Renal Flashcards
1
Q
What does utility based allocation of transplant organ mean?
A
Places the survival of the graft as the priority.
2
Q
Action of angiotensin II
A
- 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
3
Q
Normal anion gap value?
Causes of normal anion gap metabolic acidosis
A
8-16
Think HARD:
Hyperchloraemia
Acetazolamide, Addison’s disease
Renal tubular acidosis
Diarrhoea, ileostomies, fistulae
4
Q
Diseases with highest risk of recurrence after renal transplantation
A
Atypical HUS and MPGN - roughly 50%
30% - IgA nephropathy and FSGS
Risk of recurrence with anti-GBM disease is extremely uncommon, estimated around 5%.
5
Q
How would you assess metabolic alkalosis?
A
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.
6
Q
Difference between KDIGO and older KDOQI guideline on CKD
A
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.
7
Q
3 stimulus for ADH release
A
- Osmolarity >280 mOSM
- Decreased atrial stretch secondary to low blood volume
- Decreased blood pressure
8
Q
Factors responsible for formation of renal casts
RBC casts WBC casts Tubular epithelial cell casts Granular cast Hyaline cast
A
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
9
Q
Cystinuria
A
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
10
Q
Kidney’s role in acid-base balance
A
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.
11
Q
Describe the renal potassium handling
A
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
12
Q
Type 1 RTA
Disease association?
A
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
13
Q
What is the mechanism of potassium loss in distal type 1 RTA caused by proton pump defect?
A
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.
14
Q
Proximal type 2 RTA
A
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.
15
Q
2 types of cells in cortical collecting tubule
A
- 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.
16
Q
Liddle syndrome
A
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
17
Q
5 most common malignancies post renal transplant
A
- Skin cancers
- PTLD
- Kaposi sarcoma
- Renal carcinoma
- Anogenital cancers
18
Q
PLA2R antibodies
A
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
19
Q
5 secondary causes of membranous nephropathy
A
- 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
20
Q
3 major causes of AIN
A
- 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.
21
Q
5 consequences of untreated metabolic acidosis in CKD
A
- Bone resorption and osteopenia
- Increased muscle protein catabolism
- Aggravation of secondary hyperparathyroidism
- Systemic inflammation
- Impaired myocardial contractility
22
Q
What are the three benefits of treatment of metabolic acidosis in CKD?
A
- 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.
23
Q
Tetrad of IgA nephropathy
Comparison of the disease between adults and children
A
- 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.
24
Q
Typical skin biopsy findings of HSP
A
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.
25
Short gut syndrome associated nephrolithiasis
Short gut syndrome leads to calcium oxalate nephrolithiasis due to:
1. 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
2. Non absorbed bile acid in the gut increases colonic permeability to small molecules such as oxalate thereby facilitating increased absorption
3. Reduction in bacterial breakdown of oxalate
4. Diarrhoea fluid loss leading to dehydration with generalized increased risk of nephrolithiasis.
26
Renal cyst features which mandate further imaging
1. Septated
2. Calcification
3. Clusters of cysts potentially masking a solid lesion
27
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.
28
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
29
4 Extrarenal manifestations of ADPKD
Liver - cysts
Brain - aneurysms
Heart - coronary artery aneurysms, MV prolapse, aortic incompetence
Pancreas - cysts
30
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
31
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:
1. Linkage analysis by using microsatellite markers flaking PKD1/2. Requires at least 4 affected family members, hence only suitable in <50% of families
2. 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.
32
Target BP in ADPKD
130/80
| Use ACEi/ARB especially if concurrent proteinuria
33
Treatment of complicated UTI/cyst infection in ADPKD
Usually with fluoroquinolones for 2-6 weeks
34
Intracranial aneurysm screening in ADPKD
With MRA, especially if family history of aneurysms/CVA, new onset headache or neurological signs, high risk profession.
35
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.
36
What proportion of IgA nephropathy progresses to ESKD?
20-40%
37
Management of IgA nephropathy
1. 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
2. In severe IgA nephropathy with rapidly progressive course or crescentic IgA, could consider cyclophosphamide with high dose prednisone, however evidence free zone.
38
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.
39
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:
1. Those with heavy proteinuria (less likely to undergo spontaneous remission)
2. Renal dysfunction (more likely to progress)
Second line agents include cyclosporine (provided preserved eGFR), and rituximab.
40
Consequence of high dose pamidronate in malignancy such as myeloma/breast cancer
FSGS
41
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.
42
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
43
Light microscopy findings in MPGN
Common to all causes:
1. Mesangial hypercellularity
2. Endocapillary proliferation
3. Duplication of the GBM (producing double coutours)
44
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)
45
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.
46
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.
47
How does tacrolimus cause hypomagnesaemia?
Inhibits TRPM6 activity in the DCT which allows magnesium reabsorption resulting in urinary magnesium loss
48
Why does thiazide use results in hypocalciuria?
Inhibition of Na/Cl cotransporter by thiazide results in more calcium being reabsorbed via PTH dependent calcium channels on the DCT due to the electrochemical gradient resulting in hypocalciuria.
49
Gitelman's syndrome
Autosomal recessive salt wasting disorder due to loss of function mutation in the NaCl cotransporter.
Mimics thiazide effect - hypokalaemia, hypomagnesemia, hypocalciuria.
Increased renin and aldosterone seen.
Urine prostaglandin E level normal.
50
Gordon's syndrome
Also known as pseudohypoaldosteronism type 2
Autosomal dominant. Hypertension in 2nd/3rd decade
Exact opposite of Gitelman's syndrome due to GAIN OF FUNCTION mutation in Na/Cl cotransporter
Results in NAGMA, hypertension, hyperkalaemia (due to decreased K secretion at the ROMK), hypercalciuria, high aldosterone level (driven by hyperkalaemia)
Treatment is with thiazide.
51
Liddle syndrome
Autosomal dominant
Hyperactivity of the amiloride sensitive ENaC channels
Early-onset severe hypertension, hypokalemia, metabolic alkalosis in the setting of low plasma renin and aldosterone, low rates of urinary aldosterone excretion, and a family history of hypertension
52
Urine anion gap
Na + K - Cl-
Urine anion gap is an indirect measurement of unmeasured cations such as NH4+
Normal renal response to metabolic acidosis is a neGUTive urine anion gap (eg GI loss leading to more NH4+ being produced, which means more Cl- needs to accompany it)
If UAG is positive in setting of metabolic acidosis, it suggests inability of urine to acidify urine and make ammonium cations.
UAG is unreliable if urine pH >6.5 or uNa <20
53
Features of type 1 RTA
Urine pH >5.5
Hypercalciuria and hypocitraturia leading to renal calculis
Hypokalaemia
54
5 secondary causes of type 1 RTA
1. Autoimmune (sjogrens, RA< SLE)
2. Thyroid disorders
3. Drugs - amphotericin B, ifosfamide, lithium
4. Hypergammaglobulinaemia
5. Sickle cell anaemia
55
3 acquired causes of type 4 RTA
1. Decreased renin (diabetic nephropathy, NSAIDs, interstitial nephritis)
2. Normal renin, decreased aldosterone (due to ACEI/ARB, heparin)
3. Decreased response to aldosterone (spironolactone, cotrimoxazole, pentamidine, tacrolimus, tubulointerstitial diseases such as sickle cell, SLE, amyloid)
56
Explain the pathogenesis of nephrocalcinosis in distal RTA.
1. Acidemia promotes stone formation by increasing calcium phosphate release from bone during bone buffering of retained acid direct reduction in renal reabsorption of these ions
2. Persistently high urine pH favours precipitation of calcium phosphate
3. Reduce citrate excretion since acidosis enhances proximal citrate reabsorption - Urinary citrate is normally a potent inhibitor of calcium stone formation, both by forming a soluble complex with calcium and by inhibiting stone growth by agglomeration of calcium crystals.
57
4 poor prognostic indicators in lupus nephritis
1. Elevated creatinine at presentation
2. Failure to achieve remission
3. High chronicity index on biopsy
4. African American/Hispanic groups
58
Typical histology appearance for lupus nephritis
Will show features of MPGN with:
Subendothelial immune deposits with wire loops
Hypercellularity
Leucocyte infiltration
Also:
Fibrinoid necrosis and hyaline thrombi
IF will show deposits of IgG, IgA, IgM, C1q, C3
59
Mechanism of action of cyclophosphamide
The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. This metabolite is only formed in cells that have low levels of ALDH.
Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7 positions (known as interstrand and intrastrand crosslinkages, respectively). This is irreversible and leads to cell apoptosis
Cyclophosphamide has relatively little typical chemotherapy toxicity as ALDHs are present in relatively large concentrations in bone marrow stem cells, liver and intestinal epithelium. ALDHs protect these actively proliferating tissues against toxic effects of phosphoramide mustard and acrolein.
60
Mechanism of action of mycophenolate mofetil
4 major side effects of MMF
Inhibitor of inosine monophosphate dehydrogenase. Inhibits purine synthesis. Antiproliferative effect on lymphocytes.
SE:
1. GI upset
2. Pancytopenia
3. Infection
4. Malignancy
61
Indications for plasma exchange in pauci-immune ANCA related RPGN
1. Severe renal failure
2. Concurrent anti-GBM antibodies
3. Pulmonary haemorrhage
62
Effects of kidney donation on the donor
1. Hypertension
2. Mild increase in proteinuria
3. 30% reduction in eGFR with small increase in risk of ESKD
4. Kidney donors generally outlive general population
63
What is the general outcome following kidney-pancreas transplantation?
Usually the recipients are type 1 diabetics with ESKD especially if they have hypoglycaemic unawareness.
Can either be SPK or PAK (pancreas after kidney)
Simultaneous PK - excellent long term survival and better QoL, however doubles the risk of acute rejection and infection in the short term
64
Role of IL-2 in T cell proliferation and immunology of rejection
Once APC binds to T cells via signal 1 and 2, full T-cell activation leads to the calcineurin-mediated stimulation of the transcription, translation, and secretion of IL-2, an essential autocrine growth factor that induces T-cell proliferation.
Blockage of IL-2 with basiliximab is therefore a useful induction agent for kidney transplantation
65
Compare and contrast rabbit thymoglobulin and basiliximab.
Both used in induction therapy in preparation for kidney transplantation.
rabbit thymoglobulin - polyclonal antibodies against T cells, causes depletion of T cells. Significant side effects such as cytopenias, meningitis, LVF, cytokine release. More effective than basiliximab.
basiliximab - human/mouse chimeric antibody which targets CD25+ IL-2r activated T cells and inactivates them. Minimal side effects but expensive.
66
Compare and contrast cyclosporine and tacrolimus
Both are calcineurin inhibitors which inhibit IL-2 generation.
Tacrolimus is more potent than cyclosporine and is preferred.
Both are nephrotoxic and contributes to CAN.
Aim for high exposure early, minimize exposure rate.
67
Action of mycophenolate mofetil
Mycophenolate mofetil is metabolised in the liver to the active moiety mycophenolic acid.
It reversibly inhibits inosine monophosphate dehydrogenase which controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes and causing G1 arrest.
Other cells are able to recover purines via a separate salvage pathway and are thus able to escape the effect hence are more lymphocyte selective.
68
Interaction between MMF and cyclosporine A
MMF lowers cyclosporine A level by interfering with enterohepatic recycling
69
Mechanism of action of mTOR inhibtiors (rapamycin, everolimus)
Binds to FKBP-12 and forms a rapa-FKBP complex
This complex binds to mTOR and inhibits IL2/co-stimulatory triggered cell signalling resulting in inhibition of DNA and protein synthesis.
70
4 Side effect profile of MMF
1. Myelosuppression
2. GI toxicity
3. PO4/Mg loss
4. Contraindicated in pregnancy
However, compared to other signal 1/3 agents, does not have CV/renal toxicities.
71
5 Side effect profile of cyclosporine A/tacrolimus
1. Significant CVD risk - HTN, lipids, diabetes
2. Bones - AVN
3. Nephrotoxicity
4. HUS
5. Liver toxicity
Cyclosporin A and tacrolimus is safe in pregnancy
72
Management of acute rejection in kidney transplant
1. Obtain tissue diagnosis - essential, as it allows assessment of histological severity and nature and also investigates for other differential diagnosis
2. IV methylprednisolone - 90% effective
3. OKT3 or ATG lymphocyte depleting antibodies if steroid refractory
4. Plasma exchange, IVIG in antibody mediated rejection
5. If refractory or recurrent rejections, use high dose tacrolimus and mycophenolate rescue therapy.
73
Time course of infections after kidney transplant:
Any time
Early
3-12 months
4-24 months
Any time - pneumonia, HSV, varicella
Early - wound infection, UTI
3-12 months - CMV, PCP
4-24 months - BK nephropathy causing graft dysfunction
74
Diagnosis and treatment of BK nephropathy
Renal biopsy will show interstitial nephritis with intranuclear inclusions, tubular injury and necrosis.
Evidence for BK - IHC will show SV40 antigen, and decoy cells in the urine. Check blood/urine for PCR.
Management
1. Reduce immune suppression
75
Main cause of death with a functioning graft
1. CVD
2. Increasing incidence of malignancy related deaths due to increase in skin cancers, virus driven lymphomas, colon/lung ca (risk doubles)
76
Agents that are effective in the treatment of acute renal allograft rejection
Thymoglobulin
Mycophenolate
Rapamycin
Tacrolimus
Cyclosporin can help to prevent rejection but it has no role in treating acute rejection
77
Effect of tacrolimus and cyclosporine A on insulin secretion and sensitivity
They both reduce insulin sensitivity
Tacrolimus is more toxic to pancreas than CSA and decreases insulin secretion
Contributes to development of new onset diabetes after transplantation (NODAT)
78
Which glomerulopathy is the leading cause of the need for renal replacement therapy in Aus/NZ?
IgA nephropathy
79
Effect of salt restriction in CKD
Salt restriction in combination with ACEI has been shown to be more effective than dual blockade for reduction of proteinuria and BP reduction.
80
Systolic BP target in:
Diabetes
Diabetes with nephropathy
Proteinuric CKD
Diabetes = <130/85
Diabetes with nephropathy or proteinuric CKD:
<125/75
81
3 key measures in delaying CKD progression in diabetics
1. Aggressive BP control especially if proteinuria
2. Tight BSL control
3. Salt restriction and bicarbonate therapy appears beneficial
82
3 indications for urgent dialysis
1. Fluid overload
2. Hyperkalaemia
3. Uraemia causing - pericarditis, pleuritic, encephalopathy, bleeding
Also relative indication if urea >60 (creatinine level is irrelevant)
83
Pros and cons of haemodialysis
Pros: efficient solute removal and reasonable fluid removal
Cons: needs good cardiac function, intermittent dialysis leading to fluctuations in solute and fluid removal and BP, difficult access, heparin exposure, strict attention required to fluid and solute intake.
84
Pros and cons of peritoneal dialysis
Pros: smooth removal of solute and fluid, cardiac friendly, no heparin exposure, Pt can dialysis him/herself and maintain independence
Cons: inefficient, therefore require residual renal function, peritonitis/exit site wound, respiratory embarrassment due to splinting of diaphragm
85
What is the role of statins in dialysis patients?
CVD risks are extremely high in ESKD (OR of 20-1000) but reduction of cholesterol with statins or ezetimibe does not confer survival benefit.
Therefore in dialysis dependent CKD, statins or statin/ezetimibe are not initiated. They are reasonable to continue if they are already on them.
This may be due to the fact that CVD in ESKD are related to calcific disease rather than lipid rich plaques
Hence calcium and phosphate control is important. Serum phosphate in particular carry the highest mortality risk.
86
BP targets in ESKD on dialysis
No clear target, but generally treated to standard target of <140/90
Beta blockers are the only agents that reduce mortality in dialysis patients compared to other agents such as ACEI, CCB, alpha blockers, vasodilators. This may be due to reversal of LVH.
87
Haemoglobin target in ESKD
Hb 110-130
Increased mortality if Hb >130
88
Calciphylaxis in ESKD
Due to subepidermal calcific obstruction of small vessels.
May be precipitated by hypotension
Treatment is difficult, but includes hyperbaric oxygen, reduction in Ca, phosphate, use of sodium thiosulphate.
89
3 types of renal bone disease
1. Osteopenia due to low vit D - decreased bone mineralisation
2. Adynamic bone disease/aluminium deposition - results in increased fracture risk
3. Hyperparathyroidism which leeches minerals and leads to osteitis fibrosa/osteomalacia
NOT OSTEOPOROSIS
90
Anti-hypertensive of choice for:
1. Proteinuria
2. Stroke risk
3. Early after acute MI
1. ACEI/ARB
2. CCB
3. Beta blockers
91
2 hallmark pathological features of MPGN
1. Thickened glomerular basement membrane (GBM) due to deposition of immune complexes and/or complement factors, interposition of the mesangial cell and other cellular elements between the GBM and the endothelial cell, and new basement membrane formation.
2. Increased mesangial and endocapillary cellularity, often leading to a lobular appearance of the glomerular tuft. The increase in cellularity results from both proliferation of mesangial cells and influx of circulating monocytes
92
Pathological features of membranous nephropathy on:
1. Light microscopy
2. IF microscopy
3. EM
LM: diffuse thickening of the glomerular basement membrane (GBM) throughout all glomeruli in the absence of significant hypercellularity (compared to MPGN)
IFM: diffuse granular pattern of IgG and C3 staining along the GBM
EM: subepithelial electron-dense deposits on the outer aspect of the GBM, effacement of the foot processes of the overlying podocyte, and expansion of the GBM by deposition of new extracellular matrix between the deposits (which are the "spikes" seen with special stains).
93
Modified Ponticelli regimen for MN
Indications for immunosuppression in MN.
Cyclical prednisolone and cyclophosphamide.
Most evidence treatment for MN.
Indications for immunosuppression in MN
1. No spontaneous remission after 6-12 months of conservative management
2. Disabling nephrotic syndrome
3. Unexplained worsening of kidney function
4. Proteinuria >4-8g/day without improvement
94
Consequence for kidney donors
1. Mild increase in SBP 4-8mmHg
2. Mild increase in proteinuria
3. 30% reduction in eGFR with small increase in ESKD
Most kidney donors still outlive general population.
95
Compare and contrast histological appearances of cellular rejection and antibody mediated rejection
How does treatment differ?
Cellular rejection - usually interstitial inflammation with tubulitis, with or without arteritis
Antibody mediated rejection - usually intimal/transmural arteritis or acute thrombotic microangiopathy, linear C4d staining in peritubular capillaries, detection of donor specific antibodies to HLA
Cellular rejection is treated with pulse corticosteroids, anti-T cell therapies such as ATGAM (horse) or thymoglobulin (rabbit), tacrolimus or MMF.
Antibody mediated rejection is treated with intensification of maintenance immunosuppression, plasmapheresis/plasma exchange, intravenous immune globulin (IVIG), steroids, and antilymphocyte antibodies (particularly if concurrent cellular rejection)
96
Compare and contrast side effect profile of CNIs and MMF
CNIs have significant side effects relating to nephrotoxicity, increased cardiovascular risk factors, AVN and HUS.
MMF does not have the traditional side effects of CNIs, however have significant myelosuppressive effects and GI toxicity.
97
When would you use cyclosporine over tacrolimus?
Side effect profile - cyclosporine causes hair/gum hypertrophy, while tacrolimus causes alopecia.
98
Typical histological changes in minimal change disease
| Treatment?
Normal light microscopy
Electron microscopy shows flattened podocytes
Treatment is with steroids usually. Excellent response in children, adults slower to respond.
If steroid refractory, use cyclophosphamide or cyclopsorin.
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Histological changes in primary membranous nephropathy
Thickened GBM
| Silver stain will show intra-membranous immunoglobulin deposits with spikes
100
Treatment of primary membranous nephropathy
| What about secondary MN?
Unlike FSGS and MCD, steroids alone are not helpful.
Need to use cyclophosphamide plus prednisone, or cyclosporine.
In secondary membranous nephropathy, need to treat the underlying cause (eg malignancy, HBV, HCV), or remove the offending agent such as drugs.
101
Treatment of lupus nephrits class 3/4
Pulse IV methylprednisolone then IV CYC monthly for 3-6 months, followed by transition to azathioprine or MMF maintenance therapy.
IV methylprednisolone then PO MMF can also be considered in moderate severity lupus nephritis (should still use IV CYC in severe disease)
MMF is superior to azathioprine in maintenance therapy post induction and in preventing relapse.
102
Treatment options in ANCA related RPGN
IV pulse methylprednisolone
Cyclophosphamide PO/IV
PLX - in severe renal failure, when compared with IV methylprednisolone with cyclophosphamide, resulted in higher rates of renal recovery and freedom from dialysis. (specific indications are anti-GBM, Cr >500, pulmonary haemorrhage)
Rituximab + steroids - as effective as CYC and steroids in induction.
Azathioprine usually used for maintenance therapy - superior to cyclophosphamide and also to MMF (in contrast to lupus nephritis)
Rituximab is superior maintenance therapy compared to azathioprine, however cost is the issue.
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Management of diabetic nephropathy
1. ACEI/ARB - shown to slow progression of microalbuminuria to overt nephropoathy, and overt nephropathy to ESKD.
2. Intensive glycaemic control - slows progression to macroalbuminuria and ESKD. Beneficial in ALL STAGES of diabetic kidney disease.
104
4 Side effects of mTOR inhibitors
1. Proteinuria
2. Pneumonitis
3. Impaired wound healing
4. Male fertility issues and cannot be used in pregnancy
105
Mechanism of action of basiliximab and daclizumab
monoclonal antibodies to alpha chain of IL-2 receptor (CD25)
106
Principle of management of acute cellular rejection
1. Pulse methylprednisolone for 3-5 days
2. If steroid refractory, increase tacrolimus/MMF dose (remember, cyclosporine is used to prevent rejection but not treat acute rejection)
3. IVIG/ATGAM/thymoglobulin if still refractory
107
Pathogenesis and potential causes of secondary FSGS
Usually due to :
1. Adaptive response to glomerular hypertrophy or hyperfiltration
2. From scarring due to previous injury (eg, healed lesions of lupus or vasculitis)
3. Other glomerular abnormality such as thin basement membrane disease
4. From direct toxic injury to podocytes.
Therefore, causes can extend from reflux nephropathy, previous vasculitis, diabetic nephropathy, hypertensive nephrosclerosis etc.
108
How do you convert following PCR values to g/day?
g/mmol
mg/mmol
g/mmol - x10
mg/mmol - divide by 100
109
Target BP in diabetes
| What about in diabetic nephropathy or proteinuric CKD?
<130/85 if diabetic
| If concurrent nephropathy, <125/75
110
When is it appropriate to start bicarbonate therapy in CKD?
In CKD4 with metabolic acidosis - significant reduction in progression to ESKD.
If used in CKD2 WITHOUT metabolic acidosis, it does reduce rate of GFR decline.
111
Microbiology of PD peritonitis
50% - gram positives from the skin (CONS, staph aureus, enterococcus, streptococcus)
15% - gram negatives from the gut
20% - culture negative
4% - polymicrobial infection (remove tenckhoff, laparotomy should also be considered)
2% - fungal infection.... need to remove tenckhoff urgently
112
What is the most sensitive test to check for RAS?
| Treatment of unilateral/bilateral RAS
Gold standard is angiography, but CT angiogram is the most sensitive test.
Unilateral RAS
- Medical treatment with ACEI or ARB +/- thiazide
- If FMD, ANGIOPLASTY (not stent)
Bilateral RAS
- Could try careful use of ACEI
- NO evidence for stenting
113
When should you suspect renovascular hypertension?
1. Young onset HTN <35 age
2. Accelerated/severe hypertension above age of 55
3. Acute flash pulmonary oedema not explained by CVD, valvular disease
4. Worsening renal function within 14 days of introducing ACEi or ARB
5. Unexplained CKD or asymmetric kidney on USS
114
Explain the braking phenomenon in diuresis
According to KDOQI - the braking phenomenon (postdiuretic sodium retention) describes avid sodium retention that can develop in response to a rapid diuresis, thereby limiting response to further doses of diuretics. The braking phenomenon may occur during either short-term or long-term therapy and is due to haemodynamic and neurohumoral changes produced by rapid diuresis.
The main mechanisms by which frusemide resistance occurs
1. Nephron segments downstream from the site of diuretic action increase NaCl reabsorption during diuretic administration because delivered NaCl load is increased
2. When diuretic concentrations in the tubule decline, the kidney tubules act to retain Na until the next dose of diuretic is administered
3. The ability of the diuretic to increase renal NaCl excretion declines over time, an effect that results both from depletion of the extracellular fluid volume and from structural and functional changes of kidney tubules themselves
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Role of mesangial cells in the kidney
1. Phagocytosis
2. Structural support
3. Filtration - can contract and reduce glomerular filtration area
