APPROACH TO PRIMARY GLOMERULONEPHRITIS

DR GAURAV KUMAR(JR2)DR PROF J.K.L.DAS UNIT

Basic definitions: Glomerulopathy: A set of disease affecting the

glomeruli of nephron. Glomerulitis:It accounts for inflammatory

conditions of glomerulus. Glomerulonephritis: Nephritis marked by

inflammation of glomerular capillaries.primary: In which the kidney is the only or

predominant organ involvedSecondary: Accompanying systemic diseases.

CONFIRMATION OF

GLOMERULONEPHRITIS

PRIMARY VARIETY

SECONDARY VARIETY

2 DEGREE FSGS

SUSPECT GLOMERULONEPHRITIS

----------------------------------------------------------------------------------------------------------------

D/D of glomerulonephritis to be kept when a patient presents with the following symptoms as a whole or rarely when alone:

Cola colored urine(1ml BLOOD in 1 l of urine)(haemoglobinuria /myoglobinuria difference???by Ammonium sulphate solubility test)

Change in urine output to range from anuria to polyuria

A newly onset of hypertension in patients or normotensive patients

From bipedal edema to generalized anasarca

It can present as Acute nephritic syndrome/Nephrotic/NephriticNephrotic/isolated hematuria or proteinuria.

Confirmation of diagnosis:Glomerular hematuria: >3 RBC/hpf or >5RBC/microlitre >5% RBC are Acanthocytes,providing a specificity of

95% and sensitivity although 50%. Accompanying RBC cast Accompanying albumin need to be 40% of total

protein to support it

Keeping in view we must rule out : Glomerulo vascular disorders Atheroembolic disease Diabetes glomerulosclerosis Basement membrane disorder Warfarin nephropathy

History,physical examination,U/A,urine culture

Microscopic hematuria(dipstick

+ve and rbc in urine)

non glomerul

ar

Suggestive of UTI

No UTI

Glomerular

Quantitate protein and GFR,BIOPS

Y

BIOPSY BASICS Iverson and Brun performed first renal biopsy in

1951.

Indications of renal biopsy:a.In context of glomerulonephritisb.Systemic diseases with kidney involvementc.Acute kidney diseased.Renal transplant patientse.Undiagnosed etiology

Performed with a kidney biopsy gun (preferably 16 G) under USG guidance while the patient is in prone position

Generally 10-15 glomeruli are optimal,although 6-10 are sufficient most of the time.

Biopsy is read in terms of glomerular ,tubular,vascular or pathology in interstitium.

Safety in pregnancy??(<30 weeks)+ In context of focal disease of Glomerulus,we

need to go to juxtamedullary glomeruli to see the earliest involvment .

Focal glomerular disesae

25

MGN Even 1

Transplant Minimum 7

Light microscopy 8-10

Glomerular Non glomerular/Urologic/Urothelial

1.URINE COLOR DARK RED,BROWN,COLA ,SMOKY

BRIGHT RED

2.CLOTS _ +

3.PROTEINURIA + _

4.RBC MORPHOLOGY DYSMORPHIC ISOMORPHIC

5.HTN + _

6.EDEMA + -

7.URINARY VOIDING SYMPTOMS

_ +

8.BACK PAIN + +

9.F/H + _

10.UPPER RESP TRACT SYMPTOMS,FEVER RASH

+ _

11.RFT DERRANGED GENERALLY NOT

• Glomerular Proteinuria:*Generally >2g/day *Selective index<10%*UPEP shows albumin fraction much greater than globulin fraction*Albumin/B2 microglobulin ratio>1000;1*Less conc. Of proteins like N acetyl Glucosamine,Lysozyme etc.

1.Primary GN

2.secondary GGN

2 DEGREE

FSGS

Glomerulonephritisclassification

Secondary causes of GN can be ruled out by: CBC,Hb1ac 24 hour urine protein Serum albumin LDH C3,c4 level SPEP,free light chain Assay Viral markers,tropical infections profile ANA,ANCA,RA factor,cryoglobulins,APLA ,ds-DNAetc Drugs

 

EPIDEMIOLOGY First described by Munk in 1913 as lipoid nephrosis. Accounts for 70-90% of Nephrotic syndrome below

10yrs 10-15% of adults and more propensity in age >60

yrs too,with more complications.

MINIMAL CHANGE DISEASE

• In children M:F-2:1 or 3;1,Adults?3. PATHOLOGY AND PATHOGENESIS:

Effacement of foot process of podocytes(specific????) with cytoskeleton clumping near BM.

EXTENT OF EFFACEMENT ~ DURATION OF ACTIVE NEPHROTIC SYNDROME THAN WITH

MAGNITUDE OF PROTEINURIA.

• Glomerular permiabilty factor-hemopexin/IL-13 modulated by T cells.

• Increased Ig E.• Charge selectivity more imp.

IMMUNOFLUORESCENCE-

• Low level mesangial staining for Ig M(Irregular Focal staining for Ig M and C3?)

CLINICAL FEATURES Classic presentation is nephrotic syndrome HTN(30 %children,50%in adults)

• Microscopic hematuria(20% children,33% adults)• Atopy and allergy symptoms in 30-40%• Decreased renal functions (5% in children,30% in

adults)

LAB FEATURES• Urinalysis• Complement levels• ESR• Coagulation profile• Lipid profile• Selectivity index<10%?• Serum Ig E levels

• TREATMENT• Prednisolone-60mg /m2 in children,1mg/kg body wt

(<80mg),treatment continued for 6 weeks after complete remission(0.2gm/24 hrs) by DIPSTICK test at home for consecutive 3 days.

• Post remission either alternate day therapy (to 40 mg /m2) or gradual tapering (???? needed )Acute adrenal suppression may lead to relapse

• Steroid dependence(2 weeks within or during treatment aftr remission is acheived)/frequent relapse(2 or more within 6 months)

Cyclophosphamide-2mg/kg for 8-12 weeks /alternate is cyclosporine/tacrolimus/MMF.

Steroid resistant(up to 12 WEEKS in children and 16 weeks in adults)• In children need to go for biopsy• In adults or in children if its MCD,a regimen of Calcineurin inhibitors

followed by MMF .

Ig A NEPHROPATHY

EPIDEMIOLOGY:

• Most common GN worldwide• Described by Berger and Hinglais in late 1960s• Male:female-2:1 to 6:1• 2 nd to 3rd decade• 30-40% to ESRD. GENETICS:

Genetic and Environmental factors both D allele mutation of ACE gene in Asians. 6th chromosome igan1 gene Galactosyl transferase gene ,sialyl transferase gene Selectin cluster gene

PATHOLOGY AND PATHOGENESIS:

Immuno. Microscopy-

• 100% stains for Ig A/50 % for Ig G/Less consipicious C3

• If C1q +Ig A+Ig G+C3---LUPUS???• More lambda chains (kappa chains in other)/light

chain deposition disease??-kappa predominant/renal amyloidosis have lambda predominant

Electron Microscopy- Mesangial deposits with mesangial matrix

expansion and hypercellularity. Light Microscopy- 37% have focal proliferative

glomerulonephritis,28% have DPGN Wide spread damage can present lupus like.

Pathogenesis: Abnormal sialyation of N-ACETYL GALACTOSAMINE stops conversion ie its replacement by galactose ,this mutation in Ig A leads to functioning as Antigen which binds to Ig G in serum and this circulating complex deposits in glomeruli through mesangial receptors(transferrin) Ig A1 can also bind to mesangium but it cant lead to proliferation

ENVIROMENTAL CROSS REACTING ANTIGEN??? CLINICAL FEATURES:(synpharyngitic presentation)• 40-50% -Macroscopic hematuria often associated dysuria• 10% cases-Acute renal insufficiency• 30%-Asymptomatic microscopic hematuria• 30% new onset proteinuria and HTN• May be nephrotic syndrome like presentation

Prognostic factors:• Sustained hypertension• Persistent proteinuria• Impaired RFT• Nephrotic like - all signifies Bad prognosis.• Episodic macroscopic hematuria have good prognosis than

microscopic????(EPIOSDIC AND SELF RESOLVING) TORONTO FORMULA???

MAP and proteinuria Four independent parameters:1. Mesangial hypercellularity-significant association with ESRD2. Endocapillary hypercellularity-More benefit of immunosuppressive3. Tubular atrophy4. Segmental glomerulosclerosis In IgA nephropathy there been a improved prognosis with moderate alcohol consumption and mild jaundice.

Laboratory finding:• Nephritic pres.• Complement levels,IgA/C3 ratio,C3 fragments• Serum Ig A levels(Increased in 50%,importance???)

Treatment Recommendations;• For patients with proteinuria >0.5 gm/day..we need to treat• Max tolerated ACE/ARBs to target protein excretion<0.5• Steroids to come into practice when the prognostic factors are

bad,but GFR>60 and proteinuria >0.5after 3-6 months trial of ACEs.

• Still those with progressive renal insufficiency ,prednisolone with cyclophosphamide followed by azathioprine should be used.

• Omega 3 fatty acids in view of their less side effect profile ,has made a substantial benefit when used with ACE/ARBs.(12g /day)

• Recurrence after transplantation is 75-80% but graft loss is quite uncommon except in those with bad prognostic factors.

MEMBRANOUS GLOMERULOPATHY*In adult one of the commonest cause of Nephrotic

syndrome. * M:F-2:1,A:C-26:1 * Rule out secondaries-drugs,Ca lung and prostate

MC,CTDs ,hep.

PATHOLOGY AND PATHOGENESIS

• EM-Ehrenerich and Churg staging• Stage 1 from subepithelial deposition to stage 4 of

irregular electron dense deposition within irregular thickend BM.

?MESANGIAL DEPOSITS???• IM-Ig G most prominent followed by Ig M and Ig A,C3 also present in 95%..but not that

intense. • LM-Diffuse capillary wall thickening with absence of significant glomerular hypercellularity.

PATHOGENESIS- In situ immuncomplex depositon MC mechanism

1. Phospholipase A2 receptor of podocytes-MC 70% cases2. Neutral endopeptidase of podocytes3. Cationic bovine serum albumin

MC antibody involved is Ig G4

Circulating complex in SECONDARY DISEASE?Role of complements???• In complex deposited there is also paucity of complements,serum

levels are normal???• Nephritogenic serums contain antibodies to react with Crry/DAF

etc,less production of factor H.

C/F and PROGNOSIS:• 70-80% Nephrotic presentation,may be massive• 10-20% Proteinuria <2 gm/day• HTN-13-55% SUDDEN DETRIORATION-RVT(4-52%)/CRESCENTIC/DRUGS???? 35%ESRD in 10yrs,spontaneous remission(clinicians approach in MGN

good prognosis.)-35% BAD PROGNOSIS- Male /massive proteinuria/age>50 yrs/proteinuria >4gm for 4 months

even on treatment/uncontrolled HTN/crescentic/segmental sclerosis.

LAB FEATURES : Routine Urine,24 hr protein, Serum albumin???(<2) Complement levels-NORMAL

TREATMENT: Spontaneous remissions RAAS blockers Less than 4 gm/24 hrs no Rx/4-8gm depending upon

prognostic factors/.8gm-we need to treat. PONTICELLI REGIMEN-Preferred now

cyclophosphamide(2mg/kg/day )in place of chlorambucil. Other- ACTH,Rituximab,CNIs Serum albumin<2,with no C/I to anticoagulants, we can use it. RELAPSE-Repeat same regimen although alkylating agents can

be given once more.

FOCAL SEGMENTAL GLOMERULOSCLEROSIS

INTRODUCTION• Basically a histological description but per se also

refer to particular disease• M>F,much predominant in blacks PATHOLOGY AND PATHOGENESIS

LM - Focal and segmental glomerulosclerosis

• If we don’t get it,even focal tubulointerstitial injury with glomerular hypercellularity can be used as surrogate marker.

• Microcystic change in tubular epithelial cells• Endothelial tubuloreticular inclusions(others HIV,SLE,Interferon

alpha,pamidronate) HISTOLOGICAL CLASSIFICATION

1.Classical variety/NOS variant-Proto type,MC2.Cellular variant-Endocapillary hypercellualrity with capillary inclusion.3.Tip variant-Alongside of proximal tubule, outer tip of glomerulus. Steroid responsive with very good prognosis.4.Collapsing variant-Torrential nephritic syndrome and rapid declining renal function.5.Perihilar variant-Perihilar hyalinosis and sclerosis in >50%,often seen with

hyperfiltration injury . IM-• IM staining is only shown by sclerotic glomeruli• EM-V imp to rule out other causes of glomerular scarring.

PATHOGENESIS:

• As shown above the genetic mutations• Black race much vulnerable due to MYH9 SNPs ,APOL1

variants(protective against T.Brucei) on chromosome 22.• Glomerular permeability factor??• Parvovirus and SV40 virus.• Glomerular damages and inciting events

C/F and PROGNOSTIC FACTORS:• 80% Cases Nephrotic syndrome presentation• Hematuria 50%/HTN-1/3rd cases• Perihilar and collapsing variety early age , perihilar a/w hyperfiltration

and collapsing with torrential proteinuria• Tip lesions –older peoples,although severe proteinuria like MCD,but

most cases are self resolving,or good remission with steroids.• Poor prognosis are- Black male/severe proteinuria(>10gm/day)/Interstitial fibrosis on

histology/no responsive to rx/collapsing variant

TREATMENT:• Prednisolone 1mg/kg (max 80 mg) upto 16 weeks or

till remission in full dosage.If there is remission, we need to taper it to nil in 6 months.

• If we don’t get remission,prednisolone at 0.15 mg/kg to be continued with cyclosporine(3-5 mg/kg) in two divided dosages, for 6 months.If we get positive response continuation upto 12 months.

• If even not,we can try PEX(very good results in post Tx),Tacrolimus,MMF.

POST STREPTOCCCAL GLOMERULONEPHRITIS

EPIDEMIOLOGY:• Peak incidence 2-6 yrs,15% cases accounts between less than 2 and

more than 40 yrs.M>F• HLA –DRw4 are susceptible ones.• Group A Lancefield (on Carbohydrate antigen) beta hemolytic

streptococci MC type 12 and 49,other Griffith M(on protein) type strains 1,2,3,4,18,52,55,57,58,59,60,61 are highly nephritogenic.Type 2,49,55,57 and 60 are associated with post impetigo,M type 49 can lead to nephritis after both.Type C(Recent epidemic with strept. Zooepidemicus) and G has also been implicated in few cases.

• Risk is about up to 15% with nephritogenic strains.(SEEGAL &EARL)• Impetigo a/w epidemic PSGN ,Pharyngitic with sporadic mainly.

C/F:• Post Pharyngitic phase-7-21days• Post impetigo-14-21 days• Synpharyngitic <7 days.• Classic nephritic presentation,HTN in around 75%,edema is presenting

symptom in 2/3rd,with present in almost 90% cases.Flank pain is associated in about 50% cases

• Clinical manifestation usually resolves in 1-2 weeks,with complete resolution of microscopic hematuria and proteinuria can take up to 8 weeks.

• Together PSGN and Rheumatic fever very rare but can be possible.

LAB FINDING:• R/E Urine- 5% of children and 20% adults have nephrotic range proteinuria.• Streptozyme test (Anti streptococcal antibody assays.),CULTURE(10-70%),ASO

TITRE(30%),Anti DNAse-70%,Anti hyaluronidase -40%• ASO titres (2/3rd of pharyngitic and 1/3rd of impetigo)and those not

producing ,Anti –DNAse we should go for.• In first week 90% of patients have depressed CH50 and C3 and normal C4.

IM:• Garland pattern suggestive of large closely opposed granular

deposits on capillary walls have nephrotic range proteinuria.• Starry sky have scatterd granular deposits have less severe

disease.• Mesangial pattern with predominant c3 staining,corresponds to

resolving phase.• Staining with Ig G as well as c3 indicates active on going

disease,only with c3 indicates a sign of on going reemission.

PATHOGENESIS;• Implanted antigens leading to immune complex and

complement activation(alternate >classical )are most proposed ones.

• These imp antigens include Streptococcal pyogenic exotoxin B, Nephritis associated plasmin receptor.

TREATMENT:• Supportive-Diuretics ,antibiotics,anti HTN,treatment of co

morbidities• Those presenting with crescentic GN and ARF too have very good

recovery.• Permanent renal failure occur in about 1% of children. Complete

resolution generally occur within 3-6 weeks of onset of nephritis.

• No evidence to date support that early treatment of streptococcal disease either pharyngitis or cellulitis alter the risk of PSGN

• Prognosis in elders is worse with high incidence of azotemia(up to 60%),nephrotic range proteinuria and ESRD.

RPGN:NOMENCLATURE AND CATEGORAIZATION:

• Rapid loss of renal function(Upto 50% decrease in GFR) with features of glomerulonephritis accompanied by oliguria/anuria.(<3months)

• Histologically ,crescents must form in >50% of all glomeruli.

• Inciting event leads to focal rupture of capillary walls.

• MC cause –Immune complex mediated GN,and same in children.

• In adults-Paucimmune variety.• Rarest –Anti GBM.• Immuncomplex variety and Anti GBM variety we can

1/3rd to ¼ th cases +ve ANCA too.

Pictorial representation:

Immune complex mediated:• Evidence of special inciting GN ,systemic immunecomplex disease leading to it.• Idiopathic crescentic immune complex. LM• Along side of crescents in intact glomeruli we get varying combinations of

capillary wall thickening, endocapillary hypercellularity unlike in other two we get necrotizing glomeruli,with total normal glomeruli in between,associated with sclerosis widespread.

• Crescents much less evident than in Anti GBM and pauciimmune ,so a/w good prognosis.

IM:• Mesangial IgA deposits?• C3 dominant deposists??• Fine granular Ig G4 deposits??• Coarse granular capillary wall thickening??• ANA +immunecomplex?• ANA + anti GBM??

 TREATMENT:

Influenced by the underlying etiology Idiopathic variety we go for-Immunosupressive

therapy with pulse methylprednisolone 3-5 days, followed by 1 mg/kg prednisolone tapered over 2nd and 3 rd month to alternate day regimen until completely discontinued.Rituximab has also been beneficial in many trials.

Anti GBM disesase:

Two peaks-young onset in male (2 nd -3rd decade)/second peak in female in 6th-7th decade.

HLA-DR2

PATHOGENESIS:• Ig G1(MC) antibody formed against NC/Collagenase resistant alpha 3

domain of type 4 collagen.(alpha 4-TMD,alpha 5-Alport syndrome, alpha 1-paraneoplastic syndromes)

• Anti GBM antibodies(>95%) breech only the monomer subunits of hexameric quaternary structures of Nc1 which are otherwise cryptic in normal individuals, exposed by some environmental factors, genetic susceptibility.

• ANCA association in about 30% cases. MICROSCOPY:• IM-Linear Ig G staining of GBM(diabetic

glomerulosclerosis ,hypertensive vascular disease,Fibrillary glomerulopathies???)

• LM-97% have some crescents,85% have more than 50% crescents• Widespread necrotizing glomeruli with many crescents,

sclerosis, normal glomeruli in between.

C/F and prognosis:• Picture of GN and associated with pul. hemorrhages that may be subtle or

lifethreatning,same BM material may be found in pulmonary capillaries-GOOD PASTURE SYNDROME.

• Haemorrhages more common in smokers. TREATMENT:• Plasmapheresis(8-10timeneeded)+steroids+cyclophosphamide(3months

Rx)(i.v>oral??-less cumulative toxic dosage,less severe leucopenia)• Patients who need dialysis becomes readily dialysis dependent.

• > 7 mg/dl creatinine with widespread glomerular and interstitial scarring,don’t get benefit with immunosuppressive.

• If ANCA+ in same patients(cyclophosphamide is to be given )• Once remission is achieved very rare relapse.• Transplantation results are too good(Alport syndrome with alpha 3

antibody)-Should wait for at least 6 months till serum antibodies are undetectable.

Paucimmune variety C-ANCA Antibody to proteinase 3(PR3) Found in primary granules of

neutrophils and lysosomes of monocytes.

This variety is associated with less relapse. Although associated lung and upper respiratory tract involvement also signifies less relapse.

Characteristically GRANULOMATOSIS WITH POLYANGITIS have 80-90% positivity with it.

Association with patient exposed to silica dust, alpha anti trypsin deficiency.

P-ANCA Antibody to MPO Found in primary granules of

neutrophils and lysosomes of monocytes

More relapse Notable examples are

MICROSCOPIC POLYANGITIS and CHURG STRAUSS SYNDROME.

Another pathogenic antibody being detected is lamp2 antibody.

Around 1/3 rd cases presents as isolated clinical manifestation of kidney disease,although we can get pathological findings in many of cases.

Rx: Since mortality is very high in most of the cases,treatment is

urgently needed. Induction therapy usually consists of

plasmapheresis ,methylprednisolone and cyclophosphamide. Steroids are tapered(up to 20 mg in 8weeks) soon after the

acute inflammation subsides and are maintained on cyclophosphamide or azathioprine to prevent relapse for at least one yr.

Maintainence therapy is not needed in those who are dialysis dependent and have no extra renal manifestations.

Benefit with MMF or Rituximab is controversial but recently most of trials are supporting its use.IvIg have also been found beneficial in some of refractory cases.

MESANGIO CAPILLARY GLOMERULONEPHRITIS• Histological term,a rare GN .• May be idiopathic ,more common being secondary• Children 8-16yr most common,M=F PATHOLOGY AND PATHOGENESIS:• Type 1 –classical complement activation pathway mainly(Antigen???)

,generally associated with hepatitis C and autoimmune disorders.{SECONDARY MOSTLY}

• Type2-Alternate pathway activation(c3NeF/absent factor H/antibody against factor H-- leading to disinhibition of C3 convertase ie C3bBb)(DENSE DEPOSIT DISEASE),associated with partial lipodystrophy syndrome.

• Type3-Like MGN subepithelial deposition, associated with complement receptor deficiency.

• Type 2 and type 3 comes under another new category ie C3 glomerulopathies.

MICROSCOPY:

• Subendothelial dep. and mesangial hypercellularity are chief picture a/w endocapillary thickening,global capillary wall thickening leading to picture of HYPERSEGMENTATION AND LOBULATION.

• Tram track appearence on methanamine silver staining.

• IM staining is peripheral granular or band like complement specially c3(in type 2 and 3),Immunocomplex evident in type 1

C/F AND PROGNOSIS:• May present as asymptomatic,nephritic and nephrotic

poteinuria,acute nephritic syndrome,ESRD(very high chance 50% in 10 yrs.)

• MPGN 2 a/w lipodystrophy,retinal pigmentation abnormlity. Poor prognosis HTN,impaired GFR,appearance of nephrotic syndrome,appearance

of crescents,MPGN 2 (more associated CRESCENTS) LAB FEATURES: Routine test for GN Serum compliment levels-classical complement pathway

(c1q,C4),alternate pathway(c3) Consistently depressed C3 alike PSGN in which C3 return to

normal .

TREATMENT: General treatment of GN KDIGO guidelines - start of ACE inhibitor and Anti HTN

drugs if needed,in proteinuria>30mg/24hr Specific treatment is needed (ie

steroids/immunosupressants/antiplatelets)when: Proteinuria>3gm/24hr Active interstitial or glomerular disease Impaired renal function presentation Progressive deterioration of renal functions

Some trials benefits the use of Dipyridamole, aspirin and warfarin although not proven.

Post transplantation MPGN1 has been found to be of least recurrence among primary GN but type 2 has maximum.

Eculizumab has been found to be of unproven benefit.

THANK YOU