Chronic kidney disease (CKD) is defined as a progressive loss of renal function that lasts for more than 3 months, and is classified according to the degree of kidney damage – measured by the level of proteinuria – and the decline in glomerular filtration rate. Chronic kidney disease (CKD) is a lethal and rapidly increasing burden on society. Despite this, there are relatively few therapies in development for the treatment of CKD. Several recent costly phase 3 trials have failed to provide improved renal outcomes, diminishing interest in pharmaceutical investment. Furthermore, poor patient, physician, and payer awareness of CKD as a diagnosis has contributed to slow trial enrollment and successful implementation of these trials. Nevertheless, several therapeutics remain in development for the treatment of CKD, including mineralocorticoid-receptor antagonists, sodium/glucose cotransporter 2 inhibitors, anti-inflammatory drugs, and drugs that mitigate oxidative injury. Success of future CKD therapeutic trials will depend not only on improved understanding of disease pathogenesis, but also on improved trial enrollment rates, through increasing awareness of this disease by the public, policy makers, and the greater medical community. When the kidneys don’t work well, wastes and extra water build up in the body and may cause other health problems, including heart disease and high blood pressure. However, people with CKD and people at risk for CKD can take steps to protect their kidneys. The most severe form is end-stage renal disease. Adverse drug reactions commonly occur among patients with moderate to advanced chronic kidney disease (CKD), and these are often serious and may be preventable.
Renal and urinary disorders were the most frequent AEs, particularly acute kidney injury (AKI), followed by gastrointestinal, musculoskeletal, and connective tissue disorders. Renal disorders and hemorrhages or bleeding accounted for two-thirds of serious reactions. Kidney failure is among the deadliest and economically costly diseases faced by patients and modern society. More than 100,000 new patients in the United States start on dialysis each year while approximately the same number die each year. More than 20% of patients starting dialysis are dead within the first year2 and more than 70% of diabetic patients starting dialysis are dead within 5 years,3 making the prognosis of end-stage renal disease (ESRD) worse than most cancers
Patients with an eGFR of less than 30 mL/min/1.73 m2 were 56% more likely to experience any AE events and 82% more likely to experience serious AEs compared with patients who had higher eGFR values. In addition, patients prescribed more than 10 drugs had a significant 1.6 and 2.1-fold greater risk of any and serious AEs, respectively, in adjusted analyses compared with patients prescribed fewer than 5 drugs. By comparison, patients with poor medication adherence had an approximately 1.4- and 1.6-fold greater risk of any and serious AEs, respectively, compared with those who had good medication adherence.
Today, angiotensin-converting enzyme inhibitors (ACEis) or angiotensin-receptor blockers (ARBs) comprise the standard of care for treatment of diabetic nephropathy as well as many other forms of CKD. ACEi/ARB therapy not only reduces proteinuria (and albuminuria), but decreases the yearly number of diabetic patients going on to require dialysis. This renoprotective effect has been attributed to the capacity of this class of drugs to normalize glomerular hyperfiltration in the diabetic kidney. Reduced hyperfiltration is consistent with the clinical observation that introduction of ACEi/ARB therapy is associated with an acute decrease in estimated glomerular filtration rate (eGFR) and the fact that greater eGFR reductions were associated with less long-term loss of renal function. With the lack of clinically validated targets beyond the renin-angiotensin system, identification of new targets for CKD and diabetic nephropathy is critical for the development of novel therapeutics.
It is unclear whether beneficial renal outcomes from a therapeutic can be separated from the earlier-noted triad of blood pressure reduction, and acute reduction in eGFR and albuminuria. The preceding effects routinely are accompanied by a reduction in proteinuria (or albuminuria). Several therapeutics that do not acutely reduce eGFR or proteinuria have been tested clinically, but none of these have translated successfully into improved renal outcomes. In addition to immune glomerulonephritides, complement activation has been proposed to contribute to the pathogenesis of diabetic nephropathy, possibly through glucose-associated production of neoepitopes activating the lectin complement pathway.
Neither the medical community at large, nor society in general, seem prepared to deal with these events. New therapeutics offer the hope of staving off this unwelcome reality, however, their development will require more sophisticated scientific understanding of disease heterogeneity, better biomarkers predictive of disease progression, improved patient awareness, and streamlined patient enrollment to ensure success. Through concerted efforts on these fronts, the renal community will play a central role to help limit renal death.