1 Glomerulonephritis Cherelle Fitzclarence August 2009.

1

Glomerulonephritis

Cherelle Fitzclarence

August 2009

2

Plan

General over view Bit of revision re anatomy

3

Glomerulonephritis

Nephros – 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

4

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.

5 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.

6 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.

7

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.

8

Glomerular disease

Primary – confined to the kidney

Secondary – due to a systemic disease

9

Glomerular injury

Impairment 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

11

Anatomy of Kidney

Note the positions of

Glomerulus

Loop of Henle

PCT, DCT, CT

Cortex, Medulla, Pelvis.

MD consult

12

JGA

↓GFR Renin

Angiotensin

Blood Pressure

MD consult

13

Ultrastructure – Glom. capillary

MD consult

14

Capillary SpaceCapillary Space

EndotheliumEndothelium

Urinary SpaceUrinary Space

GBMGBM

PodocytePodocyte

Filtration Membrane – Electron Micro.

MD consult

15

Possible Clinical Manifestations

Proteinuria – asymptomatic Haematuria – asymptomatic Hypertension Nephrotic syndrome Nephritic syndrome Acute renal failure Rapidly progressive renal failure End stage renal failure

16

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)

17

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.

18

Diagnosis

Look for clues– History

Haematuria Proteinuria Azotemia

azote – nitrogenA – withoutZoe – life“The gas does not support life”

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

McCarthy ET, November 2008

19

Diagnosis

Can 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

20

Clinical patterns

Patients 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

21

22

Urinary patterns

3 different patterns– Focal nephritic– Diffuse nephritic– Nephrotic

23

Urinary patterns

Focal 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)

24

Urinary Patterns

Diffuse 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

25

Urinary Patterns

Nephrotic– 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

26

Non specific nature of histologic patterns

Membranous 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)

27

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

28

Pattern DiagnosisDiffuse GN

Post 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)

29

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

30

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

31

General Workup ? Glomerular disease

History 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)

32


Physical 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,

33


Laboratory work– UECB– LFT– BSL– FBC– Urine microscopy and culture– ACR– Serum and urine protein electrophoresis– Renal ultrasound

34


Laboratory 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

35

Case 1

16 year old male

Presents with headache, malaise, anorexia swollen legs. Not peeing much. Thinks he might have put on some weight, belt is bit tight

History – nasty cold with a really sore throat 2-3 weeks ago otherwise has been well. Took a while to get better from the URTI

36

Pre urinalysis

37

Case 1

Examination: Inspection – bit pale, puffy face, oedematous

legs Palpation – oedema pitting to mid thigh, nil

else to find Percussion – nil to find Auscultation – systolic flow murmur, nil else

38

Case 1

U/A – large blood, 4+ protein, large leucocytes

Microscopy – >100 red cells, >100 white cells, red and white cell casts

39

Case 1

Differential Dx at this point?– Post infectious GN

Pathogenesis is an immune reaction to certain pathogens, in this instance probably group A, ß haemolytic strep (endostreptosin and pyrogenic exotoxin B)

Throat cultures are usually negative by the time pt presents with GN but ASOT, antiDNAse B should be high along with low complements

40

Case 1

Management– Should get better over 2-3 weeks– Many cases do not present as asymptomatic– Supportive – fluid restriction, sodium restriction, diuretics to help control

hypertension– Modest protein restriction if the patient has azotemia– If pt not improving in a couple of weeks then consider biopsy– Biopsy will show, immune complex deposition in the capillary walls

(immunofluorescence), irregular subepithelial deposits along the capillary loops (EM)

– Steroids are not generally indicated but are used in patients who have renal failure or if the biopsy reveals crescents (proliferation of extraglomerular cells within Bowman’s capsule) which makes for a more guarded prognosis

– Consult Nephrologist

41

Case 1

Children usually do well Adults less like to have full recovery Acute GN follows other infections

– Bacterial sepsis, acute or subacute bacterial endocarditis, visceral abscess, infected ventriculoperitoneal shunt, osteomyelitis

– Treatment is aimed at eradicating the primary disease

42

IgA Nephropathy – Buerger’s Disease

Most 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

43


Slowly 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

44


Management– 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

45

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

46

RPGN – eg Goodpasture’s

Autoimmune 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

47

Goodpastures

48


Classic – 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

49


Treatment– 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)

50

Nephrotic Syndrome

Can 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

51

Nephrotic Syndrome eg Minimal Change Disease

Other 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

52


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)

53


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

54

Nephrotic Syndrome eg FSGN

Most 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)

55

Nephrotic Syndrome eg FSGN

Diagnosis – 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

56

Nephrotic Syndrome eg Membranous Nephropathy

Most 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

57

Nephrotic Syndrome eg Membranous Nephropathy

Diagnosis 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

58

Nephrotic Syndrome eg Membranoproliferative Glomerulonephritis

Idiopathic 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

59

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

60

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

61

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

62

Conclusions

Take 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

63

Acknowledgements

Handbook of nephrology…..Wilcox et al Up to date MD Consult

1 Glomerulonephritis Cherelle Fitzclarence August 2009.

Documents