New and Emerging Nonimmunosuppressive Drug Therapies for Primary Adult Glomerular Diseases

Primary adult glomerular diseases (GDs), including immunoglobulin A nephropathy, membranous nephropathy, and focal segmental glomerulosclerosis, are important causes of chronic kidney disease and may progress to kidney failure. Nonimmunosuppressive foundation drug therapy for primary adult GD focuses on renin-angiotensin-aldosterone system inhibition to reduce proteinuria, alleviate hypertension, and reduce the risk of kidney disease progression. Additional agents with a distinct mechanism of action may be added or substituted in patients with a high progression risk or who are intolerant to renin-angiotensin-aldosterone system inhibitors. This review highlights the role of lifestyle optimization as well as summarizing the currently nonimmunosuppressive pharmacologic treatment options, for the management of primary adult GDs. We also provide an overview of the key pathophysiologic processes contributing to disease progression. Given the safety concerns associated with immunosuppressive therapies, we discuss the future role of newer nonimmunosuppressive agents including finerenone (a nonsteroidal mineralocorticoid receptor antagonist), sparsentan (a dual endothelin-angiotensin II receptor antagonist), atrasentan (an endothelin receptor antagonist), and iptacopan (complement inhibitor), which are currently Food and Drug Administration approved or are under investigation in clinical trials for primary GDs. These and other agents may expand the currently limited treatment landscape for patients with primary adult GD. Plain-Language Summary Each kidney contains about 1 million tiny functional units called nephrons, and each nephron has a filter called a glomerulus. The glomeruli filter waste products and remove excess fluids from the blood, which exit the body through urine. When the glomeruli are damaged, there is loss of protein through the urine. This can result in a condition called glomerular disease (GD). Treatments for GD include eating a diet that is low in sodium, potassium, and protein because eating these in excess can make GD worse. People with GD may also be advised to exercise, stop smoking, and aim for an ideal target weight. Drug medicines are also an important part of treatment for GD. A type of drug called a renin-angiotensin-aldosterone system (RAAS) inhibitor helps to reduce the amount of damage to the glomeruli and also helps to reduce blood pressure in people who also have high blood pressure (called hypertension). If a person is taking a RAAS inhibitor drug (or an appropriate alternative) but their GD does not improve, then they are at a high risk of kidney disease progression. In this scenario, the person will be offered an additional drug (to take alongside their RAAS inhibitor drug) or an alternative drug that targets their GD in a different way. Some of these work by inhibiting parts of the immune system (called immunosuppressive drugs), whereas others do not do this (called nonimmunosuppressive drugs). Our review focuses on nonimmunosuppressive drugs for GD. We consider nonimmunosuppressive drugs already available for treating GD, ones that have only recently been made available, and drugs that are being tested in large clinical trials involving people with GD.