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A Pilot Study of IL2 in Drug-Resistant Idiopathic Nephrotic Syndrome.

Bonanni A, Bertelli R, Rossi R, Bruschi M, Di Donato A, Ravani P, Ghiggeri GM - PLoS ONE (2015)

Bottom Line: IL2 was safe in all but one patient who had an acute asthma attack after the first IL2 dose and did not receive further doses.We concluded that low-dose IL2 given in monthly pulses is safe and modifies the levels of circulating Tregs.We were unable to reproduce in humans the effects of IL2 described in rats and mice reducing de facto the interest on this drug in nephrotic syndrome.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Dialysis, Transplantation and Laboratory on Physiopathology of Uremia, Giannina Gaslini Children Hospital, Genoa, Italy.

ABSTRACT

Unlabelled: Tregs infusion reverts proteinuria and reduces renal lesions in most animal models of nephrotic syndrome (i.e. Buffalo/Mna, Adriamycin, Promycin, LPS). IL2 up-regulates Tregs and may be an alternative to cell-therapy in this setting. To evaluate a potential role of IL2 as Tregs inducer and proteinuria lowering agent in human nephrotic syndrome we treated 5 nephrotic patients with 6 monthly cycles of low-dose IL2 (1x106 U/m2 first month, 1.5x106 U/m2 following months). The study cohort consisted of 5 children (all boys, 11–17 years) resistant to all the available treatments (i.e. steroids, calcineurin inhibitors, mycophenolate, Rituximab). Participants had Focal Segmental Glomerulosclerosis (3 cases) or Minimal Change Nephropathy (2 cases). IL2 was safe in all but one patient who had an acute asthma attack after the first IL2 dose and did not receive further doses. Circulating Tregs were stably increased (>10%) during the whole study period in 2 cases while were only partially modified in the other two children who started with very low levels and partially responded to single IL2 Proteinuria and renal function were not modified by IL2 at any phase of the study. We concluded that low-dose IL2 given in monthly pulses is safe and modifies the levels of circulating Tregs. This drug may not be able to lower proteinuria or affect renal function in children with idiopathic nephrotic syndrome. We were unable to reproduce in humans the effects of IL2 described in rats and mice reducing de facto the interest on this drug in nephrotic syndrome.

Trial registration: ClinicalTrials.gov NCT02455908.

No MeSH data available.


Related in: MedlinePlus

Flow Chart and scheme for IL2 administration.(a) All 5 children were allocated to intervention; one (Pt 5) was excluded from the study due to a severe adverse event (asthma attack after the first IL-2 Infusion). All remaining participants remained in the study for at least 180 days. (b) All patients received the first IL2 dose of 1x106 U/m2 (subcutaneous recombinant IL2 (Proleukin®) that was repeated for additional 4 days in 4 children for the first cycle (month one). These 4 children continued with other 5 cycles of IL2 1.5x106 U/m2 per day for 5 days at the beginning of the following 5 months.
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pone.0138343.g001: Flow Chart and scheme for IL2 administration.(a) All 5 children were allocated to intervention; one (Pt 5) was excluded from the study due to a severe adverse event (asthma attack after the first IL-2 Infusion). All remaining participants remained in the study for at least 180 days. (b) All patients received the first IL2 dose of 1x106 U/m2 (subcutaneous recombinant IL2 (Proleukin®) that was repeated for additional 4 days in 4 children for the first cycle (month one). These 4 children continued with other 5 cycles of IL2 1.5x106 U/m2 per day for 5 days at the beginning of the following 5 months.

Mentions: Between February and July 2012, 5 children with long lasting nephrotic syndrome unresponsive to drugs were enrolled in the study (Fig 1A). All had normal or borderline renal function. FSGS and minimal change disease were the underlying pathology; molecular sequencing of the major genes responsible for recessive forms of nephrotic syndrome were negative. In the years preceding IL2, patients had been unsuccessfully treated with steroids, calcineurin inhibitors, Rituximab and in some cases with plasmapheresis (Table 1). Patients were treated according to the scheme shown Fig 1B. This represents a minimal modification of the original protocol utilized by Saadoun et al.[19] in adults with vasculitis that were treated with a standard dose of IL2 3 x106 not modified for the body surface area. The timing of IL2 infusions and the number of treatments were modified as well in consideration of the chronic nature of nephrotic syndrome unresponsive to drugs. Overall, the cumulative dose utilized in this study was higher than previous reports.


A Pilot Study of IL2 in Drug-Resistant Idiopathic Nephrotic Syndrome.

Bonanni A, Bertelli R, Rossi R, Bruschi M, Di Donato A, Ravani P, Ghiggeri GM - PLoS ONE (2015)

Flow Chart and scheme for IL2 administration.(a) All 5 children were allocated to intervention; one (Pt 5) was excluded from the study due to a severe adverse event (asthma attack after the first IL-2 Infusion). All remaining participants remained in the study for at least 180 days. (b) All patients received the first IL2 dose of 1x106 U/m2 (subcutaneous recombinant IL2 (Proleukin®) that was repeated for additional 4 days in 4 children for the first cycle (month one). These 4 children continued with other 5 cycles of IL2 1.5x106 U/m2 per day for 5 days at the beginning of the following 5 months.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4587361&req=5

pone.0138343.g001: Flow Chart and scheme for IL2 administration.(a) All 5 children were allocated to intervention; one (Pt 5) was excluded from the study due to a severe adverse event (asthma attack after the first IL-2 Infusion). All remaining participants remained in the study for at least 180 days. (b) All patients received the first IL2 dose of 1x106 U/m2 (subcutaneous recombinant IL2 (Proleukin®) that was repeated for additional 4 days in 4 children for the first cycle (month one). These 4 children continued with other 5 cycles of IL2 1.5x106 U/m2 per day for 5 days at the beginning of the following 5 months.
Mentions: Between February and July 2012, 5 children with long lasting nephrotic syndrome unresponsive to drugs were enrolled in the study (Fig 1A). All had normal or borderline renal function. FSGS and minimal change disease were the underlying pathology; molecular sequencing of the major genes responsible for recessive forms of nephrotic syndrome were negative. In the years preceding IL2, patients had been unsuccessfully treated with steroids, calcineurin inhibitors, Rituximab and in some cases with plasmapheresis (Table 1). Patients were treated according to the scheme shown Fig 1B. This represents a minimal modification of the original protocol utilized by Saadoun et al.[19] in adults with vasculitis that were treated with a standard dose of IL2 3 x106 not modified for the body surface area. The timing of IL2 infusions and the number of treatments were modified as well in consideration of the chronic nature of nephrotic syndrome unresponsive to drugs. Overall, the cumulative dose utilized in this study was higher than previous reports.

Bottom Line: IL2 was safe in all but one patient who had an acute asthma attack after the first IL2 dose and did not receive further doses.We concluded that low-dose IL2 given in monthly pulses is safe and modifies the levels of circulating Tregs.We were unable to reproduce in humans the effects of IL2 described in rats and mice reducing de facto the interest on this drug in nephrotic syndrome.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Dialysis, Transplantation and Laboratory on Physiopathology of Uremia, Giannina Gaslini Children Hospital, Genoa, Italy.

ABSTRACT

Unlabelled: Tregs infusion reverts proteinuria and reduces renal lesions in most animal models of nephrotic syndrome (i.e. Buffalo/Mna, Adriamycin, Promycin, LPS). IL2 up-regulates Tregs and may be an alternative to cell-therapy in this setting. To evaluate a potential role of IL2 as Tregs inducer and proteinuria lowering agent in human nephrotic syndrome we treated 5 nephrotic patients with 6 monthly cycles of low-dose IL2 (1x106 U/m2 first month, 1.5x106 U/m2 following months). The study cohort consisted of 5 children (all boys, 11–17 years) resistant to all the available treatments (i.e. steroids, calcineurin inhibitors, mycophenolate, Rituximab). Participants had Focal Segmental Glomerulosclerosis (3 cases) or Minimal Change Nephropathy (2 cases). IL2 was safe in all but one patient who had an acute asthma attack after the first IL2 dose and did not receive further doses. Circulating Tregs were stably increased (>10%) during the whole study period in 2 cases while were only partially modified in the other two children who started with very low levels and partially responded to single IL2 Proteinuria and renal function were not modified by IL2 at any phase of the study. We concluded that low-dose IL2 given in monthly pulses is safe and modifies the levels of circulating Tregs. This drug may not be able to lower proteinuria or affect renal function in children with idiopathic nephrotic syndrome. We were unable to reproduce in humans the effects of IL2 described in rats and mice reducing de facto the interest on this drug in nephrotic syndrome.

Trial registration: ClinicalTrials.gov NCT02455908.

No MeSH data available.


Related in: MedlinePlus