Pathogenesis of Glomerulonephritis

PATHOGENESIS OF GLOMERULONEPHRITIS

ADETUNJI TA

OUTLINE

• INTRODUCTION• EPIDEMIOLOGY• RELEVANT ANATOMY• DEFINITION OF TERMS• CLASSIFICATION• PATHOGENESIS• HISTOLOGY• MANAGEMENT• CONCLUSION

INTRODUCTION

• GN can be defined as a spectrum of renal diseases

of varied etiology and clinical presentations that are

characterized by clinical and histological evidence of

glomerular damage.

•Note that despite the “itis” in GN, inflammation per se

may not feature in many GNs. Associated terms include:

•Glomerulonephritides

•Glomerulopathy

•Nephritis

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– The pathophysiology

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– The pathophysiology

INTRODUCTION

The term Glomerulonephritis and Glomerulopathy are

usually used interchangeably to denote glomerular injury,

although some authorities reserve the former term for injury

with evidence of inflammation such as leucocyte infiltration,

antibody deposition, and complement activation

•It encompasses a group of disorders with wide-ranging

clinical presentations,severity,causes and

immunopathogenetic mechanisms

•GN is an important cause of both acute and chronic

kidney Disease worldwide.

STRUCTURE OF THE KIDNEY

•The functioning unit of the kidney is the nephron

•Each kidney has about one million nephrons

•The number of nephrons is established during prenatal

development.

•After birth, no new nephron can develop and a lost

nephron cannot be replaced.

Gross Anatomy • KIDNEYS– Paired organ– Each weigh 120 – 200g

– Dimensions: 10 – 12 cm vertically, 5 -7 cm transversely, and 3 cm anteroposteriorly.

– The outer surface can be divided into anterior side, dorsal side, upper pole and lower pole

– The lateral surface is convex.

– The medial surface is concave, deeply grooved (renal sinus) and forms the renal hilum

– The ureter/renal pelvis, renal artery, renal vein, lymphatic vessels and nerves enter or exit through the renal hilum the kidney.

GENERAL ARCHITECTURE OF THE KIDNEY

•Kidney

–Outer cortex

–Inner medulla

•Vasculature

–the arterial system

–Venous system

–the resistance vessels

•THE GLOMERULUS

•Structural characteristics of the

glomerular capillary wall

–the endothelial cell

–the glomerular visceral epithelial cell

–the mesangial cell

–the extracellular matrix: basement

membrane, (GBM’s and mesangial matrix)

•Filtration depends on

–Hydrostatic pressure difference

–Size of the molecule

–Charge on the molecule

ANATOMY

EPIDEMIOLOGY

•GN is recognized as the second commonest cause of

CKD worldwide.

•In developed countries, it is still the 3rd commonest

cause of ESRD in many countries.

•In developing countries, it ranks 2nd or 1st

•For every patient with clinically apparent GN receiving

medical care, an estimated additional 5 to 10 patients have

undiagnosed sub-clinical disease.

EPIDEMIOLOGY ... NIGERIA

•GN is more common in the male than in the female

population 1.4 : 1

•Peak incidence for AGN is usually October – January

( Etuk et al)

•Case average of 7.5/year calabar - to 14.5/year in

UPTH.

•GN is the commonest cause of CKD in Nigeria from

available reports

GLOSSARY OF DESCRIPTIVE TERMS

•All glomeruli

–Diffuse: Involving ≥ 50% of the glomeruli

–Focal: Involving <50% of glomeruli

•Individual glomerulus

–Global: if all or almost all of the glomerular tuft are

involved

–Segmental: if only part of the glomerulus is involved.


•Sclerosis refers to an increase in the amount of

homogenous non-fibrillar extracellular material of similar

composition to GBM and mesangial matrix.

•Fibrosis refers to deposition of collagen type I and III

and is more commonly a consequence of healing of

crescents or tubulointerstitial inflammation.


•Proliferative is used to describe an increase in glomerular cell

number, which can be either

–true proliferation of resident glomerular cells or

–glomerular hypercellularity caused by infiltration of

leucocytes.

•Proliferation of resident glomerular cells is classified as

– intracapillary or endocapillary when referring to

endothelial or mesangial cells and

–extracapillary when referring to cells in Bowman’s space.


•A crescent is a half-moon-shaped collection of cells in

Bowman’s space, usually composed of proliferating parietal

epithelial cells and infiltrating macrophages.

•Because crescentic GN is often associated with renal

failure that progresses rapidly over weeks to months, the

clinical term rapidly progressive GN and the pathologic

term crescentic GN are often used interchangeably.


•Sub-epithelial – Located between the glomerular

basement membrane and the podocytes.

•Intra-membranous – within the basement membrane

•Sub-endothelial - Between the glomerular basement

membrane and the endothelium

•Mesangial – within the mesangium

CLASSIFICATION ACCORDING TO AETIOLOGY

•Primary: idiopathic but usually immune mediated

•Secondary: there is a known cause

CLASSIFICATION ACCORDING TO CELLULAR RESPONSE/APPEARANCE OF

THE GLOMERULAR TUFT

•Non-proliferative

•Proliferative

CLASSIFICATION ACCORDING TO HISTOLOGIC PATTERN

•Focal segmental

•Diffuse

•MCD

•Membranous

•Menbranousproliferative

CLASSIFICATION OF ACCORDING TO DURATION OF DISEASE

•Acute GN refers to glomerular injury occurring over

days to weeks.

•Sub-acute or rapidly progressive GN refers to

glomerular injury occurring over weeks or a few months.

•Chronic GN refers to glomerular injury occurring over

months or years.

CLASSIFICATION BASED ON IMMUNOFLUORESCENCE

•Immune

•Pauci immune

GN….BASIC DIVISION

•Non- Proliferative

•Minimal change

•Membranous

•FSGS

•Diabetes

•Amyloidosis

•Proliferative

•Diffuse proliferative

•(crescents)

•Mesangiocapillary

•Focal and segmental

proliferative.

All these are Histological patterns and NOT a diagnosis

PATHOGENESIS OF GLOMERULAR INJURY

•Pathogenesis of glomerular injury involves a complex interplay between

•Genetic factors eg congenital Nephrotic syndrome

•Acquired: Immune and Non—immune Factors

Immune Mechanisms

–Cellular immunity

–Humoral immunity

–Complement system/cascade

–Coagulation cascade

–Soluble factors

Mechanisms of Glomerulonephritis

Cell-mediated immune mechanismsAntibody deposits

Compliment activation Influx of circulating leucocytes and cytokine and growth factor synthesis

GlomerulonephritisActivation of resident cellsChange in matrix

On-offswitch

Scarring Resolution

Persistant inflamation Exit of inflammatory molecules and leukocytes

Genetic factors Hemodynamic factors

PATHOPHYSIOLOGY.

PATHOPHYSIOLOGY….schematics

Genetic Factors

• Congenital Nephrotic Syndrome - Mutations in nephrin- Mutation in podocin- Mutation in alpha Actinin 4• Alport Syndrome• Thin basement membrane Disease

Immune Factors

•Central to the pathogenesis GN is inflammation which

is often immune mediated.

•Glomeruli have three properties that make them

vulnerable to immunological attack:

–they “filter” and trap immune complexes

–they contain immunologically competent cells capable

of processing antigen

–they have structures like the GBM and mesangial cells

which can act as “targets” for antibodies

Circulating Immune Complex

• In conditions such as - SLE- HBV Infection- Malaria P. Falciparum and Malariae- Syphillis- Strptococcal infection• Deposition of immune complexes in the glomerulus

which leads to complement activation, leucocytes recruitment, coagulation cascade activation and inflammation ensues

In-Situ Immune Complexes• Seen in Anti-GBM Ab GN• Ab directed to fixed antigens on the GBM• Ab may also react in situ with previously planted non-

glomerular antigens such as DNA, IgG, bacterial products• Ab deposition shows a linear pattern while planted antigens

induce a granular pattern of immunoglobulin deposition on immunoflorescence

• Ant-GBM can also cross react with alveolar basement membrane leading to simultaneous kidney/lung lesions as obtained in GoodPasture Syndrome.

• Α3 chain of type IV collagen is the target antigen in anti-GBM disease (Goodpasture’s syndrome

Cell mediated Immune GN

•Cell-mediated immune mechanisms

•A direct role of T cells in mediating proteinuria and

crescent formation been suggested

•T cells sensitized to endogenous or exogenous antigen

present in the glomeruli recruit macrophages, resulting in a

local delayed type hypersensitivity reaction.

•There maybe no ab or immune complex deposition and

and when present may not correlate with disease severity.

Mediators Of Immune Injury

•Main pathway of Ab-mediated injury is complement-leucocyte mediated

•Acute injury: Predominant infiltrating cells are neutrophils and monocytes

•Chronic injury:Predominant cells are monocytes/macrophages and T cells.

•The primary mechanism for attracting these cells is the secretion of chemokines and the expression of leucocyte adhesion molecules by local endothelial and resident cells;

•Local release of complement activation fragments (C5a) is very crucial(Chemotactic agent)

Soluble Factors

•Soluble factors play a role in the pathogenesis of glomerular

disease.

•Examples of soluble factors are; cytokines, chemokines,

growth factors vasoactive mediators, reactive oxygen

species, proteases, proteins in the coagulation cascade

•These factors

–promote recruitment and activation of inflammatory cells,

–activate resident glomerular cells,

–directly cause tissue injury,

–stimulate production of matrix proteins (which forms the

basis of scarring).

Non-immune Factors

• Podocyte Injury• Nephron Loss

- Any renal condition causing significant nephron destruction and reduced GFR

- Adaptive changes in the kidney such as hypertrophy to remain renal fxn occurs

- Associated maladaptive haemodynamic changes utimately perpertutes renal damage and a vicious cycle ensues

PATHOPHYSIOLOGY… minimal change dxs

VARIANT OF FSGS

PATHOPHYSIOLOGY…MEMBRANOUS NEPHROPATHY

PATHOPHYSIOLOGY… MEMBRANOPROLIFERATIVE

PATHOPHYSIOLOGY…. GOODPASTURE DISEASE

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).

HISTOLOGY ....MESANGIAL PROLIFERATIVE

Normal glomerulusMesangial proliferative

HISTOLOGY ....MESANGIAL PROLIFERATIVE

•Normal •Mesangial proliferative

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).

HISTOLOGY .... DIFFUSE

•Normal glomerulus Diffuse endocapillary hypercellularity:

post-streptococcal GN

HISTOLOGY ....MEMRANOUS NEPHROPATHY

HISTOLOGY ..... FOCAL SEGMENTAL GLOMERULOSCLEROSIS

HISTOLOGY... FOCAL SEGMENTAL GLOMERULOSCLEROSIS

HISTOLOGY... SCLEROSED GLOMERULAR TUFTS

PATHOGENESIS – CHRONIC PROGRESSIVE PHASE

•Renal damage in the chronic-progressive phase of GN

is mediated by non-immune mechanisms that develop as a

result of loss of filtering-surface with accompanying

increases in glomerular pressures in remaining nephrons.

•These features lead to glomerular sclerosis as well as

to chronic interstitial fibrosis, which is a consequence of

multiple injurious events including ischaemia, glomerular

cytokine release, and toxic effects of increased protein

filtration on tubules

MGT:HISTORY

•Family history of kidney disease and hearing difficulties

(Alport syndrome)

•Medication e.g NSAID’s ACEI, penicillamine, gold,

mercury in some skin lightening creams.

•Recent throat infection PSGN or Viral Wegener’s

granulomatosis, IgA.

•Cancer - Solid tumors, Hodgkin’s (minimal change) or

non Hodgkin’s (MPGN)

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,

CLINICAL FEATURES OF GN

CLINICAL FEATURES OF GN

• .

Useful Blood Tests in Investigations of Glomerular Disease

• FBC – High white cell count in vasculitis, infections.

• E &U,Cr – assesses severity of renal impairment

• Total serum protein, albumin – Low in those with nephrotic syndrome

• Immunoglobulins – High in vasculitis, SLE

• Complement

• Low C3, normal C4 in MPGN (type II) and sometimes SLE.

• high C3, C4 in systemic vasculitis

• Antiglomerular BM antibody – Goodpasture’s disease

• Anti-dsDNA antibodies – SLE

• C3 nephritic factor – MPGN (type II)

Investigations…• Urinalysis

• Urine Microscopy for cellular elements and casts

• 24 hr urinary protein estimation

• Creatinine clearance or estimated GFR

• Renal ultrasound

• HBsAg, anti-HCV, HIV

• ANCA (antineutrophil cytoplasmic antibodies)

• Renal Biopsy

– Light microscopy

– Electron microscopy

– Immunofluorescence

Treatment

•Control of blood pressure

–ACE inhibitors ± ARBs

–Other anti-hypertensives

•Blood pressure goal < 125 / 75 mm Hg if proteinuria is > 1 g /day and < 130 /

80mmHg if proteinuria is < 1 g / day.

•Corticosteroids

–Are effective in several types of GN owing to their ability to inhibit activity of the

transcription factor nuclear factor ĸB and consequently inhibit the proinflammatory effects of

cytokines known to promote glomerular inflammation actively, including interleukin 1β and

tumour necrosis factor α.

–Are useful in several types of GN

•Lipid lowering agents e.g. statins

TREATMENT

•Corticosteroids

•Inhibits activity of the transcription nuclear factors kB and

consequently inhibit the pro-inflammatory effects of cytokines, known

to promote glomerular inflammatory actively, including IL-Iβ and TNFα

•Immunosuppressive therapies – crescentic GN, proliferative GN,

FSGS, MCD, MN, IgAN with deteriorating renal function and

proteinuria.

•Plasmapheresis – removal of preformed antibodies from the

circulation – Goodpasture’s disease

TREATMENT

•Immunosuppressives e.g. cyclophosphamide,

azathioprine, chlorambucil, mycophenolate mofetil,

sirolimus

–Are of proven benefit in crescentic GN, proliferative

lupus nephritis, focal and segmental glomerulosclerosis,

minimal change disease, membranous nephropathy, and in

cases of IgA nephropathy with deteriorating renal function

and proteinuria.

Conclusion

• Glomerulonephritis refers to a spectrum of aetiopathogenesis and varied clinical presentations following glomerular damage

• Results from complex interplay of genetic, immunologic and environmental factors

• Histologic difference abound depending mostly on aetiology

• May result in Acute or Chronic kidney disease

• Leading cause of CKD worldwide, commonest Cause in Nigeria and Sub-Sahara Africa

• Management requires early recognition by meticulous hx taking, examination and appropriate investigation

• Some would require Steroid +/- Immunosuppressants

References

• Basic Pathology By Robins, 8th ed• Harrison’s Principles of Internal Medicine By Longo et al,

18th ed• WACP Revision Course, 2011• www.pubmed.gov

THANK YOU

Pathogenesis of Glomerulonephritis

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