Renal Manifestations of Systemic Disease

1. Renal Manifestations of Systemic Disease Angus Ritchie BPT Lecture Series 2012

2. Content • epidemiology, pathophysiology, clinical presentation, differential diagnosis, • investigations, detailed initial management, principles of ongoing management, potential complications of the disease and its management, • preventive strategies • Include SLE, vasculitis, sarcoidosis, obesity, diabetes, CCF, liver disease, dysproteinaemias, infectious diseases (HIV, syphilis, TB, hepatitis) • Not covered: • Diabetes, hypertension • Toxic nephropathy e.g. lead • Paraneoplastic nephropathies (excl dysproteinaemias)

3. Renal artery, vein Renal nerves Glomeruli Tubules Interstitium Medulla The basics

4. Markers of renal disease • Active urine sediment • UA blood, protein • Proteinuria (Nephrotic vs Non-nephrotic) • Urine A:Cr >3 • Urine P:Cr >30 • 24h urine protein >150mg • Dysmorphic RC>90% • Casts, crystals, cells • Elevated Cr • Elevated eGFR (MDRD→CKD-epi) • Abnormal imaging

5. Renal biopsy • US guided percutaneous • 1-2% major complication rate. • Tests • Light microscopy (formalin) • H&E, Trichrome, Silver • Immunofluorescence (fresh or IPEX) • IgG, IgM, IgA, kappa, lambda, C3, C4, C1q, c4D • Electron microscopy (glutaraldehyde) • Glomerular ultrastructure • Immune deposits

6. Staging of CKD

7. Major Renal Patterns • Isolated microscopic haematuria • Nephritic syndrome • Mixed nephrotic/nephritic patter • Pure nephrotic syndrome • Sub-nephrotic proteinuria • Tubulointerstitial nephritis

8. Nephrotic Proteinuria >3.5g/day Hypoalbuminaemia Oedema Hyperlipidaemia Nephritic Haematuria +/- red cell casts Proteinuria Hypertension Nephrotic v Nephritic

9. Lupus and the kidney • SLE with renal manifestations approx 50% • Lupus nephritis: 8-15% progression to ESKD • UA for all SLE patient every visit

10. Presentation Microscopic haematuria Proteinuria (any) Impaired renal function +/-SLE Renal tubular acidosis Hypertension RPGN DDx: AAV Cryoglobulinaemic GN Bacterial endocarditis Anti-GBM disease IgA disease Amyloidosis Presentation

11. Investigations Quantify proteinuria Renal biopsy Bloods ESR ANA Anti-dsDNA Anti-Sm C3/C4 Lupus nephritis

12. Lupus nephritis

13. Induction 3-6months Steroids AND Hydroxychloroquine AND Mycophenolate mofetil OR Cyclophosphamide IV v PO Rituximab - Membranous? IVIG, CyA, Maintenance up to 2y Steroids AND Hydroxychloroquine AND Mycophenolate OR Azathioprine Lupus nephritis management

14. Lupus nephritis supportive care • Control BP • ACE or ARB in particular • Cardiovascular risk factors • Bone health • Fertility

15. Monitoring & Prognosis • Monthly review • Monitor FBC, Cr, alb, eGFR, urine PCR, ESR (not CRP), C3, C4 and anti-dsDNA. • Predictors of relapse: • Rising anti-dsDNA • Causes of death • Infection • Cancer • Cardiovascular disease

16. Small-vessel, pauci-immune vasculitis Renal involvement 80-90% Often at diagnosis Age of onset 50-70s Can occur at any age Flu-like illness Progressive rise in Cr Sometime RPGN Haematuria Red cell casts Proteinuria Rarely nephrotic ANCA-associated vasculitis

17. DDx: HSP Anti-GBM disease Cryoglobulinaemic vasculitis Drug-induced vasculitis ANCA (MPO, PR3) ESR Anti-GBM C3, C4 EUC Higher Cr = worse prognosis FBC and diff Eosinophils Cryoglobulins Hep B, C serology Skin biopsy Blood cultures Investigations

18. Renal AAV biopsy • Necrotising • Crescents • Vasculitis • Tubulointerstitial nephritis • Granulomas • Eosinophils • IFTA • NEGATIVE IF (“pauci”)

19. Renal vasculitis

20. Induction 3-6m Pulse methylpred Cyclophosphamide IV better than oral Dose reduce in renal failure PJP prophylaxis Rituximab Emerging role (RAVE) PLEX Pulmonary haemorrhage Severe renal failure Benefit unknown “PEXIVAS” MMF? Success 90% @6m Maintenance up to 2y Low-dose oral pred PLUS Azathioprine OR Methotrexate Up to 50% relapse over next few years Renal AAV treatment

21. Monitoring & Prognosis • Neutrophil nadir, proteinuria, ANCA titre • Poor prognosis groups: • Severe renal failure • Older • Pulmonary haemorrhage • Biopsy: active necrosis, crescents, high IFTA • Delayed renal recovery possible • Cx: sepsis, CA bladder, cardiovascular disease

22. Renal manifestations of dysproteinaemias • Wide range of diseases • Cast nephropathy • Interstitial nephritis/fibrosis • Amyloidosis (GN, vessels) • Light chain deposition disease (GN) • ATN • Presentation “CRAB” • Proteinuria (most), often nephrotic • Renal impairment • Micro haematuria • Tubular dysfunction “Perfect storm” Hypercalcaemia Back pain CT with IV contrast NSAIDs  ARF

23. Renal dysproteinaemia Ix • FBC, EUC, albumin, CMP, urate, Igs, glucose • Proteinuria • urine BJP (light chains, missed on UA) • Serum EPG/IEPG • Serum free light chains • Abnormal ratio, • Ratio preserved in renal failure, HD. • Urine micro - casts, crystals • Renal imaging - rule out obstruction • Renal biopsy

24. Cast nephropathy • Commonest MIDD 30-50% • Presentation: renal failure, oliguria, proteinuria<3g, excess urine FLC, hypercalcaemia. • Histopath: • Eosinophilic/fractured casts with infiltrating PMN and“giant cells” • Interstitial inflammation, IFTA

25. Cast nephropathy • Primary care by Haematologist • Maintain good urine flow, control Ca, avoid nephrotoxins, urate lowering. • Urine alkalinsation - no proven benefit • Renal involved when dialysis required • High cut-off dialysis • Special dialyser with improved FLC clearance • Only effective with bortezomib-based chemo • Expensive and still not well established • Probably cost-effective through decreased dialysis

26. Renal sarcoidosis • Systemic granulomatous disorder • Extrarenal manifestations in 90% • Presentation • Renal impairment • Mild proteinuria <1g • Sterile pyuria • Hypercalcaemia • Classically acute interstitial nephritis • With granulomas (non-specific)

27. Renal sarcoidosis • DDx: drug-induced AIN, vasculitis, Sjogrens syndrome. Rarely TINU, malignant infiltration • Investigations: • FBC, EUC, LFT, CMP, urate, PTH • Urine PCR, MCS • CXR +/- CT • Renal US to exclude obstruction • Renal biopsy

28. Renal sarcoidosis • High-dose oral steroids • Slow taper over 12 months • Most return to normal or near-normal Cr

29. Hepatorenal syndromes • Reversible, functional renal failure • Associated with acute or chronic liver disease, hepatic failure and portal hypertension • Two types • Type 1 acute, rapid deterioration in renal function • Type 2 insidious onset, slowly progressive course • Hyponatraemia is predictive • Diagnosis of exclusion

30. Hepatorenal syndromes • Pathogenesis • Splanchnic vasodilatation • Intense systemic vasocontriction • Sympathetic activation • High RAAS activity

31. Hepatorenal syndromes • Defining features • Oliguria • Urine sodium <10mmo/L • Urine Osm > Plasma Osm • Serum sodium <130 mmol/L • Normal renal tract US • No sustained response to ceasing diuretics volume expansion • Exclude • Sepsis/shock • Nephrotoxic drugs • GI fluid losses • Haematuria/proteinuria

32. Hepatorenal syndromes • Prognosis depends on UNDERLYING DISEASE • Very poor prognosis without transplant • Type 1 median survival 2weeks • Management • List for Tx if a candidate • Bridging therapy: terlipressin, albumin 20-40g/d, TIPSS, MARS. • Dialysis very difficult

33. Cardiorenal syndromes • Reflect interaction between heart and kidneys • Five groups • Type 1 Acute HF with AKI • Type 2 Chonic HF with progressive CKD • Type 3 AKI causing acute HF • Type 4 Primary CKD contributing to chronic HF • Type 5 Acute or chronic systemic disorders causing cardiac and renal dysfunction

34. Cardiorenal syndromes • Pathophysiology • Arterial vasocontriction • Sympathetic activation • RAAS • Reduced renal arterial perfusion • Increased renal vein pressure, RV dysfunction

35. Prognosis and Rx • Reduced GFR associated with increased mortality. • Unclear which is chicken vs egg • No effective direct medical therapies • Focus on improving cardiac function • Fluid removal • With diuretics usually causes a rise in Cr • Ultrafiltration not proven to improve survival

36. Obesity • Associated with FSGS • Often comorbid diabetic nephropathy • Typically present with • Proteinuria • Hypertension • Renal impairment • Treatment • ACE/ARB • Weight loss

37. Renal syndromes assoc. w. infection

38. Diseases which recur post-transplant • Lupus nephritis • Vasculitis • Anti-GBM disease (Alports) • Hep B, C, HIV associated disease