Role of corticosteroid therapy in IgA nephropathy ; where do we stand ?

1Department of Nephrology, Kasturba Medical College, Manipal University, Manipal, India 2Department of Pathology, Kasturba Medical College, Manipal University, Manipal, India 3Department of Nephrology, Guntur Hospital, Guntur, India 4Department of Nephrology, Madras Medical Mission, Chennai, India 5Department of Pharmacy Practice, NGSM Institute of Pharmaceutical Sciences, Nitte University, Mangalore, India 6Department of Statistics, Kasturba Medical College, Manipal University, Manipal, India 7Department of Pathology, Manipal Hospital, Bangalore, India


Background
IgA nephropathy, also known as Berger's disease, is the most common form of primary glomerulonephritis worldwide (1).It is characterized by dominant or codominant deposition of the IgA antibody in the mesangial area of glomeruli on immunofluorescence.It has variable clinical presentation and course (1)(2)(3).The role of immunosuppressive therapy when added to supportive care in these patients is unclear.The kidney disease improving global outcomes (KDIGO) guidelines regarding IgA nephropathy suggest that the use of systemic glucocorticoids in patients who have >1 g of urinary protein excretion per day and estimated glomerular filtration rate (eGFR) higher than 50 ml/min/1.73m 2 despite supportive care (2,3).This is based on few randomized controlled trials (4)(5)(6)(7)(8).Ballardie et al showed that immunosuppressive combination therapy stabilized eGFR in patients with an aggressive course of IgA nephropathy (9).But the recent STOP-IgAN trial showed that there is no benefit with immunosuppressive therapy compared to full supportive care with angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARBs) (10).Majority of the patients in these studies had eGFR >50 mL/min/1.73m 2 .The role of steroid usage in addition to supportive care is not well studied in patients with eGFR < 50 mL/min/1.73m 2 .The KDIGO guidelines make no recommendations for use of corticosteroids (CS) in individuals with an initial eGFR ≤50 mL/min/1.73 , who are under-represented in majority of the trials (3)(4)(5)(6)(7)(8)(9)(10). The recent analysis from VALIGA study showed that steroids may be of benefit even in this group (11).

Objectives
This study was conducted to assess the effect of steroids on disease progression and proteinuria in IgAN patients with eGFR < 50 mL/min/1.73m 2 compared to those with >50 mL/min/1.73m 2 .

Study population
We reviewed the clinical records of all adults (>18 years) admitted to the hospital with a histopathological diagnosis of primary IgA nephropathy between March 2010 and February 2015 after getting ethical committee clearance.Patients who received oral CS for minimum of 3 months in addition to supportive care as treatment and had follow-up for minimum 6 months duration were included.The clinical, serological, biochemical and histopathological data were collected from the case records in detail for all the patients.The clinical and biochemical details included were age, gender, presence of hypertension, micro-or macroscopic hematuria, edema, mean arterial pressure (MAP), urine protein creatinine ratio (UPCR), 24hour proteinuria, serum creatinine at admission and on follow-up.The histopathological data was collected by using MEST score for all the patients according to OXFORD classification (12,13).The eGFR was calculated by MDRD formula for all the patients adjusted to body surface area (14).The patients were categorized into two groups as per eGFR (group 1 -eGFR <50 mL/min/1.73m 2 , group 2 -eGFR > 50 mL/min/1.73m 2 ).The baseline characteristics were compared between the two groups.The eGFR and UPCR were followed-up at study entry, 6 months, 12 months and at the end of follow-up.The renal outcomes studied were remission (complete/ partial) and progression to end stage renal disease on follow-up.The risk factors associated with renal loss and mortality were also studied.

Ethical issues
1) The research followed the tenets of the Declaration of Helsinki; 2) informed consent was obtained, and 3) the research was approved by the ethical committee of Kasturba Hospital, Kasturba Medical college, Manipal University, Manipal, India.

Statistical analysis
The descriptive statistics were applied for the analysis of baseline characteristics data and the comparison between the two groups were analyzed by student t test for normally distributed data and Mann-Whitney U test for skewed data.The statistical analysis of data was done using SPSS version 15 and P value below 0.05 was considered significant. .95.7% of group 1 and 85.7% of group 2 had proteinuria > 1g/d and all of them were on ACEi/ARBs as supportive care.All patients had received 1 mg/kg/d of oral prednisolone for at least 3 months and later tapered over 6 months.The pulse steroid and cyclophosphamide were used as per standard recommendations in few patients in both the groups based on the discretion of the treating physician and were comparable between the groups as shown in Table 1.The histological features like presence of mesangial proliferation (M1), endocapillary proliferation (E1), segmental sclerosis (S1), interstitial fibrosis and tubular atrophy (T1) according to OXFORD classification and also presence of crescents in the biopsy specimens were equally distributed between the groups.The median follow-up was 12 months in group 1 and 15 months in group 2. At the end of follow-up, it was found that with addition of steroids to supportive care, both the groups had similar reduction in proteinuria (UPCR) = 0.62; Figure 1, Table 2).In group 1, the median UPCR decreased from 2.6 mg/mg to 1 mg/mg at the end of follow-up.In group 2, the median UPCR decreased from 2.0 mg/mg to 0.4 mg/mg.However, there was a significant difference in change in median eGFR/month between the groups (P = 0.004; Table 2, The pulse steroid and cyclophosphamide were used as per standard recommendations in few patients in both the groups based on the discretion of the treating physician and were comparable between the groups as shown in Table 1.The histological features like presence of mesangial proliferation (M1), endocapillary proliferation (E1), segmental sclerosis (S1), interstitial fibrosis and tubular atrophy (T1) according to OXFORD classification and also presence of crescents in the biopsy specimens were equally distributed between the groups.The median follow-up was 12 months in group 1 and 15 months in group 2. At the end of follow-up, it was found that with addition of steroids to supportive care, both the groups had similar reduction in proteinuria (UPCR) (P = 0.62; Figure 1, Table 2).In group 1, the median UPCR decreased from 2.6 mg/mg to 1 mg/mg at the end of follow-up.In group 2, the median UPCR  decreased from 2.0 mg/mg to 0.4 mg/mg.However, there was a significant difference in change in median eGFR/month between the groups (P = 0.004; Table 2, /month, irrespective of the treatment with steroids (Table 2, Figure 2).One subject in each group reached CKD stage 5 (P = 0.73) at the end of follow-up.There was no mortality in either group.

Discussion
The treatment of IgA nephropathy with CS remains unclear despite various studies.The history of use of steroids dates back to 1986, when an uncontrolled pilot study by Kobayashi et al (15) showed a clear benefit of oral prednisone (40 mg/d tapered over 1-2 years) in patients with early disease (creatinine clearance >70 mL/min) and persisting proteinuria of >1 g/d, at 10 years follow-up (16).In the last decade, randomized controlled trials (RCTs) conducted by Pozzi et al, Manno et al and Lv et al showed a favorable outcome in patients treated with CS for 6-month duration (4-7).These trials were limited by inconsistent about use of ACE inhibitors or ARBs as supportive care (4,5) or were temporarily halted and then reinitiated at baseline (6, 7).).
The (3).The use of steroids in patients with eGFR <50 mL/ min/1.73m 2 has been addressed in the VALIGA study which examined the benefit of steroids in this subset of patients in addition to renin angiotensin system blockers (RASBs) compared with RASBs alone, (particularly in patients with proteinuria >1 g/d), suggesting a value in patients with eGFR <50 mL/min/1.73m2 as well (11).In our study, group 1 did not benefit in terms of progression of CKD compared to group 2. There was a fall in eGFR by 0.46 (-0.1,-1.08)mL/min/1.73m 2 / month in group 1.So there was no benefit found to prevent progression of disease with use of steroids in patients with eGFR<50 mL/min/1.73m 2 .In group 2 (patients with eGFR >50 mL/min/1.73m 2 ), there was a significant benefit favoring use of steroids to prevent progression of disease.Since our study is a retrospective study, with patients being on both Figure 2).Patients in group 2 had an increase in median eGFR by 0.38 mL/min/1.73m 2 /month whereas in group 1 there was a median fall in eGFR by 0.46 mL/ min/1.73m 2 /month, irrespective of the treatment with steroids (Table 2, Figure 2).One subject in each group reached CKD stage 5 (P = 0.73) at the end of follow-up.There was no mortality in either group.

Discussion
The treatment of IgA nephropathy with CS remains unclear despite various studies.The history of use of steroids dates back to 1986, when an uncontrolled pilot study by Kobayashi et al (15) showed a clear benefit of oral prednisone (40 mg/d tapered over 1-2 years) in patients with early disease (creatinine clearance >70 mL/min) and persisting proteinuria of >1 g/d, at 10 years follow-up (16).In the last decade, randomized controlled trials (RCTs) conducted by Pozzi et al, Manno et al and Lv et al showed a favorable outcome in patients treated with CS for 6-month duration (4-7).These trials were limited by inconsistent about use of ACE inhibitors or ARBs as supportive care (4,5) or were temporarily halted and then reinitiated at baseline (6, 7).The studies by  (11).
In our study, group 1 did not benefit in terms of progression of CKD compared to group 2. There was a fall in eGFR by 0.46 (-0.1,-1.08)mL/min/1.73m 2 / month in group 1.So there was no benefit found to prevent progression of disease with use of steroids in patients with eGFR<50 mL/min/1.73m 2 .In group 2 (patients with eGFR >50 mL/min/1.73m 2 ), there was a significant benefit favoring use of steroids to prevent progression of disease.Since our study is a retrospective study, with patients being on both supportive care and CS, and there was no separate group which received intensive supportive care alone like in IgAN STOP study, we cannot conclude that steroids may be of benefit in comparison to supportive care alone in patients with eGFR >50mL/ min/1.73m 2 .In our study there was a reduction of proteinuria in both the groups irrespective of their eGFR.(Table 2).Since our patients were on ACE inhibitors /ARBs in addition to steroids, whether the benefit is due to supportive care (ACE inhibitors /ARBs) or addition of steroids, it is difficult to conclude.There were no major complications related to use of steroids in the study population.The infection rates were similar between the groups.

Conclusions
In IgAN patients with initial eGFR<50 mL/min/1.73m 2 , use of CS in addition to conservative treatment seems to reduce proteinuria but not beneficial in preventing progression of disease as compared to patients with higher eGFR (>50 mL/min/1.73m 2 ).However, there is need for larger prospective randomized controlled trials with long term follow-up to confirm the role of steroids in this subset of IgAN.

Limitations of the study
It is a retrospective study with a small study population and a short follow-up period.

Table 1 .
Comparison of baseline characteristics of patients between two groups

Table 1 .
Comparison of baseline characteristics of patients between two groups

Table 2 .
Outcomes at the end of follow-up between groups

50 mL/min/1.73 m 2 ) Group 2 (n=21)(%) (eGFR > 50 mL/min/1.73 m 2 ) P value
studies by Coppo et al, Praga et al and Li et al showed clear benefit of supportive care with the use of ACE inhibitors or ARBs in preventing progression of disease and proteinuria compared to placebo or other antihypertensive drugs (17-19).

Table 2 .
Outcomes at the end of follow-up between groupsAbbreviations: eGFR, estimated glomerular filtration rate; UPCR, urine protein-to-creatinine ratio.
a Median with interquartile range.
Coppo et al, Praga et al and Li et al showed clear benefit of supportive care with the use of ACE inhibitors or ARBs in preventing progression of disease and proteinuria compared to placebo or other antihypertensive drugs (17-19).