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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2015  |  Volume : 26  |  Issue : 4  |  Page : 708-711
Spectrum of clinico-pathological profile and treatment response in children with nephrotic immunoglobulin a nephropathy

1 Department of Pediatric Nephrology, Sardar Vallabhbhai Patel Post Graduate Institute of Pediatrics, SCB Medical College, Cuttack, Odisha, India
2 Department of Pediatrics, Sardar Vallabhbhai Patel Post Graduate Institute of Pediatrics, SCB Medical College, Cuttack, Odisha, India

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Date of Web Publication8-Jul-2015


Immunoglobulin A nephropathy (IgAN) is one of the most common types of primary glomerulonephritis in the world. Nephrotic syndrome is an uncommon presentation of IgAN. To evaluate the clinico-pathological features and treatment response of nephrotic IgAN, we prospectively studied 20 nephrotic children with biopsy-proven IgAN at our center from August 2009 to December 2012. The histopathological characterization of IgAN was carried out with the HAAS classification. The demographic profile, clinical presentation, initial laboratory, biopsy findings and treatment response were analyzed. The mean age was 6.7 years. The most common indication of renal biopsy was steroid-dependent nephrotic syndrome associated with microscopic hematuria (65%) and hypertension (25%). The majority of cases were classified as HAAS-III stage. Fifteen cases responded to oral cyclosporine-A, four cases to oral cyclophosphamide and one to mycophenolate mofetil. Complete remission of the nephrotic syndrome was achieved in 90% (18/20) cases within 3 months of initiation of therapy. Two cases that had partial remission were in the HASS-II and III stages. We conclude that the majority of children with nephrotic IgAN responded to oral cyclosporine-A. However, a larger cohort and longer duration follow-up are required to confirm our results.

How to cite this article:
Pradhan SK, Sivaraj P, Das L, Swain A. Spectrum of clinico-pathological profile and treatment response in children with nephrotic immunoglobulin a nephropathy. Saudi J Kidney Dis Transpl 2015;26:708-11

How to cite this URL:
Pradhan SK, Sivaraj P, Das L, Swain A. Spectrum of clinico-pathological profile and treatment response in children with nephrotic immunoglobulin a nephropathy. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2022 Jan 26];26:708-11. Available from: https://www.sjkdt.org/text.asp?2015/26/4/708/160149

   Introduction Top

Immunoglobulin A nephropathy (IgAN) is one of the most common primary glomerulonephritidis in the world. It is characterized by mesangial deposition of IgA component, predominately of IgA type-1 polymer. It may also have C3, IgG and, rarely, IgM deposition. The incidence of nephropathy is not well documented, but it seems to be higher in Japan, Australia and Southern Europe. [1] Disease burden is mostly contributed by Asian countries. [2] However, its exact prevalence or clinicopathological spectrum in India is not well documented. Diagnosis is performed by renal biopsy, and referral from primary and secondary centers to a tertiary center for diagnosis plays an important role in diagnosis.

The male to female ratio of IgAN ranges from 2:1 to 6:1. The clinical presentation of IgAN also varies. Patients may present to the medical attention with gross/microscopic hematuria with hypertension or proteinuria with either nephritic or nephrotic syndromes. Macroscopic hematuria is more common in children with IgAN and may occur one to two days after upper respiratory tract infection or other mucosal infections. In asymptomatic patients, microscopic hematuria is almost always present and persistent.

We aim in this study to evaluate the clinicopathological features and treatment response of nephrotic IgAN in children.

   Methodology Top

This prospective study was conducted at the Sardar Vallabhbhai Patel Post Graduate Institute of Pediatrics, SCB Medical College, Cuttack, India from August 2009 to June 2013. A total of 20 nephrotic children, aged two to 18 years with biopsy-proven IgAN, were included in the study.

The nephrotic syndrome was defined by presence of edema, nephritic-range proteinuria (urine spot protein creatinine ratio >2 mg/mg), hypoalbuminemia (serum albumin <2.5 g/dL) and hypercholesteremia (>200 mg/dL).

We excluded from the study patients with lupus erythematosus, Henoch-Schonlein purpura, chronic liver disease, IgAN associated with systemic diseases and other spectra of IgAN.

Ultrasound-guided percutaneous renal biopsy was performed after obtaining written informed consents from parents or legal guardians. Those reports suggestive of IgAN were included in the study and the histopathology was classified based on the HAAS classification: [3]

Subclass I: Minimal histologic lesion.
Subclass II: Focal-segmental glomerulosclerosis.
Subclass III: Focal proliferative glomerulonephritis (GN), <50% of the glomeruli are hypercellular.
Subclass IV: Diffuse proliferative GN, >50% of the glomeruli are hypercellular.
Subclass V: Advanced chronic GN, >40% of the glomeruli are globally sclerotic and/or there is >40% tubular atrophy or loss in the cortex.

There are three types of mesangial changes in children with IgAN: [4]

  1. Mesangial hypercellularity is more prominent than an increase in matrix
  2. The increase in matrix is more prominent than the mesangial cellularity or
  3. Both matrix and cellularity are equal in presentation

All the study patients had nephritic-range proteinuria, and the end point of treatment was set as the reduction of proteinuria, i.e., protein/creatinine ratio to <0.3. Treatment of nephrotic children was based on the Indian Society Pediatric Nephrology (ISPN) protocols. Immunomodulators were added after documentation of no response to steroids or cyclophosphamide in doses of 2-2.5 mg/kg/day for 12 weeks. Treatment with cyclophosphamide was preferred in patients showing (1) significant steroid toxicity, (2) severe relapses with episodes of hypovolemia or thrombosis and (3) poor compliance or difficulty of follow-up. Cyclosporine was prescribed at a dose of 4-5 mg/kg daily for 12-24 months. Treatment with cyclosprine A or tacrolimus is recommended for patients who continue to show steroid dependence or frequent relapses despite treatment. Mycophenolate mofetil (MMF) was started at the dose of 800-1200 mg/m 2 for 12-24 months in older children and in steroid-dependent nephrotic syndrome not responding to steroids. [5] The demographic profile, clinical presentation, baseline laboratory data and renal biopsy findings were analyzed.

   Results Top

The mean age of the patients at presentation was 6.5 ± 3.5 years, and the male:female ratio was 2.6:1. All the patients had nephrotic syndrome and 60% of them had hematuria. Hypertension was observed in only 30% of the cases, as shown in [Table 1]. Only two cases had impaired renal function. The type of nephrotic syndrome observed in nephrotic IgAN patients was steroid-resistant nephrotic syndrome (SRNS) in seven cases, followed by steroid-dependent nephrotic syndrome (SDNS) in six cases and frequently relapsing nephrotic syndrome in five cases. All the patients had normal C3 levels.
Table 1: Clinical features of IgAN based on the HAAS classification.

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With HAAS staging, nine (45%) cases were in HAAS stage III, six cases in stage IV, three cases in stage I and two cases in stage II. Of 20 study patients, 15 patients received cyclosporine; 14 patients received steroid therapy along with cyclosporine and one patient was started only on cyclosporine. In addition, four patients received cyclophosphamide after the use of steroid and one child received MMF. We could achieve 89% complete remission of proteinuria with immunosuppressive therapy as shown in [Table 2], and partial remission was achieved in 11% of patients. There was a statistically significant (P <0.0001) reduction in the protein/creatinine ratio after the treatment.
Table 2: Remission–response of treatment.*

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   Discussion Top

The nephrotic syndrome presents in 15.8% of patients with IgAN, [6] and the severe form of the disease is seen in 4.4% of them. [4] In our study, nephrotic IgAN occurred in young children, with a preponderance in male patients. Various studies showed that IgAN was more common in males than in females.

Several studies from Europe and the US showed that more than 80% of the IgAN patients had recurrent macroscopic hematuria.

Hematuria is more common in children rather than in adults. In our study, although 65% of the patients had hematuria, macroscopic hematuria was only observed in three (15%) cases, which was less than the reported incidence from previous studies. We also had two cases (10%) with nephritic and nephrotic syndrome. About 25% of our study patients manifested hypertension. More than half of the nephrotic IgAN children present mainly with SRNS and SDNS. A study on the long-term outcome of IgAN in children found urine abnormalities in 47%, proteinuria in 35%, hypertension in 9% and decreased glomerular filtration rate (GFR) in only 3% of patients. However, 53% had no clinical signs of the disease. [7]

In the multivariate model, only estimated GFR at baseline was a risk factor, and histopathological lesions had no independent influence on outcome. Doubling creatinine occurred in 20% of the patients and end-stage renal disease occurred in 16% of patients. [8] Despite having benign presentation, the incidence of end-stage renal disease ranged from 20% to 50%. [9]

Nephrotic IgAN is a very severe form of IgAN, with prevalence of renal dysfunction, massive hematuria and active and chronic histopathological lesions. The cumulative renal survival rate is significantly lower in the nephrotic than in the non-nephrotic IgAN. Poor prognostic indicators include persistent hypertension, diminished renal function and heavy and prolonged proteinuria, while histological indicators include diffuse mesangial proliferation, extensive glomerular crescents, glomerulosclerosis and diffuse tubulointerstitial changes with inflammation and fibrosis.

IgAN is a therapeutic challenge in both adults and children. There is no sufficient evidence for the use of omega 3 fatty acids, warfarin, urokinase and anti-platelet drugs in IgAN. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers reduce urinary protein excretion and preserve renal function in adults, but there are no clinical trials performed in children with IgAN. Corticosteroids are widely used to treat moderate and severe IgAN, particularly in children, but their safety and effectiveness over a long-time course are still not proven. Combined therapy of cytotoxic drugs with steroids can reduce the incidence of renal failure in IgAN. [4] The use of combined or monotherapy and duration of treatment have not been established yet. In our study, the majority of patients received cyclosporine. We observed a good remission rate with immunosuppressive therapy, almost 89% achieved complete remission and 11% had partial remission. In adult patients with primary nephrotic syndrome associated with IgAN, the use of immunosuppressive therapy resulted in a high percentage of achieved remissions. [10]

In general, our results were not consistent with the HAAS classification, particularly in the prognostic significance. According to the HAAS classification, prognosis worsens from stage I to stage V. In our study, although the patients were initially classified as stages II to IV, they responded to therapy and ended with remission. None of our patients required hemodialysis during the follow-up.

Finally, controlling proteinuria and blood pressure during the follow-up of patients with IgAN is essential in reducing the risk of future loss of kidney function. [11]

We conclude that our results suggest that the kidney biopsy remains essential for the diagnosis of IgAN, but previous biopsy scoring systems were not consistent with clinical response to therapy or prognosis in children with IgAN. Immunosuppressive therapy was required in addition to steroids to reduce the relapse rate. The majority of patients in our study responded to oral cyclosporine-A. However, there is a need for clinical trials to establish the protocol for the treatment of IgAN.

   References Top

Han SH, Kang EW, Park JK, Kie JH, Han DS, Kang SW. Spontaneous remission of nephrotic syndrome in patients with IgA nephropathy. Nephrol Dial Transplant 2011;26:1570-5.  Back to cited text no. 1
Mittal N, Joshi K, Rane S, Nada R, Sakhuja V. Primary IgA nephropathy in north India: Is it different? Postgrad Med J 2012;88:15-20.  Back to cited text no. 2
Haas M. Histologic subclassification of IgA nephropathy: A clinicopathologic study of 244 cases. Am J Kidney Dis 1997;29:829-42.  Back to cited text no. 3
Avner ED, Harmon WE, Niaudet P, Yoshikawa N. Pediatric Nephrology. 6th ed., Sec. 5, Ch. 31. Berlin, Heidelberg: Springer; 2009. p. 757.  Back to cited text no. 4
Bagga A. Revised guidelines for management of steroid-sensitive nephrotic syndrome. Indian J Nephrol 2008;18:31-9.  Back to cited text no. 5
[PUBMED]  Medknow Journal  
Herzenberg AM, Fogo AB, Reich HN, et al. Validation of the Oxford classification of IgA nephropathy. Kidney Int 2011;80:310-7.  Back to cited text no. 6
Linné T, Berg U, Bohman SO, Sigström L. Course and long-term outcome of idiopathic IgA nephropathy in children. Pediatr Nephrol 1991;5:383-6.  Back to cited text no. 7
Alamartine E, Sauron C, Laurent B, Sury A, Seffert A, Mariat C. The use of the Oxford classification of IgA nephropathy to predict renal survival. Clin J Am Soc Nephrol 2011;6: 2384-8.  Back to cited text no. 8
Yoshikawa N, Tanaka R, Iijima K. Pathophysiology and treatment of IgA nephropathy in children. Pediatr Nephrol 2001;16:446-57.  Back to cited text no. 9
Rasiæ S, Uncanin S, Aganoviæ K, Rasiæ I, Dzemidziæ J, Muslimoviæ A. Treatment of IgA nephropathy of adults presented by nephrotic syndrome. Bosn J Basic Med Sci 2008;8:2303.  Back to cited text no. 10
Barbour SJ, Reich HN. Risk stratification of patients with IgA nephropathy. Am J Kidney Dis 2012;59:865-73.  Back to cited text no. 11

Correspondence Address:
Pradeep Sivaraj
Department of Pediatrics, Sardar Vallabhbhai Patel Post Graduate Institute of Pediatrics, SCB Medical College, Cuttack, Odisha
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DOI: 10.4103/1319-2442.160149

PMID: 26178542

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This article has been cited by
J Balaji, K S Kumaravel, P Punitha, B Rameshbabu
Indian Journal of Child Health. 2017; 04(03): 322
[Pubmed] | [DOI]


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