The Efficacy and Proper Doses of Steroid Pulse Therapy
inPatients with IgA Nephropathy
Tae Young Kim, Soon Bae Kim, Jung sik Park, Su-Kil Park
Division of Nephrology, Department of Internal Medicine,College of Medicine, University of Ulsan,
Asan Medical Center, Seoul, Korea
Correspondence: Su-Kil Park, M.D.
Division of Nephrology, Department of Internal Medicine,
Asan Medical Center, Seoul, Korea.
Phone:82-2-3010-3263
Fax:82-2-3010-6963
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BackgroundThe efficacy and proper doses of steroid pulse therapy in patients with immunoglobulin A nephropathy (IgAN) have not been established. We therefore investigated the effects of methylprednisolone (MP) pulse therapy in patients with histologically active IgAN and established renal impairment at the time of treatment.
Methods We assessed 22 patients (8 males, 14 females) with established renal impairment (stage 3 or under CKD and median eGFR, 34.05 ml/min/1.73m2) and active IgAN (median histological Grade 3). All patients had been maintained on an angiotensin receptor blocker or angiotensin-converting enzyme inhibitor. Patients were treated with 500mg intravenous MP every 2 weeks for 6 months to improve or stabilize renal function.The efficacy of MP pulse therapy was analyzed by comparing the slopes of the eGFR (ml/min/1.73m2) and log transformed urine albumin/creatinine ratios (mg/g) before, during, and after treatmentusing linear regression coefficients.
Results All patients completed the planned 6 months of MP pulse therapy. Linear regression analysis showed improvements in the monthly decline of eGFR in 16 of 22 patients (73%) after treatment. The rate of eGFR decline in the before treatment period differed significantly from that in the after treatment period (-0.931±0.871vs 0.141±0.998, P=0.007). Patients with initial eGFR ≥30 ml/min/1.73m2 showed significantly improved 10-month dialysis-free renal survival after MP pulse therapy (P= 0.040). In contrast, there was no improvement in urinary albumin to creatinine ratio (P=NS). MP pulse therapy was well tolerated, except for one patient with facial flushing and palpitation. There were no other serious adverse events during the study period.
Conclusions MP 500mg every 2 weeks for 6 months was safe and effective in patients with IgAN and preexisting renal dysfunction.
Key words: IgA nephropathy, proper doses of steroid, renal survival
Introduction
Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis[1], characterized by the presence of IgA-containing circulating immune complexes [2] and the glomerular deposition of IgA [3]. Although there is no specific treatment for this condition, immunosuppressive agents such as mycophenolate mofetil may be effective [4, 5, 6]. Due to their costs and adverse effects, however, immunosuppressive agents are rarely prescribed for patients with IgA nephropathy.
Although steroidshave been shown to reduce proteinuria and preserve renal function [2, 7, 8], their efficacy and proper doses have not been completely clarified. Low-dose prednisolone was shown to have anti-proteinuric activity but no effect on kidney survival [9]. We hypothesized that an insufficient dose of steroidswas ineffective in promoting kidney survival. Several randomized controlled trails have evaluated the role of steroid pulse therapy in patients with IgAN[9, 10], but, to our knowledge,none has compared estimated glomerular filtration rate (eGFR)decline before, during, and after treatment with steroid pulse therapy.We therefore prospectively investigated the effects of methylprednisolone (MP) 500mg every 2 weeks for 6 months on kidney survival and antiproteinuric effect, as measured by eGFR and urinary albumin to creatinine ratio, in 22 patients with histologicallyconfirmed IgANand stage 3 or under CKD.
Patients and Methods
During the years 2009-2010, we recruited 22 subjects with histologically confirmed IgANand renal function as stage 3 or under CKDwho were treated at Asan Medical Center,a 2,743-bed, tertiary referral, university hospital in Seoul, Korea.
All patients were maintained on an angiotensin II receptor blocker or an angiotensin converting enzyme inhibitor to achieve a normal blood pressure of < 130/80 mmHg and to reduce proteinuria. Patients were administered 500 mg MP intravenously every 2 weeks for 6 months,inaddition to their concurrent angiotensin II receptor blocker or angiotensin converting enzyme inhibitor. Additional antihypertensive drugs were allowedto achieve a normal blood pressure.Patients with glomerulopathiesother than IgAN, patients aged <20 years,those with systemic infection or malignancy,and women of childbearing agewho were pregnant, lactating, or unwilling to practice reliablecontraception were excluded.
The histological diagnosis of IgAN was based on the demonstrationof mesangioproliferative changes on light microscopy and thepresence of predominant mesangialdeposition of IgA. All renal biopsy samples werehistologically graded by a pathologist in accordance with the Haas classification.
Baseline examinations included a complete blood count, renal and liver biochemistries, urinary albumin to creatinine ratio (mg/g), and eGFR (ml/min/1.73m2). At each hospital visit, blood pressure,body weight, complete blood count, renal and liver biochemistries, urinary albumintocreatinine ratio, and eGFR were measured.Proteinuria was measured using the urinary albumin to creatinine ratio. Patients were assessed before treatment (median, 18 months; range 3-20 months), during treatment(6months), and after treatment (median, 6 months; range 4-14 months).
eGFR was calculated using the Modification of Diet in Renal Disease equation; 170 (PCr) -0.999 x (Age) -0.176 (x 0.762 for females).Dialysis-free survival after MP pulse therapy was compared in patients withinitial eGFR 30 ml/min/1.73m2 and ≥30 ml/min/1.73m2. Improved renal function was defined as an increase in the calculated linear regression coefficients ofchange of eGFR(slope of eGFR vs time plot) and a decrease in the calculated linear regression coefficients of change of urinary albumin to creatinine ratio (slope of urinary albumin to creatinine ratio vs time plot) over the study period. The study end point was defined as the time to start of dialysis.
Results were expressed as mean ± SD or median with range. Continuous variables werecompared using paired t-tests and categorical variables using χ2 tests.Urinary albumin to creatinine ratios were logarithmically transformed. The rates ofchange in eGFR (slope of eGFR vs time plot) and in log transformed urinary albumin to creatinine ratio (slope of urinary albumin to creatinine ratio vs time plot) over the study period were calculated for each patient by linear regression analysis.
The Kaplan-Meier method was used to calculate cumulativerenal survival, andcurves were compared using the log-rank test.Statistical significance for intergroup comparisons was defined as p <0.05. All statistical analyses were performed using the PASW statistical package (version 18) or GraphPad Prism (version 5) on a Windows personal computer.
Results
Table 1 shows the baseline clinical and demographic characteristics of the 22 IgAN patients. All 22 patients hadpersistent proteinuria (>400mg/24 h) despite adequatetreatment with an angiotensin blocker or an angiotensin converting enzyme inhibitor. Also, all patients had initial eGFR 60 ml/min/1.73m2 (stage 3 or under CKD) at the time of treatment.
All 22 patients completed the planned 6 months of MP pulsetherapy, and were followed up fora median 6 months (range 4 to 14 months) after therapy.All patientswere alive at the end of follow-up.Only 2of 22 patients (9%) developed progressive renal failure and required dialysis. Of these 22 patients, 6 (27%) had initial eGFR 30 ml/min/1.73m2 and 16 (73%) had initial 30 ≤eGFR< 60 ml/min/1.73m2 at the time of treatment.These 2 subgroups differed significantly in10-month dialysis-free renal survival rate(53% vs. 100%, P= 0.040; Figure 1).
The rates of eGFRdecline in each patient before, during and after treatment, as determined by linearregression analysis, are shown inFigure 2.Of the 22 patients, 16(73%)showed improvements ineGFR (slope of eGFR vs time plot) after treatment compared with before treatment.The rates of eGFR declinewere significantly more rapid before than after treatment (-0.931±0.871 vs 0.141±0.998, P=0.007) and before than duringtreatment (P=0.001).
When we compared patients withinitial eGFR 30 ml/min/1.73m2 and ≥30 ml/min/1.73m2 , we found thatthe latter group showed significantly greater improvements in rates of eGFR decline than theformerafter MP pulse therapy (P=0.025).
In contrast to changes in eGFR, we observed no significant differences in the rate of change of log transformed urinary albumin to creatinine ratio before, during, and after treatment (P= NS) (Figure 3).
MP pulse therapy was generally well tolerated, except that one patient had mild facial flushing and palpitation.All patients completed the planned 6 months oftreatment, with none having a serious adverse event throughout the study period.
Discussions
Steroids are frequently used to treat patients with IgA nephropathy [2, 7, 8, 9, 11, 12], with MP pulse therapy shown to prevent progression in patientswith IgAN[10]. This study, however,is the first to compare rates of eGFRdecline before, during and after MP pulse therapy (500mg every 2 weeks for 6 months) in individual patients.
At a median follow-up of 6 months (range 4 to 14 months), we found that patients who received MP pulse therapy had a renal survival advantage. Of our 22 patients, 16(73%)showed improvements in the rates of eGFR decline (slope of eGFR vs time plot) after than before treatment.
The rates of eGFR decline were significantly lowerafter than before treatment. The exact mechanisms by which steroids alter the course ofIgAN are still unclear.One hypothesis is that theyreduce proliferative lesions during the acute phase of the disease,thus limiting the development of glomerular sclerosis andtubular fibrosis[7, 13]
Most studies investigating the efficacy of steroid pulse therapy in patients with IgAN have used steroid pulse doses of 1 g per day [8, 10, 12]. Although two of these studies did not report the adverse effects of these doses, another study reported that adverse effectsinclude steroid induced psychosis, aseptic necrosis of the medial epicondyle of the femoral bone, diabetes mellitus, herpes zoster and tuberculosis of cervical lymph nodes[12]. In contrast, we found that MP 500mg every 2 weeks for 6 months was well tolerated, except that one patient had mild facial flushing and palpitation, but without abnormal laboratory or clinical signs, at the second administration of MP.All patients completed the planned 6 months treatment, with no serious adverse events.
We also observed that the 10 month dialysis-free renal survival rate differed significantly between patients with initial eGFR 30 ml/min/1.73m2 and ≥30 ml/min/1.73m2 suggesting that baseline eGFR is an important predictor of response to steroid pulse therapy.
In contrast to improvements in eGFR, we found that MP pulse therapy had no effect on urinary albumin to creatinine ratio, suggesting that treatment did not have an anti-proteinuric effect but rather maintained the pre-existing degree of proteinuria. However, this treatment did not worsenproteinuria in any of these patients.A low-dose prednisolone protocol (20 mg/day) showed only an anti-proteinuric effect but no effect on kidney survival[2, 9].Moreover, thislow-dose prednisolone protocoldid not have an anti-proteinuric effect in patientswith massive proteinuria.
Our study had several limitations,including the small number of patients and relativelyshort follow-up period. Larger, longer term trials are needed to determine whether MP pulse therapy improves renal survival and anti-proteinuric responses. Although histological grades were not sensitive in predicting patientoutcomes,no follow-up biopsies were performed.
The course of IgAN is extremely variable, with patientsshowing very different rates of progression to end stage renal disease and somepatients with renal function deterioration at diagnosis show nodisease progression, even after decades. Thismakes it verydifficult to assess the effectiveness of any therapeutic approach.However, our results suggest that MPpulse therapy may delay the beginning of dialysis without significant side effects in IgAN patients with stage 3CKD(30 ≤eGFR 60ml/min/1.73m2). The decision to commence steroid treatment should therefore not be based on histologic scores,at least in IgAN patients with stage 3 or under CKD.
In conclusion, MP pulse therapy (500mg every 2 weeks for 6 months)seems safe and effective in patients with IgAN and preexisting renal dysfunction.
Table 1. Baseline clinical and histological characteristics of study population
Characteristic / Treated group(n=22)
Clinical parameter
Age (years) / 42.5 ± 9.8
Men / women / 8 / 14
On ACEi / on ARB
Valsartan, n (mg/day) / 16 (87.5±30)
Losartan, n (mg/day) / 4 (50±35)
Imidapril, n (mg/day) / 2 (10)
Estimated GFR (ml/min/1.73m2) / 35.42 ± 12.23
Urine albumin to creatinine ratio (mg/g) / 1,707 ±1,597
Duration of follow-up (pre-treatment, months) / 18 (3-20)
Duration of follow-up (post-treatment, months) / 6 (4-14)
Histological grading, n (%)
Grade I / 1 (5)
Grade II / 2 (9)
Grade III / 10 (45)
Grade IV / 3 (14)
Grade V / 6 (27)
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker
Duration of follow-up reported as median (range).
Plus-minus values are means ±s.e.
Histological grade was determined in accordance with the Haas classification.
Figure 1.Kaplan-Meier analysis of dialysis-free survival of 22 IgA patients over 15-month follow-up after methylprednisolone pulse therapy.
Figure 2. Monthly changes in eGFR. The rates of change in eGFR before, during, and after treatment were calculated for each patient by linear regression analysis. The median changes in eGFR, indicated by the horizontal lines, were -0.669 ml/min/1.73m2 per month beforetreatment, 0.332 ml/min/1.73m2 per month duringtreatment and -0.172 ml/min/1.73m2 per month after treatment.
Figure 3. Monthly change in log albumin to creatinine ratio. The rates of change in log albumin to creatinine ratio over the study period were calculated for each patient by linear regression analysis. The median changes in log albumin to creatinine ratio, indicated by the horizontal lines, were -0.01 per month before, -0.007 per month during and -0.002 per month after treatment.
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