Rapidly progressive glomerulonephritis (RPGN)

Calciphylaxis

- calcific uremic arteriolopathy seen almost exclusively in patients with advanced CKD
- heralded by livedo reticularis and advances to patches of ischemic necrosis especially on the legs, thighs, abdomen and breasts
- pathologically, there is vascular occlusion associated with extensive vascular (calcification of tunica media) and soft tissue calcification
- warfarin is a risk factor of calciphylaxis ( because warfarin decrease vitamin K dependent regeneration of matrix GLA protein which is important in preventing vascular calcification)
- optimal treatment is prevention, with rigorous and continuous control of phosphate and calcium balance
- no specific treatment

Allergic interstitial nephritis (AIN)

- classically presents with fever, rash, peripheral eosinophilia and oliguric renal failure after 7 - 10 days treatment with methicillin or another B-lactam antibiotics
- atypical reactions can occur with NSAIDs in which fever, rash and eosinophilia are rare but acute renal failure with heavy proteinuria is common
- urinalysis reveal pyuria with white blood cell casts and hematuria
- renal biopsy usually not required for diagnosis but reveals extensive interstitial and tubular infiltration of leukocytes, including eosinophils
- discontinuation of offending agent often leads to reversal of renal injury

Cholesterol embolism syndrome

- should be suspected in any patients who develop worsening renal function, hypertension, distal ischemia or acute multisystem dysfunction after an invasive arterial procedure (eg:CABG), anticoagulation or thrombolysis
- triad of livedo reticularis, eosinophilia and acute renal failure
- may presents with unexplained fever, weight loss, myalgia and anorexia initially
- risk of patient developing cholesterol embolism can be reduced by using brachial or axillary approach  in patient known to have severely ulcerated aortic plaque, using soft flexible catheter and avoiding high pressure jets of contrast materials
- trash foot
- low C3 level, raised ESR/CRP, pyuria/eosinophiluria
- tissue biopsy: demonstration of cholesterol crystal in occluded arterioles is the only definitive test for cholesterol embolism
- management is supportive

Henoch-Schonlein Purpura

- a.k.a anaphylactoid purpura
- small vessel vasculitis characterised by palpable purpura (usually over buttocks and lower extremities), arthralgia, gastrointestinal signs and symptoms and glomerulonephritis
- presumptive pathogenic mechanism for HSP is immune complex deposition (usually IgA)
- palpable purpura is seen in virtually all paediatric patients
- gastrointestinal involvement is characterised by colicky abdominal pain associated with nausea, vomiting, diarrhea or constipation frequently accompanied by passage of blood and mucus per rectum, bowel intussusception may occur
- diagnosis of HSP is based on clinical signs and symptoms
- skin biopsy : leukocytoclastic vasculitis
- excellent prognosis, 1-5% of children progress to ESRF
- treatment: prednisolone (1mg/kg) has been shown to be useful in decreasing tissue edema, arthralgia and abdominal discomfort
- patients with rapidly progressive glomerulonephritis have been anecdotally reported to be benefit from intensive plasma exchange combined with cytotoxic drugs

Familial hypocalciuric hypercalcemia

- autosomal dominant
- mutation in gene on long arm of chromosome 3 encoding for calcium ion sensing G protein coupled receptor in kidney and parathyroid gland
- characterised by lifelong asymptomatic hypercalcemia associated with a relative hypocalciuria and a tendency to hypermagnesemia
- most are misdiagnosed as hyperparathyrodisim, but difference is in FHH, urinary calcium excretion
is low
- commonest presentation is renal stone, and rarely acute pancreatitis
- PTH levels are normal or slightly raised and urinary calcium is low
- can be differentiated from hyperparathyroidism by the calcium creatinine ratio in blood and urine

Membranous glomerulonephritis

- characterised by subepithelial deposits of immune complexes in glomerular basement membrane
- typically seen in the over 40 age group with a male predominance of 2:1
- majority are idiopathic and manifest as nephrotic syndrome
- associations
  malignancy (non Hodgkin lymphoma, solid organ tumor)
  autoimmune (SLE, RA)
  infections (hepatitis B, malaria)
  drugs (penicillamine, gold, captopril)
- renal biopsy: thickened GBM and granular IgG and C3 on immunostaining
- 1/3 rapid decline, 1/3 responds to steroids and chlorambucil, 1/3 remit spontaneously
- treatment: low salt diet, fluid restriction, ACE inhibitor, steroids

Lupus nephritis

- Overt renal disease occurs in at least one thrid of SLE patients and of these, 25% reach ESRF within 10 years

Classification of lupus nephritis (International Society of Nephrology/Renal Pathological Society 2004)
Class I (Minimal mesangial)
- immune deposits but normal on light microscopy.
- asymptomatic

Class II (Mesangial proliferative)
- mesangial hypercellularity and matrix expansion
- mild renal disease

Class III (Focal)
- involving less than 50% of glomeruli with subdivisions for active or chronic lesions
- presents with hematuria and proteinuria

Class IV (Diffuse)
- involving more than 50% of glomeruli
- classified by the presence of segmental and global lesions as well as active and chronic lesions
- most common and most severe form
- progression to nephrotic syndrome, hypertension and renal insufficiency

Class V (membranous)
- good prognosis

Class VI (advanced sclerosing)
- more than 90% globally sclerosed glomeruli without residual activity
- progressive renal failure

- double stranded DNA levels correlate with lupus nephritis
- drug induced lupus rarely presents with nephritis

Management
- Type 1 requires no treatment
- Type II runs benign course, some require steroids
- Type III, IV, V - steroids and cyclophosphamide / MMF for induction ; azathioprine and MMF for maintenance therapy

Hemolytic uremic syndrome (HUS)

- characterised by MAHA (microangiopathic hemolytic anemia), thrombocytopenia, and acute kidney injury
- diarrhea associated HUS is associated with E.coli strain O157 (produces verocytotoxin which has A unit which is pathogenic and B unit which facilitate entry of A unit into endothelium)
- non diarrhea HUS is associated with factor H deficiency which is treated with plasmapheresis or plasma infusion
- sporadic cases of HUS is associated with pregnancy, SLE, scleroderma, malignant hypertension, metastatic cancer and HIV
- pneumococcus associated HUS is a rare complication of Strep.pneumoniae infection (antibodies to Thomsen antigen)

Medullary sponge kidney

- prevalence 1:1000 to 1:5000
- congenital disorder of kidney characterised by cystic dilatation of collecting tubules in one or both kidneys
- cyst formation is commonly associated with development of small calculi within the cyst
- 20% have associated hypercalciuria or renal tubular acidosis
- diagnosis is made via excretion urography, showing small calculi within papillary zone with surrounding increased density

Nephronophthisis

- autosomal recessive, deveops early in childhood
- thought to be due to dysfunction of cilia
- interstitial inflammation and tubular atrophy with later development of medullary cysts
- dominant features are polyuria, polydipsia and growth retardation

Cryoglobulinemia

- cryoglobulins are immunoglobulins and complement components which precipitate reversibly in cold, which leads to small vessel damage and deposition on the wall of small vessel result in generalised vasculitis
- presents with purpura, arthralgia, leg ulcers, Raynaud's phenomenon, polyneuropathy, asymptomatic proteinuria, microscopic hematuria or nephrotic syndrome
- skin most commonly involved (>90%) - reticulated skin pattern of microthrombosis and areas of gangrene
- management : plasma exchange, high dose steroid, chemotherapy (cyclophosphamide) and treatment of underlying conditions
- 3 types are recognised

Type I
- monoclonal antibody (usually IgM)
- associated with multiple myeloma and lymphoproliferative disorder
- presents with acrocyanosis, Raynaud's phenomenon, retinal hemorrhage

Type II & III (mixed cryoglobulinemia)
- IgM or IgA with rheumatoid factor activity binds to polyclonal IgG
- type II is monoclonal ; whereas type III is polyclonal
- presents with glomerulonephritis (more common in type II), vasculitic rash and Raynaud's
- they can activate the classical pathway of complement and cause consumption therefore low C4 with normal C3
- associations: Hepatitis B and C, HIV, CMV, malaria, EBV, malaria, autoimmune disorder
  * Meltzer's triad =  Purpura + Arthralgia + Myalgia *
     (Typically seen in polyclonal CG - hepatitis C)

Alport's syndrome

- combination of nephritis and sensorineural deafness
- X-linked
- autosomal recessive/dominant form cause renal disease without deafness or lenticonus
- males are affected more severely
- mutation of COL4A5 gene (80%), on X chromosome
- caused by abnormality in type IV collagen (alpha 5 chain)
- microsopic hematuria during first decade of life
- may present with acute macroscopic hematurie post URTI
- association: anterior lenticonus, retinopathy, posterior corneal dystrophy, bilateral dot fleck marks around fovea
- diagnosis is by renal biopsy

Acute tubular necrosis

- usually arises following an acute ischemia or nephrotoxic event
- characterised by 3 phases
  i) initiation phase: acute decrease in GFR with sudden rise in creatinine
  ii) maintenance phase: sustained marked reduction in GFR
  iii) recovery phase: tubular function gradually restored with concomittant reduction in creatinine
- pigmented 'muddy brown' granular cast are characteristic of ATN and depict sloughed tubular epithelial cells
- reduced urinary osmolality < 350mOsm/kg (reduced tubular function and reduced filtration rate)
- raised urinary sodium concentration > 40mmol/L (decreased tubular reabsorption of sodium)
- associated with accelerated hypertension, hypotension, diabetes, liver failure, eclampsia, aminoglycosides.

Renal tubular acidosis

Type I RTA (distal)
- defect in excretion of acid
- associated with hypergammaglobulinemia, amphotericin B, primary biliary cirrhosis and thyroiditis
- presents with hypokalemia, acidosis and low urinary ammonium production
- inability to lower urine pH below 5.3 despite systemic acidosis
- low urinary citrate and hypercalciuria, causing nephrocalcinosis, renal stone, rickets and osteomalacia (calcium loss and buffering of retained H+ in bone)
- diagnosis: acid load (oral ammonium chloride is given - failure to lower urine pH)
- treatment: oral sodium bicarbonate or citrate

Type II RTA (proximal)
- defect in absorption of bicarbonate
- Fanconi syndrome and osteomalacia occurs
- cardinal features are acidosis, hypokalemia and hypophosphatemia
- apperance of bicarbonate in urine
- urine can be acidified
- expired tetracycline use and Wilson disease is a cause
- diagnosis: IV sodium bicarbonate load (high fractional excretion of bicarbonate)
- treatment: high dose of bicarbonate

Type IV RTA (hyporeninemic hypoaldosteronism)
- commonest RTA
- occurs in diabetes and tubulointerstitial disease
- associated with chronic ingestion of NSAIDs
- cardinal feature is hyperkalemia
- fludrocortisone treatment is effective


Note: osteomalacia can occur in both type I and II
- type III RTA is a rare combination of type I and II

Wegener's granulomatosis

- granulomatous necrotizing vasculitis
- triad of
  i) upper airways (granuloma) - rhintis (first sign), epistaxis, sinusitis, saddle nose (perforated septum), otitis, mastoiditis
  ii) lungs (granuloma and vasculitis) - multiple pulmonary nodule (coin lesions), cavitating lesion with diffuse alveolar changes, presents with hemoptysis
  iii) renal (vasculitis)- segmental crescentric necrotizing glomerulonephritis
- c-ANCA (PR3) positive (highly sensitive and specific)
- treatment: IV methylprednisolone, cyclophosphamide





Poor prognostic indicators
- presence and severity of renal involvement
- elderly
- pulmonary hemorrhage
- poor response to therapy at 2 weeks
- high degree of sclerosed glomeruli/interstitial scarring on biopsy

IgA nephropathy (Berger's disease)

- commonest form of glomerulonephritis world wide
- focal and segmental proliferative glomerulonephritis with mesangial deposits of polymeric IgA
- associated with coeliac disease, cirrhosis and HIV infection
- IgA raised in 50% of cases
- tends to occur in children and young males, presents with asymptomatic microscopic hematuria or recurrent macroscopic hematuria following URTI/gastrointestinal viral infection (usually 1-2 days after URTI as opposed to PSGN which occur some time later) - synpharyngitic haematuria
- hypertension is associated with deteriorating renal function and thus worse prognosis
- prognosis usually good, but 25% risk of developing ESRF
- commonest primary glomerulonephritis leading to chronic renal failure
- treatment: steroid, ACE inhibitor and ARB

Mesangiocapillary glomerulonephritis (MCGN)

- Type I: associated with mesangial cell proliferation and mainly subendothelial immune complex deposition (tramline appearance). Associated with hepatitis B or C infection and reduced plasma C3, C4. Classical complement activation (reduced C4 levels)
  Type I more common than type II

- Type II: idiopathic or after measles infection. Characterised by mesangial cell proliferation with electrodense, linear intramembranous deposits that stain positive for C3. Presents with hematuria, proteinuria, nephrotic syndrome or renal failure.
   Immune complex deposition is predisposed to by C3 nephritic factor rise in MCGN type II, which stabilise C3bBb and activates the alternative complement pathway

Hereditary hypokalemic tubulopathies

Things to remember for Bartter's , Gitelman's & Liddle's syndrome

- all present with hypokalemia + metabolic alkalosis

- Liddle's syndrome is autosomal dominant and associated with hypertension while the other two are recessive and normotensive. It is caused by mutation of epithelial sodium channel, thus hypertension is very sensitive to diuretics which target on ENaC (amiloride, triamterene)

- Bartter's syndrome is associated with increased urine calcium, and juxtaglomerular apparatus hyperplasia, associated with renal stone and nephrocalcinosis. Secondary hyperaldosteronism is characteristic (plasma volume is low despite normal blood pressure, thus stimulate renin release)

- Gitelman's syndrome is associated with low urine calcium and hypomagnesemia. Treatment is potassium and magnesium supplements.

Cystinuria

- autosomal recessive
- defective tubular reabsorption and jejunal absorption of cysteine and dibasic amino acids (COAL - cysteine, ornithine, arginine, lysine)
- commonest cause of renal stone in children where a metabolic cause is identified
- presents with chronic backache, recurrent urinary stones
- cysteine is highly insoluble at acid pH and form radio-opaque calculi
- urine FEME: pathognomonic hexagonal crystal

- management: large fluid intake, alkalinisation of urine and penicillamine / tiopronin /captopril