump) and amphotericin B (increased membrane permeability to H). Also other autoimmune disorders
What is the mechanism of potassium loss in distal type 1 RTA caused by proton pump defect?
3 mechanisms:
- Na needs to be reabsorbed with an anion or be exchanged with a cation to maintain electroneutrality. If H cannot be excreted, K excretion generally increases with sodium reabsorption.
- Metabolic acidosis interferes with PCT sodium reabsorption resulting in increased distal delivery
- Inhibition/defect of H/K ATPase results in inappropriate H retention and failure of K reabsorption resulting in K excretion.
Proximal type 2 RTA
Proximal tubular defect in impaired HCO3 reclamation.
Usually results in milder acidosis - HCO3 falls to a balanced point where PT is able to reclaim most filtered HCO3, then CD can start to function normally.
Causes: myeloma, amyloidosis, PNH,
Usually needs HCO3 together with K supplementation.
2 types of cells in cortical collecting tubule
- Principal cells - have sodium and potassium channels in the luminal (apical) membrane and, as in all sodium reabsorbing cells, Na-K-ATPase pumps in the basolateral membrane. Involved in sodium reabsorption and are the principal sites of potassium excretion.
- The intercalated cells are primarily involved in hydrogen, bicarbonate, and potassium handling. They do not reabsorb sodium, since they have a lower level of Na-K-ATPase activity and few, if any, apical membrane sodium channels.
Liddle syndrome
Autosomal dominant rare condition.
Primary increase in sodium reabsorption at the cortical collecting tubule.
Results in:
1. Hypertension due to sodium reabsorption
2. Hypokalaemia due to K excretion
3. Metabolic alkalosis
4. Low renin and aldosterone due to hypertension
5 most common malignancies post renal transplant
- Skin cancers
- PTLD
- Kaposi sarcoma
- Renal carcinoma
- Anogenital cancers
PLA2R antibodies
M-type phospholipase A2 receptor (PLA2R) has also been identified as a major target antigen in idiopathic membranous nephropathy in adults. Circulating autoantibodies against PLA2R have been found in 70-80% of patients with idiopathic membranous nephropathy. However, these antibodies are not found in patients with secondary membranous nephropathy
5 secondary causes of membranous nephropathy
- Autoimmune - RA, SLE etc
- Infections - HBV/HCV, enterococcal endocarditis, Syphilis
- Malignancy - in 5-10% of patients, higher especially in age over 60s
- Drugs - NSAIDs, Gold, penicilliamine
- Misc - sarcoidosis, sickle cell disease, de novo MN in renal allografts
3 major causes of AIN
- Drugs - most commonly antibiotics (penicillins, quinolones), diuretics, PPI, allopurinol
- Systemic disorders - sjogrens, SLE, sarcoidosis
- Infection - CMV, EBV, legionella, TB etc
MSU showing white cells, white cell casts or eosinophiliuria is suggestive of AIN.
5 consequences of untreated metabolic acidosis in CKD
- Bone resorption and osteopenia
- Increased muscle protein catabolism
- Aggravation of secondary hyperparathyroidism
- Systemic inflammation
- Impaired myocardial contractility
What are the three benefits of treatment of metabolic acidosis in CKD?
- Decreases progression of CKD
- Prevention of bone buffering - due of some of the excess hydrogen being buffered by bone resulting in release of calcium and phosphate from bone
- Improved nutritional status and lean muscle mass - acidosis increases skeletal muscle breakdown and diminished albumin production due to hypercatabolic state caused by acidosis inducing increased cortisol, diminished IGF-1 and inhibition of insulin signalling.
Tetrad of IgA nephropathy
Comparison of the disease between adults and children
- Abdominal pain (usually diffuse, with acute-onset)
- Arthritis or arthralgia (acute-onset)
- Renal involvement (proteinuria, hematuria)
- Leukocytoclastic vasculitis or proliferative glomerulonephritis, with predominant immunoglobulin A (IgA) deposition
In children, intussusception is common
In adults, intussusception is rare and renal disease are more common and often more severe.
Typical skin biopsy findings of HSP
Light microscopy studies (hematoxylin and eosin stains) demonstrate the classical leukocytoclastic vasculitis in postcapillary venules with IgA deposition that is pathognomonic of HSP (IgAV).
The biopsy should contain skin lesions that are less than 24 hours old because in more chronic lesions, vessel damage leads to nonspecific leakage of all isotypes of immunoglobulin.
Immunofluorescence studies, essential to confirming the diagnosis of HSP (IgAV), generally require biopsy of a second skin site.
Short gut syndrome associated nephrolithiasis
Short gut syndrome leads to calcium oxalate nephrolithiasis due to:
- Fat malabsorption leading to calcium binding to unabsorbed fatty acid, leaving oxalate to freely pass through the colon and filtered in excess amounts in the kidneys, where it can bind to calcium and form oxalate nephrolithiasis
- Non absorbed bile acid in the gut increases colonic permeability to small molecules such as oxalate thereby facilitating increased absorption
- Reduction in bacterial breakdown of oxalate
- Diarrhoea fluid loss leading to dehydration with generalized increased risk of nephrolithiasis.
Renal cyst features which mandate further imaging
- Septated
- Calcification
- Clusters of cysts potentially masking a solid lesion
Medullary sponge kidney
Relatively common disorder.
Due to malformation of the terminal collecting duct resulting in microscopic and macroscopic medullary cysts. Generally bilateral. Increased risk of nephrolithiasis and UTI due to urinary stasis.
Compare and contrast ADPKD 1 and 2
PKD -1:
Ch 16, encodes polycystin 1. More rapid deterioration in renal function with early ESRD. Increased number of cysts compared to PKD2 and cysts at earlier age.
PKD-2
Ch 4. Encodes polycystin-2. More indolent decline in renal function. ESRD around 20 years later than PKD1
4 Extrarenal manifestations of ADPKD
Liver - cysts
Brain - aneurysms
Heart - coronary artery aneurysms, MV prolapse, aortic incompetence
Pancreas - cysts
Sonographic diagnostic criteria of ADPKD
Only in patients with family history of ADPKD
15 - 39: >3 cysts unilateral/bilateral
40 - 59: >2 cysts in each kidney
60+ - more than 4 cysts in each kidney
Genetic testing in ADPKD
Usually indicated in younger individuals with negative/equivocal imaging results in whom live renal donation to an AFFECTED family member is being considered.
Also sometimes considered in pre-natal/preimplantation
Types of testing:
- Linkage analysis by using microsatellite markers flaking PKD1/2. Requires at least 4 affected family members, hence only suitable in <50% of families
- Direct DNA analysis - detects genetic abnormalities in up to 90% tested, but does not determine whether the mutation is pathogenic or not. Therefore need to compare the DNA mutation to the affected family member.
Target BP in ADPKD
130/80
Use ACEi/ARB especially if concurrent proteinuria
Treatment of complicated UTI/cyst infection in ADPKD
Usually with fluoroquinolones for 2-6 weeks
Intracranial aneurysm screening in ADPKD
With MRA, especially if family history of aneurysms/CVA, new onset headache or neurological signs, high risk profession.
What is the efficacy of tolvaptan in ADPKD?
Suppresses vasopressin release leading to reduced cAMP which promote kidney cyst cell proliferation and luminal fluid secretion.
Tolvaptan is effective in halving the rate of increase in renal volume after 3 years and rate of decline in renal function reduces with tolvaptan.
What proportion of IgA nephropathy progresses to ESKD?
20-40%
Management of IgA nephropathy
- In mild to moderate disease, conservative measures including ACEI <130/80, with proteinuria <1g/day
Combination of ACE/ARB is not useful.
The renal prognosis is progressively worse in IgA nephropathy when protein excretion exceeds 1 g/day, particularly if persistently above 3 g/day
- In severe IgA nephropathy with rapidly progressive course or crescentic IgA, could consider cyclophosphamide with high dose prednisone, however evidence free zone.
Pathogenesis of malignancy associated membranous nephropathy
presumed that tumour antigens are deposited in the glomeruli followed by antibody deposition and complement activation. This leads to podocyte and BM injury and proteinuria.
Natural history of membranous nephropathy
Who should be treated?
5-20% spontaneously undergo remission.
25-40% may undergo partial remission (proteinuria <2g/day)
Incidence of ESKD rises with time, with 14% at 5 years, 35% at 10 years, 41% at 15 years.
Therefore following patients should be treated with cyclophosphamide and prednisone:
- Those with heavy proteinuria (less likely to undergo spontaneous remission)
- Renal dysfunction (more likely to progress)
Second line agents include cyclosporine (provided preserved eGFR), and rituximab.
Consequence of high dose pamidronate in malignancy such as myeloma/breast cancer
FSGS
Management of FSGS
Immunosuppressive therapy is ONLY indicated if primary FSGS (responds in 50-60%). No role for immunosuppressive therapy in secondary FSGS.
Glucocorticoid is the cornerstone therapy in conjunction with cyclosporine provided renal function is preserved.
Other agents such as cyclophosphamide, tacrolimus, MMF, sirolimus are less well studied.
How do you distinguish between primary and secondary FSGS
On history:
In contrast to patients with secondary FSGS who present with slowly increasing proteinuria and renal insufficiency over time, patients with primary FSGS most commonly present with the acute or subacute onset of the nephrotic syndrome and the associated features of peripheral edema, hypoalbuminemia, and usually high-grade (>3.5 g/d) proteinuria. By comparison, the proteinuria in patients with secondary FSGS is often in the non-nephrotic range, serum albumin levels are usually normal, and often, there is no peripheral edema, even when protein excretion exceeds 3 to 4 g/day
The histologic findings are generally different in primary and secondary FSGS, although there is some overlap. Primary FSGS is associated with diffuse foot process fusion; in comparison, this abnormality tends to be focal in the secondary forms, being largely limited to the sclerotic areas
Light microscopy findings in MPGN
Common to all causes:
- Mesangial hypercellularity
- Endocapillary proliferation
- Duplication of the GBM (producing double coutours)
2 major types of MPGN
Immune complex mediated MPGN
Due to deposition of immune complexes in glomeruli from persistent antigenaemia. Causes:
1. Chronic infection (HCV, SBE)
2. Autoimmune diseases (SLE, RA, Sjogrens)
3. Paraproteinaemia
Complement mediated MPGN
Due to loss of complement regulation leading to activation within tissues and subsequent tissue damage. Independent of antigen/antibody stimulation.
IHC will show lack of Ig deposits, lack of classical components. Dense deposit disease/C3GN due to increased C3 convertase activity (genetic/acquired)
Tubuloglomerular feedback
Increased sodium delivery to macula densa cells of the LoH causes reflex vascular contraction of the afferent arteriole to decrease GFR and vice versa.
Bartter’s syndrome
Autosomal recessive
Mimics frusemide effect
Defect in various channels of ascending LoH such as ROMK and NKCC2
Results in hypokalaemia, metabolic alkalosis, hypercalciuria (due to decreased paracellular absorption of calcium) and hypomagnesaemia.
Increase in renin and aldosterone seen (due to volume depletion) and increase in urine prostaglandin E.
Not hypertensive due to salt loss.
