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Clinicopathological correlation and treatment response of primary focal segmental glomerulosclerosis in adults and adolescents

The incidence of focal segmental glomerulosclerosis (FSGS) is approximately 10% in children <6 years, 20% in adolescents, and 20–25% in adults. A retrospective observational study was done to document clinicopathological correlation, treatment response, and risk factors in the progression of chronic kidney disease (CKD) of primary FSGS in adults and adolescents. A total of 170 patients were studied with a mean follow-up of 4.32 ± 1.2 years. FSGS not otherwise specified was the most common subtype (56%) followed by tip variant (24%). About 32% had complete remission (CR) at a mean time of 6.4 months, 23% had partial remission (PR) at a mean time of 5.7 months, and 45% had no response to steroids. Persistent nephrotic proteinuria at 3rd and 6th month and presence of interstitial fibrosis and tubular atrophy >30% in renal biopsy are the independent predictors of poor response to treatment. Presence of anemia, interstitial fibrosis, and tubular atrophy of >30% in renal biopsy and the absence of remission after treatment were the independent predictors of CKD progression. Overall renal survival was 78% at 3 years and 54% at 5 years. Renal survival difference with or without nephrotic proteinuria at onset was 39% and 69% at 5 years. Renal survival was higher in patients with normal renal function (66%) compared with those who had renal failure (42%) at 5 years. Renal survival at 5 years for CR was 69%, PR was 49%, and no remission was 42%.


Introduction
Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome, accounting for 20-25% of nephrotic syndrome in adults. [1] Around 50% of patients reach end-stage renal disease (ESRD) at 8 years, accounting for 20% of dialysis patients. Kitiyakara et al. reported an 11-fold increase in FSGS among dialysis patients older than 21 years. [2] Remission rates of 80% can be achieved with longer treatment, Indian Journal of Nephrology 2013. All patients treated with oral prednisolone for 24 weeks with at least 6 months follow-up were included. We excluded patients with secondary FSGS, patients who did not receive steroid therapy, poor compliance with drugs, and follow-up with <6 months.
Demographic profile, clinical examination, laboratory parameters viz urine analysis, 24 h urine protein, serum creatinine, blood urea, serum albumin, and lipid profile at the onset of disease and renal biopsy details were analyzed. The diagnosis of FSGS was made when at least one glomerulus shows a typical sclerotic lesion in a segment in light microscopy. Subtyping of FSGS was performed in according to Columbia classification described by D'Agati. [4] All patients were started on oral prednisolone 1 mg/kg/day and continued for 6 months, tapered and stopped within 1-month. If there was no response to steroids at 6 months, they were started on second-line drugs that include oral cyclophosphamide, cyclosporine A (CSA), tacrolimus, or mycophenolate mofetil (MMF). All received a maximal tolerable dose of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers along with supportive treatment and statins.

Definitions
• Complete remission (CR) -proteinuria <0.3 g/day with a stable serum creatinine (<50% increase from baseline) • Partial remission (PR) -proteinuria between 0.3 and 3.5 g/day with at least 50% reduction in proteinuria from the baseline and a stable serum creatinine • Relapse -proteinuria >3.5 g/24 hr after remission • CKD -CrCl <60 ml/min/1.73 m 2 after 3 months • ESRD -CrCl <15 ml/min/1.73 m 2 or the need for dialysis or renal transplantation. [1,5] Statistical analysis All variables were expressed in mean ± standard deviation or percentage. Univariate analysis was done by Fisher's exact test and Chi-square test for categorical variables and analysis of variance was used for continuous variables. Statistical significant variables by univariate analysis were subjected to linear regression analysis to assess multivariable association. Renal survival rate was determined by the Kaplan-Meier method. The log-rank test was used to evaluate the significance of the difference between survival mean values in subgroups. Statistical analysis was done with SPSS software 16 (SPSS Inc., Chicago, IL). In all analytic procedures, P < 0.05 was considered as significant. Institutional Ethics Committee approval was obtained.

Results
A total of 170 patients were included with a mean follow-up of 4.32 ± 1.2 years. About 65% were males (male: female ratio − 1.9:1).The predominant age group was between 21 and 40 years accounting for 54% of total patients. Baseline patient characteristics at the time of biopsy are shown in Table 1. The most common symptom was edema (98%), followed by nephrotic proteinuria (79%), hypertension (41%), microhematuria (30%), sub-nephrotic proteinuria (21%), and renal failure (20%). Venous thrombosis and cellulitis due to anasarca were occurred as complications of disease process. Infection is the most common complication followed by cushingoid features due to drugs. Two patients suffered from glaucoma and eight patients had cataract due to steroid therapy.
Response to treatment as defined previously is expressed as CR, PR, and NR, and the details of immunosuppression therapy are described in Table 2. About 49% of the patients progressed to CKD at mean follow-up. Incidence of ESRD is 17% at a mean time of 4.32 years and two patients died due to uremia at a mean time of 2.4 years. During follow-up, 13 patients out of 93 who achieved remission (CR or PR) had a relapse at a mean duration of 2.8 years. Eighty percentage of them had prior PR only.
Not otherwise specified (NOS) was the most common lesion, present in 96 (56%), followed by tip variant in 41 (24%), perihilar type in 16 (10%), and cellular  Among subtypes, perihilar variant was present with less microhematuria, nephrotic proteinuria compared to NOS (P < 0.001), and cellular variety (P < 0.001). Cellular variant was present more with renal failure (P < 0.05) at presentation versus tip variant and more arterial hyalinosis in renal biopsy (P < 0.05) compared to the perihilar lesion. Hypoalbuminemia (P 0.001) was commonly seen in tip lesion and hypertension in perihilar variant (P = 0.007) compared to other groups. Interstitial fibrosis and tubular atrophy were seen more in NOS (P = 0.007) versus cellular variant. CR was seen more in tip variant (P 0.001) when compared to others. Less remission and progression to CKD was increasingly noted in NOS type compared to tip lesion (P = 0.003 and P = 0.009, respectively).
Predictors of poor response to treatment and progression to CKD are given Table 3. Overall renal survival was 78% at 3 years and 54% at 5 years. Renal survival was significantly higher in patients presented with normal renal function compared with those with renal failure at presentation with 66% versus 42% at 5 years. Renal survival difference with or without nephrotic proteinuria at onset was 39% versus 69% at 5 years [ Figure 1]. Renal survival by Kaplan-Meier analysis at 5 years with CR was 69%, PR was 49%, and NR was 42% [ Figure 2]. There was no significant difference between those achieve PR and nil response.

Discussion
FSGS is characterized by marked proteinuria, variable steroid responsiveness hypertension, and a risk of progression to CKD. [5] Classification of FSGS include primary, genetic, and secondary. Primary (idiopathic) occurs without known inciting injury. [4] A working group has defined five subtypes of FSGS [6] based on light microscopy (Columbia classification) which include collapsing FSGS, tip lesion, cellular, perihilar variant, and NOS.
The most common symptom was edema (98%), followed by nephrotic proteinuria (79%), hypertension (41%), and renal insufficiency (20%), while Singh et al. [7] showed hypertension in 42.2%, gross hematuria in 36.4%, micro-hematuria in 63.6%, and azotemia in 37.5%. Mean proteinuria was 5.53 ± 2.89 g/day while in our study it was 4.26 ± 1.9 g/day. Taheri et al. [8] reported mean systolic blood pressure of 121.19 mmHg, diastolic blood pressure of 77.52 mmHg, serum creatinine of 1.18 mg/dl, plasma albumin of 3.29 g/dl, and glomerular   On steroid therapy, PR occurred earlier in those who eventually achieved CR. Hence, early partial response is the predictor of CR. Miyata et al. [9] reviewed 32 FSGS patients with steroids alone in which 44% had CR, 12% had PR, and 44% had nil response. The prospective Regional Glomerulonephritis Registry Study [10] followed 95 adult and pediatric patients with FSGS, for a mean period of 61 months and showed a remission rate of 39% in adults after prolonged therapy with steroids.
Relapse occurred in 14% cases at a mean time of 2.8 years who achieved remission. In other studies where relapse rate was reported as high as 40%. Males (80%) had more relapse than females. CSA is the only agent tested by randomized controlled trials in adults with FSGS. [11] The main drawback of CSA is that 40-75% patients experience a relapse within 2 months of stopping or tapering the drug. [12] In a recent study of 25 patients with steroid-resistant FSGS, who were treated with tacrolimus (0.15 mg/kg/day) and full dose prednisone for at least 8 weeks, CR was achieved in 40% and PR in 8%. [13] Briggs et al. [14] reported a remission rate of 66% with MMF in steroid resistant FSGS and is an alternative to CSA in patients with progressive renal failure due to its negligible side effects on renal hemodynamics and metabolic profile. Lanewala et al. [15] showed steroid-dependent nephrotic syndrome in 63.8% and steroid resistance in 35% of children with idiopathic FSGS. They also showed that majority of them could achieve high rates of sustained remission with second-and third-line immunosuppressive drugs.
A study of primary FSGS in children <17 years from Pakistan showed NOS as the highly prevalent variant. [19] By multivariate analysis, persistent nephrotic proteinuria at 3 rd and 6 th month and presence of interstitial fibrosis and tubular atrophy >30% in renal biopsy were the independent predictors of poor renal response to treatment. Risk factors such as male gender, nephrotic proteinuria at onset, persistent nephrotic proteinuria at 3 and 6 months, renal failure at onset, persistent renal failure at 3 and 6 months, presence of hypertension, anemia, interstitial fibrosis and tubular atrophy of >30% in renal biopsy, and NR after treatment predicted the progression to CKD at mean follow-up. Of this, last three factors were the independent predictors. Absence of remission was the single strongest predictor for the progression of CKD.
Most studies demonstrated that presence of significant interstitial fibrosis was the only independent predictive factor for response to treatment. [20,21] Korbet [1] showed that serum creatinine >1.3 mg/dl, range of proteinuria, and interstitial fibrosis >20% were positive predictors of the occurrence of ESRD.
Overall renal survival by Kaplan-Meier survival analysis was 78% at 3 years and 54% at 5 years. Renal survival was significantly higher in patients presented with normal renal function (66%) compared with those with renal failure (42%) at 5 years. Renal survival difference with or without nephrotic proteinuria at onset was 39% versus 69% at 5 years. Renal survival at 5 years for CR was 69%, for PR 49%, and for NR 42%. There was no significant difference between those achieve PR and nil response. Therefore, attaining CR significantly improves renal survival. Renal survival rates were 68.6% and 27.3% at 5 and 10 years, respectively, in a study by Singh et al. [7] Cameron [22] reported 5-year and 10-year survival rates as 70% and 40%, respectively.
This study involves significant number of patients with longer duration of follow-up from India and validates the observation that nonremission of proteinuria is the strongest risk factor for CKD progression. The limitations include retrospective analysis and the role of immunosuppressants other than steroids was not studied due to less number.

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