Table 1.
Characteristics of All the Studies Included in the Systematic Literature Review for Qualitative Analysis
| Baseline Characteristics |
||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study | Study Type | Study Arm (N) | Patient |
Proteinuria, g/day | UP/C | eGFR, mL/min/1.73 m2 | CrCl, mL/min/1.73 m2 | Follow-Up and/or Therapy Duration | Clinical Outcomes Reported | Main Conclusion of the Study | ||
| Disease | Age, y | Nephrotic | ||||||||||
| Abeyagunawardena et al, 200719 | Retrospective | CYC and/or CsA ± chlorambucil ± vincristine (66) | SRNS idiopathic FSGS | <16 | 100% | — | — | — | — | Follow-up: 10 y | Response to therapy; kidney survival; progression or time to CKF; AEs and/or death | Prolonged treatment with corticosteroids increases chances of remission and preserves kidney function in patients with idiopathic FSGS; chance of remission may be increased with addition of CYC or vincristine and with prolonged use of low-dose CsA |
| Abrantes et al, 2006 (Brazil)20 | Retrospective | Pred ± CYC ± MP ± CsA ± AH (110) | Primary FSGS | <15 | 100% | — | — | — | — | Follow-up: 10 y | Kidney survival; progression/ time to CKF; HR | At presentation, 3 factors were predictive of CKD: age, creatinine level, and nonresponse to Pred; at kidney biopsy, 4 factors were predictive of CKD: age, percentage of global sclerosis, creatinine level, and presence of hematuria |
| Abrantes et al, 2006 (Brazil)21 | Retrospective | Pred ± CYC ± MP ± CsA ± AH (110) | Primary FSGS | <15 | 100% | — | — | — | — | Follow-up: 10 y | Response to therapy; kidney survival; progression or time to CKF; AEs and/or death | Long-term overall kidney survival seems to be more favorable in this cohort of FSGS than others |
| Adhikari et al, 1997 (South Africa)22 | Prospective | Arm 1: CYC + MP + Pred (7); Arm 2: Shorter CYC + MP + Pred (4) |
SR FSGS | <10 | 83% | — | 2.6 ± 1.2; 3.6 + 3.7 |
63.1 ± 50.9; 97.3 ± 76.9 |
— |
Follow-up: arm 1: mean, 38.1 ± 8.8 mo; arm 2: mean 14.6 ± 11.7 mo; Therapy duration: arm 1: up to 18 mo; arm 2: up to 6 mo |
Response to therapy; proteinuria or UP/C; SrCr; eGFR; kidney survival; progression or time to CKF; AEs and/or death | Compared with regimen A, regimen B is 6 times less costly, with a quarter of the number of hospital visits |
| Adhikari et al, 2001 (South Africa)23 | Retrospective | CYC ± MP ± CsA ± diuretics ± AH (75) | NS FSGS | <18 | 100% | — | — | — | — | Follow-up: 2 y or more | Response to therapy; kidney survival; progression or time to CKF; AEs and/or death | Similar proportion of NS between Black and Indian patients, as well as in kidney outcomes |
| Agarwal et al, 1993 (India)24 | Retrospective | Pred (42) | Idiopathic FSGS | ≥14 | 90.5% | — | — | — | — | Follow-up: 32 ± 7.6 mo | Response to therapy; kidney survival; progression or time to CKF | Steroid responders have better prognoses than nonresponders; Pred should be given an average of 8-12 weeks before categorizing the response |
| Agrawal et al, 2019 (India)7 | Retrospective | Arm 1: Tac responsive (Tac + steroids; 7); Arm 2: Tac resistant (Tac + steroids; 7) |
SR primary FSGS | ≥18 | 93% | 5.5 ± 6.1; 4.9 ± 3.8 |
— | 102.8 ± 25.8 mL/min; 91.6 ± 24.4 mL/min |
— | Follow-up: 60 wk; Therapy duration: 48 wk | Proteinuria or UP/C; SrCr; eGFR | Subpodocytic space was preserved in patients on Tac with complete remission and lost in patients with partial response and Tac-resistant cases |
| Al Salloum, 2004 (Saudi Arabia)25 | Prospective | Pred + CYC (15) | SR primary FSGS | <12 | 33% | — | — | — | — | Follow-up: 4 y | Response to therapy; kidney survival; progression or time to CKF | Beneficial therapy for initial SR FSGS remains to be determined, but CYC side effects were negligible |
| Alexopoulos et al, 2000 (Greece)26 | Retrospective | Arm 1: Pred ± CsA or CsA ± ACEi (18); Arm 2: Supportive therapy ± ACEi (15) |
SR primary FSGS | >15 | 51% | — | — | — | — | Follow-up: mean, 55 mo (range, 8-142 mo); Therapy duration: mean, 9 mo (range, 6-12 mo) | Response to therapy; SrCr; kidney survival; progression or time to CKF; AEs and/or death |
Patients with NS with FSGS may benefit from a more prolonged course of Pred; patients with NS responding to treatment have significantly better kidney survival than nonresponders |
| Arbus et al, 1982 (Canada)27 | Retrospective | Steroids ± CYC (51) | NS idiopathic FSGS | <16 | 100% | — | — | — | — | Follow-up: mean, 10.6 y (range, 2.4-24.0 y) | Response to therapy; kidney survival; progression or time to CKF |
Patients with FSGS and NS who go into remission, apparently as a result of steroid or CYC therapy, may become SR within 18 mo and ultimately experience progressive kidney failure |
| Arias et al, 2011 (Colombia)16 | Retrospective | Arm 1: FSGS NOS (Steroids, or Steroids + AZA, or CYC, or MMF, or CsA; 196); Arm 2: Tip variant (Steroids, or Steroids + AZA, or CYC, or MMF, or CsA; 37) |
Primary FSGS | 1-65 | 97% | — | — | — | — | Follow-up: arm 1: 40 mo (range, 24-132 mo); arm 2: 49 mo (range, 24-87 mo) | Kidney survival; progression or time to CKF; AEs and/or death | The study does not demonstrate a clearly favorable prognosis in a group of patients with FSGS tip variant |
| Ayar et al, 2016 (Turkey)28 | Retrospective | CsA or steroids or CYC or AZA or MMF or ACEi or ARBs (68) | FSGS | ≥18 | 41% | 3.62 (range, 0.78-46) | — | 65.91 mL/min (range, 15.05-217.13 mL/min) | — | Follow-up: mean, 22 mo (range, 8-76 mo) | Proteinuria or UP/C; eGFR; kidney survival; progression or time to CKF; AEs and/or death | Early diagnosis, follow-up and appropriate immunosuppressive medications affect mortality and clinical progress in primary GN |
| Bagchi et al, 2016 (India)29 | Retrospective | Steroids ± CsA or Tac ± CYC or MMF or Rituximab ± ACEi and/or ARBs (116) | Primary FSGS | ≥18 | 100% | 5.1 ± 2.6 | — | 96.9 ± 35.1 | — | Follow-up: 23.6 mo (range, 6-65.1 mo) | Response to therapy; kidney survival; progression or time to CKF; AEs and/or death; HR | Patients with steroid resistance have reasonable kidney survival, if proteinuria is reduced with timely use of alternate immunosuppression; CNI resistance is major hurdle in management with limited treatment options |
| Beşbaş et al, 2010 (Turkey)30 | Retrospective | Pred ± CYC or CsA ± MP (222) | Primary FSGS | ≤16 | 89.4% | — | 12.9 ± 10.9 | — | — | Follow-up: 47.9 mo (range, 0.26-270.5 mo) | Response to therapy; kidney survival; progression or time to CKF | Use of immunosuppressive treatment in conjunction with prolonged steroid seems beneficial in children with primary FSGS |
| Bhimma et al, 2006 (South Africa)31 | Prospective | Pred + Tac + ACEi + diuretics + CCB (20) | SR idiopathic FSGS | ≤16 | 100% | — | 12.5 ± 3.2 | 117.4 ± 74.0 mL/m2/min | — | Follow-up after stop of Tac therapy mean, 27.5 mo (range, 13.7-43.7 mo); Tac therapy duration: 12 mo |
Response to therapy;proteinuria or UP/C; SrCr; eGFR; AEs and/or death | Tac is a safe and effective treatment for SR FSGS; however, like CsA, some children tend to relapse following cessation of treatment |
| Brodehl et al, 1988 (Germany)32 | Prospective | CsA (13) | SRNS FSGS | ≤16 | 100% | 10.5 ± 6.8 | — | — | — | Follow-up: up to 45 mo; therapy duration: at least 6 mo | Response to therapy; kidney survival; progression or time to CKF; AEs and/or death | Only half of patients benefited from CsA, so possibly a combination of immunosuppressive drugs could be more effective than CsA alone |
| Cattran & Rao, 1998 (Canada)33 | Retrospective | Arm 1: Adults (Pred ± CYC ± AH; 55); Arm 2: Children (Pred ± CYC ± AH; 38) |
FSGS | 35; 6.0 |
55%; 76% |
— | — | — | 90 ± 66; 84 ± 30 |
Follow-up: 11 y | Response to therapy;Proteinuria or UP/C; CrCl; kidney survival; progression or time to CKF | Steroid treatment beyond 6 months does not appear to be beneficial; CR confers excellent long-term prognosis in children and adults |
| Cattran et al, 1999 (USA)34 | Prospective, single-blind, randomized trial | Arm 1: CsA + Pred ± ACEi and/or ARBs (26); Arm 2: Placebo + Pred ± ACEi and/or ARBs (23) |
SRNS FSGS | >18 | 100% | 6.9 ± 3.3; 8.7 ± 4.7 |
— | — | 86 ± 27; 86 ± 31 |
Follow-up: mean 200 wk | Response to therapy; kidney survival; progression or time to CKF | CsA does not work in every case of FSGS, but a short-term remission to subnephrotic proteinuria was observed in 69% of cases |
| Cattran et al, 2003 (USA)13 | Prospective, single-blind, randomized trial | Arm 1: CsA + Pred ± ACEi and/or ARBs (18); Arm 2: Placebo + Pred ± ACEi and/or ARBs (9) |
SRNS FSGS | >18 | 100% | 7.2 (range, 3.6-14.4); 9.5 (range, 4-22.4) |
— | — | 72 ± 24; 66 ± 30 |
Follow-up: up to 208 wk; therapy duration: 26 wk | Response to therapy; proteinuria or UP/C; SrCr; CrCl | There is no relationship between Palb and outcome, as the antiproteinuric effect of CsA appeared independent of changes in Palb |
| Cattran et al, 2004 (USA)35 | Open-label trial | Pred + MMF ± ACEi and/or ARBs (18) | SRNS primary FSGS | ≥18 | 100% | — | 9.1 ± 5.2 | — | — | Therapy duration mean, 4 mo (range, 3-19 mo) | Response to therapy; proteinuria or UP/C; SrCr; kidney survival; progression or time to CKF | MMF appears safe to use in this group of patients and did lower proteinuria in 44% of this cohort resistant to other forms of treatment |
| Chávez-Mendoza et al, 2019 (Mexico)36 | Retrospective | Arm 1: High-dose Pred ± ACEi ± statins (39) Arm 2: First-line CNI (first-line CNI + low-dose Pred ± ACEi ± statins; 11); Arm 3: Rescue CNI first-line high-dose Pred + added CNI rescue for SR disease ± ACEi ± statins; 16) |
Primary FSGS | ≥18 | 100% | — | 3.7 (IQR, 3.2-7.3); 4.9 (IQR, 3.7-7.6); 5.8 (IQR, 3.6-8.7) |
60 (IQR, 41-115 mL/min/y); 58 (IQR, 48-122 mL/min/y); 79 (IQR, 66-112 mL/min/y) |
— | Follow-up: 51 mo (IQR, 30-77 mo); CNI therapy duration: 12 mo (range, 6-16 mo) |
Response to therapy; eGFR; kidney survival; progression or time to CKF; AEs and/or death | An initial CNI plus low-dose corticosteroid approach in primary FSGS reduces corticosteroid exposure, with a response-to-therapy rate similar to that of the currently recommended high-dose corticosteroid regimen |
| Chishti et al, 2001 (USA)12 | Retrospective | Pred + CsA ± ACEi (21) | SR and SD NS FSGS | ≤16 | 100% | — | — | 115 ± 36.5 | — | Follow-up: mean, 32 mo (range, 12-72 mo); Therapy duration: mean, 20.6 ± 13.7 mo | Response to therapy; eGFR; kidney survival; progression or time to CKF | Single, daily, low-dose CsA appears to be effective for long-term treatment of children with FSGS and NS, with fewer side effects than twice-daily dosing |
| Choi et al, 2002 (USA)37 | Retrospective | MMF ± steroids or CsA or AZA + ACEi and/or ARBs (18) | Primary FSGS | ≥16 | 52.9% | — | 4.7 ± 5.1 | — | — | MMF therapy duration: 8 mo (range, 3-26 mo) | Proteinuria or UP/C; SrCr; eGFR | Empirical MMF therapy in majority of patients with primary GN was well tolerated and achieved the goal of steroid withdrawal, improvement of NS, and stabilization of kidney function |
| Chun et al, 2004 (USA)38 | Retrospective | Pred ± CsA or CYC (51) | Primary FSGS | >15 | 75% | 7.6 ± 3.7 | — | — | — | Follow-up: 73 ± 94 mo; Pred therapy duration: 3.18 ± 1.49 mo |
Response to therapy; kidney survival; progression or time to CKF | Patients with NS with primary FSGS should receive a trial of therapy, irrespective of the histologic lesion, when not contraindicated |
| Crook et al, 2005 (USA)39 | Retrospective | Steroids ± ACEi and/or ARBs (43) | Primary FSGS | >18 | 73.6% | 8.85 ± 7.2 | — | — | — | Follow-up: 46.7 ± 6.6 mo; Steroid therapy duration: 11.7 ± 2.4 mo |
Kidney survival; progression or time to CKF; HR | A beneficial effect of steroids was not observed in this predominantly African American adult cohort, as there was no significant association between steroid status and achieving remission of proteinuria |
| Dumas De La Roque et al, 2018 (France)40 | Retrospective | Steroids ± CsA ± MMF ± CYC ± ACEi ± ARB ± ACEi + ARB (68) | NS idiopathic FSGS | ≥15 | 100% | 6 (IQR, 3.9-9) | — | 42.5 (IQR, 29-58) | — | Follow-up: 66 mo (IQR, 30-92 mo); Therapy duration: 15 mo (IQR, 8-36 mo) |
Response to therapy; kidney survival; progression or time to CKF; AEs and/or death | No predictive factor for relapse was identified by multivariate analysis |
| Deegens et al, 2005 (Netherlands)41 | Retrospective | Arm 1: Initially untreated (± ACEi then Pred ± CYC; 20); Arm 2: Treated (Pred; 8) |
Primary FSGS | ≥18 | 100% | 10.0 ± 5.5; 9.8 ± 3.1 |
— | — | 101 ± 34 mL/min; 123 ± 35 mL/min |
Follow-up: Arm 1: 9.4 y (IQR, 2.1-18.6 y); Arm 2: 9.2 y (IQR, 4.0-11.2 y); Therapy duration: Pred: 2.5 ± 0.9 mo CYC: 3 mo |
Response to therapy; kidney survival; progression or time to CKF; AEs and/or death | Case definition using strict clinical criteria identifies a subgroup of patients with idiopathic FSGS who have a good prognosis; in the majority of these patients, immunosuppressive therapy is not warranted unless kidney function deteriorates |
| Deegens et al, 2008 (the Netherlands)42 | Retrospective | Arm 1: Treated (Pred or Pred + CYC ± ACEi and/or ARBs; 40); Arm 2: Untreated (± ACEi and/or ARBs; 53) |
Primary FSGS | ≥18 | 83%; 49% |
10.4 ± 5.8; 5.8 ± 3.7 |
— | — | — | Follow-up: 66 mo (range, 1-273 mo); Therapy duration: Pred: 5.6 mo (range, 1.3-55.3 mo); CYC: 3 mo (range, 2-12 mo) |
Response to therapy; kidney survival; progression or time to CKF; HR | Kidney survival and remission rates were higher in patients with the tip variant |
| Dhanapriya et al, 2016 (India)43 | Retrospective | Pred ± CYC ± CsA ± Tac ± MMF (170) | Primary FSGS | ≥13 | 79% | 4.26 ± 1.9 | — | — | 85.8 ± 34 mL/min | Follow-up: 4.32 ± 1.2 y; Pred therapy duration: 6 mo |
Response to therapy; kidney survival; progression or time to CKF; AEs and/or death | Attaining CR significantly improves kidney survival |
| Dimkovic et al, 2009 (Serbia & Montenegro)44 | Retrospective | Steroids + MMF + ACEi ± ARBs or statins (13) | Primary FSGS | ≥18 | Not specified | 5.1 (IQR, 2.7-8.9) | 3.26 (IQR, 1.52-7.92) | 56.2 ± 33.2 mL/min | — | Follow-up: 12 mo | Response to therapy; proteinuria or UP/C; eGFR | MMF proved to be efficient in 70% of high-risk patients with primary GN, who reached either complete or partial remission without safety concern after 12 months of treatment |
| Ehrich et al, 2007 (Germany)6 | Retrospective | MP + CsA + Pred ± MMF or Tac ± ACEis (52) | SRNS idiopathic FSGS | <18 | 100% | — | — | — | — | Follow-up: 5 ± 3.6 y; Therapy duration: Pred: 24 wk CsA: at least 36 wk |
Response to therapy; kidney survival; progression or time to CKF | Combined Pred +CsA therapy including IV-MP pulses resulted in a higher rate of remission when compared with previous reports on using CsA monotherapy or other immunosuppressive combination therapies |
| El-Husseini et al, 2004 (Egypt)45 | Retrospective | Arm 1: CsA + ketoconazole ± ACEi (88); Arm 2: CsA ± ACEi (28) |
SR or SD primary FSGS | <18 | Not specified | 6.53; 6.73 |
— | — | 123; 126 |
Follow-up: 33 mo (range 14-84 mo); Therapy duration: 1-2 y |
Response to therapy; proteinuria or UP/C; CrCl; kidney survival; progression or time to CKF; side effects | Coadministration of ketoconazole and CsA in children with idiopathic FSGS is safe; this combination not only reduces the costs but also may improve the response to CsA and stabilize the kidney function |
| El-Refaey et al, 2007 (USA)46 | Retrospective | Arm 1: Collapsing FSGS (Pred ± CsA ± MMF + ACEi; 11); Arm 2: Noncollapsing FSGS (Pred ± CsA ± MMF + ACEi; 28) |
Idiopathic FSGS | ≤17 | 63.6%; 36% |
— | 10.8 ± 5.7; 8.6 ± 9.4 |
96 ± 49; 136.6 ± 65 |
— | Follow-up: 31.5 ± 22.3 mo; 18.7 ± 12.9 mo |
Response to therapy; proteinuria or UP/C; SrCr; eGFR; kidney survival; progression or time to CKF | The outcome of patients with collapsing FSGS at 30 months was better than in previous reports because of stronger immunosuppression or the use of ACEi |
| El-Refaey et al, 2010 (Egypt)47 | Retrospective | Pred ± MP ± CsA ± MMF (72) | NS primary FSGS | ≤16 | 100% | 3.3 ± 2.8 | — | — | — | Follow-up: 76.3 ± 42 mo (range, 9-156 mo) | Response to therapy; kidney survival; progression or time to CKF | Kidney survival is better than in other cohorts |
| Futrakul et al, 2004 (Thailand)48 | Retrospective | ACEi + CCB + AP + vitamins E and C ± ARB + Pred (10) | FSGS | Not reported | 100% | 3.1 ± 4.4 | — | 35 ± 53.8 | 34 ± 37.9 | Follow-up: ≥10 y | Proteinuria or UP/C; eGFR; CrCl | Therapeutic intervention with multidrug regimens relaxes the arteriolar constriction, thus impacting on the pathogenetic mechanism of kidney disease progression |
| Futrakul et al, 2004 (Thailand)49 | Prospective | Arm 1: Pred + CYC + AH (11); Arm 2: ACEi, ARB, CCB + AP + baby aspirin ± heparin (18) |
FSGS | <21 | 100% | 3.2 ± 0.7; 3 ± 0.8 |
— | 60 ± 21; 51 ± 23 |
47 ± 25; 50 ± 19 |
Follow-up: 77 ± 24 mo; 97 ± 33 mo |
eGFR; BP; kidney survival; progression or time to CKF | In contrast to the therapeutic failure with conventional therapy in Arm 1, clinical improvement in response to the combined formula has been substantiated in all 18 patients in Arm 2 |
| Gellermann et al, 2012 (Germany)50 | Retrospective, uncontrolled | MP + Pred + CsA ± ACEi and/or ARBs ± diuretics, then MMF (23) | SRNS primary FSGS | <18 | 100% | — | — | 106.2 ± 26.3 (n = 16) | — | Follow-up: 7.0 y (range, 1.7-16.5 y); MMF therapy duration: 3.6 y (range, 0.8-10 y) |
Response to therapy; eGFR; AEs and/or death | In children with SRNS or FSGS achieving initial remission, a sequential steroid-free therapy consisting of a combination of CsA and MMF, followed by MMF alone (with the addition of ACEi and ARBs), can provide sustained long-term remission, preservation of kidney function, and better control of BP |
| Gheissari et al, 2018 (Iran)51 | Prospective, uncontrolled | Pred + CsA + CYC (26) | FSGS | ≤16 | Not specified | 1.09 ± 1.47 | — | — | — | Follow-up: 6 mo | Kidney survival; progression or time to CKF | TRPC6 may be useful for genetic screening in Iranian children with FSGS |
| Ghiggeri et al, 2004 (Italy)52 | Open-label, nonrandomized, retrospective | Arm 1: CsA responsive (steroids ± CYC and/or CsA ± MP; 20); Arm 2: CsA intolerant or resistant (steroids ± CYC and/or CsA ± MP; 35); Arm 3: No CsA treatment (84) |
SRNS FSGS | <45 | 100% | — | — | — | — | Follow-up: >2 y Arm 1: 81 (IQR, 4-115); Arm 2: 41 (IQR, 23-92); Arm 3: 48 (IQR, 28-106) |
Response to therapy; kidney survival; progression or time to CKF | Long-term CsA (>2 years) has a persistent antiproteinuric effect in the absence of kidney fibrosis |
| Gipson et al, 2011 (USA)53 | Open-label, randomized controlled trial | Arm 1: MMF and DEX + Pred + ACEi and/or ARB ± additional AH (66); Arm 2: CsA + Pred + ACEi and/or ARB ± additional AH (72) |
SR primary FSGS | 2-40 | Not specified | — | — | — | — | Follow-up: 78 wk | BP; AEs and/or death | The study did not find a difference in rates of proteinuria remission following 12 months of CsA compared to MMF and DEX in patients with SR FSGS |
| Gorsane et al, 2016 (Tunisia)17 | Retrospective | CsA (23) | Idiopathic FSGS | ≥16 | 100% | 7.01 ± 4.5 | — | — | — | Follow-up: 6.8 ± 3.7 y | Response to therapy; kidney survival; progression or time to CKF; AEs and/or death | CsA is effective in treatment of patients with idiopathic FSGS; initial kidney function and CsA resistance are predictive factors of CKF in SR or SD FSGS |
| Goumenos et al, 2006 (UK & Greece)54 | Retrospective | Arm 1: treated (Pred or Pred + AZA or Pred + CsA; 25); Arm 2: untreated (ACEi + CCB + beta-blockers; 26) |
Idiopathic FSGS | >18 | 80%; 50% |
5.8 ± 6.6; 4.4 ± 2 |
— | — | — | Follow-up: 5 y; Therapy duration: 20 ± 6 mo |
Response to therapy; kidney survival; progression or time to CKF | Combination of low Pred dose with CsA could be used as initial treatment in patients with higher risk for side effects from the usual Pred dose |
| Greenwood et al, 2017 (Australia)55 | Retrospective | Pred ± ACEi and/or ARBs or diuretics (98) | Primary and secondary FSGS | >18 | 51% | — | — | — | — | Follow-up: 4.32 y (range, 0-17 y) | Response to therapy; kidney survival; progression or time to CKF; AEs and/or death; HR | Concomitant diabetic nephropathy, higher serum creatinine, and lower eGFR at kidney biopsy were associated with poorer kidney prognosis |
| Gulati et al, 2000 (India)56 | Prospective | Arm 1: early onset (Pred or Pred + CYC; 36); Arm 2: late onset (Pred or Pred + CYC; 36) |
Idiopathic FSGS | ≤12 and >12 | 100% | — | — | 92 ± 11; 94 ± 14 |
— | Follow-up: 14.6 ± 13 mo; 17.8 ± 13 mo |
Response to therapy; SrCr; eGFR; kidney survival; progression or time to CKF | Early onset is more often steroid responsive and has a better prognosis than late-onset FSGS |
| Hari et al, 2001 (India)18 | Prospective | Arm 1: initial resistance (DEX or MP + CYC; 31); Arm 2: late resistance (DEX or MP + CYC; 34) |
SRNS FSGS | ≤14 | 100% | 2.6; 3.5 |
9.7; 10.0 |
— | — | Follow-up after stoppage of pulse therapy: 25.6 mo (range, 20 mo to 7.3 y); Therapy duration: up to 52 wk |
Response to therapy; proteinuria or UP/C; kidney survival; progression or time to CKF; AEs and/or death | Prolonged treatment with IV corticosteroids and oral CYC is beneficial in patients with SR FSGS; although this regimen has considerable side effects, it may prevent chronic kidney failure in a number of patients |
| Heering et al, 2004 (Germany)57 | Prospective, randomized | Arm 1: Pred + acetylsalicylic acid ± CsA (34); Arm 2: Pred ± chloroambucil or CsA (23) |
Idiopathic FSGS | ≥18 | 100% | 5.2 ± 1.1; 4.6 ± 3.1 |
— | — | — | Follow-up: 4 y; Therapy duration: 2 mo to several y CsA therapy duration: 23 ± 16.5 mo |
Response to therapy; proteinuria or UP/C; kidney survival; progression or time to CKF | Additional treatment with chlorambucil was found to be ineffective in FSGS; patients responded to treatment with steroids or CsA |
| Hogg et al, 2013 (USA)58 | Post hoc analysis | Arm 1: MMF and DEX + Pred + ACEi and/or ARB ± additional AH (20); Arm 2: CsA + Pred + ACEi and/or ARB (losartan) ± additional AH (22) |
SR primary FSGS | 7-34 | Not specified | — | 3.6 (10th-90th percentile, 1.1-9.6); 2.7 (10th-90th percentile, 1.1-5.1) |
122.6 ± 50.7; 126.8 ± 50.5 |
— | Follow-up; CsA or MMF and DEX therapy duration 78 wk; 52 wk |
Proteinuria or UP/C; eGFR | The improvement in UP/C after CsA or MMF and DEX was largely sustained for 6 months after therapy; reduction in eGFR in the CsA group was improved 6 months after CsA was stopped, although the levels were lower than baseline in 7 patients who entered the study with decreased eGFR |
| Hoseini et al, 2012 (Iran)59 | Retrospective | CYC ± CsA ± MMF (58) | Primary FSGS | ≤18 | Not specified | — | — | — | — | Follow-up: 5.7 y (range, 3-20 y) | Kidney survival; progression or time to CKF; AEs and/or death | The study demonstrates an increasing trend in the FSGS incidence in Iranian children; however, kidney survival rates were similar to those reported by others in different countries |
| Huang et al, 2018 (China)11 | Prospective, open-label, controlled trial | Arm 1: Pred + ARBs or ACEi (52); Arm 2: ARBs or ACEi (50) |
Primary FSGS | >18 | No | 1.67 (range, 1.04-3.26); 1.58 (range, 1.09-3.43) |
— | 72.94 ± 28.52 mL/min; 71.33 ± 30.82 mL/min |
— | Follow-up: 36 mo (range, 12-101); 37.5 mo (range, 12-117) |
Response to therapy; proteinuria or UP/C; AEs and/or death | Additional glucocorticoid therapy is more efficacious compared with ACEi and/or ARBs alone in the treatment of patients with primary FSGS and moderate proteinuria |
| Inaba et al, 2016 (Japan)60 | Retrospective | Arm 1: CsA (39); Arm 2: CYC (24) |
SRNS idiopathic FSGS | <18 | 100% | — | — | — | — | Follow-up: Arm 1: 9.0 y (range, 6.3-16.1 y); Arm 2: 14.6 y (range, 10.4-19.0 y); CsA therapy duration until toxicity was found: 4.8 y (range, 2.0-5.8 y) |
Response to therapy; kidney survival; progression or time to CKF, AEs and/or death; HR | Therapeutic regimen with CsA could considerably improve both the initial remission rate and the long-term kidney survival rate of children with idiopathic SRNS |
| Ingulli et al, 1995 (USA)61 | Prospective | CsA + Pred ± furosemide (21) | SR FSGS | <18 | Not specified | 6.2 ± 0.2 | — | — | — | Follow-up: 8.5 ± 4.7 y; CsA therapy duration: 27.5 ± 22 mo |
Proteinuria or UP/C; SrCr; kidney survival; progression or time to CKF; AEs and/or death | Long-term CsA therapy successfully reduces the proteinuria in Black and Hispanic children with SR FSGS and blunts the progression to kidney failure |
| Jafry et al, 2012 (Pakistan)62 | Retrospective | Pred ± CYC ± AH (124) | Idiopathic or primary FSGS | ≥17 | 72% | 6.0 ± 4.5 | — | — | — | Follow-up: 113.6 ± 118.6 wk; Steroid therapy duration: 20.2 ± 7.4 wk |
Response to therapy; proteinuria or UP/C; SrCr | Half of adults with primary FSGS achieve sustained remission with steroids and, consequently, exhibit an excellent prognosis for long-term outcome |
| Jellouli et al, 2016 (Tunisia)63 | Retrospective | Pred + MP ± CsA or MMF ± CYC (30) | Primary FSGS | ≤18 | 87% | 113 ± 87 mg/kg | — | 110.5 ± 46 | — | Follow-up: at least 1 y; Pred tx duration: 5 mo | Response to therapy; kidney survival; progression or time to ESKD | Children treated with CsA had a high response rate |
| Kallash & Aviles, 2014 (USA)64 | Retrospective | Pred + Tac (22) | SRNS primary FSGS | ≤17 | 100% | — | mean, 12.0 (range, 2.2-48.64) | mean, 92.30 (range, 31.3-142) | — | Follow-up: 2.9 y (average, 0.5-7 y) | Response to therapy; eGFR | Tac is a viable option in the treatment of children with idiopathic, SR FSGS; FSGS with nephrotic-range proteinuria should be treated aggressively because even partial remission improves kidney survival |
| Kambham et al, 2001 (USA)65 | Retrospective | Steroids ± cytotoxic agents (50, idiopathic FSGS) | Idiopathic FSGS | Mean, 32.6 y | 66% | — | — | — | — | Follow-up: 39 mo (range, 1-140 mo) | Kidney survival; progression or time to ESKD | Clinically, ORG is distinguished from idiopathic FSGS by its lower incidence of NS, more benign course, and slower progression to kidney failure |
| Kangovi et al, 2012 (USA)66 | Retrospective | Arm 1: CNI, alkilating agents ± ACEi and/or ARBs (32); Arm 2: ACEi and/or ARBs (35) |
Primary FSGS | <21 | Not specified | — | 14.4 ± 11.5; 4.5 ± 6.3 |
132.9 ± 56.1; 100.8 ± 43.1 |
— | Follow-up: 70.2 ± 49.5 mo 53.9 ± 28.9 mo; Therapy duration: 11.0 mo; 80.5 mo |
Response to therapy; kidney survival; progression or time to CKF; HR | Patients treated initially with RAASi monotherapy may have outcomes that are comparable to or better than those of patients treated with immunosuppression |
| Kirpekar et al, 2002 (USA)67 | Retrospective | Arm 1: FSGS with or without mesangial hypercellularity (Pred + MP ± alkylating agent; 10); Arm 2: FSGS plus mesangial proliferation (Pred + MP ± alkylating agent; 15) |
SRNS idiopathic FSGS | <18 | 100% | — | 6.1 ± 4.3; 14.9 ± 14.7 |
— | 122.7 ± 100.0; 149.6 ± 79.3 |
Follow-up: 91.8 ± 55.9 mo; 51.2 ± 33.6 mo; Therapy duration: 17.4 ± 19.4 mo; 9.6 ± 5.8 mo |
Response to therapy; kidney survival; progression/ time to CKF | The cause of SRNS cannot be determined by analysis of clinical variables, including age, sex, ethnicity, UP/C ratio, and initial serum creatinine and albumin levels |
| Klaassen et al, 2015 (Germany)68 | Retrospective chart review | CsA (23) | SRNS FSGS | ≤15 | 100% | 3.4 g/m2/day (range, 1-55.8 g/m2/day) | — | — | — | Follow-up: 15.5 y (range, 1.8-27.7 y); CsA therapy duration: 3.1 y (range, 0.5-14 y) |
Response to therapy; kidney survival; progression or time to CKF | CNI seems to be justified as a first-line treatment in SRNS; it is successful in many patients and, in our experience, can be stopped successfully in individual patients with CR after treatment |
| Korbet et al, 1986 (USA)69 | Retrospective chart review | Arm 1: Patients with NS (± Pred ± chlorambucil; 29); Arm 2: Patients without NS (no Pred ± chlorambucil; 17) |
Primary FSGS | >18 | 63% | 9.47 ± 1.09; 1.64 ± 0.19 |
— | — | — | Follow-up: 48.0 ± 8.9 mo; 79.9 ± 17.8 mo |
SrCr; kidney survival; progression or time to CKF; AEs and/or death | Primary FSGS and nephrotic proteinuria in adults have the same ominous prognostic significance as the similar syndrome previously observed in children; a therapeutic response appears to identify a subgroup among the patients with NS with a better prognosis; when the same glomerular lesion is seen in a patient with nonnephrotic proteinuria, the disease follows a more indolent course |
| Laurin et al, 2016 (USA)70 | Retrospective analysis of inception cohort study | Arm 1: Collapsing FSGS (ACEi, ARB, or selective aldosterone blocker ± steroids or CNI; 61); Arm 2: FSGS (ACEi, ARB, or selective aldosterone blocker ± steroids or CNI; 126) |
Collapsing and NOS FSGS | Children: ≤15; Adults: >18 |
58.3% |
12.2 (IQR, 5.6-14.8); 4.4 (IQR, 2.3-8.1) |
8.9 (IQR, 6.4-15.5); 6.6 (IQR, 2.7-10.1) |
48 (IQR, 26-73); 60 (IQR, 42-92) |
— | Follow-up: 61 mo (IQR, 17-117 mo); 73 mo (IQR, 24-148 mo); Steroids therapy duration 3.9 mo (IQR, 1.4-6.7 mo); 2.5 mo (IQR, 1.9-6.2 mo); CNI therapy duration 18.2 mo (IQR, 6.1-26.8 mo); 11.5 mo (IQR, 2.9-31.7 mo) |
SrCr; kidney survival; progression or time to CKF; HR | Patients with idiopathic, collapsing FSGS present with more severe proteinuria and kidney dysfunction and have overall worse kidney outcomes compared with patients with NOS FSGS; difference in outcomes may be attributable to the baseline severity of disease and possible differences in the decision to treat with immunosuppressive therapy |
| Laurin et al, 2016 (USA)71 | Retrospective | Arm 1: no immunosuppressants (183); Arm 2: glucocorticoids alone (173), CNIs ± glucocorticoids (90) other immunosuppressants (AZA, MMF, and CYC; 12) |
Primary FSGS | Children: <18; Adults: ≥18 |
35.6% | 3.8 (IQR, 3.5-12); 2.4 (IQR, 1.7-3.3) |
— | 43.8 (IQR, 27.2-69.9); 62.8 (IQR, 41.7-85.7) |
— | Steroids therapy duration: 3.0 mo (IQR, 1.5-5.9 mo); CNI therapy duration: 19.6 mo (IQR, 6.5-34.8 mo) |
Kidney survival; progression or time to CKF; HR | Significant association between treatment with immunosuppressive therapy and better kidney survival, despite the fact that patients treated with immunosuppressives tended to have evidence of more severe NS than those who were untreated |
| Li et al, 2014 (China)72 | Retrospective | Pred ± Tac ± ACEi and/or ARBs (109) | Primary FSGS | ≥14 | 100% | 7.52 ± 2.95 | — | 100 ± 31 | — | Follow-up: 12 mo (range, 6-24 mo) | Proteinuria or UP/C | suPAR is specifically elevated in some patients with FSGS, which differs from the finding in patients with MCD and MN; a suPAR assay may help predict steroid responses in patients with primary FSGS |
| Lieberman & Tejani, 1996 (USA)73 | Double blinded, prospectively randomized, placebo controlled | Arm 1: CsA ± CCB (15); Arm 2: Placebo (15) |
SR idiopathic FSGS | ≤19 | Not specified | 151.7 ± 162.4 mg/kg/24h; 166.9 ± 137.1 mg/kg/24h |
— | 103.4 ± 36.7; 86.0 ± 31.3 |
— | Follow-up: 6 mo | Proteinuria or UP/C; eGFR; kidney survival; progression or time to CKF; AEs and/or death | For patients with SR FSGS, CsA is an additional therapeutic approach for a disease with limited options and a virtually certain progression to CKF |
| Loeffler et al, 2004 (USA)15 | Retrospective case series | Tac ± Pred ± ACEi and/or ARBs ± other AH (16; 13 with FSGS) | Treatment-resistant NS FSGS | ≤18 | 100% | — | 729.2 ± 419.8 | — | 217.2 ± 152.3 | Follow-up: mean, 6.5 mo (range, 2.5-18 mo); Therapy duration: mean range, 0.4-13 y | Response to therapy; proteinuria or UP/C; CrCl; BP; AEs and/or death | Tac is an effective, well-tolerated medication for treatment-resistant forms of NS in children |
| Mahmoud et al, 2005 (Egypt)10 | Retrospective | Arm 1: SDNS FSGS (CsA + Pred ± ketoconazole; 61); Arm 2: SRNS FSGS (CsA + Pred ± ketoconazole; 45) |
SDNS + SRNS primary FSGS | ≤16 | 100% | 6.7 ± 2.2; 6.6 ± 2 |
— | — | — | Follow-up; CsA tx duration 12.4 ± 7 mo; 22.6 ± 10 mo; 21 ± 12 mo |
Proteinuria or UP/C; SrCr kidney survival; progression or time to CKF; AEs and/or death | Treatment with CsA can be a good therapeutic option in both children with steroid-sensitive or SR FSGS, which may save the toxic effects of long-term, large doses of steroids and improve the control of cases and possibly ameliorate the natural progressive course of the disease |
| Martinelli et al, 2001 (Brazil)74 | Prospective | Pred ± CYC (39) | Primary FSGS | ≤18 | 100% | — | — | — | — | Follow-up: 84.6 ± 79.8 mo | Response to therapy; kidney survival; progression or time to CKF; AEs and/or death | Remission of the proteinuria predicts a good long-term outcome in children with NS and FSGS; the use of immunosuppressive medication in conjunction with Pred seems beneficial in the treatment of SR FSGS |
| Martinelli et al, 2004 (Brazil)75 | Open-label, nonrandomized, long-term trial | Arm 1: Pred ± ACEi (30); Arm 2: Pred + CYC ± ACEi (24) |
NS idiopathic FSGS | 24.0 ± 12.0; 14.2 ± 12.1 |
100% | — | — | — | — | Follow-up: 51.5 ± 59.1 mo; 113.8 ± 88.6 mo |
Response to therapy; kidney survival; progression or time to CKF; AEs and/or death | CYC in combination with steroids could be a reasonable choice in the treatment of SR FSGS |
| Mendoza et al, 1990 (USA)76 | Retrospective | Pred + MP ± CYC or chlorambucil (23) | SRNS FSGS | ≤15 | 100% | — | 11.6 ± 7.1 | 133.5 ± 63.5 | — | Follow-up: 45.7 ± 26.6 mo | Proteinuria or UP/C; eGFR; kidney survival; progression or time to CKF; AEs and/or death | This group of children with FSGS has done extremely well following treatment with intravenous MP; the outcome in this retrospective study is significantly better than those in all series we reviewed of children with SR NS and FSGS |
| Meyrier et al, 1994 (France)77 | Prospective | CsA ± Pred (36; 14 with FSGS) | NS idiopathic FSGS | ≥15 | 100% | — | — | — | — | Follow-up: 78 mo; CsA therapy duration: 78 mo |
Response to therapy; SrCr | FSGS with preexisting, incipient kidney insufficiency and tubulointerstitial lesions should be considered relatively hazardous; a repeat biopsy after a year of treatment is necessary to determine whether treatment can be safely continued or should be stopped; when prolonged remission has been obtained with CsA treatment of more than a year, progressing tapering of the drug to a stop is often followed by stable remission |
| Mubarak et al, 2010 (Pakistan)78 | Retrospective | Steroids ± CsA (10) | Idiopathic, collapsing FSGS | ≥18 | 100% | — | — | — | — | Follow-up: 28.7 ± 16.7 mo | Response to therapy; SrCr; kidney survival; progression or time to CKF; AEs and/or death | These preliminary results show that CsA may be effective in the treatment of patients with NS that resist every other form of treatment and especially in the treatment of those with minimal change to lipoid nephrosis |
| Mungan et al, 2015 (Turkey)79 | Retrospective | Steroids + ACEi and/or ARBs ± cytotoxic agents (20) | Primary FSGS-tip variant | >18 | Not specified | 5167.35 ± 3975.1 | — | — | — | Follow-up: 46 mo (range, 3-137 mo) | Response to therapy; proteinuria or UP/C; SrCr | FSGS-tip variant is a favorable subtype among other FSGS forms; immunosuppressive treatment with steroids that may or may not include cytotoxic agents will resolve proteinuria in the majority of cases |
| Naseri et al, 2009 (Iran)80 | Prospective | Pred ± CYC ± CsA (62) | Idiopathic FSGS | <15 | Not specified | — | — | — | — | Follow-up mean, 7 y and 2 mo (range, 3 mo-16 mo and 4 mo) | Response to therapy; kidney survival; progression or time to CKF; AEs and/or death | Favorable response to steroid and CYC treatment is a protective factor against disease progression to CKF, and resistance to immunosuppressants implies a poor prognosis |
| Newman et al, 1976 (USA)81 | Retrospective | Steroids ± CYC or AZA (33) | FSGS | Children: ≤16 Adults: ≥17 |
57.6% | — | — | — | — | Not specified | Response to therapy; SrCr; BP; AEs and/or death | FGS in adults represents a more severe and progressive disease process and is less responsive to therapy |
| Niaudet, 1994 (France)82 | Prospective | CsA + Pred ± nifedipine and/or acebutolol (20) | SRNS idiopathic FSGS | ≤15 | 100% | — | — | — | — | Follow-up: 45 mo | Response to therapy; kidney survival; progression or time to CKF | CsA, in combination with steroids, is effective in a significant proportion of patients with SR, idiopathic nephrosis |
| Paik et al, 2007 (South Korea)83 | Retrospective | Pred ± CYC ± CsA ± MP (92) | SR primary FSGS | ≤15 | 92.4% | — | 24.4 ± 25.3 | — | — | Follow-up: 98.2 ± 63.3 mo; Therapy duration: MP: 14.2 ± 10.1 mo; CYC and Pred: 2.8 ± 0.8 mo; CsA and Pred: 9.3 ± 6.8 mo |
Response to therapy; kidney survival; progression or time to CKF; HR | A more prolonged use of corticosteroid therapy and early introduction of CsA may improve the prognosis for primary FSGS in patients with initial steroid nonresponsiveness |
| Pei et al, 1987 (Canada)84 | Prospective | Arm 1: Adults - steroids ± CYC or AZA (55); Arm 2: Children - steroids ± CYC or AZA (38) |
Idiopathic FSGS | Children: ≤16; Adults: >16 |
Not specified | — | — | — | 1.5 ± 1.11 mL/second/1.73 m2; 1.4 ± 0.511 mL/second/1.73 m2 |
Follow-up: 59 mo; 64 mo |
Kidney survival; progression or time to CKF | All patients with the “typical” lesion of FSGS and idiopathic NS should be treated with a course of steroids, with or without a cytotoxic drug, for up to 6 mo; a significant response rate for both adults and children |
| Ponticelli et al, 1999 (Italy)85 | Retrospective | Arm 1: Pred ± MP (53); Arm 2: CYC ± AZA ± MP ± Pred ± CsA ± diuretics ± ACEi ± hypolipemics (27) |
Primary FSGS | >18 | 100% | 6.96 ± 4.36; 6.58 ± 4.42 |
— | — | — | Follow-up: 86 mo (range, 12-342 mo); Therapy duration: Pred: 24.5 ± 25.68 wk MP: 19.1 ± 12.34 wk; Other immunosuppressants: 87.1 ± 84.23 wk |
Response to therapy; kidney survival; progression or time to CKF; AEs and/or death; HR | ∼70% of adults with FSGS and NS given prolonged treatment with steroids, immunosuppressive agents, or CsA may still have normal kidney function after 10 y, with a high probability of being without NS |
| Raja et al, 2016 (India)8 | Prospective, observational | Arm 1: Collapsing FSGS (Pred ± CYC ± Tac ± rituximab + ARBs; 22); Arm 2: Resistant FSGS (Pred ± CYC ± Tac ± rituximab + ARBs; 19) |
Collapsing primary FSGS | ≥14 | 50%; 57.9% |
4.6 ± 3.0; 4.5 ± 3.8 |
— | — | — | Follow-up: 6 to 24 mo | Response to therapy; proteinuria or UP/C; SrCr; kidney survival; progression or time to CKF; AEs and/or death | Cases with collapsing FSGS have a dismal outcome; the prognosis of therapy-resistant, noncollapsing FSGS and collapsing FSGS are similar and lend support to the hypothesis of therapy response being among the most important predictors of progression to CKF |
| Ramachandran et al, 2014 (India)86 | Prospective, observational study | Arm 1: Tac responsive (Tac + Pred + ARBs + atorvastatin; 23); Arm 2: Tac resistant (Tac + Pred + ARBs + atorvastatin; 21); Total: All patients (Tac + Pred + ARBs + atorvastatin; 44) |
SRNS primary FSGS | ≥18 | 100% | 4.57 ± 4.16; 4.57 ± 2.98; 4.57 ± 3.6 |
— | 98.42 ± 22.37; 105.1 ± 21.56; 101.6 ± 24.4 |
— | Follow-up; Tac tx duration, all patients: 76.64 ± 16.86 wk; 48 wk | Response to therapy; proteinuria or UP/C; SrCr; eGFR; AEs and/or death | Tac is just as effective as any other CNI, but this effectiveness comes at the cost of increased infections, impaired and fasting glucose and diabetes mellitus |
| Ren et al, 2013 (China)87 | Prospective, open-label, randomized controlled trial | Arm 1: Pulse CYC + Pred ± ACEi and/or ARBs ± CCB (18); Arm 2: Tac + Pred ± ACEi and/or ARBs ± CCB (15) |
SR or SD primary FSGS | >18 | 100% | 3.7 ± 0.5; 4.1 ± 0.5 |
— | — | — | Follow-up: 12 mo; Therapy duration: 12 mo |
Response to therapy; proteinuria or UP/C; SrCr; kidney survival; progression or time to CKF; AEs and/or death | Combination of steroids with either CYC or Tac has similar beneficial effect in treatment of patients with refractory (SD or SR primary) FSGS, as indicated by declined proteinuria, an elevated albumin level in plasma, and stable kidney function; the efficacious effect of Tac is similar to the effect of CYC in a short-term treatment |
| Rennert et al, 1999 (South Africa)88 | Prospective | CYC + Pred (10) | SRNS FSGS | 6.2 years; ± 3.8 years | 100% | — | 2.3 ± 2.81 | — | — | Follow-up after IVCP: 26 ± 9 mo; IVCP therapy duration: 6 mo |
eGFR; AEs and/or death | IV CYC is a valuable adjunctive therapy for children with SRNS and FSGS; remission can be achieved and sustained in the majority of cases, with minimal risk of drug-related side effects |
| Risler et al, 1996 (Germany)89 | Prospective | Arm 1: Pred + acetylsalicylate, then CsA (23); Arm 2: Pred ± chlorambucil if no response to corticosteroids, then CsA (24) |
Primary GN | >16 | 100% | 5.4 ± 5.2; 3.4 ± 4.9 |
— | — | — | Follow-up: 36 mo | Proteinuria or UP/C; kidney survival; progression or time to CKF | In some but not all patients with FSGS, CsA can reduce proteinuria |
| Roberti & Vyas, 2010 (USA)90 | Retrospective chart review | Tac ± CsA or ACEi, ARBs, or statins (19; 10 with FSGS) | SRNS FSGS | <15 | 100% | — | 7.3 ± 3.7 | — | — | Follow-up: mean: 55 mo (range, 17-111 mo) | Response to therapy; proteinuria or UP/C; kidney survival; progression or time to CKF; AEs and/or death |
Tac therapy in children with severe NS is well tolerated and initially quite efficacious in achieving remission |
| Rydel et al, 1995 (USA)91 | Retrospective | Pred ± cytotoxic agents (81 patients; 30 treated out of 60 patients with NS) | Primary FSGS | 35 ± 16 | 74% | 8.1 ± 8.1 | — | — | — | Follow-up: 62 ± 75 mo | Response to therapy; kidney survival; progression or time to CKF | Patients with NS with primary FSGS may benefit from a more prolonged course of therapy with Pred |
| Schwartz et al, 1999 (USA)92 | Retrospective, clinicopathologic analysis | Arm 1: FSGS-classical segmental scars (Pred; 57); Arm 2: FSGS-cellular lesion (Pred; 43) |
Primary FSGS | >18 | 63%; 91% |
4.8 ± 3.6; 12.2 ± 9.8 |
— | — | — | Follow-up: 75 ± 85 mo; 39 ± 37 mo |
Kidney survival; progression or time to CKF; HR | The favorable outcome associated with a remission of proteinuria strongly supports therapeutic intervention in patients with NS with primary FSGS, regardless of the presence of the cellular lesion |
| Segarra et al, 2002 (Spain)93 | Noncomparative, open, uncontrolled (prospective) | Pred + Tac + ACEi and/or ARBs ± other AH ± statins (25) | SR idiopathic FSGS | >18 | 56% | 10.3 ± 9.5 | — | 73 ± 15 | — | Follow-up: up to 2 y | Response to therapy; proteinuria or UP/C SrCr; eGFR; CrCl; kidney survival; progression or time to CKF; AEs and/or death |
Combined therapy of Tac and steroids induced sustained remission of proteinuria in a significant number of patients with idiopathic focal glomerulosclerosis whose disease was not controlled by the standard therapy of steroids and CsA |
| Segarra et al, 2007 (Spain)94 | Observational clinical trial | MMF + ACEi and/or ARBs ± other AH ± statins (98; 22 with FSGS) | SR primary FSGS | >18 | 100% | 7.2 ± 3.2 | — | 67.1 ± 6.3 | — | Follow-up: 12 mo; Therapy duration: 12 mo |
Response to therapy; proteinuria or UP/C; eGFR; BP | The data do not allow us either to quantify definitively the efficacy of MMF in primary glomerulonephritis that is resistant to other, conventional therapies or to establish solid treatment rules; however, when MMF is prescribed as a rescue treatment, it can cause a moderate reduction of proteinuria in more than half of the patients who do not have other treatment options |
| Segarra Medrano et al, 2011 (Spain)95 | Observational study with prospective follow-up | CsA + MMF + ACEi and/or ARBs ± amlodipine and/or furosamide ± statins (27) | Steroid- and CsA-resistant primary FSGS | >18 | 100% | 7.74 ± 3.9 | — | 88.6 ± 16.5 | — | Follow-up: 5 y | Response to therapy; proteinuria or UP/C; eGFR; BP; kidney survival; progression or time to CKF; AEs and/or death |
The data from this pilot study show that for patients with CsA-resistant FSGS, treatment combination of CsA and MMF for 12 mo does not significantly modify the evolution of kidney function, although it may induce partial reductions in proteinuria in some patients |
| Senthil Nayagam et al, 2008 (India)14 | Randomized, open-label study | Arm 1: MMF + Pred + ACEi and/or ARBs ± other AH ± diuretics ± statins (28; 17 with FSGS); Arm 2: Pred + ACEi and/or ARBs ± other AH ± diuretics ± statins (26; 16 with FSGS) |
FSGS | ≥18 | 100% | 4.68 ± 1.82 (all patients); 4.95 ± 1.65 (all patients) |
— | 87 ± 14.2 (FSGS specific); 84 ± 10.1 (FSGS specific) |
— | Follow-up: 15.3 mo (range, 12.8-18.2 mo); 16.2 mo (range, 14.5-19.6 mo) |
Response to therapy; proteinuria or UP/C; eGFR; AEs and/or death |
In the short term, MMF is as effective as a first-line agent as conventional forms of therapy in the management of adults with NS due to FSGS and MN and is well tolerated. MMF-based therapy seems to induce remission faster and reduces exposure to steroids in FSGS |
| Shatat et al, 2007 (USA)96 | Retrospective review of clinical and biochemical data | CsA ± ACEi (16) | SRNS or SDNS primary FSGS | <18 | 100% | — | — | 130.5 (95% CI, 111.7-144.8) | — | Follow-up while on CsA: 21 mo (range, 8-43.5 mo) | Response to therapy; eGFR | In primary FSGS, steroid resistance may predict CsA resistance; genetic testing for known mutations associated with resistance to immunosuppression may be advisable before treatment of patients with SR FSGS with CsA |
| Sherali et al, 2010 (Pakistan)97 | Prospective | CsA + Pred (30) | SDNS + SRNS primary FSGS | <18 | 100% | — | — | — | — | Follow-up: 12 mo; CsA therapy duration: 12 mo |
Response to therapy; SrCr; kidney survival; progression or time to CKF; AEs and/or death | CsA in combination with low-dose, oral Pred was effective in majority of the patients with primary FSGS |
| Silverstein & Craver, 2007 (USA)98 | Retrospective analysis | Steroids ± Tac or CsA ± MMF ± ACEi and/or ARBs (41) | SRNS or SSNS primary FSGS | <18 | 63.4% | — | — | 105.4 ± 4.6 | — | Follow-up: 3.9 ± 0.5 y (range, 1-17 y) | Response to therapy; eGFR; BP; kidney survival; progression or time to CKF | Impression that more aggressive treatment with CNI, in combination with ACEi and/or ARB or with MMF, may provide a more favorable prognosis for kidney survival in pediatric FSGS |
| Singh et al, 1999 (USA)9 | Retrospective | CsA (83; 42 with FSGS) | SRNS FSGS | <18 | 100% | 7.10 ± 7.13 | — | — | — | Follow-up: 22.8 mo; CsA therapy duration: at least 8 wk |
Response to therapy; proteinuria or UP/C; SrCr; kidney survival; progression or time to CKF; AEs and/or death |
CsA showed efficacy in inducing remission in many children with SRNS; whether CsA can prevent progression to CKF in patients with FSGS can only be answered in a large, multicenter trial |
| Stirling et al, 2005 (UK)99 | Retrospective record review | Arm 1: Pred ± CYC ± CsA ± AZA (76); Arm 2: untreated (60) |
NS primary FSGS | >14 | 100% | 10 (IQR, 6-15); 6.2 (IQR, 5-10) |
— | — | — | Pred therapy duration: up to 20 y | Response to therapy; HR | Patients with primary FSGS and nephrotic-range proteinuria, who are treated with corticosteroids, are more likely to enter remission than those who are not treated; remission rates of up to 80% can be achieved with prolonged treatment, and remission is an independent predictor of survival off dialysis; patients who do not achieve remission have a poor prognosis |
| Tarshish et al, 1996 (USA)100 | Prospective, randomized trial | Arm 1: Pred (25); Arm 2: Pred + CYC (35) |
SRNS idiopathic FSGS | ≤19 | 100% | 161 ± 145 mg/h per m2; 227 ± 207.06 mg/h per m2 |
— | 118 ± 42; 109 ± 51.47 |
— | Follow-up: mean, 44.5 mo; mean, 42.4 mo; range, 3-102 mo |
Response to therapy; AEs and/or death | Although 1/4 of the patients underwent CR and another quarter had a decrease in proteinuria, they could not differentiate between spontaneous resolution of the disease and an effect of alternate-day Pred; CYC therapy for children with SR FSGS is not recommended |
| Troyanov et al, 2005 (Canada)101 | Retrospective | Pred ± AZA or CsA ± CYC or MMF ± ACEi and/or ARBs (281) | Primary FSGS | >18 | 68% | — | — | — | 73 ± 31 | Follow-up: 64 mo (range, 12-346 mo) | Response to therapy; eGFR; BP; kidney survival; progression or time to CKF; AEs and/or death; HR | Achievement and maintenance of PR strongly correlated with both reduction in the rate of kidney disease progression and better kidney survival |
| Wasilewska & Zoch-Zwierz, 2004 (Poland)102 | Prospective | Pred + CsA + ACEi (24) | SDNS FSGS | <12 | 100% | 32 ± 19 | — | — | 133 ± 28 | Follow-up: 12 mo; CsA therapy duration: 12 mo |
Proteinuria or UP/C; SrCr; CrCl |
The urinary TGFβ1 level increases in proportion to proteinuria during relapse of the NS; CsA administration, in combination with an ACEi, causes a systematic reduction in urinary TGFβ1, although the concentration is still higher after 12 mo of therapy than in healthy children |
| Zagury et al, 2013 (Brazil)103 | Retrospective | CYC ± CsA + Pred ± MMF (136; 87 with FSGS) | SRNS idiopathic FSGS | <18 | 100% | — | — | — | — | Follow-up: 6.1 y (0.25-30.83 y) | Kidney survival; progression or time to CKF; AEs and/or death; HR | CsA resistance and FSGS were risk factors for CKF |
Note: Unless otherwise specified, data are reported as means ± standard deviations or medians (95% CIs, IQRs, or ranges).
Abbreviations: ACEi, angiotensin-converting enzyme inhibitors; AE, adverse event; AH, antihypertensives; AP, antiplatelets; ARB, angiotensin receptor blockers; AZA, azathioprine; BP, blood pressure; CCB, calcium channel blockers or inhibitors; CI, confidence interval; CKD, chronic kidney disease; CKF, chronic kidney failure; CNI, calcineurin inhibitors; CrCl, creatinine clearance; CR, complete remission; CsA, cyclosporine or cyclosporine A; CYC, cyclophosphamide; DEX, dexamethasone; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; FSGS, focal segmental glomerulosclerosis; GN, glomerulonephropathy; HR, hazard ratio; IQR, interquartile range; IV, intravenous; IVCP, intravenous pulse cyclophosphamide; MCD, minimal change disease; MMF, mycophenolate mofetil; MN, membranous nephropathy; MP, methylprednisone; NOS, nitric oxide synthase; NS, nephrotic syndrome; ORG, obesity-related glomerulopathy; Palb, albumin permeability; Pred, prednisone or prednisolone; SD, steroid dependent; SDNS, steroid-dependent nephrotic syndrome; SR, steroid resistant; SrCr, serum creatinine; SRNS, steroid-resistant nephrotic syndrome; SSNS, steroid sensitive nephrotic syndrome; suPAR, soluble urokinase plasminogen activator receptor; Tac, Tacrolimus; TGFβ1, transforming growth factor β; TRPC6, transient receptor potential cation channel subfamily C member 6; UP/C, urinary protein-creatinine.