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Nephrology 19 (2014) 94–100
Original Article
Leflunomide in addition to steroids improves proteinuria and renal function in adult Henoch-Schoenlein nephritis with nephrotic proteinuria YINGJUAN ZHANG,1 YUN GAO,2 ZHENGXIU ZHANG,1 GAOLUN LIU,1 HONGBING HE1 and LING LIU1 Departments of 1Nephrology and 2Hematology and Oncology, Panzhihua Central Hospital, Panzhihua City, China
KEY WORDS: adult, Henoch-Schoenlein nephritis, leflunomide, steroids, therapy. Correspondence: Mrs Yingjuan Zhang, Department of Nephrology, Panzhihua Central Hospital, no. 34. Yikang street, Easten district of Panzhihua City, Panzhihua City, Sichuan Province 617067, China. Email: [email protected] Accepted for publication 28 October 2013. Accepted manuscript online 31 October 2013 doi:10.1111/nep.12175
SUMMARY AT A GLANCE The study is a retrospective review on the effect of leflunomide given in addition to steroids on the renal outcomes of HSP nephritis. Treatment of HSP nephritis is not well defined, and the study, though associated with its innate flaws, provides novel information on a poorly researched topic.
ABSTRACT: Aim: Henoch-Schoenlein nephritis (HSPN) is a severe disease in adults and may cause renal insufficiency in a large portion of patients. But its rarity has led to lack of data. There are few controlled studies on therapy with immunosuppressants in HSPN adults. This study aims to evaluate the effect of leflunomide on HSPN adults with nephrotic proteinuria. Methods: We retrospectively studied 65 adult patients who had biopsyproven HSPN with nephrotic proteinuria. Twenty-seven patients (Group P) only received steroids, and 38 (Group P + L) were treated with leflunomide in addition to steroids. The clinical features, laboratory data and pathological findings of both groups were analyzed. Results: The two groups were well-matched at baseline. After 24 months of treatment, urinary protein excretion of both groups decreased significantly from the baseline, and the estimated glomerular filtration rate (eGFR) was higher in Group P + L. Four patients in Group P and three in Group P + L developed to end-stage renal disease at the most recent follow-up. Group P + L showed better renal outcome than Group P. The treatment group and the degree of mesangial hypercellularity were significantly related to renal prognosis. Conclusion: Leflunomide combined with steroids is effective for treating adult HSPN with nephrotic proteinuria.
Henoch-Schoenlein purpura (HSP) is a systemic vasculitic disorder mediated by immunoglobin (Ig)A that predominantly affects the skin, joints, gastrointestinal tract and kidney. HSP primarily affects children and is less common in adults (22.11 vs. 1.32 per 100 000 population). The longterm prognosis of HSP is mainly predicted by renal involvement. The incidence of renal involvement in adults varies from 44% to 84% of cases.3–7 Nearly all patients present with microscopic haematuria or macroscopic haematuria, and 20–30% of them have nephrotic range proteinuria.6,7 The risk of progression to renal insufficiency is about 30%.6,7 Since proteinuria has been found to be an independent risk factor for severe renal failure,6 patients with massive proteinuria seem to have even worse renal prognosis. 94
The management of Henoch-Schoenlein nephritis (HSPN) remains controversial. In children, corticosteroids have been proposed in patients with renal impairment,8 while immunosuppressants plus corticosteroids improve renal prognosis in severe cases.9–11 In adults, drugs such as cyclosporine, cyclophosphamide and mycophenolate mofetil have been used alone or in combination with other therapy to treat severe HSPN.12–14 Results are conflicting and most of the studies are uncontrolled. Overall, there is still a lack of data in the treatment of HSPN adults. Leflunomide (N-(4-trifluoromethylphenyl)-5-methylisoxazol4-carboxamide) is a novel immunomodulating agent, specifically inhibiting the formation of T-dependent autoantibidies15 and has been used to treat proliferative lupus nephritis16 and IgA nephritis.17 In this study, we evaluated the efficacy of © 2013 Asian Pacific Society of Nephrology
Leflunomide improves renal function in adult HSPN
(CKD) guidelines. End-stage renal disease (ESRD) was defined as eGFR < 15 mL/min per 1.73 m2 or dialysis required.
Pathology
Fig. 1 Selection of patients from April 2002 to May 2009.
Leflunomide in HSPN adults with nephrotic proteinuria for the first time, and compared the post-treatment renal outcomes between steroids alone and steroids plus leflunomide.
METHODS Patients Data were collected from 65 patients, diagnosed with HSPN in the Department of Nephrology of Panzhihua Central Hospital between April 2002 and May 2009. The entry criteria were: (i) age of 18–80 year at onset of disease; (ii) a diagnosis of HSPN, suspected when haematuria, proteinuria, and/or renal failure were associated with a characteristic purpuric eruption and/or abdominal or joint pains (at least two of the three clinical signs); (iii) Predominant mesangial IgA immune deposits on renal biopsy; (iv) proteinuria ≥3.5 g/24 h in at least two separate urine specimens; and (v) no previous treatment with steroids or immunosuppressants. We excluded patients suffering from IgA nephropathy without systemic signs, those with nephropathy and purpuric rash associated with other diseases, i.e., systemic lupus erythematosus and cryoglobulinaemia, and those with thrombocytopaenia ( 0.5; S0, absence of segmental glomeruloscleorosis (SGS); S1, presence of SGS; E0, absence of endocapillary hypercellularity (EHC); E1, presence of EHC; T0, T1 and T2, tubular atrophy or interstitial fibrosis in 0–25%, 26–50% and >50% of cortical area respectively. In addition, the prevalence of crescents was evaluated as C0, C1 and C2 for crescents in no, < 50%, and ≧50% of glomeruli, respectively.
Therapeutic intervention All patients were treated with intravenous methylprednisolone at 0.5 or 1 g/day for 3 days, followed by oral prednisone. Group P + L received leflunomide orally with a loading dose of 50 mg/day for 3 days followed by 20 mg/day for 12–18 months in addition to steroids. Both groups were also treated with dipyridamole (150 mg/ day). Antihypertensives or/and insulin were prescribed if hypertension or/and diabetes mellitus existed.
Outcome We evaluated the outcome of each patient, as of the reference date of 1 July 2011. For patients who died, the cause of death and the renal status upon death were determined. When patients were lost to follow-up, their renal status at the last visit was recorded. Outcome was classified as remission when, in absence of extra-renal involvement, eGFR was stable (at >60 mL/min per 1.73 m2) without significant proteinuria or haematuria in two or more clinic assessments. The end point was 30% reduction in initial eGFR.
Statistical analysis Results were expressed as numbers (percentages) for categorical variables and as median (first quartile to third quartile) or mean (±standard deviation) for continuous variables. Categorical variables were compared by χ2 test or Fisher’s exact test and continuous variables were by Wilcoxon test or Student’s t-test. Renal outcome and overall survival rate were calculated using Kaplan–Meier estimation. A Cox model was fit to evaluate the effects of the following variables on renal outcome: age, hypertension, diabetes, eGFR at baseline, urinary protein excretion, massive haematuria, renal pathological lesions, and the treatment group. Stepwise forward selection was used for model selection. All tests were two-tailed, and P < 0.05 was considered as significant. Statistical analyses were performed on SPSS 13.0. 95
Y Zhang et al.
Table 2 Pathological lesions of patients at baseline
Table 1 Characteristics of patients at baseline Steroids
Steroids + leflunomide
n 27 38 Male : Female 15 : 12 24 : 14 Age (years), mean (SD) 51.2 (14.7) 48.2 (12.7) Recent history of infection, n (%) 10 (37%) 15 (39%) Hypertension, n (%) 6 (22%) 3 (8%) Diabetes, n (%) 3 (11%) 2 (5%) Blood pressure (mmHg), mean 127/73 123/71 Skin lesion, n (%) 26 (96%) 37 (97%) Gastrointestinal involvement, n (%) 14 (52%) 18 (47%) Joint manifestations, n (%) 15 (56%) 22 (58%) Biological tests IgA (g/L), median (25%–75%) 4.7 (1.3–12.5) 5.3 (0.9–13.2) Creatinine (μmol/L), median 89 (71–98) 93 (83–112) (25%–75%) Albumin (g/L), mean (SD) 23 (5.3) 22.1 (4.8) Proteinuria (g/24 h), median 8.0 (5.5–8.7) 7.8 (6.3–9.0) (25–75%) Haematuria, n (%) 27 (100%) 38 (100%) Massive haematuria, n (%) 7 (26%) 11 (29%) 61.2 (17.7) 58.2 (17.4) eGFR (mL/min per 1.73 m2), mean (SD) KDOQI staging Stage 1, n (%) 0 0 Stage 2, n (%) 16 (59%) 22 (58%) Stage 3, n (%) 9 (33%) 11 (29%) Stage 4, n (%) 2 (7%) 5 (13%) Stage 5, n (%) 0 0
P-value
0.39 0.20 0.69
0.22 0.15 0.49 0.49
0.51 0.87
Steroids n Pathological lesions M0, n (%) M1, n (%) S0, n (%) S1, n (%) E0, n (%) E1, n (%) T0, n (%) T1, n (%) C0, n (%) C1, n (%) C2, n (%)
Steroids + leflunomide
27
38
4 (14.8%) 23 (85.2%) 8 (29.6%) 19 (70.4%) 3 (11.1%) 24 (88.9%) 21 (77.8%) 6 (22.2%) 1 (3.7%) 13 (48.1%) 13 (48.1%)
5 (13.2%) 33 (86.8%) 10 (26.3%) 28 (73.7%) 6 (15.8%) 32 (84.2%) 32 (84.2%) 6 (15.8%) 0 16 (42.1%) 22 (57.9%)
P-value
1 0.77 0.86 0.74 0.43
eGFR was 61.2 (± 17.7) vs. 58.2 (± 17.4) mL/min per 1.73 m2 (P = 0.51). A similar proportion of patients in each group had eGFR
Nephrology 19 (2014) 94–100
Original Article
Leflunomide in addition to steroids improves proteinuria and renal function in adult Henoch-Schoenlein nephritis with nephrotic proteinuria YINGJUAN ZHANG,1 YUN GAO,2 ZHENGXIU ZHANG,1 GAOLUN LIU,1 HONGBING HE1 and LING LIU1 Departments of 1Nephrology and 2Hematology and Oncology, Panzhihua Central Hospital, Panzhihua City, China
KEY WORDS: adult, Henoch-Schoenlein nephritis, leflunomide, steroids, therapy. Correspondence: Mrs Yingjuan Zhang, Department of Nephrology, Panzhihua Central Hospital, no. 34. Yikang street, Easten district of Panzhihua City, Panzhihua City, Sichuan Province 617067, China. Email: [email protected] Accepted for publication 28 October 2013. Accepted manuscript online 31 October 2013 doi:10.1111/nep.12175
SUMMARY AT A GLANCE The study is a retrospective review on the effect of leflunomide given in addition to steroids on the renal outcomes of HSP nephritis. Treatment of HSP nephritis is not well defined, and the study, though associated with its innate flaws, provides novel information on a poorly researched topic.
ABSTRACT: Aim: Henoch-Schoenlein nephritis (HSPN) is a severe disease in adults and may cause renal insufficiency in a large portion of patients. But its rarity has led to lack of data. There are few controlled studies on therapy with immunosuppressants in HSPN adults. This study aims to evaluate the effect of leflunomide on HSPN adults with nephrotic proteinuria. Methods: We retrospectively studied 65 adult patients who had biopsyproven HSPN with nephrotic proteinuria. Twenty-seven patients (Group P) only received steroids, and 38 (Group P + L) were treated with leflunomide in addition to steroids. The clinical features, laboratory data and pathological findings of both groups were analyzed. Results: The two groups were well-matched at baseline. After 24 months of treatment, urinary protein excretion of both groups decreased significantly from the baseline, and the estimated glomerular filtration rate (eGFR) was higher in Group P + L. Four patients in Group P and three in Group P + L developed to end-stage renal disease at the most recent follow-up. Group P + L showed better renal outcome than Group P. The treatment group and the degree of mesangial hypercellularity were significantly related to renal prognosis. Conclusion: Leflunomide combined with steroids is effective for treating adult HSPN with nephrotic proteinuria.
Henoch-Schoenlein purpura (HSP) is a systemic vasculitic disorder mediated by immunoglobin (Ig)A that predominantly affects the skin, joints, gastrointestinal tract and kidney. HSP primarily affects children and is less common in adults (22.11 vs. 1.32 per 100 000 population). The longterm prognosis of HSP is mainly predicted by renal involvement. The incidence of renal involvement in adults varies from 44% to 84% of cases.3–7 Nearly all patients present with microscopic haematuria or macroscopic haematuria, and 20–30% of them have nephrotic range proteinuria.6,7 The risk of progression to renal insufficiency is about 30%.6,7 Since proteinuria has been found to be an independent risk factor for severe renal failure,6 patients with massive proteinuria seem to have even worse renal prognosis. 94
The management of Henoch-Schoenlein nephritis (HSPN) remains controversial. In children, corticosteroids have been proposed in patients with renal impairment,8 while immunosuppressants plus corticosteroids improve renal prognosis in severe cases.9–11 In adults, drugs such as cyclosporine, cyclophosphamide and mycophenolate mofetil have been used alone or in combination with other therapy to treat severe HSPN.12–14 Results are conflicting and most of the studies are uncontrolled. Overall, there is still a lack of data in the treatment of HSPN adults. Leflunomide (N-(4-trifluoromethylphenyl)-5-methylisoxazol4-carboxamide) is a novel immunomodulating agent, specifically inhibiting the formation of T-dependent autoantibidies15 and has been used to treat proliferative lupus nephritis16 and IgA nephritis.17 In this study, we evaluated the efficacy of © 2013 Asian Pacific Society of Nephrology
Leflunomide improves renal function in adult HSPN
(CKD) guidelines. End-stage renal disease (ESRD) was defined as eGFR < 15 mL/min per 1.73 m2 or dialysis required.
Pathology
Fig. 1 Selection of patients from April 2002 to May 2009.
Leflunomide in HSPN adults with nephrotic proteinuria for the first time, and compared the post-treatment renal outcomes between steroids alone and steroids plus leflunomide.
METHODS Patients Data were collected from 65 patients, diagnosed with HSPN in the Department of Nephrology of Panzhihua Central Hospital between April 2002 and May 2009. The entry criteria were: (i) age of 18–80 year at onset of disease; (ii) a diagnosis of HSPN, suspected when haematuria, proteinuria, and/or renal failure were associated with a characteristic purpuric eruption and/or abdominal or joint pains (at least two of the three clinical signs); (iii) Predominant mesangial IgA immune deposits on renal biopsy; (iv) proteinuria ≥3.5 g/24 h in at least two separate urine specimens; and (v) no previous treatment with steroids or immunosuppressants. We excluded patients suffering from IgA nephropathy without systemic signs, those with nephropathy and purpuric rash associated with other diseases, i.e., systemic lupus erythematosus and cryoglobulinaemia, and those with thrombocytopaenia ( 0.5; S0, absence of segmental glomeruloscleorosis (SGS); S1, presence of SGS; E0, absence of endocapillary hypercellularity (EHC); E1, presence of EHC; T0, T1 and T2, tubular atrophy or interstitial fibrosis in 0–25%, 26–50% and >50% of cortical area respectively. In addition, the prevalence of crescents was evaluated as C0, C1 and C2 for crescents in no, < 50%, and ≧50% of glomeruli, respectively.
Therapeutic intervention All patients were treated with intravenous methylprednisolone at 0.5 or 1 g/day for 3 days, followed by oral prednisone. Group P + L received leflunomide orally with a loading dose of 50 mg/day for 3 days followed by 20 mg/day for 12–18 months in addition to steroids. Both groups were also treated with dipyridamole (150 mg/ day). Antihypertensives or/and insulin were prescribed if hypertension or/and diabetes mellitus existed.
Outcome We evaluated the outcome of each patient, as of the reference date of 1 July 2011. For patients who died, the cause of death and the renal status upon death were determined. When patients were lost to follow-up, their renal status at the last visit was recorded. Outcome was classified as remission when, in absence of extra-renal involvement, eGFR was stable (at >60 mL/min per 1.73 m2) without significant proteinuria or haematuria in two or more clinic assessments. The end point was 30% reduction in initial eGFR.
Statistical analysis Results were expressed as numbers (percentages) for categorical variables and as median (first quartile to third quartile) or mean (±standard deviation) for continuous variables. Categorical variables were compared by χ2 test or Fisher’s exact test and continuous variables were by Wilcoxon test or Student’s t-test. Renal outcome and overall survival rate were calculated using Kaplan–Meier estimation. A Cox model was fit to evaluate the effects of the following variables on renal outcome: age, hypertension, diabetes, eGFR at baseline, urinary protein excretion, massive haematuria, renal pathological lesions, and the treatment group. Stepwise forward selection was used for model selection. All tests were two-tailed, and P < 0.05 was considered as significant. Statistical analyses were performed on SPSS 13.0. 95
Y Zhang et al.
Table 2 Pathological lesions of patients at baseline
Table 1 Characteristics of patients at baseline Steroids
Steroids + leflunomide
n 27 38 Male : Female 15 : 12 24 : 14 Age (years), mean (SD) 51.2 (14.7) 48.2 (12.7) Recent history of infection, n (%) 10 (37%) 15 (39%) Hypertension, n (%) 6 (22%) 3 (8%) Diabetes, n (%) 3 (11%) 2 (5%) Blood pressure (mmHg), mean 127/73 123/71 Skin lesion, n (%) 26 (96%) 37 (97%) Gastrointestinal involvement, n (%) 14 (52%) 18 (47%) Joint manifestations, n (%) 15 (56%) 22 (58%) Biological tests IgA (g/L), median (25%–75%) 4.7 (1.3–12.5) 5.3 (0.9–13.2) Creatinine (μmol/L), median 89 (71–98) 93 (83–112) (25%–75%) Albumin (g/L), mean (SD) 23 (5.3) 22.1 (4.8) Proteinuria (g/24 h), median 8.0 (5.5–8.7) 7.8 (6.3–9.0) (25–75%) Haematuria, n (%) 27 (100%) 38 (100%) Massive haematuria, n (%) 7 (26%) 11 (29%) 61.2 (17.7) 58.2 (17.4) eGFR (mL/min per 1.73 m2), mean (SD) KDOQI staging Stage 1, n (%) 0 0 Stage 2, n (%) 16 (59%) 22 (58%) Stage 3, n (%) 9 (33%) 11 (29%) Stage 4, n (%) 2 (7%) 5 (13%) Stage 5, n (%) 0 0
P-value
0.39 0.20 0.69
0.22 0.15 0.49 0.49
0.51 0.87
Steroids n Pathological lesions M0, n (%) M1, n (%) S0, n (%) S1, n (%) E0, n (%) E1, n (%) T0, n (%) T1, n (%) C0, n (%) C1, n (%) C2, n (%)
Steroids + leflunomide
27
38
4 (14.8%) 23 (85.2%) 8 (29.6%) 19 (70.4%) 3 (11.1%) 24 (88.9%) 21 (77.8%) 6 (22.2%) 1 (3.7%) 13 (48.1%) 13 (48.1%)
5 (13.2%) 33 (86.8%) 10 (26.3%) 28 (73.7%) 6 (15.8%) 32 (84.2%) 32 (84.2%) 6 (15.8%) 0 16 (42.1%) 22 (57.9%)
P-value
1 0.77 0.86 0.74 0.43
eGFR was 61.2 (± 17.7) vs. 58.2 (± 17.4) mL/min per 1.73 m2 (P = 0.51). A similar proportion of patients in each group had eGFR
