Outcomes of Different Immunosuppressive Regimen in Adult Biopsy Proven Idiopathic Focal Segmental Glomerulosclerosis

A Retrospective Analysis at a Single Center

Abstract

Treatment of focal segmental glomerulosclerosis (FSGS) is frustrating, especially for steroid-resistant FSGS. Different immunosuppressive agents have been used with inconsistent outcome. We analyzed the data in our FSGS patients who, in addition to steroid, were treated with cyclosporine (CYA), cyclophosphamide (CYP), and mycophenolate mofetil (MMF) along with the long-term follow-up. This is a retrospective analysis of 113 patients diagnosed to have FSGS with 11 years’ follow-up carried out at The Kidney Center Post Graduate Training institute. Among 113 patients, 51.3% were male with a mean age of 34.4 ± 11.8 standard deviation. Patients who achieved complete remission with steroid alone and steroid with combination of CYA, CYP, and MMF were 38 (26%), 19 (16.8%), and six (5.3%), respectively, similarly those who got partial remission were three (3.6%), five (4.4%), three (2.6%), and eight (7.0%), respectively. The factors which affected the outcome were serum creatinine (SCr), tubulointerstitial fibrosis (TIF), and the treatment. In adjusted analysis, increase in 1 mg of SCr reduces the patient recovery by 56%, while the absence of TIF increases recovery by 80.75%. Taking steroid as reference category, steroid + CYA found 2.03 times more effective as compared with steroid alone. Seven patients developed end-stage renal disease (ESRD) and three died due to disease during the follow-up. CYA comes out as the most effective treatment for steroid-resistant FSGS followed by MMF and CYP. The long-term outcome of all modalities is the same in terms of mortality and developing ESRD. The degree of TIF and renal failure has strong influence on the course of the disease.

Introduction

Focal segmental glomerulosclerosis (FSGS) is a type of glomerular disorder characterized by its peculiar histological patterns and recognized by its frustrating course and poor outcome.[¹] FSGS is a principal cause of nephrotic syndrome (NS) not only in adults (around 10%–30%)[²] but also in pediatric patients. It is a frequent cause of glomerular injury which causes proteinuria or NS. This type of histopathological lesion is caused by either primary podocyte injury, which is a result of an unknown circulating toxin or caused by other secondary causes. A confirmed diagnosis can only be made by renal a biopsy, which shows focal and segmental sclerosis.

It is recognized as one of the most common cause of adult NS in this region. In an analysis of kidney biopsy from our region, Imtiaz et al[³] reported FSGS occurrence in about 20% of all biopsy lesions in adults and 25% in pediatric patients.[⁴] Similar data were reported from the other center of the same city.[⁵⁶] Even in diabetic patients who underwent kidney biopsy for other reasons, they found that FSGS is the most common nondiabetic glomerular disease.[⁷]

FSGS with nephrotic range proteinuria has a poor prognosis as compared to non-nephrotic range proteinuria and patients with nephrotic range proteinuria usually progressed to endstage renal disease (ESRD) in 50% of the cases within five years.[⁸] If this illness is left untreated, remission is rare and achieved in only 6% of the cases.[⁹]

Over the past 50 years, the treatment of FSGS had many ups and downs, once conceded as steroid nonresponsive entity, possibly due to inadequate dosing, is now recognized as steroid responsive with prolonged high dose steroid treatment.[¹⁰] Due to frequent relapses of the disease, despite steroid treatment, steroid dependence and steroid resistance emerge as an annoying problem. This has led to the introduction of other immunosuppressive agents in the treatment regimen of FSGS such as cyclosporine (CYA), mycophenolate mofetil (MMF), cyclophosphamide (CYP) and azathioprine.[¹¹] These second line therapeutics have been proven beneficial even in cases in which patients were initially steroid resistant. This was the reason Kidney Disease Improving Global Outcomes also advocate same prolonged steroid treatment as a first-line therapy, and CYA and tacrolimus for those who showed intolerance or resistance to steroids.[¹²] The reason of this preference was its favorable results in randomized controlled trials, using CYA for six months, who already used a trial of steroids for eight weeks.[¹³]

Due to the profound toxicity of the steroids, reduction of corticosteroid exposure is one of the prime focus in the treatment of glomerular diseases, especially when prescribed for the prolonged period. The Kidney Center Post Graduate Training Institute (TKC-PGTI Karachi), Pakistan is one of the tertiary nephrology/urology facilities. In our institute, we evaluated biopsy-proven FSGS patients, who were treated with steroids with or without other immunosuppressive medications, and we assessed their various outcomes. Little data existed in this region of Asia so this article might add more information regarding the outcome of various drug treatments in the context of FSGS.

Subjects and Methods

The study was conducted in TKC-PGTI. This was a retrospective study of patients with the diagnosis of FSGS from March 2008 to April 2018. We included all adult patients, >18 years at the time of biopsy, with or without nephrotic range proteinuria.

Operational definition

NS was defined as proteinuria more than 3.5 g in 24 h or urinary protein creatinine ratio (uPCR) more than 3.5. Patients who consistently had systolic blood pressure (BP) above 140 mm Hg or diastolic above 90 mm Hg were considered as hypertensive. Renal insufficiency was defined as serum creatinine (SCr) more than 1.3 mg/dL and ESRD when, renal support started in the form of hemodialysis or kidney transplantation. In renal biopsy, tubulointerstitial fibrosis (TIF) was also noted and categorized as mild if 5%–25% interstitial fibrosis, moderate 25%–50%, and labeled as severe if >50% of tubulointerstitial area was involved. The main end-point of FSGS recorded was achieving remission, ESRD, or death. The outcome was elucidated as complete remission (CR) when proteinuria <0.25 g in 24 h or protein creatinine ratio <0.25 g/g, partial remission (PR) was when proteinuria ranged between 0.26 g/g and <3 g in 24 h or >50% reduction in proteinuria from baseline. Relapse was defined as doubling of the previous uPCR to >3.5 g/g with or without appearance of the NS. Steroid resistance was categorized as no response or persistence of proteinuria. Persistence of proteinuria means as if it was at the beginning of the treatment, after at least eight weeks of full dose steroid of 1 mg/kg of body weight (some patients received 12 weeks of full dose steroid).

We have retrospectively collected the data from patient’s medical records. Clinical and laboratory parameters such as age, comorbid, BP, degree of TIF, complete blood count, SCr, albumin, edema, frothy urine, hematuria, and spot uPCR were recorded.

There were a total of 297 patients who had a diagnosis of FSGS, we included 113 patients in the analysis. All patients treated initially with steroid at the dose of 1 mg/kg body weight for at least eight to 12 weeks before labeling them to steroid resistant. After that, patients were divided into four groups according to the treatment they received, as steroid alone, steroid + CYP, steroid + CYA and steroid + MMF (Figure 1). Outcome variables were, proteinuria subsided or not and renal function recovered or not. Patient’s survival was noted by the time difference from the date of biopsy to current date and event was recorded as patient’s death or ESRD.

Figure 1: Flow chart showing distribution of patients according to treatment.

The data were analyzed using the IBM SPSS Statistics software SP version 21.0 (IBM Corp., Armonk, NY, USA). Cleaning and coding of the data was done before analysis. Mean ± standard deviation (SD) or median with interquartile range were computed for the continuous data, while for categorical variables, frequency with percentages was measured. For paired data, Paired t-test or Wilcoxon sign-rank test was used, while for more than two observations of same patients, repeated-measures ANOVA test was applied. P <0.05 was considered statistically significant. The association of baseline parameters and outcome variables with four treatment groups were observed by Chi-square test or Fisher exact test. Effect of different treatment on recovery of patients was computed by binary logistic regression analysis. In univariable analysis, regressors were analyzed individually for their effect on outcome. The variables, which had P ≤0.25 kept in multivariable analysis for adjustment of their effect. Log rank survival analysis was done to see time to ESRD or death in four treatment groups and median and mean survivals were computed.

Results

We had a total of 113 patients in our study, in which males were 51.3% and females were 48.7%. The mean age was 34.4 ± 11.8 SD. Most of our patients had microscopic hematuria (53.1%). Mild TIF was present in more than one-third of the patients (38.1%) (Table 1).

Table 1: Demographic and clinical parameters of patients (n=113).

All four groups of treatment were similar in respect to gender, age, serum albumin, and spot uPCR (P >0.05), while SCr and degree of interstitial fibrosis were significantly different in these groups (P <0.05). The baseline mean SCr was lower in steroid + CYA group (0.87 ± 0.44) as compared to other groups; on the other hand, steroid + CYA group had maximum percentage of patients with mild fibrosis (50%) as compared to others, and minimum percentage with severe fibrosis (10.7%) (Table 2)

Table 2: Differences in Base line parameters between treatment groups (n=113).

There was an overall good response with the immunosuppression at the end of six months and about 79% of the patients got either CR or PR. As all the patients received steroids as a first line treatment, 38(26%) of the patients got a CR while three (3.6) developed PR with steroid only. Those who did not get remission were subjected to other immunosuppressant. Those patients who received steroids + CYA were the second largest group and 19 (16.8%) of the patients got CR while five (4.4%) of the patients achieved PR. Similarly, with steroid + CYP and steroid +MMF showed CR in six (5.3%), six (5.3%) and PR in three (2.6%) and eight (7.0%), respectively. On the other hand, 21% did not show response to any of the treatment modality (Figure 2).

Figure 2: Effect of different treatment regimen causing complete or partial remission.

There was a significant improvement in BP, uPCR and serum albumin after the treatment (P 0.001). On the other hand, SCr and hemoglobin were also improved but not reached to a significant level (Table 3).

Table 3: Difference of clinical and laboratory parameters of patients before and after treatment.

In group analysis, we found highly significant association of outcome with treatments (P <0.001). Proteinuria was completely subsided in most of the patients who were treated with steroid alone 38 (82.6%). After steroid alone, steroid + CYA treated proteinuria completely in the majority of patients 19 (67.9%). Similarly, the number of patients with improvement in SCr was higher in steroid alone group. On the other hand, patients who received steroid + CYA treatment showed higher overall recovery (89.3%) as compared to other treatments (Table 4).

Table 4: Association of outcome with four treatment groups (n = 113).

The clinical variables of the patients were evaluated for their effect on recovery from the disease and presented in Table 5. Gender, age, BP, serum albumin, and spot uPCR had no effect on the outcome of patients both in unadjusted and adjusted analyses (P >0.05). We found that SCr, TIF, and treatment had significant effect on outcome (P <0.05) in univariate analysis. With 1 mg/dL increase in SCr, the recovery of patients was decreased by 82% in unadjusted analysis and by 56% when adjusted with other variables. The patients who did not have TIF, 80.75 times more recovered as compared to patients with severe TIF (P <0.001). Same as recovery in patients with mild and moderate degree of TIF were also 56.67 and 6.46 times respectively more than severe TIF (P <0.001). When TIF was adjusted with other variables, the odds ratio decreased from unadjusted analysis but remained higher and had a significant effect on outcome for mild and moderate fibrosis as compare to severe fibrosis (P ≤0.05) (Table 5). When we took steroid alone as reference category we found that steroid+ CYP had 85% decreased effect on recovery as compared to steroid alone (P = 0.001), on the other hand steroid + CYA was 2.03 times more effective for treatment as compared to steroid alone, although the effect was not statistically significant. In multivariable analysis, the effect of SCr and TIF same but when treatment was adjusted for TIF all treatments were statistically same (P >0.05) (Table 5).

Table 5: Effect of different parameters on recovery of patients (n = 113).

Out of 113 patients, only seven patients developed ESRD while three died due to disease during the follow-up of 11 years. Survival curve showed that each treatment had almost same survival (median survival = 11 years) (Figure 3).

Figure 3: Survival analysis of patients treated with four regimen of immunosuppression.

Discussion

Our study delineate that overall response of immunosuppression is favorable not only in terms of achieving remission but also their prognosis and long term survival. Eight of our patients were diabetic and they were chosen for the treatment due to very short history of DM with no other diabetic stigmata, and their biopsies very clearly showed FSGS without any evidence of diabetic kidney disease. Another important characteristic worth of mentioning is the degree of TIF, which has prognostic value. Severe fibrosis was found in 18% of the patients, but they were subjected for the immunosuppression due to their normal SCr and severity of proteinuria. The clinical feature most often used to predict the clinical course of FSGS such as age, gender, degree of proteinuria, and serum albumin were similar in all four groups. However, there was significant difference among the groups in terms of SCr and degree of interstitial fibrosis. The reason might be due to the toxic effects of CYA on tubules and interstitium, CYA was chosen for those who had better creatinine and TIF, and CYP and MMF was opted for those who had relatively moderate to severe derangement in these parameters.

Our result show that in general, majority of the patients responded with the immunosuppression (79%), as compared to 21.24% who did not respond to any of the treatment. As we mentioned above, all of the cohort received steroid alone as a first-line therapy, those who did not respond to the steroid was switched to any one of the three modalities. The effect of steroid alone was not as good in our population (33.63%) as reported by Banfi et al (61%), Miyata et al (44%), and Rydel et al (50%) in the literature.[¹⁴¹⁵¹⁶] Although it is comparable to the other studies such as Cattran and Rao (22% of adult patients of the study), Ponticelli et al (36%), and Alexopoulos et al (28%).[¹⁷¹⁸¹⁹]

The duration of the treatment is an important factor, which determine the outcome of steroid treatment in FSGS. Patients with FSGS were not considered for the treatment before 1980 due to poor response with steroids, less than 20% in almost all of the studies.[²⁰] Later on, the experience after that changed the scenario and response rate was reportedly increased to 40%. Since the initial dose of steroid was similar, the most obvious difference in the studies attaining the higher remission rate was the duration of the therapy.[²¹] Concomitantly, prolonging the duration of steroid treatment brought in increased side effects. Therefore, adjuvant therapy in the form of CYP, chlorambucil, CYA, and MMF was included in the armamentarium of FSGS treatment to mitigate the steroid side effects by reducing the exposure and duration of steroids treatment.

Combination of CYA and steroid was the largest group, after steroid alone, which achieved CR (16.81%) followed by steroid + MMF (5.31%) and then by steroid + CYP (5.31%). If we include the partial response too, than the combination of MMF with steroids is better than (12.39%) CYP and steroids (7.96%). Steroid alone was taken by 46 (40.7%) patients out of which 38 (82.6%) got CR while three (6.5%) developed PR and five (10.9%) showed no effect of the steroid treatment.

Similarly, all three modalities of treatment other than steroid alone showed significant association with the outcome like achieving remission, recovery in renal functions, and overall recovery. We also found significant improvement in outcome in patients treated with CYA as compared with the other two. As we described earlier that, because of toxicity of CYA there were by default less patients with raised SCr and fibrosis in CYP group. The effect of CYA has been evaluated by Cattran et al and Ponticelli et al in prospective randomized placebo trial in steroid resistant FSGS and showed a remission rate of 70% and 60% respectively.[¹⁰²²] In addition to this, CYA showed comparable result in improving proteinuria and renal functions with alkylating agent Chlorambucil in a prospective randomized study by Heering et al.[²³] Recently Chávez-Mendoza et al showed its efficacy as a first line treatment with very low dose of steroid as compared with high dose steroid in their retrospective cohort.[²⁴]

MMF also showed beneficial effect in the progression of FSGS after CYA. Among 18 patients who were treated with MMF 33% showed CR while 44% showed PR and 22% showed no effect. Similar results were reported by Segarra et al, he used MMF as a rescue therapy in 22 steroid resistant FSGS patients and reported a complete or PR in 54% of the patients.[²⁵] On the other hand, Cattran et al in an open labeled trial in steroid-resistant FSGS, after a treatment of six months with 1 g twice daily dose of MMF showed that 44% of the patients showed improvement in proteinuria, and achieved PR or reduction in proteinuria by 50% from the baseline, but no patient achieved a CR.[²⁶] In a prospective trial, Gipson et al compared CYA and MMF in steroid-resistant FSGS, after one year of the treatment 46% CYA patients and 33% MMF patients had a CR, they did not find a difference in rates of proteinuria remission in the two groups.[²⁷]

CYP was found to be least effective in all three adjuvant treatment. Twenty-one (18.6%) of the patients were treated with CYP out of which 28% showed CR and 52% showed no remission. However, patients treated with CYP had more patients with severe fibrosis and raised Cr at baseline.

One of the interesting finding of our analysis is that, when we assessed clinical variables which have an effect on the outcome with the recovery of the patients, SCr, TIF and treatment showed significant effect on outcome in univariate analysis, but when the effect of TIF was adjusted with the treatment on multivariable analysis, this effect was lost and all treatment regimen showed the same outcome. Similarly, the survival analysis showed that each treatment had nearly the same survival of 11 years.

There are a few factors which increases the strength of our study. First, the long-term follow-up of nearly 11 years, which increases its power to determine the long-term prognosis, especially for the CYA group in whom prolonged CYA toxicity may be of concern. Second, the relatively good sample size of the study for determining hard renal endpoints due to sufficient number of patients in each group. The limitation of this study is the retrospective nature of the data, due to which, the effect of supportive treatment like control of hypertension, use of renin angiotensin and aldosterone blockers, and control of serum lipids were neither completely assessed nor were controlled.

Conclusion

In conclusion, FSGS showed good response with the treatment. There were significant improvements in the clinical and laboratory parameters such as control of BP, serum albumin and degree of proteinuria after the treatment as compared with baseline functions before the treatment. CYA is the most effective treatment in steroid-resistant cases followed by MMF and CYP. TIF and SCr were noted to be important factors that predict the outcome of the treatment. We can speculate from this study that long term use of CYA and even MMF with or without low dose steroid is justified in steroid resistant patients. Long-term outcome of all treatment modalities were the same. Therefore, before choosing the treatment regimen, one should consider the side effect profile of the drug, patient’s preference after informing the side effects, cost of the treatment, TIF, and SCr level. These findings justify a randomized clinical trial to formally evaluate these results.

Acknowledgment

We acknowledged Anees Badar Soomro for his support in collecting and arranging the data and for his help in preparing and arranging the manuscript.

Conflict of interest: None declared.