Nephrology Flashcards
(192 cards)
1
Q
A probable diagnosis of a acute post-streptococcal glomerulonephritis is made on the bases of what symptoms?
A
2+ blood on dipstick, facial oedema, hypertension about ~2 weeks after a probable strep infection
2
Q
In probable cases of acute post-streptococcal glomerulonephritis, how is the diagnosis confirmed?
A
Complement levels showing a reduced C3 level, haematuria on urine microscopy, evidence of recent streptococcal infection (positive Group A strep culture from skin or throat, elevated Strep A serology).
3
Q
Is the likelihood of acute post streptococcal glomerulonephritis higher with skin or pharyngeal infections?
A
Skin. Worth noting also that is is only some strains of GAS that are associated with APSGN.
4
Q
What is the pathophysiology of acute post streptococcal GN?
A
Circulating antigen/immune complexes lodge in the glomeruli and cause complement activation locally that damages the glomeruli leading to blood and protein loss in the urine. The kidney disease rarely presents as a rapidly progressive GN.
5
Q
What is the latent period from initial streptococcal infection to GN in acute post-streptococcal GN? Hint: influecned by site of initial infection.
A
If the infection was pharyngeal, then the latent period to GN is 1-3 weeks. If the infection was in the skin, the the latent period to GN tends to be 3-6 weeks.
6
Q
What are the 5 antibodies that can be tested for to demonstrate evidence of recent group A streptococcal infection?
A
Anti: 1) streptolysin (pharyngeal infections) OR 2) hyaluronidase (pharyngeal and skin infections) OR 3) streptokinase OR 4) nictinamdie-adenine dinucleotidase aka NAD (pharyngeal infections) OR DNase B (pharyngeal and skin infections).
7
Q
Acute post streptococcal glomerulonephritis is a disease that primarily impacts low resource communities. When is it a notifiable disease?
A
Always in Australia.
8
Q
What are the cardiovascular manifestitions of polycystic kidney disease?
A
Berry aneurysms, aortic aneurysms, aortic root dilatation, and mitral valve prolapse.
9
Q
What are the non-vascular extrarenal complications of polycystic kidney disease?
A
Abdominal wall hernias, extra-renal cysts, (especially in the liver) and diverticular disease.
10
Q
What are the main genes involved in autosomal dominant polycystic kidney disease?
A
PKD1 (78%) and PKD2 (15%). These genes encode for proteins polycystin 1 and 2. The less common causes include mutations in GANAB and DNAJB11.
11
Q
Were do the cycsts devlop in polycystic kidney disease?
A
Cysts devlop from the cells in the tubular portion of the nephrons and collecting ducts.
12
Q
Which kidney disease has the most rapid delcine in renal function of all forms of CKD?
A
Autosomal dominant polycyctic kidney disease.
13
Q
Which gene, when mutated, is associated with more aggressive and rapdily progressive autosomal dominant polycyctic kidney disease?
A
PKD1. This seems to be to do with the number of cysts that form (PKD1>PKD2) rather than the size of the cysts, as PKD1 patients with the same kidney volume as an equivalant PKD2 patient will have more cysts and worse renal function.
14
Q
What is the likelihood of having end stage kidney disease by age 60 if diagnosed with autosomal dominanet polysytic kidney disease before then?
A
50%
15
Q
How do the vaptans work in the treatment of autosomal dominant polycystic kidney disease?
A
Vasopression V2-receptor antagonists (vaptans) prevent ADH/vasopressin binding to usually ADH sensitive cells of the distal convoluted tubules and collecting duct. Incidentally, these are the cells responsible for cyst formation in autosomal dominant polycyctic kidney disease. The tubular cells in this disease display a high quantity of cyclic AMP in their cytosol, and it is known that inhibitory binding of tolvaptan to V2-receptor also reduces the cytosolic concentratio of cyclic AMP in the tubular cells. It was theorised in the TEMPO and REPRISE trials that elevated cyclic AMP levels in tubular cells was linked to the progression of renal cysts and worsening GFR in ADPCKD. They demonstrated that GFR reduction could be slowed with daily tolvaptan - however drug tolerance is an issue as these patients effectively are given iatrogenic diabetes insipidus. Tolvaptan can also cause reversible but marked liver function derangement, and LFTs require monitoring monthly for 18 months, then every 3 months lifelong.
16
Q
What urinary tract related complications do patients get with autosomal dominant polycystic kidney diseae?
A
Urinary tract infections, infected cysts (which may require drainage or neprectomy), nephrolithiasis.
17
Q
What is fibrillary glomerulnephritis?
A
It’s like amyloid related kidney disease, it’s its secondary to the build up these fibrils deposits that contain a protein called DnaJ heat shock protein family member B9 (aka DNAJB9).
18
Q
What does fibrillary glomerulonephritis look like under light microscopy, DIF and EM?
A
Light microscopy - non-diagnositic. Usually congo red negative. Most commonly looks like a mesangioproliferative/sclerosing glomerulonephritis or membroproliferative GN. Less often crescentic glomerulonephritis is seen, but cases with >50% of glomeruli involved are very rare.
DIF - IgG, C3, kappa and lamba are all positive. Sometimes the fibril deposits are so extensive in the GBM that the IgG lining up along the memrane can look like anti-GBM disease. DNAJB9 positive!
Electron microscopy - random fibrillar deposts in the mesangium and glom erular capillary walls that clearly distinc from those in amyloidosis and imunntactoid glomerulopathy.
19
Q
What special stain should be used if fibrillary glomerulonephritis is suspected on the renal biopsy sample?
A
DNAJB9 DIF
20
Q
What conditions are associated wtih fibrillary glomerulonephritis?
A
About 50% are associated with a condition. Often a malignancy, monoclonal gammopathy or a autimmune disease. Pts also often have concurrent hpertension and diabetes.
21
Q
What is immunotactoid glomerulopathy?
A
A disease glomerular disease characterised by the formation of microtubules on electron microscopy. They form parralell bunches (unlike the fibrils of fibrillary glomerulonephritis) and the microtubules are larger than those fibrils.
22
Q
What does immunotactoid glomerulopathy look like on renal biopsy light/DIF and EM?
A
On light microscopy it looks like fibrillary disease - mesangioproliferative/sclerosing disease or membroliferative GN. The disease is normally associated with a monoclonal gammopathy, so classically there is monoclonal immunoglobulin or light chains seen on DIF. Importantly, the DNAJB9 stain is negative.
Under electron microscopy you see classic membranous parallel organised microtubules. To make the diagnosis, cryoglobilins must not be detected.
23
Q
How are immunotactoid glomerulopathy and fibrillary glomerulonephritis treated?
A
If there is an underlying malignacy or autoimmune disease that appears to be driving it, then treatment is focussed on treating this. If the condition appears idiopathic, there has been case series that have shown benefit with rituxumab - targetted to B-cell count. No RCT evidence for this, but lots of case series demonstrating its effects. If there is evidence of cresentric disease on biopsy, high dose steroids and cyclophophamide are used.
24
Q
What are the four subtypes of CKD releated mineral bone disease?
A
Osteitis fibrosa systica, osteomalacia, adynamic bone disease and mixed lesions.
25
What is adynamic bone disease?
It's the most common CKD related mineral bone disease with a prevalence of 18% amongst patients with bone stage 3 CKD or worse. It's characterised by low bone turnover in the absence of aluminium overload.
26
What is osteitis fibrosa cystica?
One of the four subtypes of CKD associated mineral bone disease. Characterised by very high bone turner (cf with adynamic bone disease).
27
What is osteomalacia?
A condition of diffuse boney pain, have spinal tenerness to percussion, pseudofractures and skeletal deformities. Patients have low vitamin D, with low-normal calcium and elevated PTH. Typically caused by vitamin D deficiency. This develops in CKD, as hyperphosphataemia from reduced renal phosphate excretion causes hypocalcaemia and reduced efficacy of th 1-alpha-hydroxylase enzyme responsible for creating active Vitamin D (1,25 - dihydroxyvitamin D) metabolites.
28
What is fibroblast growth facter 23?
FGF23 is a hormone produced by bones primarily by osteocytes, but to a lesser extent by osteoblasts and marrow. It's target organs are the kidneys and the parathyroid glands. It encourages loss of phosphate in the kidneys, and inhibits the production of calcitriol (1,25 dihydroxyvitmain D). At the parathyroid gland, it inhibits the parathyroid hormone a bit.
29
What is alpha-klotho?
When it has its transmembrane domain, klotho is co-receptor with FGF receptor 1 for FGF23. FGF23 binds to this co-receptor structure. Soluble klotho seems to be an amazing thing that causes antiaging, antifibrosis, and inflammation. The major source of soluble klotho is the kidneys.
30
What do FGF23 levels do in CKD?
Even at stage 2, FGF23 levels are elevated.
31
What happens to Klotho levels in CKD?
Goes down. Possibly associated with cardiovascular disease.
32
What happens first in progression of CKD, hyperphosphataemia or FGF23 elevations?
FGF23 elevation. FGF23 elevations occur much earlier than elevations in serum phosphate.
33
FGF23 decreases phosphate reabsorption in the kidneys and decreases vitamin D synthesis. What other disease has high levels of FGF23 been associated with?
Increased cardiovascular events.
34
What is known to trigger FGF23 production?
Inflammation, increased dietary and serum phosphate, anaemia and iron deficiency.
35
Do phosphate binders and reductions in dietary phosphate reduce FGF23 levels in serum?
Mixed evidence. The feeling is if patients are compliant (and they rarely are, because of GI related side effects) that they have a mild benefit.
36
What treatments other than phosphate binders are available to reduce serum phosphate, serum PTH and FGF23 levels?
Calcimimetics - e.g. cinacalcet
37
What blood parameters suggest a diagnosis of adynamic bone disease in patients with CKD?
Persistently low PTH with hypercalcaemia. Low ALP, low bone turnover makers.
38
What drugs for the treatment of mineral bone disease in CKD predispose patients to developing aydnamic bone disease?
Calcium containing phosphate binders, calcimimetics, digh diaslysate caclicum, active vitamin D analogues (calcitriol). Other factors include increased age.
39
What PTH value is recommended for patients with CKD to prevent adynamic bone disease?
2-9x the upper limit of normal to avoid adynamic bone disease.
40
What time frame does acute interstitial nephritis usually start after the offending drug?
7 to 10 days, but it can occur faster if the patient has already been sensitised to the medication.
41
What is usually seen in AIN on urinary microscopy?
WBC casts. Rarely, urine eosinophils.
42
What are the targets of antibodies that cause humoral rejection in transplant typically targeting?
HLA antigens. This is why HLA haplotype matching reduces the likelihood of humoral rejection. Note that anti-HLA abs can be present at the time of transplant leading to hyperacute rejection, or can develop slowly after the transplant procedure.
43
What hisopathological findings are typical of antibody-mediated kidney transplant rejection?
Microvascular inflammation in the allograft is present. This is characterised by capillary dilataion, presence of inflammatory cells, vacuolisation of the endothelial cells nad cyoplasmic swelling on light microscopy. DIF in 50% of cases will reveal C4d - speicifcic for ab mediated damage but not sensitive.
44
What induction thereapy is used prior to kidney transplants in HLA matched patients at high risk of rejection?
Rabit antithymocyte globulin. Eliminates all CD4 +ve T cells.
45
What induction therapy is used in HLA-matched low risk of rejcection renal transplant recipients prior to transplant?
Basiliximab, an anti IL-2 receptor monoclonal ab. Prevents the replication of T-cells.
46
What induction thereapy is used in HLA unmatched recipients prior to kidney transplant as HLA desensitisation?
Alemtuzumab - an anti-CD52 monoclonal ab. CD52 is present on T and B cells and depletes both populations.
47
What age is anti-GBM disease most likely?
Bimodal distribution - age 30 and 60 are two peaks.
48
What HLA type is associated with an increased risk of Anti-GBM disease?
HLA-DR2
49
What light microscopic renal biopsy disease is seen typically in GBM?
Rapidly progressive glomerulonephritis (cresentic) in 80-90% of cases. DIF will show a ribbon of IgG along the basement membrane.
50
What percentage of patients with anti-GBM disease will present with alveolar haemorrhage?
Only 50%
51
What is the initial treatment for anti-GBM glomerulonephritis?
Plasma exchange, oral cyclophosphadmie (three months), and corticosteroids.
52
What lifestyle behaviour has been linked to increased risk of anti-GBM recurrance?
Smoking or other hydrocarbon inhalation. In general, relapse is quite low.
53
Are anti-GBM disease patients candidates for renal transplant?
Yes - recurrence after renal transplant is rare.
54
Patient's with Alport syndrome are at risk of what other glomerular disease after renal transplant?
De novo anti-GBM disease. This is because the defective collagen in patients with alports disease that was present in their native kidney's GBM is what their immune system is tolerant to. The new, normal collagen containing GBM seen by the immune system in the donor kidney is a source of immune sensitisation and at risk of triggering anti-GBM antibodies.
55
What is the target of anti-GBM abs usually?
Collagen IV - part of the GBM and basement membranes in the lungs.
56
What protein is impacted in Alport's disease?
Collagen IV.
57
What ways can alport's disease be inherited?
X-linked disease. Men lack collagen IV on staining of the kidneys. Femal heterozygotes show patch loss in their kidneys.
Autosomal recessive disease - slightly different pathophys, but same outcome of no collage IV in the GBM.
58
What are the classic symptoms of Alport syndrome?
Sensoroineural hearing loss (due to cochlear involvement), ocular abnormalities (due to lens involvement) and glomerular disease (due to GBM involvement). The disease sees smooth muscle invovlement sometimes with leimyomas in the lungs, GI system or femal reproductive tracts.
59
What is calciphylaxis?
Also known as calcific uremic artiolopathy is a rare and life threatening condition involving occlusion of microvasculature in the subcutaneous adipose tissue and dermis. It usually affects patients with end stage kidney disease on dialysis.
60
How many months after starting dialysis does calciphylaxis usually start?
Between 30 and 105 months.
61
Are patients on haemodialysis or peritoneal dialysis more likely to be diagnosed with calciphylaxis?
Peritoneal dialysis
62
What are the risk factors for calciphylaxis?
dialysis > 2 years, obesity, diabtes, female gender, repeititve skin trauma from injections, elevation of serum calcium or phosphate, secondary/primary hyperparathyroidism, over-suppresssed PTH levels with adynamic bone disease, elevated ALP, vitamin K deficiency, warfarin use, hepatobiliary disease, thrombophilia, SLE, low albumina, metastatic cancer, rapid weight loss, recurrent hypotension, too much sun light, exposure to aluminium, elevated FGF23 levels.
63
What's the significance of aluminium in kidney disease?
It's a component of one of the old phosphate binders, but issues are that it can cause CKD-mineral bone disease like picture and is also a risk factor for calciphylaxis.
64
What risk factor must patients with ESKD on dialysis be warned about prior to commencing warfarin?
A 3-13x fold increase in risk of calciphylaxis.
65
How is calciphylaxis diagnosed?
Skin biopsy. But you can't biopsy anything with teminal circulation as it won't heal.
66
What is the management for calciphylaxis?
Wound care - surgical debridement is often required with vaccuum dressings. Hyperbaric oxygen therapy can be considered in patients with peripheral lesions. Vitamin D and calcium supplements should be eliminated. Frequency of haemodialysis should be increased. If on periotneal dialysis, should consider switching to haemodialysis. Warfarin should be changed if possible. Sodium thiosulfate (Calcium chelator) is a promising treatment.
67
Why shouldn't PTH be suppressed below 2x the upper limit of normal in patients with end stage kidney disease?
Increase in risk of adynamic bone disease and calciphylaxis.
68
Do calcimimetics (calcium analogues that trick the parathyroid gland into thinking there is enough calcium present in the serum by binding to the CASR, also by binding to to CASR on renal tubules increase calcium loss in the urine) improve CKD-mineral bone disease?
No
69
Should calcitriol and vitamin D analogues be used in all patients with CKD?
No, only for patietns with severe and progressive hyperparathyroidism.
70
What are the absolute indications for dialysis?
Related to uraemia - pericarditis, encephalopthy, bleeding diathesis, intractable nausea and vomiting, profound fatigue and pruritis. Also fluid overlaod despite diuretic treatmnet. Metabolic acidosis, hyperkalaemia and hyperphosphataemia refractory to other medical treament.
71
How is increased bleeding risk in CKD patients thought to be mediated?
Uraemia causng platelet dysfunction. However anaemia (platelet dysfunction is worsened by anaemic states), and heparin use during dialysis are thought to contribute to increased bleeding data in CKD patients.
72
What are the four most common sites of bleeding in patients with CKD?
Lower GI tract > upper GI tract > intracerebral (1%) > subarachnoid (0.1%)
73
What treatmnent has been show to reduce the rates of GI bleeding in patients with CKD and hyperuraemia?
Ostrogen medication.
74
In the outpatient setting what eGFR should be used to guide the commencement of dialysis to treat renal disease?
It shouldn't truly be guided by eGFR, but instead by symptoms and electrolytes. As symptoms of fluid overload or uraemia begin it is reasonalble to start. The IDEAL trial demonstrated no benefit in starting dialysis early in patients compared to when their disease worsened. They found there was no benefit commencing dialysis when eGFR >10ml/min compared to starting at 5-7ml/min.
75
How long dose it take to make a stable AV fistula/graft for dialysis?
2-3 months for a fistular, and very soon after for a graft.
76
Tunneled catherter vs graft/fistular for haemodialysis?
Graft or fistular is better. The catheter carries a 2-3 times greatter risk of hospitalisations due to infection or death.
77
How do cyclosporin A and tacrolimus cause hyperkalaemia?
Inhibition of adrenal aldosterone biosynthesis. Increased potassium efflux from cells. Secondary obstruction of calcium efflux by blocking renal chloride ions.
78
How does trimethorpim cause hyperkalaemia?
It blocks the luminal sodium channels in the principal cells of the renal tubule. This prevents those cells from depolarising with sodium influx, which then prevents the later luminal outflow of potassium (that would ordinarily flow through a an open voltage gated potassium channel on the luminal surface.)
79
How does digoxin cause hyperkalaemia?
It inhibits the Na/K ATPase on the basolateral membrane of tubular cells, preventing the movement of potassium into those cells then out into the lumin.
80
How does heparin cause hyperkalaemia?
Inhibits adrenal aldosterone biosynthesis and decreases the number and affinity of angiotensin II receptors the body over.
81
How do glucocorticoids cause hypokalaemia?
Increase glucose and insulin production (intrcellurisation of potassium) and partial mineralcorticoid effect causing Na retention and potassium loss at distal convoluted tubule.
82
How do beta-blockers cause hyperkalaemia?
Inhibit renin secretion and decrease cellular potassium uptake. (recall giving salbutamol to increase potassium uptake through beta-receptor agonism).
83
What is the type of nephropathy that starts with macroscopic haematuira immediately after a sore throat?
IgA neprhopathy. It is sometimes called synpharyngitic nephritis. This syndrome occurs in about 10-15% of IgAN and predominantly in patients under the age of 40. Recall that post strep GN usually occurs 2 weeks after symptomatic streptococcal infection.
84
What is the most common cause of glomerulonephritis, CKD and ESKD globally?
IgA nephropahty
85
What is the pathophysiology of IgA Nephropathy?
Circulating immune complexes made up of 1) galactose-deficient IgA1, and 2) autoantiibody to the IgA hinge region O-glycans, and 3) C3 lodge in and damage glomeruli. It is likely that this is the same disease as Henoch Schnolein Purpura, but just limited to the kidneys, as the deposits in the kidneys of patients with HSP are indistinguishable from the deposits found in IgAN.
86
What is Oxford Criteria classification score of IgAN renal biopsy made up of? What is it used for?
1) Mesangial hypercellularity, 2) endocapillary hypercellularity in IgA nephropathy, 3) Segmental golerlosclerosis in IgA nephropathy and 4) tubular atrophy/interstitial fibrosis. In 2017 the presence of absence of cresents was added as a 5th element.
MEST-C scores are used to classify and try to predict prognosis. Higher scores = worse prognosis.
87
What are the clinical/laboratory markers of poor prognosis in patients with IgA nephropaty?
Elevated serum creatinine, hypertension >140/90, preotinuria >1g/day. Importantly, macroscopic haematuria is not associated with a worse prognosis.
88
How is IgAN treated?
First, risk of severe disease is calculated using the MEST-C score and clinical/laboratory features of severe disease (proteinuria, hypertension and high serum creatinine). At risk populations are managed with ACEi to manage blood pressure into the normal range and reduce proteinuria. For patients with enduring proteinuira of >1g/day after supportive care, immunsuppression with 6 momths of corticosteroids is commenced. Japanese patients benefit from tonsillectomy.
89
How does lithium cause diabetes insipidus?
Polyuria and polydipisa are common due the effect of lithium on cells of collecting tubule. It reduces the ability of these cells to recycle cAMP (like the vaptans) making them insensitive to ADH - this a secondary form of nephrogenic diabetes insipidus. Chronic lithium toxicity can make this irreversible
90
What are the risk facotrs for polyuria and polydipsia associated with lithium?
Increased duration of treatment with shigher serum lithium levels, previousu episodes of lihtium intoxication and the ingestion of antipsychotics.
91
What are the neurological symptoms of mild-moderate lithium toxicity?
Muscle weakness, vertigo, hypothyroidism
92
What are the non-renal adverse effects of severe lithium toxicity?
Hyperreflexia, myoclonic jerks, coarse tremor, dysarthria, disorietnation, psychosis, seizures and coma.
93
What are the endocrine side effects of lithium toxicity?
Hypothyroidism, hyperparathyroidism with resultatn hypercalcaemia.
Rarely, it can cause hyperthyroidsim.
94
What are the GI symptoms of lithtium toxicity?
Metallic taste in the mouth, diaarrhoea, weight gain, epigastric pain
95
What are the cardiac symptoms of lithium toxicity?
Benign T wave chages on ECG. Can rarely cause cardiac arrhythmias.
96
What haematological abnormality is seen with lithiumm toxicity?
Leukocytsosis
97
How is severe lithium toxicity treated?
Dialysis
98
How does mycophenolate mofetil work?
Inhibits purine synthesis in B and T cells by inhibiting an enzyme they rely on to do this inosine monophosphate dehydrogenase. This prevents B and T cell proliferation and reduces the production of cytotoxic T cells. Other cells have other ways to do purine synthesis.
99
What are mycophenolate's side effects?
GI side effects are common. Can cause cytopaenias. Contraindicated in pregnancy - teratogenic. In transplant, has been associated with an increased risk of lymphoma.
100
How does azathioprine work?
Purine synthesis inhibitor. Is cytotoxic. Metabolised to mercaptopurine, which is a purine analogue that inhibits DNA synthesis. Affects B and T cells, but affects other rapidly dividing cells as well (not specific to lymphoctes like MMF is).
101
What are common azathioprine side effects?
Severe myelosuppression, especially in patients who are have low or no detectable thiopurine methyltransferase activity (responsible for the conversion of azathioprine to mercatpopurine). Dose reduction required in renal impairment.
Skin sensitivity and increased risk of skin cancer. Alopecia, diarrhoa, anorexia, mouth ulcers, oesophagitis also occur.
102
What options are available for induction treatment in class III or V (subendothelial immune complexes) lupus nepthritis?
High dose steroids and either cyclophosphamide or mycophenolate. A large trial has shown no difference in the outcomes head to head, so normally mycophenolate is used due to its less serious side effect profile (espeicially in young women).
103
Is plasma exchange is evidnece based treatment for lupus nephritis?
No, despite our understanding the disease as immune complex deposition related, plasma exchange does not effct outcomes. Could be because local inflammation in the kidney is the key issue at the time of diagnosis and not the still circulating immune complexes.
104
What is patiromer?
A non-absorbed sodium-free non-specific cation binding binding polymer that exchanges calcium for cations (mostly potassium) in the GI tract. It predominantly acts in the distal colon, and takes about 7 hourse to work. This can be very beneficial as it allows ongoing ACEi/ARB use in patients who would otherwise need to avoid them due due to recurrent hyperkalaemia.
105
What are the adverse effects of patiromer?
Mild hypomagnesasaemia as it can also bind magnesium. Also mild GI symptoms. May interact with other drugs so current advice is not to take it within 3 hours of another drug.
106
What is sodium zirconium cyclosilicate?
Sodium and hydrogen based non-absored exchange polymer that very specifically exchanges sodium and hydrogen for ptoassium. Works in the upper and lower GI tracts. Side effects include peripheral oedema and GI side effects.
107
What is the most common cause of nephrotic syndrome in patients over 40?
Membranous nephropahy. FSGS is common in middle aged people, in some series more so than MN, however even older patients are much more likely to have MN.
108
What is the most common cause of nephrotic syndreom in young children?
Minimal change disease
109
What are the causes of nephrotic syndrome?
Minimal change disease, membraneous nephropathy, focal segmental glomerulosclorsis (aka FSGS), diabetic nephropahty and amyloidosis. IgA nephropathy can cause a nephrotic syndrome, but it usually presents as a nephritic syndrome.
110
Minimal change disease is normally idiopathic, however it is sometimes associated with other things. What are they?
NSAID over use or Hodgkin's lymphoma.
111
What are the light microscopy findings in minimal change disease?
Diffuse effacement of epithelial cell foot processes is the classic finding.
112
What is the treatment for minimal change disease?
It is usually very responsive to steroids. If steroids fail, its normally because the disease is actually FSGS.
113
What are three catagories of causes for FSGS?
Primary, secondary or genetic. Differentitating between primary and secondary is key as this will change management. Primary FSGS responds to treatment with immunsuppression, however secondary FSGS will not and are treated with RAAS blockade.
114
What are the secondary causes of FSGS?
HIV, reflux nephropathy, class III obesity (BMI >40) chronic glomerular hyperfilltrration from a soliaary kidney, or any other cause of extensive nephron loss. It may also be drug induced.
115
What are the genes associated with an increased risk of FSGS?
NPHSA1/2 LAMB2, WT1 combined account for about 85% of steroid resistent nephrtoic syndrome in children. It remains important in young adults however, as one case series found that a causative mutation was found in 30% adult patients presenting with FSGS before the age of 25.
116
How does FSGS present?
Nephrotic syndrome , however patietns often also have haematuria, hypertension and reduced renal function.
117
What does FSGS look like on light microscopy of renal biopsy?
Segmental areas of mesangial collapse and sclerosis affecting some but not all glomerulia ('focal' disease).
118
What does FSGS look like on light microscopy of renal biopsy?
Segmental areas of mesangial collapse and sclerosis affecting some but not all glomerulia ('focal' disease).
119
What is seen on light microscopy, DIF and electron microscopy of renal biopsy specimens taken from patients with membranous nephropathy?
Light microscopy shows basement membrane thickening without assocaited cellular proliferation or infiltration. DIF shows granular IgG deposition throught the capillary walls and EM shows electron dense deposits in the subepithelial space. Classic 'spike and dome' appearence is also seen on EM where new basemen membrane has gown between subepithelial immune deposits.
120
How are the causes of membranous nephropahty catagorised?
Primary (70%) and secondary (30%).
121
What is the cause of primary mebranous nephropathy?
Antibodies to M-type phospholipase A2 receptor (PLA2R) in 70-80% of patients who are believed to have parimary membranous nephropathy.
122
What are some of the secondary causes of membranous nephropathy?
Malignancy, infections (e.g. hepatitis, syphilis, malaria and tuberculosis) , autoimmune diseases (e.g. lupus membranous nephropathy) or dugs (e.g. gold, NSAIDs, penicillamine)
123
Apart from the consequences of hypoalbuminaemia (e.g. oedema) what other life threatening concern should be considered in patients with any form of nephrotic syndrome?
Thrombosis and hypercoagulability. The loss of anti-thombin III, protein C and S in the urine, plus increased sybnthesis of pro-coagulant factors and increased platelet activity, lead to increased risk of DVT, PE and so on.
124
How is primary MN stratified?
Patients are stratified into low, moderate, high or very high risk based on urine protein, serum albumin, eGFR, urinary alpha-1-microglobulin, urinary IgG, urinary beta-2microglobulin, or serum PLA2Rab, and selectivity index.
125
How is moderate risk MN managed?
With either a watch and wait approach, OR rituximab, OR calcineruin inhibtior +/- steroids.
126
How is high risk MN treated?
With rituximab, or cyclophosphamid + steroids, or with calcineurin inhibitor and rituximab
127
How is very high risk MN treated?
With cyclophosphamide and steroids
128
How high does the CK need to be in someone with rhabdomyolysis before an AKI becomes more likelyl?
CK >5000. Additionally, there normally needs to be an additional renal insult to lead to kidney injury like volume depletion or NSAID use.
129
What is the treatment for rhabdomyolysis? When is safe to stop treating?
The treatment is agressive normal saline IVT until the CK has decreased by at least 50%.
130
When does CK peak following muscle insult leading to rhabdomyolysis?
24-36hrs after the event.
131
What is roxadustat?
It's hypoxia-inducible factor prolyl hydorxylase (PHD) inhibtor. Bascially, this oral incrases the availability of hypoxia inducible gene transcription factors so they are available during normoxic conditions. This activates erythropoeisis as it would in a chronically hypoxic state. It also generates more hepcidin allowing greater access to macrophage iron stores and increases iron absorption. Has good evidence in CKD related anaemia.
132
What is membranoproliferative GN?
It describes the pattern of glomerular injury (different to say, mesangioproliferative disease). The pattern includes hypercellularity and thickening of the glomerular basement membrane. Patients with MPGN present with a nephritic syndrome. Compare with say, membranous nephropathy, which also is a problem with the GBM (but it usually looks thinner) which causes nephrotic syndrome. Or compare with Anti-GBM disease, which has a much more explosive onset.
133
What are the 3 groups of diseases that can cause a MPGN picture?
3 groups of diseases cause and MPGN light microscopy pattern - immune complex/monoclonal immunoglobulin mediated, complement medtiated, and MPGN without immunoglobulin or complement deposition.
134
What can cause immune complex/monoclonal immunoglobulin mediated membranoproliferative GN?
Infections - especially those associated with high rates of immune complex formation - hepatitis B/C, HIV, as well as chronic baterial infections. Autoimmune diseases - Sjogren's disease, SSc. Monoclonal immunoglobulin diseases - MGUS with renal significance, multiple myeloma.
135
What causes complement mediated MPGN?
Two subtypes - C3GN and dense deposit diseaes. DDD in 80% of cases is secondary to a circulating factor that stabilises the alternative pathway C3 convertase. C3Nef is also found in about 40% of C3GN. The remainder of C3GN and DDD are likely caused by germline mutations that disrupt regulation of alternative pathway activation. Rarely, autoantibodies to Factor H, stablising C5 convertase abs (C5Nef), or stabilising classical pathway convertase abs (C4Nef) are implicated.
136
What other disease are associated with C3 glomerulopathy?
Age related macular degeneration, acquired partial lipodystrophy (subcutaneous fat loss in the upper part of the body). Both are also caused dysregulation of the alternative pathway.
137
What causes MPGN without complement, immune complex or immunoglobulin deposition on DIF?
Usually, chronic thrombotic microangiopathy is the cause (TTP, HUS) antiphospholipid syndrome.
138
What percentage of kidney transplant recipiets have BK viraemia? What percentage get BK virus nephropathy?
10-30% have viraemia. 2-5%.
139
When is BK virus nephropathy most likley to occur in a renal transplant recipient?
In the first weeks to months post biopsy when immunosuppression is at its highest. Also, if repeat immunosuppression needs to be given for rejection.
140
How is BK virus nephropathy diagnosed in kidney transplant recipients?
Kidney biopsy.
141
What is the treatment for BK virus nephropathy?
Immunosuppression reduction is the cornerstone of treatment. Calcineurin inhibitor reduction by 25-50% is recommended, or conversion to an mTOR inhibitor (sirolimus or everolimus). Treatments with less evidence: cidofovir, leflunomide, quinolones, IVIG.
142
What are the possible complications of giving EPO or and EPO like agent to stimulate erythropoesis?
Can worses pre-existing hypertension, lead to ischaemic cardiovascular disease, can drive haemtological or other malignancies, worsen epilepsy or seizure activity.
143
What should be the target haemoglobin for patients on EPO replacement therapy with CKD?
100-115g/L. Hb levels over 110 are associated with stroke, VTE, challenging to control hypertension, MI and increased overall mortality.
144
In patietnts with CKD and low bicarb without another cause of metabolic acidosis, what is the management?
Commence oral sodium bicarb.
145
Untreated metabolic acidosis is in CKD is associated with a number of bad outcomes. What are they?
Frther CKD prgoression, bone deminerialisation, skeletal muscle catabolism and metabolism.
146
At what level of serum bicarb in patients with CKD should oral sodium bicarbonate therapy be commenced?
When the bicarcb is <22mmol/L.
147
How is peritonitis in peritoneal dialysis diagnosied?
Any 2 of the 3: 1) clinical features of peritonitis with cloudy dialysis effluent. 2) dialysis effluent white cell count of > 100 with >50% PMNs. 3) positive dialysis effluent culture.
148
What are the possible sources of infection in periotonitis associated with PD?
Skin source is the most common - S epidermidis. Categorised as catheter related if there is a concurrent catheter entry site infection. Enteric sources are also seen and carry a high mortality - mixed gram +ve and -ve organisms are often grown from the diasylate.
149
Whenever patients doing peritoneal dialysis are given antibiotics, what should be given at the same time?
Anti-fungal. Latest PD guideliens. This is to reduce fungal peritonitis.
150
What abx should be used to treat suspected peritoneal dialysis related peritonitis?
Whilst awaiting cultures, need to cover staph epi and possible enteric sources. Vancomycin and ceftriaxone would work and can be given systemically or intraperitoneally. Alternatively, giving a 4th generation cephalosporin is acceptable.
151
What are the most important possible side effects of peritoneal dialysis?
Low blood pressure, infection, muscle cramps (due to rapid fluid loss), insomnia, hernia, weight gain due tot he presence of glucose in the diasylate.
152
What cell is responsible for synthesis, maintenance and repair of glomerular basement membrane?
The podocyte
153
What growth factors are produced to maintain the endothelialium and mesangial cells by the podocyte?
VEGF and platelet derived growth factors respectively
154
What is post-transplant lymphoproliferative disease?
It is the most common malignancy complicating solid organ transplant (excluding non-melanomatous skin cancer). The most common cause is EBV reactivation causing proliferation of an infected B cell population, and outgrowing a depleted T cell population in the setting of transplant related T-cell mmunsuppression.
155
What determines the risk of, and what transplant types are most often associated with, post-transplant l ymphoproliferative disease?
Risk of disease is dependent mostly on EBV status mismatch of the recipient and donor (donor positive, recipient negative, provides the greatest risk) and degree of immunosuppression - particulalry the amount of T cell immunosuppression. So the transplants that require less immunosuppression are less often associated with PTLD. Lowest incidence is seen with haematopoeitic stem cell transplant/renal/liver transplatns. It's higher amongst heart and lung transplants, and highest amongst patients with multiorgan and intestinal transplants.
156
How does IV iodinated contrast cause kidney injury?
They are directly toxic to renal tubules, and they also create disturbances in renal blood flow due to their viscosity and osmolality leading to microvascular thrombi and mild ischaemic changes in the kidney.
157
How does metformin impact renal function?
It doesn't. The reason we are concerned about ongoing metformin use during acute kidney is that it is primarily renally excreated in the proximal tubule. If the GFR reduces, increased plasma concentrations of metformin lead to increased mitochondrial augmentation towards anaerobic metabolism, favoring the production of lactic acid and posing a risk of metabolic lactic acidsosis.
158
Where are SGLT2 transportors located?
S1 segment of the proximal renal tubule, but als in the pacnreated alpha cells, and in the cerebllum. SGLT1 is located in S2/3 of the proximal tubule, but also in the intestines, heart lung and skeletal muscle.
159
How does trimethoprim influence serum creatinine levels?
It reduces creatinine secretion into the urine from the plasma at the proximal tubule of the nephron. This leads to increased serum creatinine levels without worsening GFR.
160
What cancers become more likely in patients who are having immunosuppression for a renal transplant?
Non-melanomatous skin cancers are the most common and review with a dermatologist annually is required. Colon cancer, lung cancer, melanoma, and lympoma (PTLD) risk increases substantially after transplant. Interestingly, breast, ovarian, prostate and brain cancer is unaffected.
161
How does belatacept work?
It binds to CD80, CD86 on antigen-presenting cells (recall these are the co-stimulatory molecules that oridinarly bind to T-cell CD28 in order to provide signal T in 2 cell activation). This prevents the signal 2 being provided to naive T cells and encourages tolerance of presented antigens.
162
How does bortezomib work?
Bortezomib reversibly binds to the 'chymotrypisn-like subunit of the 26S proteasome', which prevents the degradation of pro-apototic facotrs and leads to via caspease-mediated cell death pathways. It preferentially causes controlled cell death in rapidly proliferating cells and is indicated for used in multiple myeloma - particularly effective against plasma cells. It is also used off label however to manage sollid organ transplant rejection refractory to other options.
163
What part of the cell cycle does Everolimus target?
mTOR inhibitors act just downstream from tyrosine kinase associated membrane receptors used to transmit growth signals. This growth signalling phase occurs in G1, before DNA replication that occurs in the S phase.
164
Name as many Anti-CD20 monoclonal abs as you can
Rituximab, ocrelizumab, ofatumumab, veltuzumab
165
Name as many TNF-alpha antagonists as you can
infliximab, adalimumab, golimumab, certolizumab
166
What is the name of the dummy CTLA4 molecule that floats around and disable T-cells?
Abatacept
167
What is the name of the name of the TNF receptor dummy that floats around and mops up all the TNF-alpha?
Etanercept
168
How do belimumab and atacicept work?
Belimumab and Atacicept are both Anti-BAFF/blys drugs. They stop BAFF (a cytokine that activates B cells and causes the to proliferate) from binding.
169
How does leflunomide work?
It's a prodrug that is metabolised into teriflunomide - active form. This inhibits de novo pyrimidine synthesis and prevents cell cycling from S to G2 by inhibiting the mitochondrial enzyme dihydro-oroate. It triggers cell death of and halts proliferation of autommine lymphocytes.
170
What are the common side effects of leflunomide? Any other things to know regarding its use?
Diarrhoea, LFT derangement, hypertension, abdominal pain, back pain, alopecia, rash. Rarely, cytopoenias and pulmonary disorders (ILD, pneumonitis) have been associated with leflunomide use. Teratogenic. Long half life (2 weeks). Contraindicated if underlying lung disease exisits.
171
What is the cause of primary FSGS? How do we know this?
Some circulating factor. We know this because when you transplant a patient with primary FSGS they have a very high rate, and sometimes rapid return to nephrotic syndrome. The circulating factor has not been identified.
172
How is recurrence of nephrotic syndrome managed following renal transplantation to treat primary FSGS?
Plasma exchange, increased calcineurin inhibition, and immunoadsorption with 'protein A'. Protein A is a protein derived from Staph aureus that has a very high affinity for immunglobulin and is able to mop it up. Further, rituximab may be attempted if there is no response to plasma exchange.
173
What is thin basement membrane nephropathy?
Patients present with persistent micrscopic haematuria with no proteinuria. The normally have no deafness, normal renal function and are normotensive. It is possibly caused by heterozygous non-X-linked collagen IV gene mutations.
174
What is the classic appearence under light micrscopy of diabetic nephropathy?
Kimmelstiel-Wilson nodules - nodulare lesions containing areasa of marked mesangial expansion forming large round fibrillary mesangial zones with palasading of mesnagial nuclei around the periphery of the nodule and compression of the associated glomerular capillaries.
175
What other non-renal disease are patients with primary membranous nephropahty at marked increased risk of experiencing?
Arterial and venous thromboembolic events. Note that othe glomerular diseases are also associated with thrombosis, but MN is the most common.
176
Which cause of neprhrotic syndrome can be triggered by NSAIDs and COX-2?
Minimal change disease.
177
What type of FSGS is HIV associated with?
Collpasing glomerulopathy
178
What is Chinese Herbal Nephropathy?
Extensive virtually hypocellular cortical interstitial fibrosis with associated tubular atrophy and global sclerosis of glomeruli. It's caused by aristolochic acid found in chinese herbal medicinces. It usually presents with mild proteinuira, hypertension, severe anaemia and uroepithelial atypia. Urothelial malignancy develops in around half of patients with chinese herbal nephropathy.
179
What is renal tubular acidosis?
It's a clinical syndrome characterised by hyperchloraemic metabolic acidosis with normal anion gap. It is a group of disorders (types 1-4) that have imipairment of excretion of fixed acids (distal RTA) OR impairment of the reabsorption of filtered bicarbonate (proximal RTA).
180
How is acidaemia managed by kidney's during the initial stages of chronic kidney disease?
Increased acid excretion is acheived thruogh increased ammonium prodcution and tubular excretion. As renal function continues to worsen however, ammonium production fails to keep pace with acidaemia and renal tubular acidosis eventuates.
181
What is type 1 renal tubular acidosis?
Distal RTA - characterised by impaired distal nephron proton scecretion OR failure to reabsorb bicarbonate at the intercalated cells of the collecting duct.
182
What is the most common cause of type 1 distal renal tubular acidosis?
Autoimmune diseases including SLE, Sjogren's syndreom, RA, systemic sclerosis, thyroiditis, hepatitis and primary biliary cirrhosis.
There are 2 genetic primary causes of RTA1 - mutations of the AE1 chloride-bicarbonate exchanger or the subunits of the H-ATPase pump (causing RTA1 and sensorineural hearing loss).
Other associations - Marfan syndrome, Ehler Danlos, sickle cell disease, congenital obstruction of urinary tract. Neprhocaclcinosis, tubulointerstitial disease. Hypergammaglobulinaemic states.
Medications: Lithium, amphotericin B, NSAIDs, lead and some antivirals, glue sniffing.
183
What is the most common type of renal tubular acidosis seen in Sjogren's disease?
Around 25% of Sjogren's patients have a defect in distal tubular bicarb reabsorption of proton excretion (RTA 1).
Alternatively, Sjogren's syndrome patient's can develop hypokalaemia usually to tubulointerstitial damage causing potassium wasting - emlulates a Gitelman syndrome.
184
What is type 2 renal tubular acidosis?
Metabolic acidosis secondary to impaired proximal reabsorption of bicarbconate. Often associated with hypokalaemia due to accelerated movement of filtrate through the tubule with the extra bicarb - causes more K excretion. Can be associated witha full fanconi syndrome.
185
What are the main causes type 2 RTA?
Overall much less common that type 1 RTA. Hypergammagloulinaemic states (amyloidosis, MM, MGUS) are most common cause. There are inherited causes that affect mutations in the proximal tubule sodium/proton antiporter (apical membrane) or the Na-HCO3 cotransporter (basolateral membrane).
Can be caused by drugs: lead or other heavy metals, carbonic anhydrase inhibtiors (topiramate, acetazolamide), aminoglycosides, valproate, tenofovir, ifosfamide
Can be caused by sjogren syndrome and SLE, but less often thant RTA1.
Intersitial nephritis, vit D deficiency, chronic hepatitis and secondary hyperparathyroidism have all been associated with it.
186
What is renal tubular acidosis type 3?
Mixed proximal and distal deficits in acid management. Caused by mutations in carbonic anhydrase II mutations and subseqnet defcicency.
187
What is renal tubular acidosis type 4?
The so called hyperkalaemia renal tubular acidosis. It's caused by hypoaldosteronism or reduced sodium availablity to the distal nephron (genetic, dietary, overabsorption in the proximal tubule) which leads to reduced sodium absorption at the distal convoluted tubule/collecting duct junction. This leads to a loss of the positive change in electrical gradient intracellularly required to drive potassium and protons from the principal cells into the lumen. The result is hyperkalaemic hyperchloraemic non-anion gap acidosis.
188
What is renal tubular acidosis type 4?
The so called hyperkalaemia renal tubular acidosis. It's caused by hypoaldosteronism or reduced sodium availablity to the distal nephron (genetic, dietary, overabsorption in the proximal tubule) which leads to reduced sodium absorption at the distal convoluted tubule/collecting duct junction. This leads to a loss of the positive change in electrical gradient intracellularly required to drive potassium and protons from the principal cells into the lumen. The result is hyperkalaemic hyperchloraemic non-anion gap acidosis.
189
Which type of renal tubular acidosis requires the most bicarbonate to correct?
RTA type 2 - proximal. Because this is caused by a failure a reducaed ability to absord filtered bicarb at the proximal tubule.
190
What is Fanconi syndrome?
Global dysfunction of the proximal tubule, characterised by the inability fo the proximal tubule to reabsord - bicarbonate, amino acids, glucose, phosphate, urate and other solutes.
191
What causes Fanconi syndrome?
Fanconi syndome is otherwise caused normally by toxins, drugs, as part of nephrotic syndromes, vitamin D deficiency, secondary hyperparathyroidism.
Most common drug causes: aminogylcosides, cisplatin, ifosfamide, valproate, and deferasirox.
Lot's of rare metabolic diseases. Lowe syndreom, Dent's disease, cystinosis, heridtary fructose intolerance, galactoasaemia, glycogenosis, tyrosinaemia, Wilson's disease, Fanconi-Bickel syndreom, inherited diseases affecting mitochondrial metabolism.
192
How is type 4 RTA treated?
Bicarb to correct acidosis, but also fludrocortisone to treate aldosterone deficiency.
