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World Journal of Nephrology & Urology

Case Report

Volume 000, Number 000, January 2016, pages 33-36

Steroid Retrial After Rituximab and Mycophenolate Mofetil in Pediatric Refractory Nephrotic Syndrome

Steroid-resistant nephrotic syndrome (SRNS) is a challenging medical condition. In children with SRNS, cyclosporine is considered to be the first-line treatment option [1-3]. However, the treatment algorithm is less defined in those who do not respond to cyclosporine. Mycophenolate mofetil (MMF) [4], plasmapheresis [5], vincristine [6], Mendoza protocol (combination of high dose steroid and cyclophosphamide) [7], tacrolimus [8] and galactose [9] have shown some value in cyclosporine-resistant SRNS. Recently, rituximab has been found to be another useful option in SRNS although with variable success [10, 11]. The absence of response to any of these medications makes the management of SRNS extremely challenging due to the lack of further treatment options and the likelihood of progressive chronic kidney disease.

In this paper, we report a patient with cyclosporine-resistant SRNS, who did not respond to above stated medications and the response to rituximab was moderate. Subsequent retrial of prednisone however induced a complete remission.

The 2-year-old Caucasian boy initially presented in the year 2007 with generalized edema, nephrotic-range proteinuria, hypoalbuminemia (< 25 g/L) and hypercholesterolemia, consistent with the diagnosis of nephrotic syndrome. The evaluation for an underlying primary disease was unremarkable, including normal serum complement C3 and C4 levels. Prednisolone given at a dose of 60 mg/m² per day did not induce remission in 6 weeks. A kidney biopsy confirmed underlying focal segmental glomerulosclerosis (FSGS). Given the diagnosis of FSGS, genetic testing showed no disease-causing mutations in NPHS2 (podocin), ACTN4 (alpha-actinin-4), TRPC6 (transient receptor potential cation channel 6), CD2AP (CD2-associated protein) or NPHS1 (nephrin).

Earlier he was diagnosed with type 1 diabetes at 11 months of age and hypothyroidism in the second year of life. Further evaluation in view of these diagnoses did not reveal hearing impairment, autoimmune thyroiditis or another endocrinopathy. The parents did not have diabetes, thyroid, kidney or an autoimmune disorder.

With no response to steroid, cyclosporine was administered at a dose of 150 mg/m² per day in two divided doses and prednisolone at a dose of 0.5 mg/kg per day. On cyclosporine, he attained remission. While on stable cyclosporine dose (trough level 150 - 250 ng/mL), there were five relapses, which responded favorably to prednisone (May 2009, December 2009, December 2010, January 2011 and July 2011). The first relapse was complicated by sepsis and acute kidney injury, requiring short-term hemodialysis.

While on cyclosporine, the patient relapsed again in October 2011 with no response to prednisone. Over time, the edema became significantly worse such that he required multiple diuretics and 25% albumin infusions regularly 3 - 4 times a week. In view of persistent relapse despite adequate cyclosporine exposure (trough level 150 - 250 ng/mL), cyclosporine was discontinued and the following medications were tried.

In December 2011, four intravenous vincristine doses, 1.5 mg/m² each, followed by the fifth dose a month after the fourth dose were administered with no response [9].

In February 2012, intravenous methylprednisolone (MP) infusions at a dose of 30 mg/kg weekly for 12 weeks along with cyclophosphamide (2 mg/kg/day) for 8 weeks were administered [7]. While on MP for 2 weeks, oral prednisone was started at a dose of 2 mg/kg every other day for 10 weeks [7]. On this regimen, there was a transient improvement in serum albumin to 34 g/L for a week followed by the drop to the baseline of < 10 g/L.

The patient received a combination of tacrolimus 0.15 mg/kg/day in two divided doses (trough level 6 - 10 µg/L), MMF 600 mg/m² per dose twice daily (trough mycophenolic acid-MPA level 3 - 5 mg/L) and prednisone 0.5 mg/kg daily for 6 months, with no change in proteinuria and edema control measures.

Oral galactose (0.2 g/kg/dose twice daily) was administered for 16 weeks, with no response [9].

In April to May 2013, six sessions of plasmapheresis were performed in a dose of one and a half plasma volume replacement by 5% albumin [5], with no response.

Between May and July 2013, the patient received four rituximab infusions at a dose of 375 mg/m² each [10, 11], resulting in B-cell depletion (CD19 < 1%). Following rituximab, his urinary protein to creatinine ratio decreased from 2,200 - 2,400 mg/mmol to 1,100 - 1,300 mg/mmol and serum albumin increased from < 10 g/L to 15 - 17 g/L (Fig. 1); the requirement of multiple diuretics continued although the frequency of 25% albumin infusions became intermittent.

Click for large image

Figure 1. Trend of proteinuria (urine spot protein to creatinine ratio) and serum albumin levels (before rituximab, after rituximab and after prednisone retrial). Before rituximab: proteinuria and serum albumin levels prior to rituximab. After rituximab: plateau levels of proteinuria and serum albumin after rituximab. After prednisone retrial: plateau levels of proteinuria and serum albumin level after prednisone.

Based on previous reports suggesting the benefit of MMF in maintaining remission after a complete response to rituximab [12, 13], MMF was restarted in January 2014, 6 months after rituximab, at a dose of 600 mg/m² per dose twice daily (trough MPA target level 3 - 5 mg/L). On MMF for the next 6 months, no further improvement in proteinuria and serum albumin level was noted.

Based on the reported benefit of prednisone retrial after rituximab in two patients [14, 15], in August 2014 a year after rituximab and 6 months of MMF, oral prednisone was re-initiated in the dose of 60 mg/m² daily. Within 2 weeks of prednisone start, urine protein to creatinine ratio decreased from 1,100 - 1,300 mg/mmol to 30 - 50 mg/mmol and serum albumin increased from 14 - 16 g/L to 39 - 41 g/L (Fig. 1); edema resolved and diuretics were discontinued. Prednisone was administered at 60 mg/m² daily for 6 weeks, 40 mg/m² every other day for 6 weeks, followed by a slow wean to 10 mg daily.

When last seen in March 2016, the patient had maintained a remission for more than a year on MMF 600 mg/m² per dose twice daily (trough MPA target level 3 - 5 mg/L) and prednisone 10 mg daily. He remained normotensive and his estimated glomerular filtration rate was 124 mL/min/1.73 m². During follow-up, he did not develop any major infection or other adverse effect except exaggerated appetite and challenges in diabetic control while on high-dose prednisone.

The response to prednisone retrial in our patient, manifested by the resolution of proteinuria, normalization of serum albumin and discontinuation of diuretics within 2 weeks of prednisone initiation, suggested that rituximab and MMF can induce steroid sensitivity despite previous SRNS and multi-drug resistance.

The response to prednisone retrial in our patient was clinically significant considering a high risk of future chronic kidney disease in refractory SRNS and significant complications of unremitting nephrotic syndrome. There is limited evidence in literature to support the effectiveness of rituximab in inducing steroid sensitivity in refractory SRNS. A synergy between rituximab and steroid was suggested by a response to rituximab in eight of the 10 patients with refractory SRNS when rituximab was combined with methylprednisolone [16]. To add up to this observation, two children with refractory SRNS responded to prednisone when prednisone was retried shortly after a failed response to rituximab [14, 15].

The strength of our finding was an adequate time gap between various interventions to differentiate the effectiveness of individual treatments. Rituximab was separated from previous immunosuppression by a year. Prednisone retrial was separated from rituximab by a year and from MMF by 6 months, suggesting against a delayed effect of rituximab and MMF while interpreting the effectiveness of prednisone retrial. A disease-mitigating effect of rituximab in our patient was suggested by a moderate clinical response to it, in association with rituximab-induced B-cell suppression. In absence of a clinical response to MMF re-initiation, its additive benefit to rituximab remains speculative; however, it remains a possibility considering targeting of B cells by both rituximab and MMF and previous reports suggesting lesser relapses with MMF use in complete responders to rituximab [12, 13].

We conclude that prednisone can be a potential treatment option in refractory SRNS when retried after rituximab. An additive role of MMF in this context needs further evaluation. Larger studies are needed to establish the benefit of prednisone retrial in refractory SRNS and to assess the adverse effect profile of this treatment approach.

Funding Source

None.

Conflicts of Interest

None.

Abbreviations

FSGS: focal segmental glomerulosclerosis; MMF: mycophenolate mofetil; MP: methylprednisolone; SRNS: steroid-resistant nephrotic syndrome

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World Journal of Nephrology and Urology is published by Elmer Press Inc.