Saudi Journal of Kidney Diseases and Transplantation

ORIGINAL ARTICLE
Year
: 2019  |  Volume : 30  |  Issue : 1  |  Page : 129--137

Tacrolimus as the first-line agent in adult-onset minimal change disease: A randomized controlled study


Malagouda R Patil1, Smita Subhash Divyaveer2, Arpita Raychaudhary2, Mayuri Trivedi3, Chetan Mahajan2, Dipankar Sarkar2, Rajendra Pandey2,  
1 Department of Nephrology, Karnataka Institute of Medical Sciences, Hubli, Karnataka, India
2 Department of Nephrology, Institute of Postgraduate Medical Education and Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, West Bengal, India
3 P. D. Hinduja National Hospital and Medical Research Centre, Mumbai, Maharashtra, India

Correspondence Address:
Smita Subhash Divyaveer
Department of Nephrology, Institute of Postgraduate Medical Education and Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, West Bengal
India

Abstract

Steroids have been the cornerstone of first-line therapy in adult-onset minimal change disease (MCD). The period of exposure to high dose steroids may be longer in adult MCD patients and would result in higher rates of steroid-related side effects. Although tacrolimus (TAC) is known to be effective in steroid-dependent/resistant MCD as well as in nephrotic syndrome due to other causes, there are minimal data available for assessing the effectiveness of TAC as the first-line agent in adult MCD. This is a prospective, open-label, randomized controlled study conducted from April 2014 to March 2016. Patients were randomized into two groups A and B which received TAC for 12 months and oral steroids for six months, respectively. Primary outcomes were remission rates, drug resistance was measured at 6, 12,and 18 months in each group and secondary outcomes were relapse rates, sustained remission rates, dependency, and adverse effects were measured at 18 months in both groups. At six months, total response (TR, i.e., complete and partial remission) was achieved in 80% in the TAC group and 78.26% in the steroid group (P = 1.000). At 12 months, TR was 60% in the TAC group and 43.48% in the steroid group (P = 0.386). At 18 months, TR rate was 44% in the TAC group and 43.48% in the steroid group (P = 1.000). About 32% in the TAC group and 39.13% in steroid group had relapsed by 18 months. Serious adverse effects were similar in the two groups, but overall adverse effects were more in the steroid group. TAC as a primary agent is not inferior to steroids in inducing remission. TAC may be considered as an alternative agent to steroid in high-risk groups such as elderly patients, uncontrolled diabetes and young females as a primary agent in the management of adult MCD.



How to cite this article:
Patil MR, Divyaveer SS, Raychaudhary A, Trivedi M, Mahajan C, Sarkar D, Pandey R. Tacrolimus as the first-line agent in adult-onset minimal change disease: A randomized controlled study.Saudi J Kidney Dis Transpl 2019;30:129-137


How to cite this URL:
Patil MR, Divyaveer SS, Raychaudhary A, Trivedi M, Mahajan C, Sarkar D, Pandey R. Tacrolimus as the first-line agent in adult-onset minimal change disease: A randomized controlled study. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Sep 17 ];30:129-137
Available from: http://www.sjkdt.org/text.asp?2019/30/1/129/252902


Full Text



 Introduction



Idiopathic minimal change disease (MCD) accounts for 10%–15% of cases of primary nephrotic syndrome (NS) in adults.[1],[2],[3] In children; however, MCD is the most common cause of NS and accounts for 70%–90% of NS in children <10 years of age and around 50% of older children. There is abundant data regarding the presentation, the course of the illness, treatment outcomes and long-term follow-up of this disease in the pediatric population, but relatively little data exist for the same in adults.[4],[5],[6],[7],[8],[9] As is the case in childhood MCD, steroids have been the cornerstone of first-line therapy in adult MCD patients. However, in adults response to steroids is often delayed in comparison with children, and 25% fail to remit after three to four months.[4],[5],[10] After achieving remission current guidelines suggest continuing steroids in tapering doses for six months.[10] Hence, the total duration of exposure to steroids, high dose initially followed by tapering doses may be longer in adult MCD patients and this may result in higher rates of steroid-related adverse effects such as diabetes mellitus (DM) and osteoporosis in a significant number these patients as compared to the pediatric population. Some adults, for example, those with impaired glucose tolerance, postmenopausal women, obesity, etc., may be predisposed to adverse effects of steroids even with shorter duration of therapy. In addition, idiopathic MCD in adults is not as benign a disease as thought to be in the pediatric population and are associated with higher rates of hypertension, impaired glomerular filtration rate (GFR), and renal insufficiency which may require aggressive therapeutic approach.[11] Tacrolimus (TAC), an immuno-suppressive macrolide of the calcineurininhi-bitor (CNI) group widely used following organ transplantation,[12],[13] is known to be effective in treating patients with steroid-dependent and steroid-resistant NS.[14],[15] TAC is effective in MCD due to its potent immunosuppressive as well as direct nonimmuno-suppressive effects on podocyte slit-diaphragm, cytoskeleton repair and suppression of vascular permeability factor production.[14],[16] However, the available data on clinical efficacy of CNIs, especially TAC as the first-line agent in adult MCD is minimal.[17] Therefore, given the adverse effects of relatively long-term steroids therapy in adults as well as the effectiveness of TAC in NS, we planned this study with the purpose of evaluating the efficacy, safety, and long-term effects of TAC as first-line agent in the treatment of adult MCD and comparing it with the traditional steroid-based regimen.

 Materials and Methods



We conducted a prospective, open-label, randomized controlled trial with the approval of the Institutional Ethics Committee. The study was conducted at the Institute of Postgraduate Medical Education and Research, Kolkata from April 2014 to March 2016. Written informed consent was obtained from all the participants. Patients of nephrotic range proteinuria (>3.5 g/day) aged 18 years or above and a biopsy proven MCD were included in the study. The patients with any other glomerular or tubulointerstitial pathology in the biopsy (including any overlap syndrome or variants of MCD), chronicity features on histopathology (interstitial fibrosis and tubular atrophy >20%), the presence of active infection and prior exposure to any immunosuppressive agents for the same disease were excluded from the study. Patients with systemic diseases like SLE, diagnosed lymphoma/leukemia or suspicion of drug-induced MCD were excluded from the study.

The patients were randomized into the TAC group (Group A) and steroid group (Group B) using a table of random numbers. The TAC group patients were initiated on oral TAC capsules at a dose of 0.075 mg/kg/day in two divided doses 12 h apart. The patients in the steroid group were initiated on oral predni-solone at a dose of 1 mg/kg/day (maximum dose 80 mg/day) as a single daily dose. All the patients in both groups were to receive calcium supplements and antihypertensive drugs like angiotensin-convertingenzyme inhibitors, angiotensin-receptor blockers or nondihydro-pyrolidine calcium channel blockers to maintain their blood pressure levels if found hypertensive during the study period. TAC trough levels (T0 levels) were measured using micro-particle enzyme immunoassay two weeks after initiation of therapy and repeated weekly till target T0 levels were reached and subsequently repeated at any suspicion of acute CNI toxicity. Previous studies[18],[19] in steroid resistant NS with target T0 level set as 5–10 ng/dL showed a response rate of around 78%. For the purpose of this study we set target T0 range of 8–10 ng/mL (as the patients in TAC arm were not to receive any steroids at all) till the achievement of complete remission (CR) (referred to hereafter as initial dose) and for three months thereafter. In such patients, the TAC dose was subsequently tapered by 0.5 mg/day every two weekly so as to maintain T0 in the range of 4–8 ng/mL (referred to hereafter as maintenance dose) until total duration of 12 months inclusive of initial and maintenance dose was completed. TAC was administered for at least a minimum period of six months to all patients and was continued further only if the patient achieved CR or partial remission (PR). If neither of the responses were achieved after six months of TAC therapy, patient was declared to be TAC resistant and was switched to steroid therapy. In case of PR at six months TAC was continued further at initial dose till CR was achieved, if at all it was achieved, followed by maintenance dose until the completion of 12 months of therapy (inclusive of initial and maintenance dose). In steroid group (Group B), oral steroids were given as suggested by the KDIGO guidelines,[20] i.e., for a minimum period of four weeks if CR was attained and a maximum of 16 weeks after which patient was declared as steroid resistant. After attaining CR the drug was slowly tapered over six months and stopped. Each participant underwent investigations including 24 h urine protein, serum creatinine, serum albumin, random blood sugar (RBS) every 15 days for first two months, monthly for the next 10 months and then as and when needed for a total of 18 months. Blood pressure and weight were recorded at each visit. Other investigations like CBC were done as and when indicated. Patients who did not follow-up according to the study protocol were contacted on telephone and the data were recorded.

Primary outcomes

CR, PR in each group, TAC and steroid resistance measured at 6, 12, and 18 months in each of the groups.

Secondary outcomes

Relapses, sustained remission, complications of therapy.

Definitions used in the study to assess the primary and secondary outcomes have been given in supplementary data.

 Statistical Analysis



Statistical analysis was performed by Statistical Package for Social Science (SPSS) software 20.0.1 (SPSS Inc., Chicago, IL, USA) and GraphPad Prism version 5 (La Jolla California USA, www.graphpad.com). Data have been summarized as mean and standard deviation for numerical variables and count and percentages for categorical variables. Student's independent sample's t-test was applied to compare normally distributed numerical variables between groups; unpaired proportions were compared by Chi-square test or Fischer's exact test, as appropriate.

 Results



During the study period 53 patients were diagnosed as idiopathic MCD. Five patients were excluded from the study because of non-adherence to study protocol and presence of acute kidney injury. Forty-eight patients were randomized; 25 patients were assigned to the TAC group and 23 patients were assigned to the steroid group [Figure 1]. The mean age of the patients was 28.04 ± 7.84 years (range 18–44 years). The baseline characteristics were similar in the two groups as shown in [Table 1]. The diastolic blood pressure was significantly higher in the steroid group; however none of the patients were hypertensive as per JNC 7 guidelines.[21] The mean dose of TAC administered was 2.642 ± 0.657 mg/day during the initial therapy in TAC group and 1.738 ± 0.331 mg/day during maintenance therapy.{Figure 1}{Table 1}

At six months, as shown in [Figure 2], CR rates in the TAC and steroid groups were 64% and 78.26%, respectively. This difference was not statistically significant (P = 0.207). PR was achieved in 16% of patients in the TAC group while none of the patients in steroid group had only PR. Total response (TR, i.e., CR and PR taken together) was achieved in 80% in the TAC group and 78.26% in the steroid group (P = 1.000). Time to CR was 77.69 ± 48.07 days in the TAC group and 65.83 ± 28.32 days in the steroid group (P = 0.381). Time to PR was 53.50 ± 32.4 days in the TAC group and 45.65 ± 19.01 days in the steroid group (P = 0.387). Five patients in both TAC and steroid group had resistance to therapy i.e. 20% and 21.74%, respectively.{Figure 2}

At 12 months, as shown in [Figure 3], CR rates in the TAC and steroid groups were 56% and 43.48%, respectively (P = 0.563). PR rates were 4% of patients in the TAC group while none of the patients in steroid group had only PR. TR rate was 60% in the TAC group and 43.48% in the steroid group (P = 0.386). The mean T0 levels in TAC group at 6th month were 8.44 ± 1.5 and 5.8 ± 0.95 at 12th month.{Figure 3}

At 18 months, CR rates in the TAC and steroid groups were 40% and 43.48%, respectively (P = 1.000). PR rates were 4% of patients in the TAC group, whereas none of the patients in the steroid group had the only PR. The TR rate was 44% in the TAC group and 43.48% in the steroid group (P = 1.000). Eight (32%) in the TAC group and nine (39.13%) patients in steroid group, who had achieved either CR or PR earlier had relapsed. This was statistically comparable (P = 0.744). The time to relapse was 193.57 ± 77.07 (range 150 to 365) and 147.14 ± 63.50 (range 150 to 210) days in TAC and steroid group, respectively; this difference was not statistically significant (P = 0.242). Of the patients who relapsed in the TAC group two patients who had earlier attained only PR became TAC resistant. TAC resistance was seen in seven patients (28%) while steroid resistance was seen in five (21.74%). Three (12%) patients were TAC dependent. In steroid group, five (21.74%) were steroid dependent.

The average change in MDRD estimated GFR (eGFR) at 18 months was 4.44 ± 29.25 and 3.00 ± 31.99 in TAC and steroid group, respectively. This was not statistically significant (P = 0.887). The average change in systolic (SBP) and diastolic blood pressures (DBP) in the TAC and steroid groups was 8.64 ± 13.54; 4.70 ± 15.85 and 8.0 ± 11.93; -3.91 ± 11.18, respectively. The average change of SBP and DBP was comparable in the two groups (P = 0.357 and 0.228, respectively). There was a significant increase in serum albumin and decrease in 24 h urineprotein in both groups at 18 months (P <0.05) in each group.

Adverse effects in each group were as shown in [Table 2]. Serious adverse effects were seen in two (8%) patients in the TAC group and three (13.04%) patients in the steroid group. There was an increase in RBS levels in both the groups but none in the TAC group developed DM while two patients in the steroid group who were steroid dependent developed DM. Despite the increase in blood pressure compared to the baseline no patient in either group required the initiation of antihyper-tensive therapy. Average change in weight (in kg) in TAC group at 6, 12 and 18 months was 1.6 ± 2.63, 1.36 ± 3.24, and 0.33 ± 3.82. The average change in weight (in kg) in steroid group at 6, 12, and 18 months was 1.78 ± 2.09, 2.33 ± 2.77, and 0.29 ± 2.43, respectively.{Table 2}

 Discussion



CNIs have been used in childhood-onset as well as adult-onset NS, but majorly as a steroid-sparing therapy or in cases of steroid resistance. There are little data regarding the use of TAC as primary therapy in adult-onset NS. The aim of this study was to analyze the efficacy and safety of TAC in comparison with steroid as primary therapy for adult-onset NS. As mentioned above, the baseline characteristics were comparable except for higher average diastolic pressure in the steroid group. However, none of the patients had hypertension. At the last follow-up, i.e., 18 months none had new-onset hypertension.

We decided to measure the primary outcomes at different time periods, i.e., 6, 12, and 18 months because the total duration of therapy was different in the two groups and outcomes (primary and secondary) measured at different time periods would allow a more comprehensive analysis of comparison of the efficacy of the two therapies. At six months, the patients in the steroid group completed their therapy while the patients in TAC group continued their therapy unless they had resistance as defined in the study protocol. In childhood-onset NS, CNIs have been suggested to be given for at least 12 months if patients are responsive.[10] TAC therapy used in some of the previous studies on adult MCD had a minimum duration of one year.[19],[22] Hence, for this study a total duration of therapy in TAC group was decided as one year. The CR and TR rates were comparable at six months. In steroid group, all patients either achieved CR or were resistant. None in the steroid group achieved the only PR unlike TAC group where 16% achieved PR.

At 12 months CR and TR rates were comparable; however, numerically more patients in the TAC group were in CR as compared to steroid group. This was probably because the patients in the TAC group were still on TAC therapy (according to the study protocol). Despite this two of the 16 patients who had achieved CR and three of the four patients who had achieved PR at six months in TAC group had relapsed. In the steroid group, eight patients relapsed and were restarted on steroid therapy.

At the last follow-up time point, i.e., at 18 months, only around 40% in each group maintained some remission, i.e., CR or PR compared to about 80% in each group at six months. The number of relapses as well as time to relapse was comparable in the two groups. Time to relapse was numerically higher (though insignificant) in TAC group probably because the duration of therapy was longer in TAC group. The proportion of patients who became steroid/TAC dependent is shown in [Figure 1].

The efficacy (considering both primary and secondary outcomes) of TAC and steroids in adult-onset NS were similar at 6, 12, and 8 months. However, the CR and TR rates in both groups decreased progressively over time. Time to CR and PR was longer in TAC group compared to steroid group. Serious adverse events requiring hospitalization occurred in a similar proportion of patients in the two groups, but the number of overall adverse effects was higher in steroid group which was mainly contributed by cosmetic side effects, i.e., cushingoid facies. Acute kidney injury occurred in two patients in TAC group which recovered on decreasing TAC dose.

Our study protocol was different from the one used in a previously published Chinese trial.[23] In that study, intravenous steroids were given to all patients before randomization to either TAC or steroid group. The treatment course for both groups in that study was 36 weeks which was longer than the duration of steroid therapy in this study and shorter than duration of TAC therapy. The remission rates obtained in that study were 96 to 98% which was higher than the rates we obtained (i.e., about 80%), but the relapse rates were higher, i.e., 45 to 49%; higher than the relapse rates found in this study. The difference in the duration of therapy may have been the reason for lower relapse rates particularly in the TAC group in our study. Another single-arm pilot study showed a TR rate of 92% using TAC and low dose steroids.[24] A previous study[21] compared cyclosporine, steroids as well as a combination of both and found the combination to be superior to other groups in terms of CR rates as well as relapses. The CR obtained in the cyclosporine group was 75% which is comparable to the CR rates obtained in our study. It remains to be conclusively established if the combination of steroids and TAC would result in higher rates of remission as well as sustained remission. Despite the comparatively lower overall responses in our study, we did not find a significant difference between steroid and TAC therapy and both were equally efficacious. The two groups however differed in certain other aspects, particularly the rate of partial response and adverse effects. Patients in steroid group either attained a CR or had no response and none had only PR. While in TAC group, a small number of patients attainedonly PR and but most of these patients (75%) relapsed compared to those who attained CR at six months (12.5%). It may thus be inferred that those who achieve only PR had higher chance of relapse compared to those who had achieved CR while on TAC therapy. Furthermore, these patients had higherchance of eventual TAC resistance.

The number of serious adverse effects requiring hospitalization was similar in the two groups. These were mainly infectious complications that occurred before remission. Overall adverse effects were more common in the steroid group mainly due to the appearance of cushingoid facies. Both TAC[25],[26] and steroids[27],[28],[29] are diabetogenic, but we found new-onset DM only in steroid group; in those who were steroid dependent. On the other hand, reversible AKI was found only in TAC group. The change in eGFR was not significantly different in the two groups. Both groups had increase in mean weight from the baseline while on therapy but later it decreased at 18 month follow-up. It is difficult to determine the weight gain that was caused by the drugs as patient were edematous as presentation and baseline dry weight was not available for most patients.

Limitations of the study include relatively smaller number of patients and open label design. Other adverse effects of drugs such as dyslipidemia, metabolic syndrome, osteoporosis, and impaired glucose tolerance at base-linewere not looked into. We excluded the patients who had AKI at presentation because in these patients TAC is likely to worsen AKI and steroids may be the preferable choice of therapy. Whether prolonging the therapy in those achieve only PR initially would be beneficial to prevent relapse needs further study. The economic impact of the two therapies was not compared in the present study; however, TAC therapy is generally more expensive.

 Conclusion



TAC has comparable efficacy to steroids in adult-onset MCD. Time to remission was longer with TAC therapy though this was not statistically significant. Relapse rates were similar in the two groups. TAC resistance was seen more often if only PR was achieved initially. Serious adverse effects were comparable in both groups, whereas cosmetic side effects like cushingoid features occurred only in steroid group. TAC may be considered as an alternative agent to steroid, especially in high risk groups like elderly patients, uncontrolled diabetes and young females (when cosmetic adverse effects can be a concern) as a primary agent in the management of adult-onset MCD.

Conflict of interest:

None declared.

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