RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS

Dr Santosh K MInternal Medicine

Narayana Health-MSH

History The term rapidly progressive glomerulonephritis was first used to

describe a group of patients who had an unusually fulminant poststreptococcal glomerulonephritis and a poor clinical outcome.

Several years later, the antiglomerular basement membrane (anti-GBM) antibody was discovered to produce a crescentic glomerulonephritis in sheep, and, following this discovery, the role of anti-GBM antibody in Goodpasture syndrome was elucidated.

Soon afterward, the role of the anti-GBM antibody in rapidly progressive glomerulonephritis associated with Goodpasture disease was established.

In the mid 1970s, a group of patients was described who fit the clinical criteria for rapidly progressive glomerulonephritis but in whom no cause could be established.

Many of these cases were associated with systemic signs of vascular inflammation (systemic vasculitis), but some cases were characterized only by renal disease.

A distinct feature of these cases was the virtual absence of antibody deposition after immunofluorescence staining of the biopsy specimens, which led to the label pauci-immune rapidly progressive glomerulonephritis.

Rapidly progressive glomerulonephritis (RPGN)

Clinically - rapid loss of renal function (usually >/= 50% decline in the glomerular filtration rate [GFR] within 3 months)

Histopathology-Glomerular disease characterized by extensive crescents (usually >50%) as the principal finding

Classification based on Immunologic,pathology and presence or absence of ANCAs.

anti-GBM antibody disease (3% of cases), immune complex disease (45% of cases), pauci-immune disease (50% of cases).

RPGN can develop in any of the following clinical settings

Complication of acute or subacute infectious process Renal complication of multisystem disease: Secondary forms

comprise more than 40% of cases. In association with use of certain drugs: A review of

published data on an association between hydrocarbon exposure and anti-GBM antibody-mediated disease suggests the possibility of a casual relationship.

Primary glomerular disease in which the kidney is the sole organ involved and in which extrarenal manifestations are caused by renal function disturbances

Epidemiology RPGN type III is more common than RPGN types I or II. More than 50% of patients with crescentic

glomerulonephritis present with acute nephritic syndrome and rapidly deteriorating renal function.

Death or dialysis occurs in 73% of patients who are treated with conventional therapy and in 88% of patients if they are oligo-anuric at time of presentation.

Sex-For RPGN types I and III, a predilection for males exists.

Epidemiology from India 46 cases of CrGN[1]

71.7% of cases were pauci-immune (PI) 28.3% were immune complex-mediated(IC)

Gender PI 1.5:1 IC 2:11 Circulating ANCA positive in 80% of PI

Anti GBM-prevalence of 3.8%[2]

1. Gupta R, Singh L, Sharma A, Bagga A, Agarwal SK, Dinda AK. Crescentic glomerulonephritis: a clinical and histomorphological analysis of 46 cases. Indian J Pathol Microbiol. 2011 Jul-Sep. 54(3):497-500.

2. M Ahmad,et al Anti glomerular basement disease - An Indian scenarioIndian J Nephrol 2004;14: 182-186

causesINFECTIOUS DISEASES

MULTISYSTEM DISEASES

Poststreptococcal glomerulonephritis (PSGN)

Infective endocarditis Occult visceral sepsis Hepatitis B infection (with

vasculitis and/or cryoglobulinemia)

SLE Henoch-Schönlein purpura Systemic necrotizing vasculitis

(including Wegener granulomatosis) Microscopic polyarteritis Goodpasture syndrome Essential mixed (IgG and

immunoglobulin M [IgM]) cryoglobulinemia

Malignancy Relapsing polychondritis Rheumatoid vasculitis

Causes contd…..DRUGS Penicillamine Hydralazine (rare case reports) Allopurinol (with vasculitis) Rifampin (rare case reports) Propylthiouracil, thiamazole, carbimazole, benzylthiouracil Aminoguanidine

Type 1 Lung and kidney –Goodpasture’s

Syndrome. • 60%-70%

Kidney only

Symtomatology 15% -asymptomatic. anemia hematuria fluid retention oliguria, or uremia Flu like symptoms cough Hemoptysis Respiratory failure

Blood pressure may be normal or slightly elevated.

Peripheral edema may be present in 10% of patients.

Pallor is common. Skin rash: A lesion suggesting

leukocytoclastic vasculitis may be present.

investigations CBC count may show leukocytosis and anemia. Erythrocyte sedimentation rate (ESR) is usually elevated. Blood urea nitrogen (BUN) and serum creatinine levels are usually

elevated. Electrolytes, especially the serum potassium level, are consistent

with the degree of renal failure. Urinalysis shows modest proteinuria (1-4 g/d), microscopic

hematuria, RBCs, and RBC and WBC casts. Proteinuria could be quantified by timed (24-h collection) or spot

urine protein/creatinine ratio.Rarely, urine findings may be minimal. An absence of active urine sediment does not exclude a diagnosis of

RPGN.

imaging Abdominal ultrasound is used to assess renal size and

echogenicity and to exclude obstruction. Chest x-ray films are indicated for patients with suspected

Goodpasture’s Syndrome and vasculitides and to help manage pulmonary renal syndromes.

Sinus x-ray films and/or CT scans may show evidence of sinusitis in patients with GPA (Wegener granulomatosis).

Chest CT scans may show reticulonodular infiltrate, even when chest radiographic findings are normal and often mimics a neoplastic process.

Complement levels (C3 and C4) are within reference ranges in patients with RPGN types I and III and may be decreased in patients with RPGN type II.

Circulating anti-GBM antibodies are detected in plasma of patients with RPGN type I, but this finding is neither 100% sensitive nor 100% specific for type I.

ANCAs: Typically, myeloperoxidase (MPO)–ANCA (previously known as perinuclear ANCA [p-ANCA]) is observed in 80-90% of patients with RPGN type III pauci-immune, but neither MPO-ANCA nor PR3-ANCA is 100% specific for type III.

Antinuclear antibody findings are usually negative (unless lupus related)

Serum cryoglobulin levels may be elevated in cryoglobulinemias and may be falsely negative.

Renal biopsyINDICATIONS1. Unexplained renal failure2. Acute nephritic syndrome3. Nephrotic syndrome4. Isolated non-nephrotic proteinuria5. Isolated glomerular hematuria6. Renal masses (primary or secondary)7. Renal transplant rejection8. Connective-tissue diseases (eg, systemic lupus erythematosus)

Absolute contraindications to renal biopsy Uncorrectable bleeding diathesis Uncontrollable severe hypertension Active renal or perirenal infection Skin infection at biopsy siteRelative contraindications Uncooperative patient Anatomic abnormalities of the kidney which may increase risk Small kidneys Solitary kidneyComplicationsBleeding –1. collecting system2. Perinephric fat3. SubcapsularPain Fibrosis(18%)

Gross specimen of RPGN

Renal Biopsy and IF demonstrating the linear deposits along the basement membrane of the glomerulus

Anti GBM disease S Creat <5.7 100%patient survival and 95% renal survival @

1st year 84% and 76% at he end of 3 years

S Creat >5.7 but no dialysis 63% and 82% @1st year 69% and 62% at 3yrs

Requiring dialysis 65% and 8% 56% and 5% 2 3yrs

I.Levy JB, Turner AN, Rees AJ, Pusey CD. Long-term outcome of antiglomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med 2001;134:1033-42.

Treatment of Goodpasture’s Syndrome

40 to 45 percent of patients will benefit by not progressing to end-stage renal disease or death, when treated with plasmapheresis in combination with immunosuppression

Bolton WK. Goodpasture's syndrome. Kidney Int 1996; 50:1753. Madore F, Lazarus JM, Brady HR. Therapeutic plasma exchange in renal diseases. J Am Soc Nephrol

1996; 7:367. Couser WG. Rapidly progressive glomerulonephritis: classification, pathogenetic

mechanisms, and therapy. Am J Kidney Dis 1988; 11:449.

Treatment of GP initial plasmapheresis therapy for two to three weeks, with

serial assessment of anti-GBM titers and clinical status. If the patient still has hemoptysis or positive anti-GBM titers at the end of the two- to three-week regimen, we suggest continuation of plasmapheresis until hemoptysis resolves and anti-GBM titers are markedly suppressed or negative (grade 2B)

Monitoring anti-GBM antibody levels every week during plasmapheresis, then approximately every two weeks, until they are negative on two occasions.

Treatment of GP To minimize antibody formation, and recurrence of disease

manifestations, we recommend an initial two- to three-month course of immunosuppressive therapy ( Grade 1B )

Oral prednisone (1 mg/kg per day to a maximum of 60 to 80 mg/day),

A three day pulse of intravenous methylprednisolone (15 to 30 mg/kg, maximum dose of 1000 mg) on each of the three days.

The dose of prednisone is tapered after remission is induced (usually by three weeks) to 20 mg/day.

This dose is maintained until six weeks, then slowly tapered until discontinuation at approximately six months.

Cyclophosphamide Oral cyclophosphamide (2 mg/kg per day) for two to three

months.

Hepatic impariment: Give 75% of normal dose if transaminase levels are >3 times upper limit of normal or bilirubin is 3.1-5 mg/dL

Renal impairment: CrCl <10 mL/min, give 75% of normal dose; CrCl >10 mL/min, give full dose

contraindications Severe myelosuppression Hypersensitivity

Cautions Use with caution in patients with hepatic or renal impairment,

leukopenia, thrombocytopenia, recent radiation therapy or chemotherapy

Pelvic irradiation potentiates hemorrhagic cystitis Potential for radiation recall when used in conjunction with radiation

therapy Risk of potentially fatal and irreversible interstitial pulmonary fibrosis if

given over prolonged periods May cause infertility in male patients who received high doses as

children Monitor for secondary malignancies

Cyclops trial Pulse VS daily oral cyclophosamide for

induction of remission in ANCA-associated vasculitis

Hypothesis

Primary Outcomes Median time to remission pulse cyc 3 months (range 0.5-8) vs. oral cyc 3 months (range 1-

7.5)Hazard ratio 1.098 (95% CI 0.78-1.55; P=0.59)

Secondary Outcomes -pulse VS oral

Proportion in remission at 9 months 88.1% vs. 87.7% Relapses 78.9% of patients who achieved remission by 9

months. 13 vs. 6 patients (HR 2.01; 95% CI 0.77-5.30)

Adverse events 77% vs. 77% Severe or life-threatening: 19 vs. 31 patients All-cause mortality 6.5% vs. 12.3% (P=0.79) Changes in renal function (improvement in eGFR)

5 ml/min/1.73 m2 vs. 8 ml/min/1.73 m2 (P=0.36)

Secondary Outcomes contd…..

Leukopenia 26% vs. 45% (P=0.016)

Infection 20 vs. 21 patients

Cumulative dose of cyclophosphamide 8.2 grams vs. 15.9 grams (P<0.001)

Cumulative dose of prednisolone 7587 mg vs. 7586 mg

Role of azathioprine Effective substitute for cyclophosphamide 1-3mg/kg/day Oral suspension 50mg/ml Iv as an infusion in NS or 5D over 1hr

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Henoch-Schönlein purpura (HSP) An acute immunoglobulin A (IgA)–mediated disorder

characterized by a generalized vasculitis involving the small vessels of the skin, the gastrointestinal (GI) tract, the kidneys, the joints, and, rarely, the lungs and the central nervous system (CNS)

Rash (95-100% of cases), especially involving the legs; this is the hallmark of the disease

Abdominal pain and vomiting (35-85%) Joint pain (60-84%), especially involving the knees and

ankles Subcutaneous edema (20-50%) Scrotal edema (2-35%) Bloody stools

Skin findings (usually the first sign of HSP) - Erythematous macular or urticarial lesions, progressing to blanching papules and later to palpable

Renal findings - Acute glomerular lesions, including mesangial hypercellularity, endocapillary proliferation, necrosis, cellular crescents, and leukocyte infiltration

investigations Antinuclear antibody (ANA)

and rheumatoid factor (RF) Factors VIII and XIII Urinalysis Complete blood count (CBC) Platelet count Erythrocyte sedimentation

rate (ESR) Stool guaiac test Blood urea nitrogen (BUN)

and creatinine Amylase and lipase Electrolytes Renal biopsy

Plasma D-dimer Plasma thrombin-

antithrombin (TAT) complex, prothrombin fragment (PF)-1, and PF-2

Prothrombin time (PT) and activated partial thromboplastin time (aPTT)

Serum IgA Antistreptolysin O (ASO) CH50 C3 and C4 Immunocomplexes of IgG

and IgA Endoscopy

Management Supportive measures may include the

following:• Ensuring adequate hydration• Monitoring for abdominal and renal complications• Treating minor symptoms of arthritis, edema, fever, or

malaise• Eating a bland diet• Discontinuance of any drugs suspected of playing a

causative role• NSAIDS for joint inflammation

CORTICOSTERIODS

Persistent nephrotic syndrome

Crescents in more than 50% of glomeruli

Severe abdominal pain Substantial GI hemorrhage Severe soft tissue edema Severe scrotal edema Neurologic system

involvement Intrapulmonary

hemorrhage

Azathioprine Cyclophosphamide Cyclosporine Dipyridamole High-dose IV

immunoglobulin G (IVIg)

Plasmapheresis may be effective in delaying the progression of kidney disease.

Cryoglobulinemia Cryoglobulins are single or mixed immunoglobulins that

undergo reversible precipitation at low temperatures Cryoglobulinemia is characterized by the presence of

cryoglobulins in the serum Kidneys and skin

Brouetclassification

f;:m 3:1Mean age 42-52yrs

type I cryoglobulinemia clinical manifestations are related to hyperviscosity and

thrombosis Acrocyanosis Retinal hemorrhage Severe Raynaud phenomenon with digital ulceration Livedo reticularis Purpura Arterial thrombosis

Type II and III purpura, arthralgia, and weakness (25-30%) Joint involvement (usually, arthralgias in the proximal

interphalangeal [PIP] joints, metacarpophalangeal [MCP] joints, knees, and ankles)

Fatigue Myalgias Renal immune-complex disease Cutaneous vasculitis Peripheral neuropathy  erythematous macules and purpuric papules

(90-95%), as well as ulcerations (10-25%)

Meltzer M, Franklin EC, Elias K, McCluskey RT, Cooper N. Cryoglobulinemia--a clinical and laboratory study. II. Cryoglobulins with rheumatoid factor activity. Am J Med. 1966 Jun. 40(6):837-56

RENAL disease

Survival rates reported among patients with renal involvement vary from >60% at 5 years of follow-up to 30% at 7 years

The risk of renal failure appears to be greater in those with HCV-associated disease

secondary to thrombosis (type I cryoglobulinemia) or immune complex deposition (types II and III). The incidence of renal disease varies from 5-60%.

Clinically-nephritic/nephrotic/acute renal failure Histology- MPGN

thickening of the capillary walls in the glomeruli and an increased number of cells.

Type I cryoglobulinemia

36 patients .skin or vasomotor symptoms were present in 75%; nephropathy in 30%; and neuropathy in 47%.

The underlying B cell disease was a nonmalignant monoclonal gammopathy in 36%and hematologic malignancy in 64%.

Treatments included fludarabine and rituximab-based regimens.

Five-year survival was 82%

Néel A, Perrin F, Decaux O, Dejoie T, Tessoulin B, Halliez M, et al. Long-term outcome of monoclonal (type 1) cryoglobulinemia. Am J Hematol. 2014 Feb. 89(2):156-61. [Medline].

To evaluate for serum cryoglobulins

The blood specimen must be collected in warm tubes (37°C) in the absence of anticoagulants.

Allow the blood sample to clot before removal of serum with centrifugation (at 37°C).

The period required for the serum sample to incubate (at 4° C) depends on the type of cryoglobulin present, as follows:

Type I tends to precipitate within the first 24 hours (at concentrations >5 mg/mL) Type III cryoglobulins may require 7 days to precipitate a small sample (< 1

mg/mL)

Repeat centrifugation is performed to determine cryocrit (volume of precipitate as a percentage of original serum volume). Cryoglobulin concentration may be determined via spectrophotometric analysis

treatment

Treat the underlying cause Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used

in patients with arthralgia and fatigue. Immunosuppressive medications are indicated upon

evidence of organ involvement Plasmapheresis is indicated for severe or life-threatening

complications

NIH for lupus nephritis National Institute of Health (NIH) protocol which consists of

intravenous cyclophosphamide [0.5-1 gm/m2, adjusted to white blood cell (WBC)], given monthly for the first six months then quarterly for at least 12 months

summary

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