Rapidly progressive glomerulonephritis
| Rapidly progressive glomerulonephritis | |
| ICD-10 | N00-N08 with .7 suffix |
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| DiseasesDB | 3165 |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords:: Crescentic glomerulonephritis; RPGN
Overview
Rapidly progressive glomerulonephritis (RPGN) is one of the few nephrological emergency. However, it fortunately only affects 1-4% of all cases of glomerulonephritis. It is a clinical syndrome that includes signs and symptoms of glomerulonephritis, including hematuria, proteinuria, and edema with signs of renal failure and diffuse crescent formation on histopathology. Without appropriate treatment, RPGN progresses into end-stage renal disease within several days to only a few months yielding a very poor prognosis and renal outcome. RPGN is classified based on the presence of absence of anti-neutrophil cytoplasmic antibody (ANCA) and anti-GBM antibodies. Due to its rarity, the pathogenesis of RPGN is poorly understood and most probably is related to the type of RPGN and the circulating antibodies associated with each type. Evidence on treatment options for RPGN is poor; but the use of glucocorticoids and cyclophosphamide is currently recommended. Basic research and clinical data are currently emerging to better understand the disease pathogenesis and optimal therapeutic options.
Definition
Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by features of glomerulonephritis associated with renal impairment that rapidly worsens over a very short duration - from weeks to a few months – into end-stage renal disease (ESRD). In RPGN, renal failure is the rapid loss of renal function beyond 50% over a short span ranging to a maximum of 3 months. RPGN is thus one of several causes of rapidly progressive renal failure (RPRF).
Classification
Old Classification
Following its initial description in 1914, crescenteric glomerulonephritis was first classified by Couser in 1988 based on features of immunofluorescence.[1]
Type I: Anti-GBM Glomerulonephritis
20% of patients
Presence of linear staining of glomerular basement membrane (GBM)
Type II: Pauci-Immune Glomerulonephritis
50% of patients
Absent or minimal immune deposits
Type III: Immune Complex-Mediated Glomerulonephritis
30% of patients
Presence of granular patterns of immune deposits within the glomerulus. Immune deposition may be associated with any of the following conditions:
- Infections
- Systemic illnesses
- Other primary glomerular diseases
New Classification
Upon the detection of new serological markers such as anti-GBM antibodies and anti-neutrophil cytoplasmic antibodies (ANCA)[2], the classification of RPGN has changed to involve several types of primary glomerulonephritis that correspond to the quantity and quality of such findings in patients’ sera. ANCA and anti-GBM may co-exist in approximately 20% of the patients.[3]
Type I: Anti-GBM Disease
- Anti-GBM antibody-mediated without pulmonary involvement
- Goodpasture’s disease: Anti-GBM antibody-mediated with pulmonary hemorrhage
Type II: Immune Complex-Mediated Disease
Type III: Pauci-Immune Disease
ANCA positive
- Idiopathic renal-limited vasculitis / renal-limited necrotizing crescenteric glomerulonephritis (NCGN)
- Granulomatosis with polyangiitis (formerly “Wegener’s granulomatosis")
- Microscopic polyangiitis
- Churg-Strauss syndrome
Type IV: Mixed Anti-GBM and ANCA Associated Disease
Type V: Pauci-Immune
ANCA negative
Pathophysiology
The pathogenesis of RPGN is unclear and is poorly understood. Nonetheless, circulating factors are thought to play a significant role in the disease and its progression.[4] RPGN, as an outcome, seems to be actually related to the type of RPGN. As such, there does not seem to be a unifying pathophysiology, but rather a combination of pathways that lead to a similar renal outcome. Genetic susceptibility has been shown to be associated with elevated levels of circulating antibodies, such as anti-GBM and ANCA, but little has been elaborated.[3]
In type I anti-GBM glomerulonephritis, antibodies against the non-collagenous domain of alpha-3 chain of type IV collagen of the glomerular basement membrane with a linear pattern on immunofluorescence are responsible for renal involvement.[5][6][7] The granular distribution along the GBM exhibit IgG and C3 deposits. Crescent formation is predominantly due to the formation of fibrin/fibrinogen.[7]
In Type II pauci-immune glomerulonephritis, such as in polyangittis with granulomatosis (formerly Wegener granulomatosis) and polyarteritis nodosa, findings of p-ANCA and c-ANCA in patients are considered landmarks in understanding these diseases; but their true significance has not yet been delineated.[4][8] Studies have shown that ANCA may in fact interact with neutrophils due to the presence of myeloperixoidases on the surface of neutrophils. The interaction drives neutrophils to undergo activation via oxidative burst that finally leads to their “dose-dependent” degranulation and release of toxic oxygen radicals.[4] TNF priming also seems to play an important role in the ANCA-induced degranulation of neutrophils.[9][10] As such, it is perhaps that TNF production during infections and inflammatory diseases in vivo may prime neutrophils in ANCA-positive patients to facilitate neutrophilic activation and subsequent pro-inflammatory cascade of RPGN disease.[4][9][10]
While the majority of patients with pauci-immune RPGN indeed have elevated levels of ANCA, the remaining 20% of patients with the same disease do not. Interestingly, 30% of patients in remission continue to have elevated levels of ANCA. Both these problematic findings raise the question of the actual importance of ANCA in the pathogenesis of RPGN.[11] A novel hypothesis currently suggests that RPGN is in fact a podocytopathy, defined as an intrinsic disease of the podocytes that normally maintains glomerular capillary membranes.( 16906157) As such, it is thought that the CXCR4 and VHL-HIF pathway target gene expression in renal biopsies, based on experimental studies on mice.[12]
Causes
Primary RPGN
RPGN may be a primary condition. The diagnosis of primary glomerulonephritis is made when the clinical syndrome of the disease complies with the new classification of RPGN based on the 5 types of disease. Nonetheless, ruling out other causes of RPGN is necessary before the diagnosis of primary RPGN is made.
The cause of ANCA levels in patients with ANCA-associated glomerulonephritis is not known. Environmental and genetic factors have been postulated. It is believed that infectious etiologies, such as arboviruses, may be contributory. These findings are based only on observations and small studies that patients with ANCA-associated glomerulonephritis are more commonly diagnosed during “flu season”, flu-like prodrome is usually the most common presenting symptoms of these patients, and presence of serological proof of previous arbovirus infection. Further disease progression in ANCA-associated diseases into clinical syndromes of polyarteritis nodosa and Wegener granulomatosis has been postulated to be caused by activation of autoantibody-induced leukocytes.[13] However, no consistent validation of such claims has been made.
Secondary RPGN
Infections
- Infective endocarditis
- Sepsis
- HBV infection with vasculitis or cryoglobulinemia
- HCV infection with vasculitis or cryoglobulinemia
Drugs
- Allopurinol
- D-penicillamine
- Hydralazine
- Rifampin
Multi-Organ Disease
- Systemic lupus erythematosus
- Henoch-Schonlein purpura
- Systemic necrotizing vasculitis
- Relapsing polychondritis
- Cryoglobulinemia
- Other vasculitides
Malignancies
- Colon cancer
- Pulmonary cancer
- Lymphoma
Other Conditions
- Behcet’s disease
- Membranoproliferative glomerulonephritis
- IgA nephropathy
- Poststreptococcal glomerulonephritis
- Hereditary nephritis
Differential Diagnosis
During the evaluation of RPGN, the differential diagnosis of RPGN must first include secondary causes of RPGN and other forms of primary glomerulonephritis before the diagnosis of primary RPGN is to be made and before considering other differential diagnoses.
Other diseases that need that to be considered as differential diagnoses include:
- Amyloidosis
- Antiphospholipid syndrome
- Malignant hypertension
- Multiple myeloma
- Polyarteritis nodosa
Epidemiology and Demographics
RPGN accounts for a small minority of all cases of glomerulonephritis. Only 1-4% of kidney biopsies are RPGN. The prevalence and predominance of RPGN among different ethnicities and geographical locations is currently not known.
Clinical Presentation
RPGN is a difficult diagnosis because of its presenting insidious non-specific symptoms, especially when uncomplicated by other diseases or associated with secondary etiologies.[2] Perhaps the most common presenting symptom of RPGN is just fatigue.[2] Other constitutive symptoms, such as nausea, vomiting, unintentional weight loss, loss of appetite, and diffuse nonspecific abdominal and musculoskeletal pain, are also common. This nonspecific “flu-like” prodrome has raised the suspicion of whether RPGN is a rare unfortunate complication of an infectious etiology.[2]
Renal symptoms, such as azotemia, oliguria, and nephritic syndrome, with gross hematuria are frequently seen in patients with RPGN.[7] Patients might present with several chief complaints, such as symptoms associated with hypertension, such as headache or blurry vision, symptoms of renal insufficiency, or even symptoms of associated diseases such as hemoptysis, sinusitis, cough, and dyspnea in those who that have pulmonary involvement. It has been noted that adult population is less likely to experience hypertension in RPGN as compared to the pediatric population.[7] As such, the presenting symptoms might vary significantly depending on the type of RPGN.
Most findings on physical examination are related to diseases that are associated with RPGN, such as skin lesions in vasculitis, or those associated with renal failure.
Prognosis
The prognosis of RPGN is poor due to the rapid deterioration of kidney function into end-stage renal disease (ESRD) within a few weeks or months. Early diagnosis and management are both important factors to improve prognosis and avoid progression into ESRD.[14][15][16] Histopathologically, the extent of fibrous crescents is associated with poorer renal survival.[17] The degree of renal impairment at diagnosis is also a significant prognostic factor. Serum creatinine > 6 mg/dL is associated with very poor renal outcomes in patients with anti-GBM disease.[18]
The prognosis of RPGN also depends on the exact diagnosis within subtypes of RPGN. The amount of studies that studied the natural history and prognosis of RPGN and its subtypes are very rare, especially because the disease itself is uncommon. Appropriate therapy in patients with anti-GBM disease and Goodpasture’s disease was shown to significantly alter prognosis, with survival rates reaching as high as 70-90%; but only 40% of patients do not require dialysis after 1 year.[19]
Another study that enrolled patients with microscopic polyangiitis and glomerulonephritis and positive ANCA.[20] Following appropriate therapy, more than 70% of the patients were in remission; almost half of which continued to be disease-free after 4 years. Similarly, renal function at diagnosis is associated with renal outcome in patients with positive ANCA.[20]
Patients with poststreptococcal RPGN generally have better outcomes compared to those with primary RPGN. But these findings were observed in the adult population, and may not be true for pediatric patients.[21][7]
Diagnosis
Diagnosis
Blood Work-Up
- Complete blood count (CBC) differential and platelet count
- Serum electrolytes
- Creatinine and blood urea nitrogen (BUN)
- Lactate dehydrogenase (LDH)
- Creatine phosphokinase (CPK)
- Liver function tests
- Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
- Antinuclear antibody (ANA)
- Anti-GBM antibodies
- ANCA
- Cryoglobulins
- HBV and HCV titers
- Complement C3 and C4 levels
- Serum protein electrophoresis
Anemia is common among patient with RPGN, mostly due to renally impaired production of erythropoietin or GI bleeding. Eosinophilia may be seen in a subset of patients with Churg-Strauss disease.
Patients with RPGN may show formation of immune complexes and cryoglobulins. Complement C3 levels is usually low in immune-complex mediated RPGN. The presence of ANCA and anti-GBM is variable; their presence is important for classification of disease and further management planning. Anti-GBM levels is However, anti-GBM antibody level is not prognostic and is not associated with disease activity.[2] On the contrary, literature regarding ANCA-associated glomerulonephritis suggests that levels of ANCA is associated with disease activity and may be used as an index for such purposes.[22][23][13]
ESR and CRP may be elevated and are correlated with the level of inflammation and thus activity of the disease.
Urine Work-Up
- Urinalysis
- Urinary protein electrophoresis
Patients with RPGN do not usually have a full-blown picture of nephrotic syndrome; Nephrotic syndrome only occurs in less than 30% of cases.[2] Proteinuria, if present, is usually mild to moderate. Hematuria of glomerular type with dysmorphic red blood cells is usually present on urinalysis and associated with red cell casts. Mild to moderate leukocyturia may be seen and other casts, such as epithelial cell leukocyte, or fatty casts. Urinary findings in RPGN are important features that not only favor diagnostic work-up, but also follow-up and therapeutic effectiveness.
Kidney Ultrasound
Kidney ultrasound is usually done during diagnostic biopsy. Due to its rapid progression, renal biopsy usually shows normal-sized kidneys. Although the test is not diagnostic, its non-invastive nature and the necessity to rule out other etiologies of renal impairment are both in favor of performing a renal ultrasound.
Kidney Biopsy
An ultrasound or CT-guided kidney biopsy is the only gold standard to diagnose RPGN and determine prognosis of the disease. The pathological hallmark of RPGN is presence of epithelial crescents in the Bowman’s capsule with or without endocapillary proliferation.[7] The extent of fibrous crescents along the glomerulus are considered a poor prognostic element.
Treatment
Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies
Case Studies
References
- ↑ Couser WG (1988). "Rapidly progressive glomerulonephritis: classification, pathogenetic mechanisms, and therapy". Am J Kidney Dis. 11 (6): 449–64. PMID 3287904.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Hricik DE, Chung-Park M, Sedor JR (1998). "Glomerulonephritis". N Engl J Med. 339 (13): 888–99. doi:10.1056/NEJM199809243391306. PMID 9744974.
- ↑ 3.0 3.1 Short AK, Esnault VL, Lockwood CM (1995). "Anti-neutrophil cytoplasm antibodies and anti-glomerular basement membrane antibodies: two coexisting distinct autoreactivities detectable in patients with rapidly progressive glomerulonephritis". Am J Kidney Dis. 26 (3): 439–45. PMID 7544065.
- ↑ 4.0 4.1 4.2 4.3 Falk RJ, Terrell RS, Charles LA, Jennette JC (1990). "Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro". Proc Natl Acad Sci U S A. 87 (11): 4115–9. PMC 54058. PMID 2161532.
- ↑ Ramaswami A, Kandaswamy T, Rajendran T, Aung H, Jacob CK, Zinna HS; et al. (2008). "Goodpasture's syndrome with positive C-ANCA and normal renal function: a case report". J Med Case Rep. 2: 223. doi:10.1186/1752-1947-2-223. PMC 2475522. PMID 18590526.
- ↑ Lewis EJ, Cavallo T, Harrington JT, Cotran RS (1971). "An immunopathologic study of rapidly progressive glomerulonephritis in the adult". Hum Pathol. 2 (2): 185–208. PMID 4937848.
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 Cunningham RJ, Gilfoil M, Cavallo T, Brouhard BH, Travis LB, Berger M; et al. (1980). "Rapidly progressive glomerulonephritis in children: a report of thirteen cases and a review of the literature". Pediatr Res. 14 (2): 128–32. doi:10.1203/00006450-198002000-00012. PMID 7360526.
- ↑ Davies DJ, Moran JE, Niall JF, Ryan GB (1982). "Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology?". Br Med J (Clin Res Ed). 285 (6342): 606. PMC 1499415. PMID 6297657.
- ↑ 9.0 9.1 Klebanoff SJ, Vadas MA, Harlan JM, Sparks LH, Gamble JR, Agosti JM; et al. (1986). "Stimulation of neutrophils by tumor necrosis factor". J Immunol. 136 (11): 4220–5. PMID 3009619.
- ↑ 10.0 10.1 Gallin JI, Fletcher MP, Seligmann BE, Hoffstein S, Cehrs K, Mounessa N (1982). "Human neutrophil-specific granule deficiency: a model to assess the role of neutrophil-specific granules in the evolution of the inflammatory response". Blood. 59 (6): 1317–29. PMID 7044447.
- ↑ Hedger N, Stevens J, Drey N, Walker S, Roderick P (2000). "Incidence and outcome of pauci-immune rapidly progressive glomerulonephritis in Wessex, UK: a 10-year retrospective study". Nephrol Dial Transplant. 15 (10): 1593–9. PMID 11007827.
- ↑ Ding M, Cui S, Li C, Jothy S, Haase V, Steer BM; et al. (2006). "Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice". Nat Med. 12 (9): 1081–7. doi:10.1038/nm1460. PMID 16906157.
- ↑ 13.0 13.1 Falk RJ, Hogan S, Carey TS, Jennette JC (1990). "Clinical course of anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and systemic vasculitis. The Glomerular Disease Collaborative Network". Ann Intern Med. 113 (9): 656–63. PMID 2221646.
- ↑ Hogan SL, Nachman PH, Wilkman AS, Jennette JC, Falk RJ (1996). "Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis". J Am Soc Nephrol. 7 (1): 23–32. PMID 8808106.
- ↑ Lal DP, O'Donoghue DJ, Haeney M (1996). "Effect of diagnostic delay on disease severity and outcome in glomerulonephritis caused by anti-neutrophil cytoplasmic antibodies". J Clin Pathol. 49 (11): 942–4. PMC 500837. PMID 8944617.
- ↑ Heilman RL, Offord KP, Holley KE, Velosa JA (1987). "Analysis of risk factors for patient and renal survival in crescentic glomerulonephritis". Am J Kidney Dis. 9 (2): 98–107. PMID 3826068.
- ↑ Whitworth JA, Morel-Maroger L, Mignon F, Richet G (1976). "The significance of extracapillary proliferation. Clinicopathological review of 60 patients". Nephron. 16 (1): 1–19. PMID 1244562.
- ↑ Mokrzycki MH, Kaplan AA (1994). "Therapeutic plasma exchange: complications and management". Am J Kidney Dis. 23 (6): 817–27. PMID 8203364.
- ↑ Levy JB, Pusey CD (1997). "Still a role for plasma exchange in rapidly progressive glomerulonephritis?". J Nephrol. 10 (1): 7–13. PMID 9241619.
- ↑ 20.0 20.1 Nachman PH, Hogan SL, Jennette JC, Falk RJ (1996). "Treatment response and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis". J Am Soc Nephrol. 7 (1): 33–9. PMID 8808107.
- ↑ Leonard CD, Nagle RB, Striker GE, Cutler RE, Scribner BH (1970). "Acute glomerulonephritis with prolonged oliguria. An analysis of 29 cases". Ann Intern Med. 73 (5): 703–11. PMID 5476201.
- ↑ van der Woude FJ, Rasmussen N, Lobatto S, Wiik A, Permin H, van Es LA; et al. (1985). "Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis". Lancet. 1 (8426): 425–9. PMID 2857806.
- ↑ Tervaert JW, van der Woude FJ, Fauci AS, Ambrus JL, Velosa J, Keane WF; et al. (1989). "Association between active Wegener's granulomatosis and anticytoplasmic antibodies". Arch Intern Med. 149 (11): 2461–5. PMID 2684074.