Abstract: PUB255
Repurposing Loop Diuretics in Sickle Cell Nephropathy: A Hypothetical Framework for Renoprotection
Session Information
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Sweis, Jaleel Jerry, Southern Illinois University System, Carbondale, Illinois, United States
- Sweis, Nabil William, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Zayed, Ayman, The University of Jordan, Amman, Amman Governorate, Jordan
Background
Sickle cell nephropathy (SCN) is a significant cause of morbidity and mortality in patients with sickle cell disease. The hypertonic, hypoxic and acidic environment of the renal medulla is central to the pathogenesis of SCN as it promotes red blood cell (RBC) dehydration and deoxygenation with resultant sickling and microvascular occlusion. This hypoxic and hypertonic environment can theoretically be targeted by loop diuretics.
Methods
A hypothetical mechanistic framework for the potential utility of loop diuretics for SCN is presented alongside the challenges.
Results
Inhibition of Na+/K+/2Cl− transport by loop diuretics reduces solute accumulation in the renal medulla, diminishing the osmotic gradient that promotes erythrocyte dehydration (Fig 1A). Reduced transport by the furosemide-sensitive ATP-driven pumps may additionally lower ATP consumption, and hence O2 utilization, improving medullary O2 tension, limiting hemoglobin deoxygenation and sickling. Evidence in animals also shows that diuresis may decrease sickling in vasa recta. Together, these effects could decrease ischemic injury and slow SCN progression (Fig 1B). Limitations include volume depletion and hemoconcentration, emphasizing the importance of dosing strategy and hydration status.
Conclusion
We hypothesize that early and long-term loop diuretic therapy, with appropriate hydration and dosing, may afford reno-protective benefits and delay development of SCN. Although loop diuretics are feared as a precipitant of sickling crises due to volume depletion, weighing the benefit derived from the hypothetical mechanisms proposed here against any harm secondary to the preventable risk of volume depletion is warranted. Experimental and clinical studies are needed.
Fig 1. Mechanistic framework for hypothetical reno-protective mechanisms of loop diuretics for sickle cell nephropathy.