Renal Manifestations of Systemic Disease

Angus RitchieBPT Lecture Series 2012

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)

The basics

• Renal artery, vein• Renal nerves• Glomeruli• Tubules• Interstitium• Medulla

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

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

Staging of CKD

Major Renal Patterns

• Isolated microscopic haematuria• Nephritic syndrome• Mixed nephrotic/nephritic patter • Pure nephrotic syndrome• Sub-nephrotic proteinuria• Tubulointerstitial nephritis

Nephrotic v Nephritic

• Nephrotic– Proteinuria >3.5g/day– Hypoalbuminaemia– Oedema– Hyperlipidaemia

• Nephritic– Haematuria– +/- red cell casts– Proteinuria– Hypertension

Lupus and the kidney

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

Presentation

• 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

Lupus nephritis

• Investigations– Quantify proteinuria– Renal biopsy– Bloods

• ESR• ANA• Anti-dsDNA• Anti-Sm • C3/C4

Class Description

I Normal by light

II Pure mesangial alterations

III Focal segmental GN

IV Diffusve proliferative GN

V Diffuse membranous GN

VI Advanced sclerosing

Lupus nephritis

Lupus nephritis managementInduction 3-6months

Steroids AND

Hydroxychloroquine AND

Mycophenolate mofetilOR

Cyclophosphamide IV v PO

Rituximab - Membranous?IVIG, CyA,

Maintenance up to 2ySteroids

AND Hydroxychloroquine

ANDMycophenolate

ORAzathioprine

Lupus nephritis supportive care

• Control BP– ACE or ARB in particular

• Cardiovascular risk factors• Bone health• Fertility

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

ANCA-associated vasculitis

• 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

Investigations

• 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

Renal AAV biopsy

• Necrotising• Crescents• Vasculitis• Tubulointerstitial nephritis

– Granulomas– Eosinophils– IFTA

• NEGATIVE IF (“pauci”)

Renal vasculitis

Renal AAV treatment• 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

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

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

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

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

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

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)

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

Renal sarcoidosis

• High-dose oral steroids– Slow taper over 12 months

• Most return to normal or near-normal Cr

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

Hepatorenal syndromes

• Pathogenesis– Splanchnic vasodilatation– Intense systemic vasocontriction– Sympathetic activation– High RAAS activity

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

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

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

Cardiorenal syndromes

• Pathophysiology– Arterial vasocontriction

• Sympathetic activation• RAAS

– Reduced renal arterial perfusion– Increased renal vein pressure, RV dysfunction

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

Obesity

• Associated with FSGS• Often comorbid diabetic nephropathy• Typically present with

– Proteinuria – Hypertension– Renal impairment

• Treatment– ACE/ARB– Weight loss

Renal syndromes assoc. w. infectionInfection Presentation Syndrome

TyphoidMalaria

MicrohaemProteinuria (non-nephrotic)

Mesangioproliferative GN

Endocarditis, PIGN, Pneumococcus

Renal failure, HT, proteinuria, microhaematuria, oedema

Diffuse, proliferative GN

Hep C, Schisto Malaria

ProteinuriaImpaired GFR

Membranoproliferative GN +/- cryoglobulins

Hep B, Syphilis Nephrotic Membranous GN

HIV, Parvo B19 Nephrotic, reduced GFR FSGS

Hep B, HIV, PIGN HT, reduced GFR, microhaem Vasculitis

Leprosy, Schisto Nephrotic syndrome Amyloidosis

E. coli 0157:H7Shigella

ARF, thrombocytopaenia, haemolytic anaemia

HUS/TTP

EBV, Lepto, Legionella, TB

Renal failure, microhaem, Proteinuria <1g

Interstitial nephritis

Diseases which recur post-transplant

• Lupus nephritis• Vasculitis• Anti-GBM disease (Alports)• Hep B, C, HIV associated disease