Review Highlights Therapeutic Efforts to Delay CKD Progression

Improved understanding of the early mechanisms of chronic kidney disease (CKD) is the next research step in efforts to delay or even reverse disease progression, according to a newly published review of therapeutic options.

Clinicians have a considerable toolbox to delay CKD progression, including renin-angiotensin aldosterone (RAS) blockage, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and bicarbonate therapy. New drugs targeting fibrosis and inflammation as well as regenerative therapy may be the next areas to bear fruit in treating the disease, according to an article published in Frontiers in Medicine.

CKD, with diabetes possibly accounting for more than half the disease burden and obesity its leading cause, is recognized as a leading public health problem. The global estimated prevalence of CKD is 13.4%; there were 1.2 million deaths in 2017. The high cardiovascular risk that CKD carries, and the risk of end stage kidney disease (ESKD) make further advances critical to lowering those numbers.

Most clinical trials focus on limiting glomerular hyperfiltration, the authors wrote, but other factors such as cell loss, chronic inflammation, and fibrosis are known to contribute to CKD as well.

“Therefore only a more holistic approach targeting all of these factors will likely achieve a more complete response and better kidney outcomes, aiming not only to delay kidney progression but also to reverse CKD,” wrote the authors, who come from Hospital Universitario Fundación Alcorcón in Madrid.

Pirfenidone (Esbriet), an antifibrotic agent, is a novel therapy under evaluation for targeting fibrosis, according to the review. Trial results suggest that the drug can slow progression of kidney disease, but without reducing proteinuria. Pentoxifylline (Trental) is being studied for its inflammatory modulation and antioxidative stress. Studies have indicated a reduction in proteinuria when added to RAS blockade.

Efforts to predict early CKD progression have proven frustrating so far due to a lack of biomarkers, the authors said. Studies are identifying potential biomarkers and therapeutic targets by using micro-RNA analysis, proteomics, peptidomics, and urinary transcripomics.

Animal studies indicate that the possibility of reversing interstitial fibrosis, the article said. The concept of kidney regeneration centers around using growth factors or directing multipotent cells to regenerate kidneys with chronic lesions. Stem cell studies also are being conducted.

RAS blockade with angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) continues as a cornerstone therapy to reduce proteinuria, CKD progression, and cardiovascular risk, the authors said. There is increasing evidence that doses higher than the maximum used for high blood pressure may provide additional protection for renal function; a study of candesartan (Atecand) achieved a 33% additional reduction in proteinuria.

The goal should be the maximum well-tolerated RAS blockade dose, regarding of whether by using ARB, ACEi, or both, the authors said. It is not known if the benefits from RAS inhibitors in proteinuric CKD extends to elderly patients because they are underrepresented in clinical trials.

Spironolactone and the more selective aldosterone antagonist eplerenone have shown substantial benefit for high blood pressure, cardioprotection, and antiproteinuric effects even at low doses and during combined ACEi-ARB therapy. The drugs have not been used in high-risk CKD patents due to risk of high potassium levels. Finerenone is a more selective nonsteroidal mineralcorticoid receptor antagonist that reduced albuminuria in several short-term clinical trials and may prove more effective than the other two agents, the authors said.

SGLT2 inhibitors have been highly effective in reducing cardiovascular risk among patients with type 2 diabetes and have performed well for protecting kidney and heart function, the review said.

Oral bicarbonate has shown high potential in delaying CKD progress. Patients receiving sodium bicarbonate had a 64% risk of creatinine doubling, a 50% lower risk of having to start dialysis, and a reduction of 57% in all-cause mortality, the authors said.

Reference

Shabaka A, Cases-Corona C, Fernandez-Juarez G. Therapeutic insights in chronic kidney disease progression. Front. Med. Published online February 23, 2021. doi:10.3389/fmed.2021.64518