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Therapeutic role of sirolimus in non-transplant kidney disease
Gopala K Rangan1, Tina Nguyen, Rahul Mainra
1Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead Hospital, Sydney, Australia. g.rangan@wmi.usyd.edu.au
Abstract:
Sirolimus is a member of a novel class of immunosuppressant drug that potently suppresses T cell proliferation and expansion by inhibition of the Target of Rapamycin Complex 1 (TORC1) protein kinase. Sirolimus also has anti-proliferative effects on intrinsic cells of the kidney, and increasing evidence suggests that it may have a therapeutic role in non-transplant renal diseases. In the normal kidney, sirolimus is considered to be non-nephrotoxic. In the diseased kidney, sirolimus may be beneficial or detrimental, depending on the type of renal injury. In polycystic kidney disease, TORC1 activation mediates renal tubular epithelial cell (TEC) proliferation and cyst growth in animals, and Phase III clinical trials are underway to determine the effect of sirolimus in attenuating disease progression in humans. In contrast, in acute kidney injury, sirolimus transiently impairs proximal TEC regeneration and delays renal recovery. In animal models of lupus nephritis and diabetic kidney disease, sirolimus prevents disease progression. However, the efficacy of sirolimus in human glomerulonephritis as well as in diabetic chronic kidney disease remains unclear, as it paradoxically exacerbates renal dysfunction when the baseline glomerular filtration rate is low (< 40 ml/min/1.73 m(2)) and there is heavy proteinuria (> 300 mg/day). This may, in part, be due to inhibition of compensatory glomerular capillary repair through the suppression of endothelial cell proliferation and angiogenic growth factor production by podocytes. Therefore, at present, polycystic kidney disease is the most promising therapeutic application for sirolimus in non-transplant renal diseases, and further studies are needed to clarify its role in other situations.
Insights
Sirolimus, an immunosuppressant, shows promise for treating polycystic kidney disease by inhibiting cell proliferation. However, its use in other kidney diseases is complex, potentially harming recovery in acute kidney injury and worsening dysfunction in severe chronic conditions.
Area of Science:
- Nephrology
- Pharmacology
- Immunosuppression
Background:
- Sirolimus inhibits Target of Rapamycin Complex 1 (TORC1), suppressing T cell proliferation.
- Sirolimus exhibits anti-proliferative effects on intrinsic kidney cells, suggesting therapeutic potential in non-transplant renal diseases.
- While generally non-nephrotoxic in healthy kidneys, sirolimus's impact varies in diseased kidneys.
Purpose of the Study:
- To evaluate the therapeutic role of sirolimus in various non-transplant renal diseases.
- To understand the mechanisms underlying sirolimus's beneficial or detrimental effects in different kidney injury models.
- To identify the most promising applications for sirolimus in non-transplant renal disease management.
Main Methods:
- Review of existing evidence on sirolimus's effects in animal models and human clinical trials for renal diseases.
- Analysis of TORC1 pathway activation in polycystic kidney disease and its modulation by sirolimus.
- Assessment of sirolimus's impact on tubular epithelial cell regeneration in acute kidney injury.
- Examination of sirolimus's efficacy in lupus nephritis and diabetic kidney disease models.
- Investigation of sirolimus's paradoxical effects in glomerulonephritis and chronic kidney disease with low GFR and proteinuria.
Main Results:
- Sirolimus targets TORC1, a key mediator of renal tubular epithelial cell proliferation and cyst growth in polycystic kidney disease.
- Clinical trials are ongoing to assess sirolimus's efficacy in slowing polycystic kidney disease progression.
- Sirolimus impairs proximal tubular epithelial cell regeneration and delays recovery in acute kidney injury models.
- Sirolimus has shown promise in preventing disease progression in animal models of lupus nephritis and diabetic kidney disease.
- Sirolimus can paradoxically worsen renal dysfunction in human glomerulonephritis and diabetic chronic kidney disease when GFR is low and proteinuria is high, possibly by inhibiting repair mechanisms.
Conclusions:
- Polycystic kidney disease represents the most promising therapeutic application for sirolimus among non-transplant renal diseases.
- Further research is required to elucidate the precise role and safety of sirolimus in other renal conditions, particularly those with significant proteinuria and reduced GFR.
- Sirolimus's complex effects necessitate careful patient selection and monitoring in non-transplant renal disease settings.
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