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Partial remission of resistant nephrotic syndrome after oral galactose therapy

Therapeutic Apheresis and Dialysis 15(3):269–272doi: 10.1111/j.1744-9987.2011.00949.x 2011 The AuthorsTherapeutic Apheresis and Dialysis 2011 International Society for Apheresis Partial Remission of Resistant Nephrotic Syndrome After Matjaž Kopacˇ, Anamarija Meglicˇ, and Rina R Rus Department of Nephrology, Division of Pediatrics, University Medical Centre Ljubljana, Ljubljana, Slovenia Abstract: Focal segmental glomerulosclerosis is sometimes
decreased by 50%. Seven months later, galactose was again associated with a circulating permeability factor. It was added for six months, after which proteinuria remained proposed that this factor interacts with the sugars of the below 2 g/24 h and the plasma albumin and cholesterol glycocalyx, and its high affinity for galactose was shown on concentrations normalized. An adolescent girl with a neph- the basis of chromatographic studies. Galactose inactivates rotic syndrome resistant to corticosteroids was admitted. A it and seems to lead to its clearance from plasma. A toddler renal biopsy revealed mesangioproliferative glomerulone- with a nephrotic syndrome resistant to corticosteroids was phritis with C1q nephropathy. Therapy with tacrolimus admitted. A renal biopsy revealed minimal change disease failed to induce remission. After six months, we added with deposition of immunoglobulin M. Immunosuppressive galactose for three months, which reduced proteinuria to therapy with pulses of cyclophosphamide, low-dose combi- 0.76 g/24 h. After the discontinuation of galactose therapy, nation immunosuppressive therapy, and later with myco- proteinuria increased to 2.48 g/24 h, despite further treat- phenolate mofetil failed to induce remission. A renal ment with tacrolimus. It seems that oral galactose at a dose biopsy six years later showed transformation to FSGS.
of 0.2 g/kg twice a day could be a promising new and non- After unsuccessful treatment with monthly pulses of cyclo- toxic therapy for the treatment of resistant nephrotic syn- phosphamide, we began therapy with tacrolimus, which Key Words: Focal segmental glomerulosclerosis,
showed no effect. After two months, we added oral galac- Galactose, Immunosuppressive therapy, Nephrotic syn- tose to tacrolimus for one month, after which proteinuria Steroid-resistant nephrotic syndrome is a specific cant decrease in permeability factor in a patient with clinical phenomenon with a varied histological diag- FSGS-PF-associated nephrotic syndrome, but with nosis. One of these is focal segmental glomeruloscle- no improvement in proteinuria, as the patient was rosis (FSGS), which is the most frequently acquired already dialysis-dependent (2). In another report, disease resulting in end-stage renal disease in chil- remission was achieved after galactose therapy in an dren (1). FSGS is sometimes associated with a cir- adult male with a nephrotic syndrome that was resis- culating factor, called FSGS-permeability factor tant to corticosteroids, other immunosuppression, (FSGS-PF) (2). This disease often recurs after trans- and plasmapheresis. The patient was given oral galac- plantation (3). Savin et al. proved a high affinity of tose as a last resort treatment, which was followed by FSGS-PF for galactose, based on chromatographic a long-standing remission of his nephrotic syndrome studies. Galactose inactivates FSGS-PF and seems to that correlated with the reduction of FSGS-PF activ- lead to its clearance from plasma. In vivo administra- tion of galactose has been associated with a signifi- CASE REPORTS
Case report 1
Address correspondence and reprint requests to Dr Matjaž A three-year-old boy was admitted in June 2002 Kopacˇ, Department of Nephrology, Division of Pediatrics, Univer-sity Medical Centre Ljubljana, Bohoricˇeva 20, 1000 Ljubljana, after failure to induce remission of nephrotic syn- drome after four weeks of therapy with cortico- Presented in part at the Symposium Celebrating the 40th Anni- steroids in a regional hospital. A renal biopsy was versary of Chronic Dialysis and Kidney Transplantation inSlovenia held 4–5 November 2010 in Bled, Slovenia.
performed and the findings were consistent with CYCLOPHOSPHAMIDE
time (dates)
minimal change disease (variant with focal mesangial two months of tacrolimus therapy, proteinuria was proliferation with deposition of immunoglobulin similar to the level before therapy (3.68 g/24 h). We [Ig]M in the mesangium). Electron microscopy then added galactose (Fagron, Barsbuttel, Germany) revealed a thinned glomerular basement membrane, at a dose of 0.2 g/kg/dose twice a day for one month, which was considered normal for the boy’s age. Due after which proteinuria decreased to 1.8 g/24 h two to failure to induce remission with corticosteroid months after stopping galactose treatment. Since pro- treatment, we began immunosuppressive therapy teinuria repeatedly rose up to 2.5 g/24 h, about six with cyclophosphamide in October 2002. After three months later we added galactose once again at the monthly pulses, proteinuria was still over 2 g/24 h, same dose, this time for six months. All this time, the and both the sedimentation rate (SR) and the blood patient regularly received tacrolimus as well. At cholesterol level were high. We introduced low-dose follow-up after three months of galactose treatment, combination immunosuppressive therapy with meth- proteinuria slightly decreased to 1.96 g/24 h, but the ylprednisolone 0.1 mg/kg, cyclophosphamide, aza- plasma albumin concentration rose to 3.2 g/dL after thioprine, and indomethacin (all three drugs in doses previously being constantly below the normal of 0.3 mg/kg once per day). After about six months of level. The plasma cholesterol level decreased to this therapy, proteinuria had slightly decreased, but 5.6 mmol/L compared to previous concentrations hypercholesterolemia persisted. For this reason, a between 6.5 and 8 mmol/L. At the last follow-up statin was added to the therapy regimen. In Novem- about three months after the second course of galac- ber 2006, proteinuria was 1.89 g/24 h and combina- tose treatment, proteinuria was stable at 1.8 g/24 h tion immunosuppressive therapy was replaced with and, for the first time, the albumin (3.4 g/dL) and mycophenolate mofetil (250 mg twice daily). Pro- cholesterol concentrations (4.1 mmol/L) in the blood teinuria was transiently decreased to 0.67 g/24 h after two months, but soon returned to previous levels ofup to 3.63 g/24 h. In June 2008, a renal biopsy was Case report 2
performed, showing transformation to the perihilar A 16 1 -year-old girl with a nephrotic syndrome, variant of focal segmental glomerulosclerosis (33%) resistant to corticosteroids, was admitted. A renal with diffuse mesangial immune deposits with pre- biopsy revealed mesangioproliferative glomerulone- dominance of C1q and IgG. We discontinued therapy phritis with C1q nephropathy. The patient was with mycophenolate mofetil and began therapy with treated with pulse therapy using corticosteroids, six monthly pulses of cyclophosphamide. Despite this which decreased proteinuria from 7.3 g/24 h to 1.5 g/ treatment, proteinuria persisted (up to 3.42 g/24 h), 24 h, but the effect was only transient as the pro- as did other parameters of nephrotic syndrome. For teinuria returned to similar levels soon afterwards.
this reason, a repeat biopsy was performed in Febru- Additionally, severe depression developed after ary 2009, the result of which was very similar to the pulse therapy. Therapy with tacrolimus was initiated previous one, only this time the immunofluorescent together with tapering of corticosteroids. Despite deposits were slightly less prominent. We decided to regular treatment with tacrolimus, consistent with begin therapy with tacrolimus in March 2009. After appropriate blood levels of the drug between 5 and Ther Apher Dial, Vol. 15, No. 3, 2011 Therapeutic Apheresis and Dialysis 2011 International Society for Apheresis Galactose Therapy for Nephrotic Syndrome TACROLIMUS
time (dates)
8 mg/L, nephrotic proteinuria persisted and contin- may depend on FSGS-PF binding to glomerular ued to remain above 2.5 g/24 h. After six months of galactose. Galactose inactivates it and seems to lead tacrolimus treatment, galactose was added at a dose to its clearance from plasma. In addition, the FSGS- of 0.2 g/kg/dose twice a day for three months, which PF–galactose complex may be susceptible to uptake reduced proteinuria to 0.76 g/24 h, with the plasma and catabolism by asialoglycoprotein receptors in albumin concentration being 37 g/L. After the dis- hepatocytes or macrophages (2). A previous study continuation of galactose, proteinuria increased showed that plasmapheresis in patients with FSGS despite further treatment with tacrolimus. At the last lowered PFa and decreased proteinuria, and PFa follow-up, proteinuria was again 2.48 g/24 h one year was detected in plasmapheresis fluid. Its decrease after the discontinuation of galactose treatment. The serum albumin concentration gradually increased removal of a substance that is primarily confined to from 3 g/dL during corticosteroid treatment and at the plasma space and is not rapidly synthesized the beginning of tacrolimus treatment to 4 g/dL in the after its removal (5). It seems, therefore, that the following months (Fig. 2). The serum cholesterol restoration of PFa is a slow process. Mechanisms level was also elevated during corticosteroid treat- other than just simple removal of FSGS-PF from ment and at the beginning of tacrolimus treatment, the circulation may contribute to this prolonged effect. The uptake and catabolism of the FSGS-PF–galactose complex by receptors in the liver is DISCUSSION
perhaps only one of them. The dose of galactosethat we used was 0.2 g/kg/dose twice a day. An inter- The addition of galactose to therapy seems to ventional study is presently recruiting patients with have induced a partial remission of nephrotic syn- primary FSGS to determine if the oral administra- drome in our two patients, which was sustained for seven years in one of them. To our knowledge, these are the first reported cases of at least the partial Previous observations have provided evidence that success of galactose treatment in children; however, a glomerular permeability factor can be transferred a late contribution of tacrolimus to the beneficial through the placenta, and that it loses its proteinuric effects of galactose cannot be ruled out. We did not effect within a few days. In the reported case of tran- measure the permeability factor activity (PFa), as sient nephrotic syndrome in the infant of a mother was done in other reports (2,4), because it is not who had FSGS, in utero exposure did not cause available at our institution; however, owing to the chronic glomerular disease in the neonate. This indi- clinical and laboratory improvements observed cated that the molecular size of the factor was smaller during galactose treatment, we have decided to con- than that of IgG, which would persist in the infant’s tinue with it. We assume with high probability that this factor was present in our patients and had high The use of galactose as a new therapeutic agent has activity. The long-term decrease in proteinuria after also been investigated in other areas of medicine. Its oral galactose is consistent with the clearance of successful use in an adult patient was reported for the FSGS-PF from the plasma. Savin et al. showed that treatment of the cardiac variant of Fabry’s disease interaction between FSGS-PF and the glomeruli 2011 The AuthorsTherapeutic Apheresis and Dialysis 2011 International Society for Apheresis Ther Apher Dial, Vol. 15, No. 3, 2011 CONCLUSION
2. Savin VJ, McCarthy ET, Sharma R, Charba D, Sharma M.
Galactose binds to focal segmental glomerulosclerosis perme- It seems that galactose could be a promising new, ability factor and inhibits its activity. Tansl Res 2008;151:288–92.
3. Hoyer JR, Vernier JL, Najarian JS et al. Recurrence of idio- harmless, and relatively inexpensive therapy for the pathic nephrotic syndrome after renal transplantation. J Am treatment of resistant nephrotic syndrome, but more Soc Nephrol 2001;12:1994–2002.
studies are needed. As mentioned, a few case reports 4. DeSmet E, Rioux JP, Ammann H, Déziel C, Quérin S. FSGS permeability factor-associated nephrotic syndrome: remission of the successful use of galactose have already been after oral galactose therapy. Nephrol Dial Transplant 2009;24: described. It has the potential to reduce proteinuria as well as to delay the progression to renal failure, but 5. Savin VJ, Sharma R, Sharma M et al. Circulating factor associ- ated with increased glomerular permeability to albumin in to the best of our knowledge, this is the first report recurrent focal segmental glomerulosclerosis. N Engl J Med about the partial success of galactose treatment of resistant nephrotic syndrome in children.
6. Moudgil A, Sgambat K. Oral galactose in children with focal segmental glomerulosclerosis (FSGS). identi-fier NCT01113385.
7. Kemper MJ, Wolf G, Müller-Wiefel DE. Transmission of glom- REFERENCES
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Ther Apher Dial, Vol. 15, No. 3, 2011 Therapeutic Apheresis and Dialysis 2011 International Society for Apheresis



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