Review Assesses Current, Emerging Therapies for Kidney Manifestations in SCD

A review published in Kidney 360 outlined emerging therapies and advances in sickle cell disease (SCD) that focus on renal manifestations.

Both albuminuria and chronic kidney disease (CKD) are major predictors of mortality in patients with severe SCD, authors explained, noting that monitoring and management of renal function is crucial to comprehensive care for patients.

“The kidneys are sensitive to chronic hemolysis, anemia, and vaso-occlusion that are hallmarks of SCD, resulting in ‘regional’ dysfunction in the kidney,” they wrote. In addition, because albuminuria persistence predicts the risk of renal disease progression, early detection of albuminuria and initiation of therapy make up the general approach to managing sickle cell nephropathy.

“Before determining that a patient has SCD-related kidney disease, clinicians should exclude other potential causes of non-sickle cell related renal disease in people with SCD,” the researchers added.

Managing SCD-Related Kidney Manifestations

Managing nephropathy in these individuals can be achieved through SCD-directed therapies and/or CKD-directed therapies.

Hydroxyurea is one of the SCD-directed therapeutics in nephropathy. The ribonucleotide reductase inhibitor was approved by the FDA in 1998 and works by increasing expression of fetal hemoglobin, reducing white blood cell and platelet counts, and increasing nitric oxide (NO) levels. Hydroxyurea has also been linked with decreased prevalence and/or improvement of albuminuria, authors wrote, although studies assessing its effects on estimated glomerular filtration rate (eGFR) have yielded conflicting results.

Chronic red blood cell transfusions and L-glutamine mark two other SCD-directed therapies that may help manage nephropathy, in addition to crizanlizumab and voxelotor.

Crizanlizumab is a monoclonal antibody first approved by the FDA in 2019 to reduce vaso-occlusive episodes frequency. Voxelotor was approved that same year with the indication to increase hemoglobin concentration, researchers added.

When it comes to CKD-directed therapeutics in SCD, Angiotensin inhibition with angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers, cumulatively known as renin-angiotensin aldosterone system (RAAS) blockers, have been used in the treatment of sickle nephropathy.

Other treatments include sodium-glucose cotransporter-2 (SGLT-2) inhibitors and mineralocorticoid receptor antagonists (MRA).

SGLT-2 inhibitors dapagliflozin and empagliflozin are able to slow down CKD progression independent of diabetes diagnosis, while canagliflozin has shown similar efficacy in albuminuric nephropathies, authors said.

The selective MRA finerenone was also approved for diabetic kidney disease and “because of its proposed ability to abrogate inflammation and fibrosis, both relevant in SCD nephropathy, some have suggested finerenone may have particular benefit for this disease entity.”

However, these therapies have not yet been investigated in SCD nephropathy and the benefits in this setting remain unclear, researchers cautioned.

Emerging therapies in this setting include endothelin (ET) receptor antagonists and pyruvate kinase activators.

Unique Considerations for Patients With SCD

Several special considerations in the SCD population also ought to be considered, authors said. For example, as iron overload is a complication of chronic or recurrent transfusion therapy, iron chelation is necessary to prevent morbidity. However, the widely used oral chelator deferasirox has been implicated in kidney-specific adverse events. “Therefore deferasirox should be used cautiously and with frequent monitoring of renal function,” authors said.

Non-steroidal anti-inflammatory drugs (NSAIDs) also play a role in SCD-mediated pain management. However, researchers caution these drugs should be used sparingly in the sickle nephropathy setting as “the vasoconstrictive mechanism of NSAIDs can worsen glomerular hyperfiltration and contribute to renal insufficiency.”

Overall, there’s a need for “larger, longer-term, prospective, controlled, and real-world studies to better evaluate the effect of interventions on albuminuria, eGFR, tubular dysfunction, and overall renal health,” the authors concluded.

Reference

Obadina M, Wilson S, Derebail VK, and Little J. Emerging therapies and advances in sickle cell disease with a focus on renal manifestations. Kidney360. doi:10.34067/KID.0000000000000162