GLOMERULONEPHRITISAMBER Z JAFFERIEMERGENCY DEPARTMENT SIH

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PLANGeneral over view

Little revision anatomy

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GLOMERULONEPHRITISNephros – kidney

-itis – inflammation of

Glomus – small round ball or knot

Pathos – suffering or disease

-osis – diseased condition

Glomerulonephritis – inflammation of the glomeruli

Glomerulopathy – disease of the glomeruli

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Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows). Courtesy of Helmut G Rennke.

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Light micrograph in membranoproliferative glomerulonephritis showing a lobular appearance of the glomerular tuft with focal areas of increased glomerular cellularity (large arrows), mesangial expansion (*), narrowing of the capillary lumens, and diffuse thickening of the glomerular capillary walls (small arrows). Courtesy of Helmut Rennke, MD.

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Electron micrograph of a normal glomerular capillary loop showing the fenestrated endothelial cell (Endo), the glomerular basement membrane (GBM), and the epithelial cells with its interdigitating foot processes (arrow). The GBM is thin and no electron dense deposits are present. Two normal platelets are seen in the capillary lumen. Courtesy of Helmut Rennke, MD.

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Electron micrograph in dense deposit disease (DDD) showing dense, ribbon-like appearance of subendothelial and intramembranous material (arrow) and narrowing of the capillary lumen due to proliferation of cells (double arrow). Courtesy of Helmut Rennke, MD.

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GLOMERULAR DISEASEPrimary – confined to the kidney

Secondary – due to a systemic disease

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GLOMERULAR INJURYImpairment of selective filtering properties of the kidney leading to a decreased GFR

Molecules normally not filtered such as constituents of the blood, pass into the urine and are excreted

10 MD consult

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Anatomy of Kidney

Note the positions of

Glomerulus

Loop of Henle

PCT, DCT, CT

Cortex, Medulla, Pelvis.

MD consult

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JGA

↓GFR Renin

Angiotensin

Blood Pressure

MD consult

ULTRASTRUCTURE – GLOM. CAPILLARY

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POSSIBLE CLINICAL MANIFESTATIONSProteinuria – asymptomatic

Haematuria – asymptomatic

Hypertension

Nephrotic syndrome

Nephritic syndrome

Acute renal failure

Rapidly progressive renal failure

End stage renal failure

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GLOMERULONEPHRITIS

Presence of glomerular disease as opposed to tubulointersititial or vascular disease is suspected from history

Haematuria (especially dysmorphic red cells)

Red cell casts

Lipiduria (glomerular permeability must be increased to allow the filtration of large lipoproteins)

Proteinuria (may be in nephrotic range of >3.5 g/24hours)

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Phase contrast microscopy showing dysmorphic red cells in a patient with glomerular bleeding. Acanthocytes can be recognized as ring forms with vesicle-shaped protrusions (arrows). Courtesy of Hans Köhler, MD.

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DIAGNOSISLook for clues

• History• Haematuria• Proteinuria• Azotemia

• Azote – nitrogen • A – without • Zoe – life • “The gas does not support life”

(French chemists Gayton de Morveau (1737-1816) and Antoine Lavoisier (1743-1794) )

McCarthy ET, November 2008

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DIAGNOSISCan be difficult to distinguish between Glomerular disease and tubulo-interstitial disease

Tubular disease does not directly increase protein excretion but nephron loss due to the disease can have the same end result

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CLINICAL PATTERNSPatients age and characteristics of the urine sediment can allow narrowing of the differential diagnosis options prior to biopsy

‘URINE IS THE LIQUID BIOPSY OF THE KIDNEY’ Walter Piering MD – Prof Med Wisconsin

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URINARY PATTERNS3 different patterns

• Focal nephritic• Diffuse nephritic• Nephrotic

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URINARY PATTERNSFocal nephritic

• Associated with inflammatory to less than half of the glomeruli on light microscopy

• Red cells – often dysmorphic• Occasional red cell casts• Mild proteinuria (<1.5g/day)

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URINARY PATTERNSDiffuse nephritic

• Damage to all or almost all of the glomeruli• Similar to focal disease but may also have heavy

proteinuria (even nephrotic range), oedema, hypertension and/or renal insufficiency

• - ‘full house’ urinary sediment – red cells, white cells, red cell casts, white cell casts, hyaline casts

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URINARY PATTERNSNephrotic

• Heavy proteinuria• Lipiduria – refractile fat bodies that look like a maltese

cross under polarised light• Few cells• Few casts – but those present are hyaline and granular

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NON SPECIFIC NATURE OF HISTOLOGIC PATTERNSMembranous GN – usually Immune complex disease (infective endocarditis, SLE, Hepatitis C)

Membranous nephropathy – drugs (gold, penicillamine), SLE, Hepatitis B, malignancy

Focal glomerulosclerosis can be primary ( minimal change), or secondary (intraglomerular hypertension, or healing previous glomerular injury)

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PATTERN DIAGNOSISFOCAL GN

<15 years – mild post infectious GN, IgA nephropathy, thin basement membrane disease, hereditary nephritis, Henoch Schonlein Purpura, mesangial proliferative GN

15-40 years – IgA nephropathy, thin basement membrane disease, lupus hereditary nephritis, mesangial proliferative GN

>40 years – IgA nephropathy

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PATTERN DIAGNOSISDIFFUSE GNPost infectious GN, lupus GN, membranoproliferative GN, mixed cryoglobulinaemia

Often associated with decreased complement

Classic findings • PSGN (anti strep antibodies)• Lupus nephritis (ANA)• Anti-GBM disease (anti GBM Abs) • Mixed cryoglobulinaemia (circulating cryoglobulins)• Wegener's granulomatosis (anti neutrophil cytoplasmic

abs)

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PATTERN DIAGNOSISDIFFUSE GN<15 years – Post infectious GN, membranoproliferative GN

15-40 years – Post infectious GN, rapidly progressive GN, fibrillary GN, membranoproliferative GN

>40years – rapidly progressive GN, vasculitis, fibrillary glomerulonephritis

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PATTERN DIAGNOSISNEPHROTIC SYNDROME<15 years – minimal change disease, focal glomerulosclerosis, mesangial proliferative GN

15-40 years – focal glomerulosclerosis, minimal change disease, membranous nephropathy including lupus, diabetic nephropathy, preeclampsia, post infectious GN

>40 years – focal glomerulosclerosis, membranous nephropathy, diabetic nephropathy, minimal change disease, IgA nephropathy, primary amyloidosis or related disorder – light chain deposition disease (up to 20% of pts over 60), benign nephrosclerosis, post infectious GN

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GENERAL WORKUP ? GLOMERULAR DISEASEHistory

• Family history kidney disease and hearing trouble (Alport’s syndrome)

• Medications that can damage the kidney (NSAID’s, ACEI, penicillamine, gold, mercury in some skin lightening creams)

• Recent throat infection - ? Strep- PSGN or viral – Wegener's granulomatosis, IgA

• Cancer – solid tumours, Hodgkin’s (minimal change) or non Hodgkin’s (MPGN)

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GENERAL WORKUP ? GLOMERULAR DISEASEPhysical Examination

• Inspection – appearance, colour, pitting oedema, xanthelasma, alopecia, facial rash, purpura, clubbing, livedo reticularis

• Palpation – pulse, hepatomegaly, palpable kidneys, splenomegaly, palapable bladder

• Percussion – hepatomegaly, splenomegaly• Auscultation – renal artery bruits, other bruits, cardiac

lesions, hypertension,

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GENERAL WORKUP ? GLOMERULAR DISEASELaboratory work

• UECB• LFT• BSL• FBC• Urine microscopy and culture• ACR• Serum and urine protein electrophoresis• Renal ultrasound

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GENERAL WORKUP ? GLOMERULAR DISEASELaboratory work

• Specific serology• For a nephrotic type picture

• HIV, HCV, HBV, ANA, serum cryoglobulins, anti DNA ab, complements

• For a nephritic type picture• Blood cultures, ASOT, AntiDNAse B, ANA, Anti DNA ab,

anti GBM ab, anti neutrophil cytoplasmic ab, complements

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Pre urinalysis

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IGA NEPHROPATHY – BUERGER’S DISEASEMost common cause of GN in Asia but uncommon in Sth America or Africa

15-40% of all biopsy proven GN

Male > Females

2nd-3rd decade

Most commonly asymptomatic with serendipitous finding of haematuria and mild proteinuria

Another classic presentation is macroscopic haematuria in conjunction with a viral infection

Renal function is usually normal but occasionally a patient will present with acute renal failure due to acute tubular necrosis secondary to the gross haematuria

Biopsy – mild to moderate mesangial cell proliferation, IgA deposits in the mesangium on immunofluorescence, often with C3 deposition also

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IGA NEPHROPATHY – BUERGER’S DISEASESlowly progressive

By 20 years, 50% have end stage kidney disease

Worse prognosis if >1g/day proteinuria, hypertension, increased creatinine of glomerular fibrosis at biopsy, on presentation

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IGA NEPHROPATHY – BUERGER’S DISEASEManagement

• Aggressive control of blood pressure and proteinuria with ACEI’s or AR2B’s

• Corticosteroids +/- azathiprine – varied schools of thought• However if rapidly progressive GN with crescent

deposition treatment should be aggressive with high dose steroids and cyclophosphamide

• Consult the Nephrologist

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RAPIDLY PROGRESSIVE GN (PRGN)Medical emergency

‘full house’ nephritic urinary sediment

Immediate hospitalisation and biopsy

Crescentic GN – proliferation of cells outside the glomerulus, but within Bowman’s space

If IgG present in linear stain along the basement membrane – consistent with anti glomerular basement membrane antibiodies (AGBM ab’s) which is a marker of Goodpasture’s syndrome

Presence of a linear pattern or complement in a granular pattern on the capillary wall suggests an immune complex associated disease such as lupus, IgA nephropathy of PSGN

Absence of immune deposition suggests a vasculitic process such as Wegener’s granulomatosis or microscopic polyangiitis

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RPGN – EG GOODPASTURE’SAutoimmune

Commonly 2nd-3rd decade and second peak in 60+ age group

Some present with renal involvement (Goodpasture’s disease)

Some present with pulmonary haemorrhage and nephritis (Goodpasture’s syndrome)

Rarely some present with only pulmonary involvement

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GOODPASTURES

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RPGN – EG GOODPASTURE’SClassic – haemoptysis after upper respiratory infection and have nephritic urinary sediment

History of smoking or hydrocarbon exposure is common

CXR – pulmonary haemorrhage

Lab- iron deficiency anaemia and renal dysfunction, circulating anti-GBM antibodies

Kidney biopsy crescentic GN with linear staining IgG and C3 along the glomerular basement membrane

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RPGN – EG GOODPASTURE’STreatment

• High dose IV steroids (methyl pred 500mg daily for 3 days) followed by oral prednisolone and cyclophosphamide

• Plasma exchange every other day until anti-GBM Ab titire is negative

• Px guarded (if present with oliguria and elevated creatinine, or severe scarring – unlikely to recover renal function)

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NEPHROTIC SYNDROMECan be due to systemic or local renal disease

Diabetic nephropathy most common cause

Other common causes include amyloidosis (often secondary to multiple myeloma), light chain deposition disease, minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, membranoproliferative glomerulonephritis, fibrillary glomerulonephritis

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NEPHROTIC SYNDROME EG MINIMAL CHANGE DISEASEOther name lipoid nephrosis or nil disease

Most common cause of nephrotic syndrome in kids 2-12 years but also in adults

Onset often acute and precipitant my be beesting, viral infection, allergy or immunization

Association with Hodgkin’s lymphoma and other T cell malignancies

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NEPHROTIC SYNDROME EG MINIMAL CHANGE DISEASE

Clinical – dramatic weight gain, pitting oedema, normal blood pressure. Urine – proteinuria, hyaline casts, oval fat bodies. Usually no red cells. Normal renal function but sometimes failure secondary to severe hypoalbuminaemia or prerenal azotemia leading to volume contraction.

Children don’t need biopsy unless hypertensive or other complications

If biopsy done, EM fusion of podocytes (foot processes of glomerular visceral epithelial cells)

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NEPHROTIC SYNDROME EG MINIMAL CHANGE DISEASE

Treatment

• Oral corticosteroids – prednisolone 2mg/kg/day• Cyclophosphamide if relapsing diseas

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NEPHROTIC SYNDROME EG FSGNMost common cause of nephrotic syndrome in young adults

Classic nephrotic syndrome and a small amount of blood in the urine

Can occur in minimal change disease which becomes resistant to prednisolone

Can be secondary heroin use

Can be secondary to HIV infection

Associated with other diseases (morbid obesity, persistent reflux nephropathy, sickle cell disease , cyanotic congenital heart disease)

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NEPHROTIC SYNDROME EG FSGNDiagnosis – biopsy – light microscopic pattern of segmental or total sclerosis of glomerular tufts

Treatment – prednisolone 1mg/kg/day often for 6-8 months

Complete remission only in 50%

ACEI

Poor prognosticators – tubulointerstitial disease, increased creatinine, marked proteinuria

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NEPHROTIC SYNDROME EG MEMBRANOUS NEPHROPATHYMost common cause of nephrotic syndrome in 40-60 yo’s

Usually frank nephrotic syndrome, low grade microhaematuria, relatively preserved renal function

Some people asymptomatic

Others can lose 10-20g of protein a day and be quite sick

Associated with certain medications eg penicillamine, gold, captopril, NSAID’s, certain viral infections eg Hep B and HCV and malignancies

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NEPHROTIC SYNDROME EG MEMBRANOUS NEPHROPATHYDiagnosis is on kidney biopsy; glomeruli appear normocellular with thickening of the GBM, immune deposits on outer side of GBM

Mx – rule out secondary causes

Mx – supportive – ACEI/AR2B for proteinuria, statins for hypercholesterolaemia, prophylactic warfarin (if very low albumin markedly increased risk of venous thrombosis)

Prednisolone may be used

Some may not progress over 10 years, but marked proteinuria and increased creatinine – 40 % progress to ESKD

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NEPHROTIC SYNDROME EG MEMBRANOPROLIFERATIVE GLOMERULONEPHRITISIdiopathic if between 10-30 year

Between 35-60 years usually secondary to Hepatitis C

Clinical- hypertension, mild nephrotic syndrome, microhaematuria, relatively preserved renal function

Pts with HCV may have circulating cryoglobulins including triad of weakness, arthralgias and palpable purpura

In kids 2 forms

• MPGN 1 – circulating immune complexes passively trapped in glomeruli

• MPGN 2 – circulating IgG (nephritic factor) that activates complement via the alternative pathway

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NEPHROTIC SYNDROME EG MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

Diagnosis – serum complement (depressed), hepatitis serologies, biopsy – glomeruli are hypercellular, often lobular in appearance – more detailed changes.

Treatment – manage hypertension, ACEI/AR2B, salt restriction, diuretics, treat HCV with interferon

50% progress to ESKD

Tends to recur in a kidney transplant

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NEPHROTIC SYNDROME EG FIBRILLARY GLOMERULONEPHRITIS

Recently recognised – 40-60 years

Similar to MPGN but serum complement normal and microscopy of biopsy demonstrates fibrilllar deposist in the mesangium.

Prognosis guarded

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Diseases PSGN IgA Nephropathy MPGN RPGN

Age and Sex All ages, mean 7 years, 2:1 male

2:1 male, 15-35 yrs 6:1 male, 15-30 yrs Mean 51yrs, 2:1 male

Clinical Manifestations 90% 50% 90% 90%

Acute nephritic syndrome

Occasionally 50% Rare rare

Asymptomatic haematuria

10-20% Rare Rare 10-20%

Nephrotic syndrome 70% 30-50% Rare 25%

Hypertension 50% Rare 50% 60%

Acute renal failure Latent 1-3 weeks Follows viral infection Pul haemorrhage, iron def

none

Lab findings ASOT IgA +anti GBM membrane + ANCA

Positive streptozyme IgA in dermal caps

C3-C9 N C1 and C4

Immunogenetics HLA B12

Light microscopy Diffuse proliferation Focal proliferation Focal- diffuse crescentic Crescentic GN

Immunoflourescence Granular IgG and C3 Diffuse mesangial IgA Linear IgG and C3 No immune complexes

Electron microscopy Subepithelial humps Mesangial deposits No deposits No deposits

Prognosis 95% cure5% progress

Slow progression in 25-50 years

75% stabilise or improve if treated early

75% stabilise or improve if treated early

Treatment Supportive None established Plasman exchange, cyclosphosphamide, steroids

Pulsed steroid therpy

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CONCLUSIONSTake a history

Do a urine test

If haematuria and proteinuria - ?GN

Exclude secondary causes

Biosy is the definitive way to diagnose but some hints from history and

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ACKNOWLEDGEMENTSHandbook of nephrology…..Wilcox et al

Up to date

MD Consult