Table 4.
Summary of pediatric lupus nephritis treatment studies from 2012 including tacrolimus or mesenchymal stem cell therapy.
| Study | Patients | Treatment | Outcome measures | Main result(s) | Safety outcomes | Level of evidence |
|---|---|---|---|---|---|---|
| Long-Term Tacrolimus-Based Immunosuppressive Treatment for Young People with Lupus Nephritis: A Prospective Study in Daily Practice. Tanaka et al. (52) Study type: Open label prospective study Type of LN: any proven-on biopsy |
Adult study including some JSLE patients Total 19 M 6 F 13 Median age: 18 (range 9–38 years) |
Re- induction and maintenance When a lupus flare was diagnosed, the previous cytotoxic agent was replaced by TAC. Other drugs: Prednisolone and MZR depending on clinical picture |
Complete, partial or no renal response. Urinary PCR, serum C3 level, serum CH50 value, anti-dsDNA antibody, serum creatinine, ECLAM index (SLE disease activity), prednisolone dose–Measured at baseline, 3, 6, 12, 24 and 36 months and last visit. |
Complete response−12/19 (63%) Partial response−5/19 (26%) No response−2/19 (11%) Despite tapering of prednisolone, a marked improvement compared with baseline values was observed in all laboratory results as early as 3 months after the initiation of TAC. Sustained improvements in the outcome measures compared with baseline values and after a mean of 42 months of treatment: ECLAM index, serum CH50, anti-dsDNA antibody (all p < 0.01), urinary PCR, serum C3 level (both p <0.05). Serum creatinine level remained within the normal range in all patients. |
No serious adverse effects were observed. | 2B |
| Outcomes of maintenance therapy with tacrolimus vs. azathioprine for active lupus nephritis: a multicenter randomized clinical trial. Chen et al. (53) Study type: Prospective randomized, open label and controlled trial Type of LN: active LN (ISN/RPS Classes III, IV or V) |
Adult study including some JSLE patients Total 70 F 61 M 9 Age, mean +/- SD Tac 30.7 +/- 10.2 Aza 33.1 +/- 10.9 |
Maintenance: TAC plus prednisone (TAC group) or AZA plus prednisone (AZA group). Other drugs: ACE/ARB Statins/fibric acid derivatives |
Primary outcome: incidence of renal relapse Secondary outcome: ‘maintaining’ response (defined as complete or partial remission), changes of clinical parameters (including proteinuria, serum albumin, serum creatinine, eGFR and serum C3), and adverse effects (including leucopenia, infections, gastrointestinal complaints, liver function disorder and nephrotoxicity) |
After six months of therapy, two patients in AZA group developed renal relapse compared to none of the TAC group [p = 0.49; odds ratio, 1.06; 95% CI (0.98, 1.15)]. | Leucopenia was significantly more frequent in the AZA group than the TAC group (47% vs. 9%, p < 0.001). | 1B |
| Low-dose tacrolimus in treating lupus nephritis refractory to cyclophosphamide: a prospective cohort study. Fei et al. (54) Study type: Prospective cohort study Type of LN: Refractory LN (Class III, IV, V, III+V, IV+V, unknown) resistant to CYC Refractory (failed CYC >8 g over 6 months induction treatment) |
Total: 26 Adult study including some JSLE patients F 22 M 4 Age 29.36 +/- 9.45 years |
TAC (initial dose of 2 mg/day (body weight <60 kg) or 3 mg/day [body weight ≥60 mg)] and prednisolone Other drugs: Pre-existing drugs such as ACE/ARBs were maintained throughout |
Primary end point: Complete remission following 6 months of treatment. Secondary end points: complete or partial remission, changes in serum creatinine, serum C3 values, 24-h urinary protein excretion, and adverse effects |
Complete remission at 6 months: 10/26 patients (38.5%) Partial remission at 6 months: 13/26 (50%) Mean urinary protein significantly decreased from 6.91 ± 4.50 g at baseline to 1.11 ± 1.10 g at 6 months (p < 0.001). Mean serum albumin level significantly increased from 25.56 ± 7.94 g/L at baseline to 38.12 ± 2.42 g/L at 6 months (p < 0.001). Mean SLEDAI score decreased from 11.42+/- 6.74 at baseline to 3.61+/- 2.73 at 6 months (p <0.0001). |
TAC was well tolerated at the administered dose, though one patient developed severe lung infection. | 2B |
| A randomized double-blind, placebo-controlled trial of allogeneic umbilical cord-derived mesenchymal stem cell for lupus nephritis Deng et al. (55) Study type: Randomized double-blind, placebo-controlled trial Type of LN: WHO class III or IV |
Adult study including some JSLE patients Total: 18 F 17 M 1 Age, years, mean (SD) Placebo: 29 (7) hUC-MSC: 29 (10) |
Allogeneic hUC-MSC or placebo. Induction therapy: IV methylprednisolone at the discretion of the investigator plus low-dose IV CYP six pulses at a fixed dose of 500 mg every 2 weeks. After the first 11 patients were treated, the induction CYP was changed to a rescue treatment [i.e., the investigator considered initiating CYP 4 weeks after commencing the study treatment (hUC-MSC or placebo)]. Earlier initiation of CYP was however still permitted (investigators discretion). |
Primary outcome: Remission of nephritis (combined partial and complete remission defined as stabilization or improvement in renal function, urinary red blood cells <10 per high power field and reduction of proteinuria <3 g/day if baseline proteinuria >3 g/day or at least a 50% reduction in proteinuria or <1g/day if baseline proteinuria was in the sub nephrotic range. |
Remission of nephritis occurred in 9 of 12 patients (75%) in the hUC-MSC group and 5 of 6 patients (83%) in the placebo group (no p value stated). A similar proportion of patients in each treatment arm achieved complete remission (no p value stated). Improvements in serum albumin, complement, renal function, SLEDAI, BILAG were similar in both groups (no p value stated). The trial was abandoned after 18 patients were enrolled, clear it would not demonstrate a positive treatment effect. |
One patient on placebo had a stroke and another had ascites. One patient on hUC-MSC had leucopenia, pneumonia and subcutaneous abscess and another died of severe pneumonia. | 1b |
| Maintenance therapy: prednisolone and MMF. | Stabilization of renal function was defined as change in serum creatinine concentration of <20% compared with baseline concentration and improvement in renal function was defined as a reduction in serum creatinine of at least 20% compared with baseline. Complete response was similarly defined except for reduction of proteinuria <0.3g/day. | Secondary endpoints: improvement in lupus activity scores (SLEDAI and BILAG), complement concentration, anti-dsDNA antibody and ANA titres, death and commencement of permanent dialysis or renal transplantation. |
LN, lupus nephritis; M, Male; F- female; MMF, mycophenolate mofetil; PCR, protein creatinine ratio; ESRD, End stage renal disease; BILAG, British Isle Lupus Assessment; ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; TAC, tacrolimus; CYC, cyclophosphamide; ELNT, Euro Lupus Nephritis treatment regimen; BILAG, British Isle Lupus Assessment; NSAID, nonsteroidal anti-inflammatory drugs; TAC, tacrolimus; MZR- mizoribine; AZA, azathioprine; ECLAM, European Consensus Lupus Activity Measurement; TAC, tacrolimus; SLEDAI score, Systemic Lupus Erythematosus Disease Activity Index scores; hUC-MSC, human umbilical cord-derive mesenchymal stem cell; UPC ratio, urine protein creatinine ratio.