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Published ahead of print on November 30, 2005
Clin J Am Soc Nephrol 1: 109-116, 2006
© 2006 American Society of Nephrology
doi: 10.2215/CJN.00120605
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A Prospective, Open-Label Trial of Sirolimus in the Treatment of Focal Segmental Glomerulosclerosis

James A. Tumlin*, Danlyn Miller*, Mitzi Near*, Sasi Selvaraj*, Randolph Hennigar{dagger}, and Antonio Guasch*

* Department of Medicine, Division of Nephrology, and {dagger} Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia

Address correspondence to: Dr. James A. Tumlin, Department of Medicine, Renal Division, Emory University School Medicine, 1639 Pierce Drive, WMB Room 338, Atlanta, GA 30322. Phone: 404-727-2974; Fax: 404-727-3425; E-mail: jtumlin{at}emory.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Calcineurin inhibitors are effective therapy for steroid-resistant focal segmental glomerulosclerosis (FSGS) but are associated with significant morbidity and nephrotoxicity. Sirolimus is a novel immunosuppressive agent that is structurally related to tacrolimus but demonstrates no long-term nephrotoxicity. For determination of the efficacy of sirolimus in reducing proteinuria, a prospective, open-label trial was conducted of 21 patients with idiopathic, steroid-resistant FSGS. A complete response was defined as <300 mg protein/24 h after 6 mo, whereas a partial response was defined as a 50% reduction in baseline proteinuria. After 6 mo of therapy, sirolimus induced complete remission in four (19%) of 21 patients and partial remissions in eight (38%). Among sirolimus-responsive patients, 6 mo of therapy decreased proteinuria from a mean of 8.8 ± 1.7 to 2.1 ± 0.5 g/24 h (P = 0.0003). In responsive patients, GFR was maintained (45 ± 6 versus 47 ± 7 ml/min per 1.73 m2 at 6 mo) throughout the study, whereas nonresponders tended to decrease (31 ± 4 versus 28 ± 5 ml/min per 1.73 m2). Using dextran sieving analysis, complete or partial response was associated with an increase in the glomerular ultrafiltration coefficient (Kf, 7 ± 1. versus 8 ± 0.9 units at 6 mo; P < 0.05). Glomerular permselectivity and Kf tended to decrease in nonresponders (8.2 ± 1.9 versus 6.2 ± 1.3 units at 6 mo; P = 0.07). Patients with complete remission had a higher GFR (45 ± 6 versus 31 ± 4 ml/min per 1.73 m2) at the end of 6 mo compared with nonresponders. In patients with steroid-resistant FSGS, sirolimus reduced proteinuria and glomerular pore size and increased Kf in patients with steroid-resistant FSGS.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Primary focal segmental glomerulosclerosis (FSGS) is a significant cause of the nephrotic syndrome within adult and pediatric populations (1). Recent epidemiologic studies demonstrated that the incidence of FSGS has increased significantly over the past 2 decades and now accounts for >35% of all cases of adult-onset nephrotic syndrome (1,2). Black individuals are two- to four-fold more likely to develop FSGS compared with age-matched white individuals and are at increased risk for progression to ESRD (2,3).

The pathogenesis of FSGS is unknown, but numerous human and animal model studies suggest that alteration in podocyte structure and function is central to the development of the disorder (4). The de-differentiation and proliferation of podocytes leads to effacement of footplate processes, detachment of podocytes from glomerular basement membranes, and expansion of the mesangial matrix (4–7). The resulting loss of glomerular barrier function allows for massive proteinuria, sclerosis, and adhesions of the glomerular tuft to Bowman’s capsule (8). Other data suggest that cytokines such as TGF-ß or the presence of circulating vascular permeability factors contribute to footplate effacement and glomerular sclerosis (9,10).

Oral steroids remain the primary therapy for patients with adult-onset FSGS, but the need for prolonged therapy and the development of steroid-induced toxicities have limited its widespread use (11). Cyclosporin A (CsA) and tacrolimus are effective alternatives, but long-term toxicity limits their use (12–14). In an attempt to find safe and effective treatments, we investigated the efficacy of sirolimus in patients with steroid-resistant FSGS. Sirolimus is a novel immunosuppressive agent that blocks cytokine-dependent T cell proliferation but has significantly less nephrotoxicity compared with CsA or tacrolimus (15,16). In this study, we prospectively treated 21 patients who had steroid-resistant FSGS with a 26-wk course of oral sirolimus. We found that sirolimus induced complete or partial remission in 57% of patients with steroid-resistant FSGS and reduced proteinuria by a mean of 51%.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
After signing informed consent, 21 consecutive nephrotic patients who were referred to Emory University with steroid-resistant FSGS were enrolled in a prospective, open-labeled trial of oral sirolimus. This protocol was reviewed and approved by the Human Investigations Committee of Emory University and met all of the requirements of the Declaration of Helsinki. All patients were required to have renal biopsy within 6 mo of study enrollment and demonstrate histopathology consistent with FSGS. Patients with HIV, ureteral reflux, recurrent pyelonephritis, the collapsing or cellular variants of FSGS, or >50% cortical fibrosis were excluded from the study. A single renal pathologist confirmed the diagnosis of FSGS in all 21 patients using the method of D’Agati et al. (5). Of the 21 patients, 20 were identified as having the "classical" form; one patient had the TIPS variant.

All patients who were enrolled in the study had steroid-resistant FSGS as defined by continued proteinuria >2.0 g/24 h after a 90-d trial of high-dose prednisone treatment (1.0 mg/kg per d). In addition to prednisone therapy, seven patients received a course of oral CsA or tacrolimus and two additional patients received therapy with cyclophosphamide or mycophenolate mofetil. Patients who received >20 mg/d prednisone, azathioprine, calcineurin inhibitors, or mycophenolate were excluded from the study. Patients who were on angiotensin-converting enzyme (ACE) inhibition or angiotensin receptor blocker therapy were maintained on the same dose for the duration of therapy. Non-ACE/angiotensin receptor blocker antihypertensive agents were used to maintain BP <135/75 mmHg throughout the 6-mo treatment period.

Glomerular Function Studies
Patients were admitted to the General Clinical Research Center (GCRC) for a complete physical examination and measurement of serum electrolytes, white blood cell count, and fasting lipid profiles. Two 24-h urine collections for proteinuria were used to confirm that 24-h proteinuria exceeded 2.0 g/24 h. Measurement of GFR, renal plasma flow (RPF), and glomerular permeability using polydisperse dextrans and differential solute clearance was performed as previously reported (17,18). All 21 patients underwent GFR measurements at baseline and after 6 mo of therapy, except for two patients, who failed to undergo 6-mo studies. Thus, we report the results of glomerular function and permeability of the 19 patients (10 responders, nine nonresponders) who had paired observations.

Analytical Determinations
Concentrations of albumin and IgG in plasma were determined by a turbidimetric technique using specific antibodies (Turbitime System, Behring Co., Lake Bluff, IL). Urinary albumin was measured by RIA (DPC, Los Angeles, CA), and urinary IgG was measured by an ELISA technique. The concentrations of inulin and para-aminohypuric acid in plasma and urine were determined by the resorcinol and Marshall’s methods, respectively. Concentrations of dextran were assayed as previously reported (19,20). For computational purposes, we assumed that the intraglomerular hydraulic pressure ({Delta}P) was constant during the duration of the study at 40 mmHg. In nonresponders, we also calculated ultrafiltration coefficient (Kf) at {Delta}P of 45 mmHg to account for a possible increase in intraglomerular pressure associated with worsening hypertension in the latter group (Table 1).


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  		Table 1. Glomerular function and protein excretiona

 
Definitions: Primary and Secondary End Points
A patient with <300 mg protein/24 h was considered to have achieved a complete response, whereas patients with >50% reduction from baseline proteinuria were considered partial responders. Secondary end points included drug safety and tolerability and changes in GFR, RPF, and glomerular permeability after 6 mo of therapy. A sirolimus-responsive patient was defined as any patient with a complete or partial response. Nonresponsive patients were defined as patients with <50% reduction in proteinuria.

Statistical Analyses
Data are expressed as mean ± SEM for continuous variable or number (percentage) for dichotomous variable unless otherwise stated. Statistical differences between baseline and posttreatment values for basal and peak serum creatinines (Cr); slope of 1/serum Cr; proteinuria; and changes in GFR, RPF, and glomerular permeability were calculated using a t test and a two-sample paired analysis. Values for albumin and IgG excretion rates were log-transformed before analysis. Statistical calculations were conducted using GB Stat for Windows (Dynamic Microsystems, Version 9.0, Silver Spring, MD). P <0.05 was considered to be statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patient Demographics
Table 2 lists the demographic data of 21 patients who had steroid-resistant FSGS and were enrolled in the protocol. The mean age was 35 ± 3 yr; 62% of the patients were female, and 67% of the patients were black. Among sirolimus-responsive and -unresponsive patients, there were no significant differences in age, mean arterial pressure, percentage of black patients, or baseline Cr or proteinuria (Table 2).


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  		Table 2. Patient demographics

 
Sirolimus and Proteinuria
The majority (76%) of patients were nephrotic at the time of enrollment, with five additional patients excreting <3.5 g protein/24 h (range 2.3 to 18.8 g/24 h). As shown in Figure 1, 6 mo of sirolimus therapy resulted in a reduction in baseline proteinuria from 8.0 ± 1.2 to 3.9 ± 0.7 g/24 h (P = 0.002). Among sirolimus-responsive patients, 24-h urine proteinuria decreased from 8.8 ± 1.7 to 2.1 ± 0.5 g/24 h (P = 0.003). In contrast, sirolimus failed to reduce proteinuria among the nonresponsive patients (7.0 ± 1.7 to 6.5 ± 1.1 g/24 h; NS). Proteinuria fell in 16 (76%) of 21 patients, but only 12 of 21 patients met the definition of a partial or complete remission. After 6 mo, patients with >30% reduction in proteinuria were offered a 6-mo extension of sirolimus therapy. Figure 2A demonstrates individual changes in 24-h proteinuria among the sirolimus-responsive patients at baseline, 6 mo, and 12 mo. At baseline, proteinuria fell significantly (P = 0.0013) from a mean of 8.8 ± 1.6 to 2.1 ± 0.5 g/24 h by 6 mo, whereas prolonged treatment resulted in a further reduction in proteinuria to 1.5 ± 0.3 g/24 h by 12 mo. However, the reduction in proteinuria between 6 and 12 mo did not reach statistical significance (P = 0.11). The mean proteinuria at baseline and after 6 mo of sirolimus therapy is shown in Figure 2B. In addition to the 12 sirolimus-responsive patients, two patients with a 30% reduction in proteinuria at 6 mo were given an additional 6 mo of sirolimus. Prolonged therapy with sirolimus decreased proteinuria from a mean of 8.4 ± 1.6 g/24 h at baseline to 2.4 ± 0.50 and 1.4 ± 1.41 g/24 h at 6 and 12 mo, respectively (P = 0.003 and P = 0.08, respectively).



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  		Figure 1. Effect of sirolimus on proteinuria. Six months of rapamycin therapy significantly (P = 0.0013) reduced 24-h urinary proteinuria. The change in proteinuria after 6 mo of sirolimus therapy is shown for responsive and nonresponsive patients. Sirolimus significantly (P < 0.0013) reduced 24-h urinary protein among sirolimus-responsive patients but did not alter proteinuria among resistant patients.

 


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  		Figure 2. Individual patient response to sirolimus. Change in 24-h proteinuria from baseline to 6 mo is shown for sirolimus-responsive and -nonresponsive patients. (A) 24-h proteinuria decreased significantly during 6 mo of sirolimus therapy. Prolonged therapy with sirolimus tended to reduce proteinuria further, but this did not reach statistical significance (P = 0.08). (B) Proteinuria did not change among the nonresponsive group.

 
Two additional patients who received extended sirolimus therapy achieved a partial remission after 12 mo of therapy. Of the 21 patients, urinary protein excretion fell to <300 mg/24 h in four (19%) patients. Eight (38%) additional patients achieved at least a 50% reduction in protein excretion, giving an overall complete or partial response rate of 57% (Figure 3).



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  		Figure 3. Percentage of complete or partial response to sirolimus. Percentage of patients who achieved complete response (<00 mg protein/24 h), partial response (>50% reduction in baseline proteinuria), and failed response in 21 enrolled patients.

 
During the initial 6 mo of the protocol, the mean serum albumin fell significantly (P = 0.001) from a baseline of 2.6 ± 0.2 to 2.3 ± 0.9 mg/dl. After 6 mo of sirolimus, serum albumin increased significantly (P = 0.001) from a nadir of 2.3 ± 0.9 mg/dl to a mean of 2.8 ± 0.2 mg/dl (data not shown).

To determine the effects of sirolimus on clinical renal function, we analyzed serial serum Cr in sirolimus-responsive and -unresponsive patients. As shown in Figure 4, baseline serum Cr was 1.8 ± 0.3 and 1.7 ± 0.2 mg/dl in the sirolimus-responsive and -unresponsive groups, respectively (NS). After 6 mo of therapy, the mean serum Cr in the sirolimus-unresponsive group tended to be higher than that in the responsive group (2.2 ± 0.4 versus 1.8 ± 0.3 mg/dl, respectively), but this trend did not reach statistical significance (Figure 4). Data on serum Cr values at 1 yr were available in all 21 patients. Figure 4 demonstrates that after 12 mo of follow-up, the mean serum Cr was 1.9 ± 0.4 versus 3.2 ± 1.1 mg/dl in the sirolimus-responsive group versus in the sirolimus-unresponsive group (P = 0.28; Figure 4).



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  		Figure 4. Change in serum creatinine (Cr) at 12 mo in sirolimus-responsive and -nonresponsive patients. Serum Cr levels at 6 mo were not significantly different between sirolimus-responsive and -unresponsive patients. At 12 mo, serum Cr levels among nonresponsive patients was significantly higher (P = 0.022) than baseline levels. The serum Cr among nonresponsive patients tended to be higher at 12 mo than among sirolimus-responsive patients, but this trend was not statistically significant.

 
To determine whether specific clinical characteristics or underlying renal histology correlated with sirolimus responsiveness, we measured the degree of cortical fibrosis and the number of obsolescent glomeruli in each kidney biopsy. Of the 21 enrolled patients, five (24%) had cortical fibrosis between 5 and 10%; four (19%) of 21 had fibrosis estimates between 10 and 20%. Moderate cortical scarring (20 to 30%) was found in seven (33.3%) patients, whereas advanced scarring of 30 to 50% was observed in six (28.6%) patients. There was no difference in the percentage of cortical fibrosis or sclerotic glomeruli in sirolimus-responsive and -unresponsive patients. Patients with complete or partial remissions had a mean duration of FSGS of 12 ± 3 and 17 ± 4 mo, respectively, compared with 57 ± 34 mo for sirolimus-unresponsive patients (Figure 5).



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  		Figure 5. Duration of disease and response to sirolimus. Patients with complete, partial, or lack of response to sirolimus are plotted as a function of duration of disease. Duration of disease was significantly longer among sirolimus-nonresponsive patients.

 
The effect of sirolimus therapy on glomerular function is shown in Table 1. For the 19 patients combined, treatment with sirolimus resulted in a significant reduction in the excretion rates of albumin (1977 ± 289 versus 1562 ± 248 µg/min) and IgG (92 ± 28 versus 82 ± 24 µg/min) at baseline versus 6 mo, respectively (P < 0.05 for both). GFR and RPF remained stable during the course of treatment (38 ± 4 versus 38 ± 5 ml/min per 1.73 m2 and 349 ± 42 versus 331 ± 35 ml/min per 1.73 m2, pre- and posttreatment, respectively), and mean arterial BP was unchanged. In the responders group, the reduction in proteinuria resulted in an increase in the plasma oncotic pressure from 22.6 ± 1.5 to 25.2 ± 1.2 mmHg (P < 0.05), the RPF tended to increase (228 ± 45 versus 377 ± 46 at 6 mo; P = 0.07), and the GFR remained stable (45 ± 6 versus 47 ± 7 ml/min per 1.73 m2 at 6 mo). In nonresponders, the mean arterial pressure increased significantly from 101 ± 5 to 106 ± 6 mmHg at 6 mo, despite antihypertensive treatment (P < 0.05).

The results of the dextran sieving are shown in Table 3. In responders, the fractional clearances of dextran decreased significantly for dextrans 48 to 66 Å in size. In contrast, in nonresponders, an increase in the fractional clearances of dextrans larger than 44 Å was observed (Table 3). We computed glomerular membrane parameters using the "isoporous plus shunt" model of the glomerular capillary wall. For all 19 patients combined, shown in Table 3, there was no difference in the glomerular Kf, the size of the mean glomerular pores, and shunt parameter before and after treatment. The magnitude of the shunt parameter, {omega}o, tended to decrease with treatment as indicated by the median values at baseline of 1.5 x 10–2 versus 1.1 x 10–2 at 6 mo (P = 0.15; Table 3). In responders, the reduction in proteinuria was due to a reduction in the magnitude of the shunt pathway from 1.3 to 0.7 x 10–2; there was also a mild reduction in the size of the mean glomerular restrictive pores from 70 ± 3 to 68 ± 2 Å (P = 0.09). The reduction in proteinuria and partial restoration of permselectivity was associated with a mild but significant improvement in Kf from 7.0 ± 1.0 to 8.0 ± 0.9 (P < 0.05). In nonresponders, the magnitude of the shunt pathway was unchanged with treatment (median value 1.5 x 10–2 before and after therapy); the size of the mean restrictive pores increased significantly from 66 ± 2 to 70 ± 1 Å (P < 0.05). In nonresponders, the glomerular Kf was numerically reduced by 25% at 6 mo versus baseline (8.2 ± 1.9 versus 6.2 ± 1.3, respectively; P = 0.07).


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  		Table 3. Glomerular filtration barrier and membrane parametersa

 
Safety and Tolerability
Overall, sirolimus was well tolerated, but adverse effects were present in a significant number of patients (Table 4). A single (4.7%) patient experienced a rapid decline in renal function after study enrollment. For this patient, baseline serum Cr was 1.6 mg/dl and proteinuria was 17.0 g/24 h. The level of cortical scarring in this patient was extensive, with >70% or renal cortex showing evidence of interstitial fibrosis. Renal function rapidly declined, with the patient ultimately requiring dialysis. The protocol was subsequently modified to exclude patients with baseline cortical fibrosis that exceeded 50%. Hyperlipidemia is a common complication of sirolimus therapy. Of the 21 patients enrolled in our study, total cholesterol increased in seven patients by a mean of 43.0 mg/dl. Among sirolimus-responsive patients, serum cholesterol decreased by a mean of 89 mg/dl. This is in contrast to unresponsive patients, in whom total cholesterol increased by a mean of 9.0 mg/dl. Among all 21 patients, 43% developed anemia with hematocrits ranging from 30 to 35%. Of those patients, approximately one third required supplementation with erythropoietin. Oral apthos ulcers were observed in a single (4.3%) patient. Abdominal pain with or without nausea, vomiting, or diarrhea was observed in 19% of patients. With the exception of anemia, all sirolimus-induced side effects spontaneously resolved over 4 to 6 wk. No patient was withdrawn from the study because of sirolimus intolerability.


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  		Table 4. Sirolimus side effect profile

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Primary FSGS is a significant cause of the nephrotic syndrome within adult and pediatric populations. Although various treatments, including high-dose steroids, oral cyclophosphamide, and calcineurin inhibitors, can reduce proteinuria, no single therapy that can induce long-term remissions without the development of significant patient morbidity has been identified (1,13,21,22).

Oral steroids are widely regarded as the primary therapy for FSGS, but the duration and the intensity of these treatments remain controversial. In a recent review, Korbet et al. noted that only 20% of patients with adult-onset FSGS achieved a complete or partial remission after 8 wk of therapy, but remission rates of 40 to 50% could be achieved with longer therapy (1). Similarly, Ponticelli et al. demonstrated that prolonged (4 mo) steroid therapy could increase remission rates to >60% but resulted in significant side effects, including gastric hemorrhage, diabetes, and sepsis (21). Moreover, steroid-induced side effects seem to be more common among black individuals. In a review of 223 patients who underwent renal transplantation, Prasad et al. (23) demonstrated that excessive weight gain and the development of steroid-induced diabetes was significantly greater among black patients. In our study, we investigated the safety and the efficacy of oral sirolimus in 21 patients with steroid-resistant FSGS or patients who failed to complete a full 6 mo of therapy as a result of steroid-induced side effects. All patients had received a minimum of 3 mo of prednisone (1.0 mg/kg per d); seven patients received more prolonged (4 to 6 mo) therapy. Of the 21 patients, none achieved a partial response as defined as a 50% reduction in proteinuria. However, half experienced significant side effects, including excessive weight gain, steroid-induced diabetes, and cushingoid features. As noted by Korbet (1) and others, prolonged therapy (6 mo) with oral steroids may have resulted in a partial response in some of our patients, but the high rate of steroid-induced toxicity led the referring nephrologists to discontinue prednisone therapy.

CsA and tacrolimus have been used extensively to treat steroid-resistant nephrotic syndrome (13,24). Gregory et al. (13) treated 22 children who had steroid-resistant nephrotic syndrome with CsA for 8 wk and was able to induce a complete remission in >87% of patients. In a similar study, Cattran et al. used CsA to treat 49 patients with steroid-resistant FSGS and found that 70% of patients achieved a complete or partial response within 26 wk (12). Despite the high remission rates, up to 75% of patients experienced a return of the nephrotic syndrome within 6 mo of stopping CsA (12,25).

The high rates of recurrent glomerulonephritis have led many clinicians to extend the duration of CsA treatment, thus contributing to the development of calcineurin nephrotoxicity (13,14,24). To determine the time course of CsA nephrotoxicity, Meyrier et al. (24) performed serial renal biopsies in patients with FSGS and noted that after 2 yr of therapy, glomerulosclerosis and interstitial fibrosis were detectable in up to 20% of patients. Similarly, Hino et al. (14) noted that up to 15% of patients who received CsA for treatment of idiopathic nephrotic syndrome developed interstitial fibrosis within 24 mo. In our series, seven (33%) of 21 patients had been treated previously with tacrolimus but were stopped because of a lack of efficacy or the development of nephrotoxicity.

Sirolimus is a structural analogue of tacrolimus, which binds to the same immunophilin receptors but does not alter calcineurin phosphatase activity (26). At therapeutic levels, sirolimus blocks cytokine-dependent T cell proliferation at the G1-S phase of the cell cycle (15). Because podocytes exhibit hypertrophic and proliferative changes early in the course of FSGS, we questioned whether sirolimus could alter proteinuria in patients with steroid-resistant FSGS (4,7). A few trials have used sirolimus in the treatment of glomerulonephritis. Fervenza et al. (27) treated six patients with various forms of chronic glomerulonephritis and noted that sirolimus increased serum Cr after 12 mo of therapy. In contrast, we found that sirolimus stabilized renal function in patients with FSGS. After 12 mo of therapy, serum Cr increased by <10% among the sirolimus-responsive patients compared with a doubling of serum Cr among resistant patients. The question of long-term sirolimus toxicity remains controversial. Early animal studies by Ninova et al. (16) found that toxic concentrations of both sirolimus and tacrolimus increased serum Cr in a rat model of transplantation, but this effect was comparatively less in the sirolimus-treated animals. Similarly, the level of interstitial fibrosis after prolonged therapy was less in the sirolimus-treated animals. Moreover, 71% of our patients achieved a complete or partial remission in proteinuria after 12 mo, which is consistent with the observations of Ponticelli et al. (21) and others, who found that prolonged immunosuppressive therapy in FSGS can improve renal survival.

Anemia was the most common side effect, with nearly 50% experiencing a decrease in hematocrit. Abdominal pain with nausea and emesis developed in 19%, but these symptoms tended to decrease after 4 to 6 wk of therapy. A single (4.7%) patient experienced a rapid decline in renal function after study enrollment. Consistent with the observations of Fervenza et al. (27), sirolimus-unresponsive patients tended to have longer duration of disease and >50% interstitial fibrosis at study entry.

The observation that immunosuppressive therapy and plasmapheresis (9) can reduce proteinuria and stabilize renal function in patients with FSGS has led to the speculation that vascular permeability factors in the serum of patients with FSGS alter glomerular permeability (28,29). Moreover, recent studies by Coward et al. (30) demonstrate that serum from patients with nephrotic syndrome downregulates nephrin, synaptopodin, and other proteins that are critical to slit pore function. As indicated by our dextran sieving analysis (Figure 6, Table 1), sirolimus reduced proteinuria in patients with FSGS by improving the glomerular permselectivity. Moreover, sirolimus was devoid of renal vasoconstrictive effects and did not affect the RPF, the GFR, or the filtration fraction (Table 1). This is in contrast to "nonspecific" antiproteinuric agents such as CsA or ACE inhibitors, which decrease proteinuria through renal vasoconstriction and a reduction in transglomerular pressure (31–33). In sirolimus-responsive patients, the reduction in proteinuria correlated with an increase in the glomerular Kf (Table 1), whereas Kf, glomerular permselectivity, and GFR all tended to decrease over the course of the study. These observations suggest that sirolimus reduces proteinuria by improving glomerular ultrafiltration and altering permselectivity. It is tempting to speculate that sirolimus exerts its effects by restoring foot processes to a more "normal" morphology or increases the number of filtration slits per glomerulus, but without repeat renal biopsies to correlate glomerular function with structural changes, this cannot be fully established.



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  		Figure 6. Fractional clearance of dextran in sirolimus responsive and nonresponsive patients at baseline and after 6 mo of sirolimus therapy is shown. Fractional clearance is significantly reduced after 6 mo of sirolimus among responsive patients. In contrast, fractional clearance of dextran significantly increased among sirolimus-nonresponsive patients. *Significance at P < 0.05.

 
In summary, we conducted a prospective, open-labeled trial of sirolimus in 21 patients with steroid-resistant FSGS. We showed that 6 mo of therapy significantly reduced proteinuria and stabilized renal function in 57% of patients. In sirolimus-responsive patients, glomerular filtration and permeability studies demonstrated that albumin and IgG excretion rates were reduced after 6 mo and renal function was stabilized. Conversely, all renal functional parameters declined among nonresponsive patients. In conclusion, sirolimus seems to reduce proteinuria and stabilize renal function in patients with steroid-resistant FSGS and may offer an alternative to calcineurin inhibitors in the long-term treatment of FSGS.


   Acknowledgments
 
This research was performed with support from NIH MO1 RR00039, the Carlos and Marguerite Mason Transplantation Research Fund, and a grant from Wyeth Pharmaceutical Corporation.

This article was presented in abstract form at the 2003 American Society of Nephrology Annual Meeting, San Diego, November 11, 2003.

We thank Dr. Scott Adler for suggestions and critical review of the manuscript and data.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

Received June 10, 2005. Accepted October 24, 2005.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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