Nephrology Flashcards
A probable diagnosis of a acute post-streptococcal glomerulonephritis is made on the bases of what symptoms?
2+ blood on dipstick, facial oedema, hypertension about ~2 weeks after a probable strep infection
In probable cases of acute post-streptococcal glomerulonephritis, how is the diagnosis confirmed?
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).
Is the likelihood of acute post streptococcal glomerulonephritis higher with skin or pharyngeal infections?
Skin. Worth noting also that is is only some strains of GAS that are associated with APSGN.
What is the pathophysiology of acute post streptococcal GN?
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.
What is the latent period from initial streptococcal infection to GN in acute post-streptococcal GN? Hint: influecned by site of initial infection.
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.
What are the 5 antibodies that can be tested for to demonstrate evidence of recent group A streptococcal infection?
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).
Acute post streptococcal glomerulonephritis is a disease that primarily impacts low resource communities. When is it a notifiable disease?
Always in Australia.
What are the cardiovascular manifestitions of polycystic kidney disease?
Berry aneurysms, aortic aneurysms, aortic root dilatation, and mitral valve prolapse.
What are the non-vascular extrarenal complications of polycystic kidney disease?
Abdominal wall hernias, extra-renal cysts, (especially in the liver) and diverticular disease.
What are the main genes involved in autosomal dominant polycystic kidney disease?
PKD1 (78%) and PKD2 (15%). These genes encode for proteins polycystin 1 and 2. The less common causes include mutations in GANAB and DNAJB11.
Were do the cycsts devlop in polycystic kidney disease?
Cysts devlop from the cells in the tubular portion of the nephrons and collecting ducts.
Which kidney disease has the most rapid delcine in renal function of all forms of CKD?
Autosomal dominant polycyctic kidney disease.
Which gene, when mutated, is associated with more aggressive and rapdily progressive autosomal dominant polycyctic kidney disease?
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.
What is the likelihood of having end stage kidney disease by age 60 if diagnosed with autosomal dominanet polysytic kidney disease before then?
50%
How do the vaptans work in the treatment of autosomal dominant polycystic kidney disease?
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.
What urinary tract related complications do patients get with autosomal dominant polycystic kidney diseae?
Urinary tract infections, infected cysts (which may require drainage or neprectomy), nephrolithiasis.
What is fibrillary glomerulnephritis?
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).
What does fibrillary glomerulonephritis look like under light microscopy, DIF and EM?
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.
What special stain should be used if fibrillary glomerulonephritis is suspected on the renal biopsy sample?
DNAJB9 DIF
What conditions are associated wtih fibrillary glomerulonephritis?
About 50% are associated with a condition. Often a malignancy, monoclonal gammopathy or a autimmune disease. Pts also often have concurrent hpertension and diabetes.
What is immunotactoid glomerulopathy?
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.
What does immunotactoid glomerulopathy look like on renal biopsy light/DIF and EM?
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.
How are immunotactoid glomerulopathy and fibrillary glomerulonephritis treated?
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.
What are the four subtypes of CKD releated mineral bone disease?
Osteitis fibrosa systica, osteomalacia, adynamic bone disease and mixed lesions.
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.
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).
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.
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.
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.
What do FGF23 levels do in CKD?
Even at stage 2, FGF23 levels are elevated.
What happens to Klotho levels in CKD?
Goes down. Possibly associated with cardiovascular disease.
What happens first in progression of CKD, hyperphosphataemia or FGF23 elevations?
FGF23 elevation. FGF23 elevations occur much earlier than elevations in serum phosphate.
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.
What is known to trigger FGF23 production?
Inflammation, increased dietary and serum phosphate, anaemia and iron deficiency.
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.
What treatments other than phosphate binders are available to reduce serum phosphate, serum PTH and FGF23 levels?
Calcimimetics - e.g. cinacalcet
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.
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.
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.
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.
What is usually seen in AIN on urinary microscopy?
WBC casts. Rarely, urine eosinophils.
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.
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.
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.
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.
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.
What age is anti-GBM disease most likely?
Bimodal distribution - age 30 and 60 are two peaks.
What HLA type is associated with an increased risk of Anti-GBM disease?
HLA-DR2
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.
What percentage of patients with anti-GBM disease will present with alveolar haemorrhage?
Only 50%
What is the initial treatment for anti-GBM glomerulonephritis?
Plasma exchange, oral cyclophosphadmie (three months), and corticosteroids.
What lifestyle behaviour has been linked to increased risk of anti-GBM recurrance?
Smoking or other hydrocarbon inhalation. In general, relapse is quite low.
Are anti-GBM disease patients candidates for renal transplant?
Yes - recurrence after renal transplant is rare.
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.
What is the target of anti-GBM abs usually?
Collagen IV - part of the GBM and basement membranes in the lungs.
What protein is impacted in Alport’s disease?
Collagen IV.
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.
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.
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.
How many months after starting dialysis does calciphylaxis usually start?
Between 30 and 105 months.
Are patients on haemodialysis or peritoneal dialysis more likely to be diagnosed with calciphylaxis?
Peritoneal dialysis
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.
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.
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.
How is calciphylaxis diagnosed?
Skin biopsy. But you can’t biopsy anything with teminal circulation as it won’t heal.
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.
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.
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
Should calcitriol and vitamin D analogues be used in all patients with CKD?
No, only for patietns with severe and progressive hyperparathyroidism.
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.
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.
What are the four most common sites of bleeding in patients with CKD?
Lower GI tract > upper GI tract > intracerebral (1%) > subarachnoid (0.1%)
What treatmnent has been show to reduce the rates of GI bleeding in patients with CKD and hyperuraemia?
Ostrogen medication.
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.
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.
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.
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.
How is moderate risk MN managed?
With either a watch and wait approach, OR rituximab, OR calcineruin inhibtior +/- steroids.
How is high risk MN treated?
With rituximab, or cyclophosphamid + steroids, or with calcineurin inhibitor and rituximab
How is very high risk MN treated?
With cyclophosphamide and steroids
