|Year : 2018 | Volume
| Issue : 2 | Page : 66-73
Response of calcineurin inhibitors therapy in frequently relapsing and steroid resistent nephrotic syndrome: A single-center experience
Umesh Godhani1, Manish R Balwani2, Dinesh Gera3, Praveen Ghule4, Rajesh Singh5, Vivek Kute3
1 Department of Nephrology, Devasya Kidney Hospital, Ahmedabad, Gujarat, India
2 Department of Nephrology, Jawaharlal Nehru Medical College, Sawangi, Maharashtra, India
3 Department of Nephrology, IKDRC and ITS, BJMC, Ahmedabad, Gujarat, India
4 Department of Nephrology, Aster Aadhar Hospital, Kolhapur, Maharashtra, India
5 Department of Nephrology, Merck Hospital, Bilaspur, Chhattisgarh, India
|Date of Web Publication||11-Oct-2018|
Dr. Manish R Balwani
Department of Nephrology, Jawaharlal Nehru Medical College, Sawangi - 442 001, Maharashtra
Source of Support: None, Conflict of Interest: None
Background and Objectives: This observational study was conducted to evaluate and compare the efficacy of calcineurin inhibitors in frequently relapsing nephrotic syndrome (FRNS) and steroid-resistant nephrotic syndrome (SRNS). Subjects and Methods: Each group comprised 15 patients who were studied prospectively. These patients were treated with tacrolimus (Tac) or cyclosporine (CSA) concomitant with prednisone, which was subsequently tapered off and stopped. The primary outcome variable was the number of patients who attained a complete remission (CR) or partial remission (PR). Results: Out of 15 patients with FRNS, 11 were children and 4 were adults. In SRNS, out of total 15 patients 7 were children and 8 were adults. There was male preponderance in FRNS children, whereas in SRNS, gender distribution was almost equal. Hypertension was more common in steroid-resistant group (80%) as compared to FRNS (33%). In FRNS, focal segmental glomerulosclerosis (FSGS), and immunoglobulin M variant of minimal change disease were the most common cause, each accounting for 5 patients, whereas FSGS (8 patients) was the most common etiology in SRNS. In FRNS, out of total 4 patients who were treated with CSA, 2 achieved CR and 2 achieved PR. Mean time to achieve remission was 3.2 months. In FRNS, out of 13 patients who were treated by Tac, 7 patients achieved CR and 6 patients achieved PR. Mean time to achieve remission was 2.1 months. In SRNS, out of 3 patients treated with CSA, 1 achieved PR whereas 2 patients did not respond. Time to achieve remission was 5 months. In SRNS, 11 of 14 patients achieved CR and 2 achieved PR. Mean time to achieve remission was 2.5 months. Among 2 patients resistant to CSA 1 achieved CR with Tac and one did not respond to Tac also. Conclusion: Thus, in FRNS patients, both CSA and Tac are almost equally effective whereas in SRNS patients Tac was more effective than CSA and was also effective in 1 patient resistant to CSA.
Keywords: Complete remission, cyclosporine, frequently relapsing mephrotic syndrome, partial remission, steroid-resistant nephrotic syndrome, tacrolimus
|How to cite this article:|
Godhani U, Balwani MR, Gera D, Ghule P, Singh R, Kute V. Response of calcineurin inhibitors therapy in frequently relapsing and steroid resistent nephrotic syndrome: A single-center experience. J Integr Nephrol Androl 2018;5:66-73
|How to cite this URL:|
Godhani U, Balwani MR, Gera D, Ghule P, Singh R, Kute V. Response of calcineurin inhibitors therapy in frequently relapsing and steroid resistent nephrotic syndrome: A single-center experience. J Integr Nephrol Androl [serial online] 2018 [cited 2019 Jul 15];5:66-73. Available from: http://www.journal-ina.com/text.asp?2018/5/2/66/243121
| Introduction|| |
The nephrotic syndrome (NS) refers to a classic triad of proteinuria 3.5 g/day/1.73 m2 (in practice >3–3.5 g/day), hypoalbuminemia (<3 g/dL), and edema. Most patients also presents with hypercholestrolemia. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) GN guidelines defines NS as edema, 3+ protein on urine dipstick or 24 h urinary protein >3.5 g/day for adults or >40 mg/h/m2 for children or urine protein creatinine ratio (uPCR) >2000 mg/g and hypoalbuminaemia <2.5 g/dL. Based on the underlying disorder, the NS is classified as follows: (a) primary nephrotic syndrome, (b) inflammatory glomerular lesions, and (c) glomerulopathy secondary to a disease affecting the kidneys. Approximately 80% of children have primary NS as opposed to only 25% in adults. Primary NS is defined as clinical picture of NS that occurs in the absence of evidence of glomerulonephritis or systemic disease that would be sufficient to account for massive proteinuria. Primary NS includes minimal change disease (MCD) and its variants (mesengial proliferation and immunoglobulin M (IgM) deposition); diffuse mesengial sclerosis which usually presents as congenital nephrotic syndrome, focal segmental glomerulosclerosis (FSGS) and collapsing glomerulopathy. Idiopathic NS has an incidence of 2–7 cases per 100,000 and a prevalence of 16 cases per 100,000. MCD remains the most common cause of NS in children, with a peak incidence at 2–4 years of age. Corticosteroid remains the mainstay of therapy for idiopathic primary NS in both children and adults. With corticosteroid therapy, 80%–90% of patients with childhood NS achieve complete remission (CR)., However, 80%–90% of these children have one or more relapses, following the 2-month steroid regimen proposed by the International Study of Kidney Disease in Children. To achieve long-term remission and avoid steroid toxicity, these patients require steroid sparing agents, which includes alkylating agents, calcineurin inhibitors (CNIs), mycophenolate mofetil, or levamsole. With this background, present study was undertaken to know clinical profile, underlying different etiologies with special emphasis to CNIs as a treatment options for frequent relapsing and steroid-resistant nephrotic syndrome (SRNS) in both children and adults.
| Materials and Methods|| |
The present study was an observational analysis of 30 patients with frequently relapsing nephrotic syndrome (FRNS) or SRNS treated with CNIs (cyclosporine [CSA] or tacrolimus [Tac]) in addition to low dose steroid therapy presenting to the Institute of Kidney Diseases and Research Center– Institute of Transplantation Sciences, Ahmedabad. Patients were studied prospectively. A detailed history was recorded in each case including age, sex, and present illness, duration of present illness, past illness, treatment taken, personal and family history along with other demographic and anthropometric profile. Thorough clinical examination was followed by detailed laboratory investigations which included proteinuria estimation, kidney function tests, serum protein levels, serum cholesterol levels, hepatitis B virus surface antigen, hepatitis C virus, HIV seropositivity. All patients fulfilled the criteria for NS as defined by KDIGO. Ethics committee approved the study. After consent, renal biopsy was performed on enrolled patients. All biopsy samples were interpreted by in-house pathologist. CSA or Tac were initiated along with low dose of steroids subsequently in subset of patients.
Relapse was defined in children as 3+ or more protein on urine dipstick for three consecutive days or uPCR >2000 mg/g (>200 mg/mmol) or >40 mg/m2/h and in adults as Proteinuria >3.5 g/day occurring after CR has been obtained for >1 month. Infrequent relapse was defined as one relapse within 6 months of initial response or one to three relapses in any 12-month period. Frequent relapse was defined as two or more relapses within 6 months of initial response, or four or more relapses in any 12-month period. Steroid resistance was defined in children as failure to achieve CR after 8 weeks of full dose corticosteroid therapy (prednisolone 60 mg/m2/day) and in adults as persistence of proteinuria despite prednisone therapy 1 mg kg/day for 4 months. Steroid dependence was defined as two consecutive relapses during corticosteroid therapy, or relapse within 14 days of ceasing therapy. Late non responder was defined as persistent proteinuria during 4 or more weeks of corticosteroids following one or more remissions. Majority of patients received Tac, whereas few patients were put on CSA. In case of failure of CSA treatment, trial with Tac was given. CSA was used in a dose of 3–4 mg/kg to maintain a trough level (C0) 80–150 ng/mL. Tac was used in a dose of 0.05–0.08 mg/kg to maintain a trough level 5–10 ng/mL. Low dose corticosteroid therapy (5–10 mg/day) was continued with CNI therapy. After a period of 6–8 months steroids were tapered wherever possible. Patients were monitored with monthly urinary dipstick test. Kidney function tests and serum protein estimation were performed three monthly. 24 h urine protein estimation was used in patients for assessment of proteinuria. Patients who did not achieve CR or partial remission (PR) at 6 months were discontinued of CNI therapy, and were considered as treatment failure.
Treatment outcome was defined as following:
24 h urine protein <300 mg/day or <1+ protein on urine dipstick for three consecutive days.
Proteinuria reduction of 50% or greater from baseline value and absolute 24 h urine protein excretion between 300 mg and 3.5 g/day.
Failure/calcineurin inhibitor resistance
Failure to achieve CR or PR with 6 months of therapy.
Calcineurin inhibitors dependence
Two consecutive relapses during CNI therapy or within 2 weeks of ceasing therapy.
Patients who achieved CR or PR within 6 months were continued on CNI for 1 year withdrawal or tapering was attempted after 1 year of therapy in patients who were at least 3 months in remission.
| Results|| |
Out of 30 patients included in the study, 15 (50%) had FRNS and 15 (50%) had SRNS. They were evaluated for demographics, histology, and various parameters and response to CNI (CSA or Tac) therapy.
Out of 15 patients with FRNS, 11 (73%) were children and only 4 (27%) were adults. 10 out of 11 (90%) children with FRNS were male. There was male preponderance in FRNS children [Figure 1].
|Figure 1: Age and gender distribution of frequently relapsing nephrotic syndrome. yrs: years|
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In SRNS, out of total 15 patients 7 were children and 8 were adults. And almost equal sex distribution was seen [Figure 2].
|Figure 2: Age and gender distribution of steroid-resistant nephrotic syndrome. yrs: years|
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Clinical presentation of FRNS and SRNS was different in children and adult patients [Figure 3] and [Figure 4]. Majority of children (72%) had florid presentation with ascites and anasarca and 44% children had oliguria. Most adults presented with edema face and feet and only one patient presented with ascites, anasarca, and oliguria. Hypertension was more common in steroid-resistant group (80%) as compared to FRNS (33%). Children had more severe proteinuria per body surface area (4.2 g/m2/d) as compared to adults (2.9 g/m2/d) and more severe hypoalbuminemia at baseline [Table 1].
|Table 1: Mean proteinuria, serum albumin, renal function and serum cholesterol before starting calcineurin inhibitors therapy|
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Renal histology in frequently relapsing nephrotic syndrome
Out of total 15 patients with FRNS, FSGS, and IgM variant of MCD were the most common histology, each accounting for 5 patients. Next common etiology was MCD (27%) and mesangial proliferative glomerulonephritis (MePGN) was the least common among FRNS patients (8%). One patient with FRNS had previous renal biopsy suggestive of MCD which on subsequent biopsy showed IgM nephropathy [Figure 5].
|Figure 5: Renal histology in frequently relapsing nephrotic syndrome. MCD: Minimal change disease, FSGS: Focal segmental glomerulosclerosis|
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Renal histology in steroid-resistant nephrotic syndrome patients
FSGS was the most common etiology for SRNS in our study (8 patients), followed by MePGN and IgM nephropathy and then MCD (6%). One patient with MCD was found to have MePGN on subsequent biopsy [Figure 6].
|Figure 6: Renal histology in steroid-resistant nephrotic syndrome. MCD: minimal change disease, FSGS: focal segmental glomerulosclerosis|
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Complications of steroid therapy (Before calcineurin inhibitor treatment)
Cushingoid features were the most common steroid side effect followed by dermatological side effects such as striae and acne. Two patients developed localized fungal infection and 1 septic shock. Five patients developed hypertension after steroid therapy and 1 developed cataract [Figure 7].
Outcome of calcineurin inhibitor in frequently relapsing nephrotic syndrome and steroid-resistant nephrotic syndrome patients
As shown in [Figure 8], after 3 months of treatment with CNI in majority of patients proteinuria decreased to subnephrotic range and S. albumin increased to >2.5 g/dL. Renal function remained stable during CNI treatment and cholesterol levels also declined gradually over 6 months period [Figure 9].
|Figure 8: Proteinuria and serum albumin during calcineurin inhibitors treatment. CNI: Calcineurin inhibitors|
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|Figure 9: Serum creatinine and cholesterol during calcineurin inhibitors treatment. yr: year, CNI: Calcineurin inhibitors|
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Outcome of calcineurin inhibitors in frequently relapsing nephrotic syndrome
Drug levels were maintained within recommended range [Table 2]. Out of total 4 patients treated with CSA, 2 achieved CR and 2 achieved PR. Two patients were able to sustain long-lasting remission without relapses after CSA was stopped. 1 patient was CSA dependent and relapsed within 2 weeks of stopping therapy. 1 patient remained in remission for a period of about 2 years and relapsed after that. Overall CSA was successful in 75% of patients in treating frequent relapses. Mean time to achieve remission was 3.2 months.
Two patients previously treated with CSA, and 11 other patients with FRNS (total n = 13) were treated with Tac and low dose steroid. Seven patients achieved CR and 6 patients achieved PR. Three patients were Tac dependent and developed frequent relapses while tapering, and were considered treatment failure. Two patients developed 1 episode of relapse while tapering which was not defined as dependence. Overall Tac was successful in 77% of patients in treating frequent relapses. Mean time to achieve remission was 2.1 months.
CSA and Tac had a comparable efficacy in FRNS patients and we found no significant difference. Tac was also effective in achieving sustained remission in 1 CSA dependent patient [Figure 10].
|Figure 10: Outcome of calcineurin inhibitors in frequently relapsing nephrotic syndrome. CNI: Calcineurin inhibitors|
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Outcome of calcineurin inhibitor in steroid-resistant nephrotic syndrome
Drug levels were maintained as shown in [Table 3]. Out of 3 patients treated with CSA, 1 achieved PR whereas 2 patients did not respond. Time to achieve remission was 5 months. Two patients resistant to CSA and 12 steroid-resistant patients were treated with Tac (total 14 patients). Eleven of 14 (79%) patients achieved CR and 2 (14%) achieved PR. Mean time to achieve remission was 2.5 months. Among 2 patients resistant to CSA 1 achieved CR with Tac and 1 did not respond to Tac also [Figure 11].
|Figure 11: Outcome of calcineurin inhibitors in steroid-resistant nephrotic syndrome. CSA: Cyclosporine, CNI: Calcineurin inhibitors|
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Outcome in primary steroid resistance versus late resistance
All 4 patients with late steroid resistance achieved complete or PR with CNI, whereas 2 (18%) patients with primary steroid resistance were resistant to CSA and 1 (9%) patients was resistant to both CSA and Tac [Table 4].
|Table 4: Outcome of calcineurin inhibitors in primary steroid resistance versus late resistance|
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Comparison of cyclosporine and tacrolimus in frequently relapsing nephrotic syndrome versus steroid-resistant nephrotic syndrome
In FRNS patients both CSA and Tac are almost equally effective. In SRNS patients Tac was more effective than CSA and was also effective in 1 patient resistant to CSA [Table 5].
|Table 5: Comparison of cyclosporine and tacrolimus in frequently relapsing nephrotic syndrome versus steroid-resistant nephrotic syndrome|
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Complications of calcineurin inhibitor therapy
In both groups FRNS and SRNS patients, CSA and Tac were tolerated well. Three patients developed hypertension, but controlled with antihypertensives. One patient developed seizures during CNI therapy which was controlled with anti-epileptic. No patient required CNI discontinuation due to side effects.
Salt restriction was used in all patients. ARB/ACE I were used in patients with hypertension and Statins in patients with persistent hypercholesterolemia. More patients in SRNS group required ARB/ACE I and statin therapy as compared to FRNS group.
| Discussion|| |
Children with NS who respond to corticosteroids have an 80%–90% chance of having one or more relapses., Half of those that relapse have infrequent relapses and can be managed with short courses of prednisone. The long-term prognosis for most children with SSNS is for CR of their disease over time and maintenance of normal kidney function. Therefore, limiting the long-term adverse effects of treatment is an important objective. Children with Frequently Relapsing and Steroid-Dependent (FR or SD SSNS) require prolonged corticosteroid therapy, which is associated with significant adverse effects; including impaired linear growth, behavioral changes, obesity, Cushing's syndrome, hypertension, ophthalmological disorders, impaired glucose tolerance, and reduced bone mineral density. Adverse effects may persist into adult life in young people, who continue to relapse after puberty. To reduce the risk of corticosteroid-related adverse effects, children with FR or SD SSNS may require other agents, including alkylating agents (cyclophosphamide, chlorambucil) and CNI (CSA, Tac). Patients successfully treated with corticosteroid-sparing therapy have improved growth rates, reduced body mass index, reduction of Cushingoid features, and improvement in other corticosteroid-related adverse effects.,, There are no data from RCTs to determine which corticosteroid-sparing agent should be used as the first agent in a child with FR or SD SSNS. Alkylating agents are cheap and more likely to induce long lasting remission in patients with FRNS, however side effect needs to be considered and CNIs may be a reasonable option.
In our study, we found male preponderance in FRNS and nearly equal gender distribution in SRNS as was also seen in another study by Sabry et al.
We found that clinical presentation of FRNS and SRNS was different in children and adult patients. Majority of children (72%) had florid presentation with ascites and anasarca and 44% children had oliguria whereas most adults presented with edema face and feet. Differential presentation may be due to more severe proteinuria per body surface area in children as compared to adults. Hypertension was more prevalent in SRNS group as compared to FRNS. More prevalence of hypertension in SRNS group could be explained by FSGS being more common etiology and lack of remission leading to salt and water retention. This prevalence of hypertension in SRNS group was also seen in other studies conducted by Kim et al. and Otukesh et al.
The present study found children had more severe proteinuria per body surface area (4.2 g/m2/d) as compared to adults (2.9 g/m2/d) and more severe hypoalbuminemia at the time of presentation, thus explaining probably presence of anasarca and ascites more commonly in children as compared to adults.
In steroid-resistant group, present study found FSGS as the most common histology which was comparable with other studies., Whereas in FRNS group, FSGS and IgM variant of MCD were the most common histology findings which differs from the study findings by Siegel et al. where MCD followed by FSGS were common.
In the present study, after 3 months of treatment with CNI therapy, proteinuria reduced to subnephrotic range and serum albumin increased to >2.5 g/dL which is consistent with the study findings by Butani and Ramsamooj. Renal function remained stable during CNI treatment and cholesterol levels declined gradually over 6 months period.
In FRNS, the present study and few other studies showed very good remission induction rate (CR and PR) with CSA and low dose steroid treatment., Another study from India by Phadke et al. showed low sustained remission rate of 19% and very high CSA dependence in 62% of patients. However as number of patients on CSA in the present study are small, they may not be comparable.
In FRNS, the present study showed remission rate of 100% with Tac. This was in comparision with ther studies., Tac dependence was seen in around 23% of patient in our study as compared to 35% and 10% of patients, respectively, in studies by Kim et al. and Li et al.
In SRNS, our study found CSA resistance in 67% (2/3) patients. However as number of patients on CSA are small in our study, so results may not be comparable with other studies which found remission ranging from 58% to 80%.,
Our study shows combined response rate of 93% with Tac in SRNS as compared to combined remission rate of 77%–94% in other studies.,,
Thus in FRNS patients, both CNIs are almost equally effective. However in patients who are CSA dependent, Tac still can achieve a durable response without relapses. In SRNS patients, Tac was more effective than CSA and was also effective in 1 patient resistant to CSA.
| Conclusion|| |
Hypertension was more common in SRNS as compared to FRNS patients. FSGS and IgM nephropathy were the most common causes of FRNS, whereas FSGS was common cause of SRNS. We also found MePGN and IgM nephropathy were commonly associated with steroid resistance as compared to MCD. In frequent relapsing NS patients, both CSA and Tac showed comparable efficacy. In SRNS patients, Tac was more effective than CSA and also effective in CSA resistant patient. Late steroid resistance was associated with better response to CNI therapy as compared to primary CNI resistance. CNI therapy was well tolerated in almost all patients. However, number of patients treated with Tac and especially CSA were small, so findings are difficult to generalize. More studies with larger sample size are needed to confirm the findings.
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Conflicts of interest
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]