In 1992, we described our experience on the clinical features and renal histology in 43 consecutive patients with crescentic GN [4]. Immunofluorescence examination showed immune complexes in 17 of 20 cases; testing for antineutrophil cytoplasmic antibodies (ANCA) was not available. Outcomes were unsatisfactory irrespective of etiology, with progressive renal impairment in 86% cases. During the last decade we have noticed a reduction in proportion of patients with postinfectious GN and increasing occurrence of pauci-immune crescentic GN. While recent reports are limited [1,8], prompt diagnosis and intensive therapy has resulted in better patient outcomes. The present report describes the etiological profile and clinical course among 36 patients with crescentic GN evaluated at this centre. The short-term course in nine patients has been reported elsewhere [9].

Management included maintenance of fluid and electrolyte balance, dialysis if indicated, and therapy of coexisting infections and hypertension.

Immune complex crescentic GN. Initial therapy with IV methylprednisolone was followed by tapering doses of oral steroids for 6 months. Patients with crescentic GN secondary to SLE, IgA nephropathy and HSP received IV cyclophosphamide for 6 months, followed by long-term therapy with azathioprine or mycophenolate mofetil. Patients with postinfectious GN also received oral cyclophosphamide (2 mg/kg/day) for 12 weeks.

Statistical analysis: Data were analyzed using STATA 11.0 (College Station, Texas). Summary statistics are presented as median (interquartile range, IQR). Clinical features were compared using chi square and ranksum tests; renal survival (free of renal loss) was compared using Kaplan Meier analyses. Factors impacting outcome were examined by Cox regression and reported as hazards ratios (HR) with 95% confidence intervals (CI).

Of 36 patients with crescentic GN, 21 were boys. The median (IQR) age at onset of disease was 10 (8-11.5) years; 15 (41.7%) children were younger than 10 years. The clinical and laboratory features are presented in Table I. Based on histopathology and IF examination, immune complex GN and pauci-immune crescentic GN were present in 17 and 19 patients, respectively. Fifteen (88.2%) patients with the former and 18 (94.7%) with the latter presented with rapidly progressive GN; 3 had puffiness and mildly impaired renal function. Six patients in each group had systemic symptoms at presentation, including one with Wegener’s granulomatosis. Thirteen patients with pauci-immune GN had isolated renal involvement.

TABLE I Patient Characteristics at Presentation

Histology: Adequate tissue for histopathology was available in 35 patients; renal biopsy in one showed only 4 glomeruli, 3 of which had crescents. The median (IQR) proportion of glomeruli showing crescents was 62% (50-89%) in patients with immune complex GN and 67% (50-96%) in pauci-immune crescentic GN; crescents involving >80% glomeruli were seen in 6 and 7 cases, respectively. In immune complex GN, crescents were cellular and fibrocellular in 8 patients each (47.1% each); one patient showed fibrous crescents. The proportion of sclerosed and normal glomeruli was 20% (0-41%) and 14.5% (0-29%), respectively. Tubular atrophy and interstitial fibrosis was noted in 10 biopsies, while 8 showed chronic inflammatory infiltrate.

Biopsies in patients with pauci-immune crescentic GN showed cellular (n=11, 57.9%), fibrocellular (n=6, 31.6%) or fibrous (n=2, 10.5%) crescents. The median proportion of sclerosed and normal glomeruli was 8.5% (IQR 0-40%) and 5% (0-21%) respectively. Tubular atrophy and interstitial fibrosis were seen in 14 (73.7%) and 12 (63.2%) biopsies. Fibrin deposition was present in 12 (63.2%) cases and tuft necrosis in 4 biopsies. Faint deposits of C3 and IgM were seen in 3 and 1 patients, respectively.

Immune complex GN was secondary to SLE in 4 patients, and IgA nephropathy, Henoch Schonlein purpura and membranoproliferative GN type II in two cases each; GN was postinfectious in 3 cases and idiopathic in 5 patients. Three patients with pauci-immune crescentic GN were ANCA positive. Two patients had microscopic angiitis based on constitutional symptoms and specificity against myeloperoxidase and one with chest infiltrates and specificity against proteinase-3 was diagnosed as Wegener’s granulomatosis. Serology for ANCA was negative in 16 patients with pauci-immune GN.

Twelve (33.3%) patients required dialysis at presentation. Eight patients, all with pauci-immune GN, underwent plasma exchanges. Therapy for induction included IV methylprednisolone (n=31; 86.1%), IV cyclophosphamide (27; 75%) and oral cyclophos-phamide [4]. Maintenance immunosuppression included oral prednisolone (36; 100%), azathioprine (18; 50%) and mycophenolate mofetil (11; 30.6%).

TABLE II Outcome at Last Follow Up

The outcome at last follow up, at 34 (19-72) months, is shown in Table II. Seven (19.4%) patients had complete recovery, while 10 (30.6%) had CKD 4-5. The latter includes 3 patients who were followed for 53-121 months after renal transplantation. Fig. 1 shows that renal survival was 94.1% at 1, 3 and 5-yr, and 75.3% at 8 and 10-yr in patients with immune complex crescentic GN. Renal survival in patients with pauci-immune GN was lower at 63.2% at 1 and 3-yr, and 54.1% at 5 and 8-yr (log rank test; P=0.054).

Fig. 1 Kaplan Meier survival estimates for proportion of patients with renal loss (chronic kidney disease stage 4 and 5) or death in patients with immune complex (solid line) and pauci-immune crescentic glomerulonephritis (interrupted line) (log rank test P=0.054).

On univariate analysis, factors predicting renal loss were presentation with oliguria (HR 10.5; 95% CI 1.16-95.25; P=0.037), need for dialysis at presentation (HR 6.33; 1.27-31.57; P=0.024), and the proportion of glomeruli showing fibrous or fibrocellular crescents (HR 4.74; 0.99-22.52; P=0.050). Renal loss was inversely correlated to the proportion of normal glomeruli (HR 0.91, 0.83-0.99; P=0.042). There was no relation between renal loss and the presence of hypertension (P=0.22) at disease onset.

The present report describes the etiology and outcome of disease in children with crescentic GN evaluated at a single center over nine years. A similar proportion of patients had pauci-immune and immune complex GN. These findings are in contrast to previous case series in children (Web Table I) showing that immune complex GN constitutes the majority of cases with crescentic GN. The causes for immune complex GN are varied and include post-infectious GN, systemic lupus erythematosus, IgA nephropathy, Henoch Schonlein syndrome and membranoproliferative GN [1-5, 8, 15]. Pauci-immune crescentic GN, characterized by absence of significant glomerular immune deposits, is a severe illness that represents an important cause of crescentic GN in adults [6,7,16,17]. Data on pauci-immune crescentic GN is limited in children, with most previous reports suggesting that these account for 4.6-20% of all cases [1-3,5,8]. Therefore our finding, that pauci-immune GN constitutes more than one-half of all cases with crescentic GN, suggests a changing etiologic profile of the illness in children. However, the change in proportions might reflect a decline in rates of post-infectious GN [18]. Alternatively, it may represent a referral bias, with more cases with severe presentation, and therefore, a higher proportion of patients with pauci-immune crescentic GN, being referred to a tertiary care center.

A large proportion of patients with pauci-immune crescentic GN have circulating ANCA. Since early 1990s, the application of immunofluorescence and ELISA to detect ANCA and define its specificities, has allowed diagnosis of ANCA-associated vasculitis, including microscopic polyangiitis, Wegener’s granulomatosis and renal limited vasculitis [6, 10, 14]. However, a recent review suggests that 10-30% patients with pauci-immune GN are negative for ANCA [19]. Compared to those who are ANCA positive, patients with negative serology are younger, show less constitutional and extrarenal symptoms, have higher proteinuria and severe lesions on histology, and an unsatisfactory renal survival [19, 20]. A recent report from northern India showed that 21 of 48 adults with pauci-immune rapidly progressive GN were negative for ANCA [21]. The diagnosis of ANCA negative serology is chiefly based on negative results on immunofluorescence [19-22]. Based on this examination, and confirmed in most by specific ELISA, 84.2% of the present patients with pauci-immune GN were negative for ANCA. While the outcome of patients with ANCA negative pauci-immune crescentic GN is considered unsatisfactory, we did not demonstrate differences in view of small patient numbers.

Outcomes in crescentic GN are generally unsatisfactory and progressive renal failure has been seen in 18.9-86% (Web Table I) [1-5,8,15]. One-third of the present patients, followed for median duration of three years, progressed to CKD 4-5. Compared to our previous experience [4], the improved outcomes may reflect intensive immunosuppressive therapy and early institution of dialysis and/or plasmapheresis. We also found that outcome of patients with pauci-immune GN was less satisfactory compared to immune complex GN. Of 19 patients with the former, 8 progressed to CKD stage 4-5, compared to only 2 of 17 with the latter. The findings are similar to that in adult patients, where pauci-immune GN has inferior outcome compared to immune complex GN [6]. While the cellularity of crescents is a marker of outcome [1-3], the proportion of fibrous and fibrocellular crescents was similar in pauci-immune and immune complex GN (42.1% versus 53%) and was unlikely to account for difference in outcomes. Other predictors of prognosis in the present cases were similar to those reported previously, including dialysis dependence at onset [2, 4, 6] and proportion of normal glomeruli [23].

The current report highlights the change in etiological profile of crescentic GN in children that mirrors trends in adult onset disease. The distinction between subtypes based on immunofluorescence and serological findings has important implications for therapy and outcome. Patients with pauci-immune GN show a higher risk of progressive kidney disease. Further studies are necessary to characterize the natural history of disease in children with ANCA-negative pauci-immune crescentic GN.

Contributors: AS and KP retrieved information from case records, collated and analyzed the data. PH and AB provided analytical inputs and guided in analysis and review of literature. AKD reviewed and interpreted histological specimens. All authors contributed to the preparation of the manuscript, provided significant inputs during preparation for final publication and approved the final manuscript. AB supervised the study and shall be its guarantor.

Funding: None; Competing interests: None stated.

1. Dewan D, Gulati S, Sharma RK, Prasad N, Jain M, Gupta A, et al. Clinical spectrum and outcome of crescentic glomerulonephritis in children in developing countries. Pediatr Nephrol. 2008;23:389-94.

2. Jardim HM, Leake J, Risdon RA, Barratt TM, Dillon MJ. Crescentic glomerulonephritis in children. Pediatr Nephrol. 1992;6:231-5.

3. A clinico-pathologic study of crescentic glomerulonephritis in 50 children. A report of the Southwest Pediatric Nephrology Study Group. Kidney Int. 1985;27:450-8.

4. Srivastava RN, Moudgil A, Bagga A, Vasudev AS, Bhuyan UN, Sunderam KR. Crescentic glomerulonephritis in children: a review of 43 cases. Am J Nephrol. 1992;12:155-61.

5. Tapaneya-Olarn W, Tapaneya-Olarn C, Boonpucknavig V, Boonpucknavig S. Rapidly progressive glomerulonephritis in Thai children. J Med Assoc Thai. 1992;75:32-7.

6. Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int. 2003;63:1164–77.

7. Koyama A, Yamagata K, Makino H, Arimura Y, wada T, Nitta K, et al. Japan RPGN Registry Group. A nationwide survey of rapidly progressive glomerulonephritis in Japan: etiology, prognosis and treatment diversity. Clin Exp Nephrol. 2009;13:633-50.

8. Alsaad K, Oudah N, Al Ameer A, Fakeeh K, Al Jomaih A, Al Sayyari A. Glomerulonephritis with crescents in children: etiology and predictors of renal outcome. ISRN Pediatr. 2011; doi:10.5402/2011/507298.

9. Gupta R, Singh L, Sharma A, Bagga A, Agarwal SK, Dinda AK. Crescentic glomerulonephritis: A clinical and histomorphological analysis of 46 cases. Ind J Pathol Microbiol. 2011;54:597-61.

10. Savige J, Pollock W, Trevisin M. What do antineutrophil cytoplasmic antibodies (ANCA) tell us? Best Pract Res Clin Rheumatol. 2005;19:263–76.

11. Bagga A, Mantan M. Nephrotic syndrome. Indian J Med Res. 2005;122:13-28.

12. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114:555-76.

13. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271-7.

14. Ozen S, Ruperto N, Dillon MJ, Bagga A, Barron K, Davin JC, et al. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis. 2006;65: 936–41.

15. Miller MN, Baumal R, Poucell S, Steele BT. Incidence and prognostic importance of glomerular crescents in renal diseases of childhood. Am J Nephrol. 1984;4:244-7.

16. López-Gómez JM, Rivera F; Spanish Registry of Glomer-ulonephritis. Renal biopsy findings in acute renal failure in the Cohort of patients in the Spanish registry of glomer-ulonephritis. Clin J Am Soc Nephrol. 2008;3: 674-81.

17. Lin W, Chen M, Cui Z, Zhao M-H. The immunopathological spectrum of crescentic glomerulonephritis: a survey of 106 patients in a single Chinese center. Nephron Clin Pract. 2010;116:c65–c74.

18. Kanjanabuch T, Kittikowit W, Eiam-Ong S. An update on acute postinfectious glomerulonephritis worldwide. Nat Rev Nephrol. 2009;5:259–69.

19. Chen M, Yu F, Wang SX, Zou WZ, Zhao MH, Wang HY. Antineutrophil cytoplasmic autoantibody–negative pauci-immune crescentic glomerulonephritis. J Am Soc Nephrol. 2007; 18:599-605.

20. Eisenberger U, Fakhouri F, Vanhille P, Beaufils H, Mahr A, Guillevin L, et al. ANCA-negative pauci-immune renal vasculitis: histology and outcome. Nephrol Dial Transplant. 2005;20:1392-9.

21. Minz RW, Chhabra S, Joshi K, Rani L, Sharma N, Sakhuja V, et al. Renal histology in pauci-immune rapidly progressive glomerulonephritis: 8-year retrospective study. Indian J Pathol Microbiol. 2012;55:28-32.

22. Csernok E, Ahlquist D, Ullrich S, Gross WL. A critical evaluation of commercial immunoassays for antineutrophil cytoplasmic antibodies directed against proteinase 3 and myeloperoxidase in Wegener’s granulomatosis and microscopic polyangiitis. Rheumatology (Oxford). 2002;41:1313-7.