Raised serum creatinine at presentation does not adversely affect steroid response in primary focal segmental glomerulosclerosis in adults

1101 Nephrol Dial Transplant (2012) 27: 1101 1106 doi: 10.1093/ndt/gfr430 Advance Access publication 29 July 2011 Raised serum creatinine at presentation does not adversely affect steroid response in primary focal segmental glomerulosclerosis in adults Nazrul Jafry 1, Ejaz Ahmed 1, Muhammed Mubarak 2, Javed Kazi 2 and Fazal Akhter 1 1 Department of Nephrology, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan and 2 Department of Histopathology, SIUT, Karachi, Pakistan Correspondence and offprint requests to: Muhammed Mubarak; E-mail: info@siut.org Abstract Background. There is no information in international literature on the mode of presentation, laboratory and clinical features, treatment and prognosis of primary focal segmental glomerulosclerosis (FSGS) in adults in Pakistan. Methods. This is a retrospective review of 124 adults (17 years) with a diagnosis of primary FSGS who presented to the adult nephrology clinic at Sindh Institute of Urology and Transplantation between January 1995 and June 2006. The clinical records and biopsy reports were reviewed to determine the demographic, clinical, laboratory and pathologic features, treatment responses and outcome of the disease. Renal biopsies were performed and evaluated by light microscopy, immunofluorescence and electron microscopy. Standard therapeutic regimens and response to therapy definitions were used. Outcome data were obtained at last follow-up. Results. Mean age of all patients was 30.9 6 13.6 years (range: 17 85 years). Of these, 86 (69%) were males and 38 (31%) females, with a male to female ratio of 2.2:1. Of 124 patients, 79 (63.7%) were treated with steroids for a median duration of 5 months. Remission was achieved in 40 (50.6%) patients. Relapse occurred in 14 (17.7%) steroid-treated patients. These achieved sustained remission with retreatment. None of the steroid-treated patients went into end-stage renal disease over a mean follow-up of 2.3 years. Conclusions. Results from this study show that half of adults with primary FSGS achieve sustained remission with prolonged steroid treatment and consequently exhibit an excellent prognosis for long-term outcome. Moreover, raised serum creatinine at presentation does not in itself adversely affect steroid response in adults with primary FSGS. Keywords: adults; focal segmental glomerulosclerosis; nephrotic syndrome; renal biopsies; Pakistan Introduction Primary focal segmental glomerulosclerosis (FSGS) is a clinicopathologic syndrome in which variable amounts of proteinuria, usually of nephrotic range, are associated with the renal biopsy finding of focal and segmental scarring of the glomeruli [1 4]. First described by Rich in 1957 in an autopsy series, it has now become the leading cause of idiopathic nephrotic syndrome (INS) in adult populations worldwide [1, 5 7]. The clinical course of patients with primary FSGS is one of the progressive renal insufficiency leading to end-stage renal disease (ESRD) >5 10 years in >50% of cases [8 12]. It is currently the most common primary glomerulonephritis in theusathatleadstoesrdinbothadultsandchildren [11]. Hence, its accurate diagnosis has considerable therapeutic and prognostic implications. We have earlier reported FSGS as the leading cause of INS in adults in Pakistan [13]. Ó The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

1102 N. Jafry et al. Although the natural course of primary FSGS has been well described, its treatment is still a matter of debate [14 28]. Although steroids constitute the mainstay of treatment, primary FSGS in adults has historically been regarded as a steroid-resistant disease. However, more recent studies using high-dose steroids for prolonged periods have produced promising results [15 28]. Detailed clinicopathologic analysis of primary FSGS in adults, particularly its treatment and prognosis, has not been reported from Pakistan in international literature to date. In this study, we report our single-center experience on the clinical presentation, laboratory features, response to treatment, clinical course and long-term prognosis in adults with primary FSGS. Materials and methods This is a retrospective review of 124 consecutive adults (17 years) with a biopsy diagnosis of idiopathic or primary FSGS who presented to the adult nephrology clinic of Sindh Institute of Urology and Transplantation between January 1995 and June 2006 with at least 6 months of regular follow-up. Patients with known secondary causes of FSGS, including systemic diseases with glomerular involvement, acquired immunodeficiency syndrome, intravenous heroin abuse, solitary kidney and urinary obstruction and/or reflux, were excluded from the study. The original biopsy reports and clinical records were reviewed to determine the patients age, sex, level of protein excretion, presence of hypertension, serum creatinine, total protein and serum albumin and presence of hematuria. All patients underwent percutaneous native renal biopsies under real-time ultrasound guidance. Informed consent was obtained from patients prior to undertaking the biopsy. Renal biopsy specimens were examined jointly by two experienced renal pathologists and classified according to standard criteria [2]. Nephrotic syndrome (NS) was diagnosed in accordance with standard guidelines [13]. Hypertension was defined as blood pressure (BP) readings exceeding 150 mmhg for systolic BP and 90 mmhg for diastolic BP in two consecutive measurements in the supine position or the need for antihypertensive therapy. Elevated serum creatinine was defined as serum creatinine value of >1.4 mg/dl in males and >1.2 mg/dl in females. ESRD was defined as the permanent need for renal replacement therapy [11]. Standard therapeutic regimen and response to therapy definitions with slight modifications were used [14 19, 22, 23]. Briefly, the patients were treated with 1.0 mg prednisone/kg body weight per day for 6 weeks, followed by 0.75 mg/kg/day of prednisone for six additional weeks, which was then gradually tapered >3 months. Complete remission was defined as a decrease in the rate of urinary protein excretion to at least 0.2 g/day for at least 1 month, with plasma creatinine persistently <1.5 mg/dl. Partial remission was defined as a decrease in the rate of urinary protein excretion to between 0.21 and 2 g/day for at least 1 month, with plasma creatinine <1.5 mg/dl [19]. Time to remission was calculated from the date of first treatment to the date of remission [22]. Relapse was defined as recurrence of the nephrotic range proteinuria and edema while tapering the dose of steroids or on stopping steroid treatment. Relapsers received a second course of steroid treatment alone or in combination with cyclophosphamide. The persistent doubling of serum creatinine over baseline values was used as a surrogate marker for progressive renal insufficiency [19]. The clinical course and outcome of each patient were evaluated by recording current medications, BP, serum creatinine and albumin levels, urinalysis and 24-h urinary protein excretion. Pathologic study At our center, two cores of native renal tissue are routinely obtained for complete pathologic evaluation by light microscopy (LM), immunofluorescence (IF) and electron microscopy (EM) as described in detail in our previous study [13]. The pathological diagnosis was taken from the original biopsy reports in our histopathology record and was not formally reexamined by the pathologists. Light microscopy (LM) For LM, routinely 10 serial sections are cut with Levels 1, 5 and 10 stained by hematoxylin and eosin, Level 7 is stained with trichrome, Level 8 by periodic acid-schiff and Level 9 by Jones methenamine silver stain. FSGS was diagnosed according to established criteria by two experienced renal pathologists first independently and then jointly to arrive at a consensus diagnosis [2]. Immunofluorescence (IF) Tissue specimens for IF were stained by the direct method using fluorescein isothiocyanate-conjugated antisera monospecific for IgG, IgA, IgM, C3 and C1q (Dako, Glostrup, Denmark) as detailed in our earlier report [13]. IF findings on the biopsy specimens were obtained from the original biopsy reports. Electron microscopy (EM) Tissue samples for EM were processed according to a presently established technique [13]. Briefly, EM tissue was fixed in 4% glutaraldehyde, post-fixed in 1% osmium tetroxide at 0.02 M Sorenson Phosphate buffer at ph 7.4, processed for EM and embedded in Eponate resin. Ultra-thin sections (100 nm) were cut on Leica ultramicrotome. Sections were stained on copper 300-mesh girds with Uranyl acetate and Lead citrate and examined with a JEM 1200 EX II electron microscope. EM study was performed in all cases and the EM findings were obtained from the original biopsy reports. Statistical tests Statistical analysis was carried out using IBM-compatible SPSS for Windows version 10 (SPSS, Chicago, IL). Simple descriptive statistics such as mean SD and median (interquartile range) were used for continuous variables such as age and clinical and laboratory parameters. Numbers (%) were used for categorical data. For comparisons of various parameters among the groups, Student s t-test and chi-square tests were used. Pearson s correlation was used to find a relationship, if any, between the elevated serum creatinine and the other clinical and laboratory findings at the time of presentation. A P-value of <0.05 was considered significant. Results Patients demographic, clinical and laboratory features on presentation The patient characteristics at the time of presentation are shown in Table 1. A total of 124 patients satisfied study criteria and were entered into the study. Of these, 86 (69%) were males and 38 (31%) were females, with a male to female ratio of 2.2:1. The mean age was 30.9 13.6 years with a range of 17 85 years. The mean 24-h urinary protein excretion was 6 4.5 g/day [median: 4.7 (2.5 8.9)]. Of 124 patients, 72% had nephrotic-range proteinuria, with 24% having heavy proteinuria, defined as protein excretion of >8 g/day. Mean serum albumin was 2.3 0.9 g/dl (median: 2.0 g/dl). The mean serum creatinine was 1.48 1.36 mg/100 ml (median: 1.1 mg/100 ml). An elevated serum creatinine was found at presentation in 42 (33.8%) patients; among these, 32 (37.2%) were males and 10 (26.3%) were females. Pearson s correlation testing of elevated serum creatinine on presentation showed a poor and non-significant correlation of this parameter with the duration of disease (r ¼ 0.11, P ¼ 0.47), systolic BP (r ¼ 0.26, P ¼ 0.94), diastolic BP (r ¼ 0.22, P ¼ 0.15), serum albumin (r ¼ 0.15, P ¼ 0.42), initial proteinuria (r ¼ 0.13, P ¼ 0.41), antihypertensive treatment (r ¼ 0.17, P ¼ 0.28) and

Primary FSGS in adults in Pakistan 1103 Table 1. Patient demographic, clinical and laboratory findings at presentation and at last follow-up in all patients with primary FSGS a Age (in years) Mean 6 SD (range) 30.9 6 13.6 (17 85) Median (IQR) 26 (20 38) Sex Male 86 (69%) Female 38 (31%) Male to female ratio 2.2:1 Duration of symptoms (in weeks) Mean 6 SD 69.4 6 111.6 Median (IQR) 26 (8 57) Systolic BP (mmhg) Mean 6 SD 131.4 6 20.6 Median (IQR) 130 (120 140) Diastolic BP (mmhg) Mean 6 SD 87.9 6 13.4 Median (IQR) 90 (80 100) Initial proteinuria (mg/24 h) Mean 6 SD 6006 6 4440 Median (IQR) 4695 (2470 8901) Serum albumin (g/dl) Mean 6 SD 2.3 6 0.9 Median (IQR) 2.0 (1.6 3.0) Serum creatinine (mg/dl) Mean 6 SD 1.48 6 1.36 Median (IQR) 1.1 (0.7 1.8) Elevated serum creatinine [n (%)] Male (>1.4 mg/dl) 32 (37.2%) Female (>1.2 mg/dl) 10 (26.3%) Final proteinuria (mg/24 h) Mean 6 SD 46106 5068 Median (IQR) 3344 (1394 6675) Follow-up duration (weeks) Mean 6 SD 113.6 6 118.9 Median (IQR) 64 (32 156) a IQR, interquartile range. the number of antihypertensive drugs (r ¼ 0.02, P ¼ 0.87). The mean systolic BP was 131.4 20.6 mmhg and mean diastolic BP was 87.9 13.4 mmhg. Treatment responses and follow-up Of all patients with primary FSGS, 79 (63.7%) were treated with doses of steroids as envisaged in our treatment protocol. The total dose, duration and response to steroid treatment are given in Table 2. Of 79 patients, 40 (50.6%) achieved remission with this regimen. Of these, 36 (45.5%) achieved complete remission, while 4 (5%) showed partial remission. The mean time to remission was 12.6 7.9 weeks. It is of note that about half of the patients showed delayed response to steroids (>3 months) and the response continued for as long as 6 months in a few patients, as shown in Figure 1. Among initial responders, 14 (35%) patients relapsed after a mean duration of 46.4 50.7 weeks (range: 4 169 weeks). These patients were treated with a second course of steroids alone (11 patients: 78.6%) or steroids in combination with cyclophosphamide (3 patients: 21.4%). All 14 relapsers again achieved complete remission of proteinuria. All these patients were in remission till the end of this study. A comparison of some clinical, laboratory and treatment parameters between steroid-responsive and non-responder groups is shown in Table 3. This shows that steroid non-responder group had Table 2. The duration and dose of steroids and remission rates in 79 patients with primary FSGS who were treated with steroids at our center a Duration of steroid treatment (weeks) Mean 6 SD 20.1 6 7.4 Median (IQR) 20.0 (16.0 24.0) Total steroid dose (mg) Mean 6 SD 4527.5 6 1705.9 Median (IQR) 4340 (3385 5600) Steroid dose (mg/kg) Mean 6 SD 76.8 6 26.9 Median (IQR) 74.2 (61.5 88.8) Remission (n ¼ 40) Complete remission 36 (50.6%) Partial remission 04 (5%) Time to remission (in weeks) Mean 6 SD 12.6 6 7.9 Median (IQR) 12.0 (6.0 17.7) a IQR, interquartile range. Fig. 1. Time to remission in weeks in steroid-responsive patients with primary FSGS. more severe disease as reflected by higher levels of proteinuria and lower serum albumin levels and higher systolic BP at the time of presentation. A comparison of elevated serum creatinine among steroid-responsive and steroid non-responder groups on presentation and at last followup is shown in Table 4. An elevated serum creatinine on presentation was more common in the steroid-responsive group and on last follow-up in the steroid non-responder group (P < 0.05). An elevated serum creatinine was not considered in itself a contraindication to the treatment of these patients. In fact, a majority of these patients (29; 69%) were treated with steroids. An analysis of the clinical course in this subgroup of steroid-treated patients is shown in Table 5. It is apparent from this table that in these cases, serum creatinine either decreased or stabilized with steroid treatment and was most likely related to hemodynamic alterations rather than chronic renal damage. A poor correlation of this parameter with other presenting clinical and laboratory features also favors this hemodynamic origin. A comparison of some clinical and laboratory features between treated and untreated patients is shown in Table 6. It is evident that the untreated patients had less severe disease as shown by a higher serum albumin and lower level of proteinuria compared with treated patients, but there were some other reasons for not treating these patients. The mean follow-up duration for all patients was 113.6 118.6 weeks (median: 64 weeks). A persistent doubling of serum creatinine over baseline values was observed in eight

1104 N. Jafry et al. Table 3. Comparison of clinical, laboratory and treatment parameters among steroid-responsive and -resistant primary FSGS groups Parameters Steroid-responsive group (n ¼ 40) Steroid-resistant group (n ¼ 39) P-value Age (years) (mean 6 SD) 28.5 6 12.2 31.7 6 15.4 0.31 Sex (M:F) 28:12 25:14 0.57 Systolic BP (mmhg) 126.6 6 17.4 136.1 6 22.1 0.03 a Diastolic BP (mmhg) 87 6 12 87 6 15 0.97 Initial protein (mg/24 h) 5460 6 4339 7652 6 4237 0.03 a Initial serum creatinine (mg/dl) 1.73 6 1.8 1.3 6 0.95 0.19 Initial serum albumin (g/dl) 2.07 6 1.0 1.83 6 0.5 0.27 Total steroid dose (mg) 4420 6 1513 4638 6 1897 0.57 Steroid dose (mg/kg) 78.4 6 23.4 75.1 6 30.1 0.59 Steroid duration (weeks) 21.5 6 5.7 18.7 6 8.6 0.08 a Statistically significant. Table 4. Comparison of elevated serum creatinine at presentation and last follow-up among steroid-responsive and steroid-resistant FSGS groups Parameters Steroid-responsive group (n ¼ 40) Steroid-resistant group (n ¼ 39) P-value Duration of follow-up (in weeks) 132 6 104 104 6 115 0.25 Elevated serum creatinine on presentation 18 (47.4%) 9 (24.3%) 0.03 a Elevated serum creatinine on last follow-up 5 (13.5%) 13 (36.1%) 0.02 a Doubling of serum creatinine 1 (2.5%) 7 (17.9%) 0.0001 a a Statistically significant Table 5. Clinical course of 29 patients with elevated serum creatinine who were treated with steroids Initial serum creatinine (mg/dl) Mean 6 SD (range) 2.62 6 1.96 (1.23 11.2) Median 2.0 Repeat serum creatinine after treatment (mg/dl) Mean 6 SD (range) 1.8 6 1.2 (0.5 5.40) Median 1.4 Duration of repeat serum creatinine (in weeks) Mean 6 SD (range) 14.2 6 10.28 (2.14 51) Median 12.6 Serum creatinine at last follow-up (mg/dl) Mean 6 SD (range) 2.05 6 2.06 (0.5 10.3) Median 1.37 Duration of last serum creatinine (in weeks) Mean 6 SD (range) 114.9 6 125.8 (2.14 512) Median 48.3 Table 6. Comparison of some clinical and laboratory parameters between steroid-treated and -untreated groups at our center Parameters Treated group (n ¼ 79) Non-treated group (n ¼ 45) P-value Age (in years) (mean 6 SD) 30.1 6 13.8 32.3 6 13.3 0.37 Sex (M:F) 53:26 34:11 0.27 Initial proteinuria (mg/24 h) 6479 6 4401 5073 6 4430 0.12 Initial serum albumin (g/dl) 1.95 6 0.82 2.73 6 0.87 0.0001 a Initial serum creatinine (mg/dl) 1.51 6 1.51 1.44 6 1.07 0.80 Duration of follow-up (weeks) 118 6 110 105 6 135 0.57 a Statistically significant. (20%) patients; seven (17. 5%) of these belonged to steroid non-responder group and one (2.5%) to steroid-responsive group. None of the treated patients went into ESRD till last follow-up. Discussion We herein present our experience in one of the largest case series of primary FSGS in adults with regard to clinical presentation, laboratory features, treatment responses and long-term outcome in Pakistan. We acknowledge that the study has certain limitations. These include the retrospective nature of the study, heterogeneity of the disease at presentation, relatively short follow-up and its origin from a single center. Although it is single-center-based study, the catchment area of our adult nephrology services extends more or less to the whole country. We provide all the consultation and medications free of cost, which ensures a fairly high rate of compliance and regular follow-up. Our patient population is homogenous with respect to racial origin. Uniform clinical and pathologic criteria for the

Primary FSGS in adults in Pakistan 1105 diagnosis of primary FSGS and its management have been used over the study period by the same nephrologists and the pathologists. Thus, we believe that our study results fairly accurately represent the clinical course and the outcome of this entity in adults from this country. The presenting clinical and laboratory features of this relatively young adult population of primary FSGS were not different from that described previously in literature [12, 14]. Almost, all patients (98%) had symptomatic edema despite varying degrees of proteinuria, which was sub-nephrotic in 28% subjects. It is well known that when serum albumin concentration is very low, albumin excretion in urine may fall to sub-nephrotic range [2 4]. In addition, there is mounting evidence that a significant portion of filtered albumin is taken up by proximal tubular epithelial cells and catabolized and measured protein excretion in urine underestimates the actual leakage [4]. This would lead to hypoalbuminemia without manifesting as nephrotic range proteinuria. Moreover, fluid retention in glomerular diseases may be disassociated with degree of proteinuria and serum albumin concentration [4]. The underrepresentation of asymptomatic patients in our study is most likely due to the infrequent referral of such patients or biopsy policy. The number of patients with elevated serum creatinine at presentation (42; 33.8%) is similar to most of the previously reported series [12, 14]. An elevated serum creatinine in these cases could be due to chronic and irreversible loss of renal function or may well be a reflection of homodynamic alterations in acute onset NS [12]. The fact that the majority of steroid-responsive patients with an elevated serum creatinine at presentation showed improvement or stabilization of renal function supports the latter mechanism in our patients. There was also a poor correlation of this parameter with other clinical or laboratory features at presentation, further supporting its hemodynamic origin and the reversibility. Since corticosteroids are the mainstay of treatment and the therapeutic response to steroids seems to be the best predictor of long-term outcome and prognosis, it is our policy to treat all eligible adults with primary FSGS with standard doses of steroids, if not otherwise contraindicated [17]. We were able to perform a detailed analysis of steroid response in 79 (63.7%) patients who received primary treatment at our center according to our protocol. It is worth mentioning here that in the current clinical practice, 40 50% of patients with FSGS and nephrotic-range proteinuria are not treated with immunosuppression [22]. The overall remission rate achieved in our steroid-treated cohort was 50.6%. The steroid response rates in different studies have varied from 30 to 67%, depending on the dose and duration of steroid treatment [22, 23]. Our treatment protocol consisted of daily high-dose steroid treatment for 3 months followed by tapering over next 2 3 months. This is shorter than the current recommendation of high-dose steroid treatment for 4 6 months [23]. A response rate as high as 80% has been reported in some series with protracted steroid treatment [22, 23]. However, steroid dose was not maintained at a high dose after 3 months in these studies. This suggests that steroids in a lower dose but for longer period after initial high dose do have remission-inducing effects. Steroid dosage in our study was usually reduced to 0.5 mg/ kg/day by the beginning of fourth month and the median duration of steroid treatment was 5 months. The fact that half of the patients responded after 3 months (Figure 1) also supports the phenomenon of delayed response to prolonged lower dose treatment. This may have important implications for future treatment as side effects of high-dose steroids are considerable, and if these observations are confirmed in prospectively conducted trials, it may decrease steroid-related morbidity. A lower baseline protein excretion and a lower systolic BP were associated with favorable response to steroid treatment in our cohort as shown in Table 3. It is generally assumed that patients with heavy proteinuria have more severe disease, which may not respond well to steroids [12, 14]. On the other hand, a lower protein excretion has not been consistently shown to be predictive of steroid response [23]. The clinical significance of lower systolic BP among responders is not known. The baseline serum creatinine was unexpectedly high among steroid-responsive group, although it did not reach statistical significance. An elevated creatinine at presentation is usually considered a poor prognostic marker in terms of subsequent renal survival and has also been shown to influence steroid response [14]. In one study providing a stratified analysis, remission was achieved in only 5 of 21(23.8%) patients with a serum creatinine exceeding 1.4 mg/dl compared to 36 of 60 (60%) with lower serum creatinine concentration [12]. In our study, elevated serum creatinine at presentation was not predictive of steroid responsiveness and we suggest that it should not deter the clinician from starting steroid treatment, especially in subjects with short duration of illness. The proportion of subjects with elevated creatinine at baseline was significantly higher in steroid-responsive group but decreased significantly after attaining a remission. Although the cumulative steroid dose in the steroid-resistant group was similar to the steroid-responsive group, the former received steroids for slightly shorter duration. This may reflect relatively rapid tapering in subjects responding poorly to steroid treatment after 3 months of high-dose therapy. Among responders, 14 (35%) patients relapsed after initial successful response; 11 of these were retreated with steroids alone and 3 with steroids in combination with cyclophosphamide. Both subgroups responded again with complete remission. There is paucity of data in adults regarding management of initially steroid-responsive patients, who later relapse [14]. We did not encounter frequent relapsers in our adult patients. Response to steroids is associated with long-term preservation of renal function in patients with FSGS [12, 14, 23]. Only one patient in the steroid-responsive group experienced a doubling of serum creatinine during follow-up and none developed ESRD. In a study of FSGS patients followed for a longer period, renal function was well preserved for up to 10 years in steroid-responsive patients, whereas steroid resistance was predictive of development of ESRD in 57% of cases within an average period of 6.5 years [12]. The fact that nearly 18% of our steroid-resistant cases have already doubled their serum creatinine after a mean follow-up of 2.3 years highlights the poor renal prognosis of this group of patients.

1106 N. Jafry et al. We did not observe any spontaneous remission in subjects who were not treated with steroids either at our center or elsewhere. Due to their relatively shorter follow-up which was erratic as well, they were not analyzed in detail. But, spontaneous remissions have been rare in previously reported series also ranging from 5 to 23% of primary FSGS in adults [22, 23]. In conclusion, results from this study show that half of adults with primary FSGS achieve sustained remission with steroids and consequently exhibit an excellent prognosis for long-term outcome. Moreover, a raised serum creatinine at presentation does not in itself adversely affect steroid response in adults with primary FSGS and may result from hemodynamic alterations rather than chronic irreversible renal damage. Conflict of interest statement. None declared. References 1. Rich AR. A hitherto undescribed vulnerability of the juxtamedullary glomeruli in lipoid nephrosis. 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