CSIM2.71 THE PATIENT WITH PROTEINURIA AND HAEMATURIA THEMED WEEK 8: INVESTIGATION OF ABNORMAL RENAL FUNCTION

Glomerulonephritis Inflammatory condition of the glomeruli. Presented with Nephrotic or Nephritic Syndrome Common cause of ESRF in adults. Presentation: Asymptomatic, haematuria (could be microscopic), proteinuria, renal failure or HPT. Abnormal Glomerulus Altered glomerular basement membrane (GBM) frequently result in significant renal dysfunction. Crescent formation -> destruction of the affected glomerulus and is replaced by fibrous scaring Causes of PROTEINURIA Glomerular dx Tubulo-interstitial dx rarely causes significant proteinuria Physical exercise Orthostatic proteinuria Fever Heart failure Pregnancy Inflammation of the glomeruli and nephrons which leads to; Damage to the glomerulus restricts blood flow, leading to compensatory ^BP Damage to the filtration mechanism allows protein and blood to enter urine. Loss of the usual filtration capacity leads to acute kidney injury Looking for degree of damage and potential cause Imaging: CXR, renal ultrasound. Blood: FBC, U&E, LFT, ESR, CRP; immunoglobulins, electrophoresis, complement (C3, C4); autoantibodies (p555): ANA, ANCA, anti-dsDNA, anti-GBM; blood culture, ASOT, HBsAg, anti-HCV Urine: RBC casts, MC&S, Bence Jones protein, ACR (see p286).

PresentationDiagnosisTreatmentPrognosis

IgA Nephropathy altered regulation of IgA ^IgA possibly due to infection, which forms immune complexes and deposits in mesangial cells. Common cause of GN in adults Young man (20-30 yo), Asians and Caucasians with episodic macroscopic haematuria, recovery is often rapid between attacksMesangial proliferation, immunofluorescence (IF) shows deposits of IgA and C3Control BP with ACEi, immunosuppression may slow decline of renal function.~20% -> ESRF. POOR prognosis: Male, ^BP, proteinuria or renal failure at presentation.

Henoch-Schonlein Purpura (HSP)Systemic IgA nephropathy, causing a small vessel vasculitis. purpuric rash on extensor surfaces Arthralgias Purpura Abdominal pain, GI bleeding Hematuria + IF for IgA and C3 in skin or renal biopsy.same as IgA nephropathy~15% -> ESRF. If both nephritic and nephrotic 50% -> ESRF

Systemic lupus erythematous (SLE)

Cough, chest pain, nasal congestion Maculopapular rash over her chest Haematuria, proteinuria, ~1/3 SLE have renal disease with vascular, glomerular and tubulointerstitial damage.

Anti-glomerular basement membrane (GBM)A.k.a. Goodpastures disease caused by auto-antibodies to type IV collagen an essential component of the GBM Pulmonary haemorrhage Haematuria/nephiritc syndrome AKI may occur within days of onset of symptoms Malaise, fatigue, anorexia, weight loss, arthralgias, myalgiasA/b develop against 3 chain type IV collagen in GBM. Linear deposition of IgG along GBMA/b detected by ELISAANCA capillary loop staining with IgG and C3 and extensive crescent formationPlasma exchange, steroids,CyclophosphamideRelapse are rare. Prognosis is poor if dialysis-dependent presentation.

Post-streptococcal Strep. Ag is deposited on the glomerulus causing a host rxn and immune complex form. Occurs 1-12 wks after a sore throat or skin infection Nephritic syndrome Urinalysis Inflammation rxn affecting mesangial and endothelial cells IF: IgG and C3 deposits ^ASOT ^C3Complication Severe HPT, renal failure, primary disease (SLE)

Rapidly progressiveMost aggressive GN. Could cause ESRF over days. AKI +- systemic features (fever, myalgia, weight loss, haemoptysis) Pulmonary haemorrhage is the commonest cause of death ANCA +ve patientsAggressive immunosupresion with high-dose IV steroids and cyclophophamide +- plasma exchange 5 year survival 80%

Nephrotic syndrome 1. Definition: the renal excretion of more than 3.5g of protein during a 24 hour period2. Assessed by the collection of a cumulative 24h urine specimen. 3. As a result of abnormalities of the basement membrane, large amounts of plasma proteins are filtered into the glomerular ultrafiltrate4. Not associated with significant glomerular inflammation and red blood cell casts or other signs of glomerular inflammation are present5. The loss of nephrotic quantities of proteins for prolonged periods can result in hypoproteinamia6. Peripheral oedema because of loss of plasma oncotic pressureCriteria

PROTEINURIA (> 3.5 g/day/1.73 m2)OEDEMA

Structural damage to the glomerular basement membrane leads to an increase in the size and number of pores -> allow more and larger molecules. Fixed negatively charged components are present in the glomerular capillary wall, which repel negatively charged protein molecules. Reduction of this fixed charge occurs in glomerular disease and appears to be a key factor in the genesis of heavy proteinuria. Expansion of the interstitial compartment is secondary to the accumulation of sodium in the extracellular compartment. This is due to an imbalance between oral (or parenteral) sodium intake and urinary sodium output, as well as alterations of fluid transfer across capillary walls.

HYPOALBUMINAEMIA (< 3.5g/dL)HYPERLIPIDAEMIA (C > 250 mg/dL)

Urinary protein loss of the order 3.5g daily or more in adult required to cause hypoalbuminaemia Increased of catabolism of reabsorbed albumin in the proximal tubules though actual albumin synthesis is increased. Hyperlipidaemia is the consequence of increased synthesis of lipoproteins in the liver, abnormal transport of circulating lipid particles, and decreased catabolism. HypoA stimulates protein synthesis in the liver. Protein synthesis, lipid synthesis.

Nephrotic syndrome is NOT a diagnosis. Therefore, the underlying cause should always be sought.Presentation THEMED WEEK 8: INVESTIGATION OF ABNORMAL RENAL FUNCTIONi. ii. Facial oedema iii. Peripheral oedemaiv. Pleural effusion v. Ascites vi. Genital and sacral oedema

Histological patterns of NS; Minimal change, membranous nephropathy 1. Attributed to minimal change, membranous nephropathy. Consequence rather than cause of nephrotic syndrome. Membranous nephropathy (common cause, 20-30% in adult)1. 75% are primary or idiopathic form but can be associated to 2 to; Malignancy (e.g. carcinoma of lung, colon, stomach, breast and lymphoma) drugs (penicillamine, gold, NSAIDs, probenecid, mercury, captopril), autoimmune disease (e.g. SLE, thyroiditis), Chronic infection (e.g. hepatitis B, hepatitis C, schistosomiasis, Plasmodium malariae), SLE2. At all stages, IF shows the presence of diffusely thickened GBM of IgG and C3 3. COMMON: Adults, males4. Asymptomatic proteinuria or frank nephrotic syndrome. 5. May present with macroscopic haematuria, hypertension and/or renal impairment6. POOR PROGNOSIS: HPT and higher degree of renal impairment 7. 40% develop CKD8. GOOD PROGNOSIS-> Younger, females, and asymptomatic proteinuria of modest degree 9. 3 stages Early: deposits are small can be missed on LM. EM reveals small electron-dense deposits in the sub-epithelial aspects of the capillary walls Intermediate: deposits are encircled by basement membrane => appearance of spikes of basement membrane perpendicular to the basement membrane on silver staining Late: uniform thickening of the capillary basement membraneMinimal change disease 1. PAEDS: common cause, MALE good prognosis. X leads to CKD, facial oedema 2. ADULT: asso. Idiopathic With drugs (NSAIDs, lithium, antibiotics ( rifampicin, ampicillin, cephalosporins) , Hodgkins Lymphoma 3. Glomeruli appear normal on light microscopy but on EM, fusion of podocytes could be seen4. Tx: high dose corticosteroid therapy with prednisolone 60 mg/m2 daily (up to a maximum of 80 mg/day) for a maximum of 46 weeks followed by 40 mg/m2 every other day for a further 46 weeks corrects the urinary protein leak in more than 95% of children5. Two-thirds children have relapse and further courses of corticosteroids are required. 6. One-third of these children regularly relapse on steroid withdrawal, so that cyclophosphamide should be added after repeat induction with steroids. A course of cyclophosphamide 1.52.0 mg/kg daily is given for 812 weeks with concomitant prednisolone 7.515 mg/day.Mesangiocapillary GN1. Immune complex (IC) Driven by circulating immune complexes, which deposit in the kidney and activate complement via the classical pathway. An underlying cause can be found in most cases, eg Hep C, SLE and monoclonal gammopathies. 2. Complement mediated Less common and involves persistent activation of the alternative complement pathway3. BIOPSY: mesangial and endocapillary proliferation, a thickened capillary basement membrane, double contouring (tramline) of the capillary walls. IF can show Ig staining, complement staining or light chains depending on cause. EM shows electron dense deposits. Focal segmental glomerulosclerosis (FSGS)1. May be 1 or 2 (VUR, IgA nephropathy, Alports syndrome, vasculitis, sickle-cell disease)2. Presentation: nephrotic syndrome or proteinuria. ~50% have impaired renal function. 3. BIOPSY: scarring of the glomeruli at certain segments (focal sclerosis). IF: IgM and C3 deposits at affected area. 4. Tx: corticosteroid. Resistant: cyclosphamide or ciclosporin5. Untreated most progress ESRFComplication A. DVTa. Hypercoagulable state due to urinary losses of anti-thrombin and thrombocytosisb. Exacerbated by steroid therapy c. Increased synthesis of clotting factorsd. Increased blood viscosity from the raised haematocrit e. This is usually arterial and may affect the brain, limbs, and splanchnic circulation. B. Pulmonary infection, Sepsis a. Serum: IgG, complement, T cell function b. Steroid: immunosuppressant toxicityC. Accelerated atherosclerosis. Lipid abnormalities D. Hypovolaemia E. Acute renal failure (rare)Investigation

Diagnostic 1. Proteinuria +1> on 2/3 dipstick2. P:C (> 200mg/mmol) (early morning)3. Serum lipid4. C3 level (sensitive n specific if other than MCD)5. BPFurther investigation6. 1. Full blood count: HCT, WBC2. Renal profile: normal in MCD U+Es; Creatinine3. Serum albumin: