Preserving Kidney Function Instead of Replacing It

For the past 50 years, public and private funding priorities in the field of nephrology focused on kidney replacement therapy for ESKD: dialysis and transplantation. This focus was appropriate in a world where there were very few effective therapies to save lives or halt progressive loss of kidney function for the majority of CKDs. The time has come to change that paradigm as new strategies have emerged to prevent CKD progression and cardiovascular events in patients with CKD and diabetes.

Until the latter half of the 20th century, the emerging discipline of nephrology examined the function of normal kidneys, the interaction of the kidneys with other vital organs, the kidneys’ role in multisystem dysfunction, and the physiology and pathophysiology of the many diseases affecting kidney function. In that era, physicians and scientists drawn to nephrology worked hard to preserve kidney function because there was no effective treatment for patients who developed irreversible kidney failure, and death was inevitable. Once it was shown that dialysis could remove uremic toxins and perform as an artificial kidney, attention turned to creating ways to preserve life once the kidneys failed. It was quickly shown that this technology could significantly extend the life of patients with ESKD and, in 1972, Congress passed the Social Security Amendments that provided Medicare coverage for virtually all Americans of any age who had ESKD (1). This public policy was the first and only to underwrite the care of a chronic disease for patients of any age. Currently, Medicare spends $35 billion annually for ESKD care (2). This public funding spawned the large dialysis industry and shaped the way we think about and treat kidney diseases.

The prevalence of CKDs in the general population is approximately 15%. More than two thirds of those with CKDs or ESKD also have concurrent diabetes and/or cardiovascular disease (3). A system to classify the severity of CKDs was introduced in 2002. This helped quantify the burden of disease and anticipate ESKD, but a frequent unintended consequence was to focus on disease progression, rather than its underlying cause. In an era when research shed little light on treatments to ameliorate or stop progression of CKD to ESKD, public policy focused on treating kidney failure was appropriate. Although the mortality rate of CKD in diabetes is nearly 20% per year once kidney function begins to decline (4,5), research on ways to prevent CKD or slow its progression lagged behind similar research in other disciplines. Perhaps the wide availability of dialysis and underappreciation of the fatality risk contributed to the dearth of clinical studies. In other fields, where the risk of death and the unavailability of end stage disease treatment were apparent, a combination of activist pressure and federal government action accelerated research efforts that led to the rapid development of effective treatments.

Perhaps the best example is the response to HIV/AIDS. During the first years of the AIDS epidemic, federal government responses were lackluster and conflicted. But eventually, largely due to the pressure of activists and a number of congressional supporters, legislation was passed to markedly enhance research into the etiology and treatment of AIDS and to underwrite the delivery of effective treatments to a largely marginalized AIDS population. Critical among these efforts was the expansion of AIDS research funding from <0.1% of the National Institutes of Health (NIH) budget in fiscal year 1982 to 9.8% of the NIH budget in fiscal year 1990 (6).

In addition, the Health Resources and Services Administration’s Ryan White HIV/AIDS Program, enacted in 1990, provided “a comprehensive system of HIV primary medical care, essential support services, and medications for low-income people living with HIV who [were] uninsured and underserved. The Program funded grants to states, cities/counties, and local community-based organizations to provide care and treatment services to people living with HIV to improve health outcomes and reduce HIV transmission among hard-to-reach populations” (7). In addition, the Minority AIDS Initiative, passed in 1999 by Congress under the Ryan White Program, provided a new set of appropriations to improve access to HIV care and health outcomes for disproportionately affected minority populations, such as black people. As a result of all of these initiatives, by the end of the 1990s highly active antiretroviral therapy was widely disseminated and the number of new AIDS cases and deaths from HIV/AIDS plummeted. Importantly, federal funding for research, medical care, and community delivery of HIV/AIDS programs has continued now for >20 years.

Fortunately, times are also changing for patients living with CKD. Recently published studies have shown clear evidence that new treatments for diabetes can slow or stop CKD progression and, importantly, reduce cardiovascular events, death, and the need for dialysis. Will public policy keep up with this dramatic innovation, and support earlier recognition and treatment of CKD?

Diabetes is the single largest cause of CKD, in 2016 it accounted for about half of the 511,000 patients receiving dialysis in the US (8). Treatments that stop or delay progression of CKD in diabetes will have a major effect on clinical outcomes and will reduce, by billions of dollars, the cost of CKD and ESKD care. Although dietary interventions may slow CKD progression somewhat, until recently angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) were the only drugs shown to reduce progression of CKD in diabetes, and their effect was modest. Randomized controlled studies of newer classes of medications, such as the sodium-glucose transport protein-2 (SGLT2) inhibitors, have demonstrated great potential to surpass the benefits of ACE inhibitors and ARBS (9). Moreover, a new era is dawning to tailor care to individual patient characteristics, including personal values and preferences, with a menu of other emerging agents including glucagon-like peptide 1 receptor agonists, endothelin A receptor blockade, and anti-inflammatory agents. It will be essential to understand when, and if, combinations of agents from different classes should be applied. Whether patients with CKD who are not diabetic will receive similar benefits, particularly for conditions thought to share biologic mechanisms such as hypertension- or obesity-related CKD, will also be determined soon.

It is time for nephrology to embrace a change in paradigm: returning to our traditional focus on pathophysiology and kidney preservation. While kidney replacement therapies will not disappear, the exciting opportunity to use SGLT2 inhibitors and other agents alone or in combination have the potential to eliminate the need for dialysis and transplantation for thousands of patients each year. This change in focus will require patient and caregiver education, an infrastructure to identify candidates for this therapy, and public policy to incentivize and underwrite the delivery of these therapies. Can this be done quickly? When ACE inhibitors and ARBs were shown to reduce progression of CKD in diabetes, the uptake of these treatments was remarkably slow. For example, although evidence-based clinical practice guidelines recommended use of ACE inhibitors or ARBs for patients with diabetic and CKD in 2006, and again in 2012, a study of 31,000 health-plan members given these recommendations in 2015 showed acceptance by only 14.5% of these patients (10). We will need strategies to increase use of drugs to preserve kidney function like SGLT2 inhibitors.

Efforts to intervene earlier in CKD to prevent ESKD will be facilitated as payment models move from fee-for-service to population health. Early identification of high-CKD-risk populations, including patients with diabetes and CKD, will help these individuals implement lifestyle modifications and adopt preventative medication regimens. However, to make this a reality, there needs to be support for multidisciplinary teams and community health interventions critical to operationalize these changes. Effective medications must be available and affordable for all who need them. The HIV/AIDS model showed that expansion of research funding coupled with federal support for advocacy and dissemination of effective therapy to all, including historically marginalized populations, can convert a rapidly fatal disease to a treatable one that allows patients to live virtually normal lives without symptoms. One can only wonder what the CKD landscape would look like today had similar federal support been forthcoming for prevention of CKD progression.

These changes will require significant effort, including involvement of the nephrology team, other health care providers, public health officials, legislators, regulators, and—critically—patients and their advocates. Nephrologists and our primary care colleagues can start by understanding the benefits and risks of these new therapies, developing better ways to identify appropriate candidates for these therapies, and taking a proactive role in initiating their use. At the same time, clinicians can develop robust clinical research consortia, working together to enroll patients in clinical trials to determine how use of different regimens provide benefit. Such participatory research consortia have already been proven to accelerate knowledge and improve care in oncology. Providers, patients, and advocates need to press public health officials, legislators, and regulators to devote adequate resources to education and to ensure these therapies are available to underserved patients with CKD.

SGLT2 inhibitors and other emerging agents offer new hope to preserve kidney function and save lives. Translating these exciting opportunities to the start of a new era in nephrology will require a radical, upstream shift of focus from kidney replacement treatments to kidney preservation. Effective public policy to promote patient identification, underwrite an effective care infrastructure, and pay for these medications will be a critical component for success.

Disclosures

Dr. Brosius reports receiving fees from the American Diabetes Association through his position of associate editor with the journal Diabetes. Dr. Brosius also reports that the University of Michigan has an agreement with Gilead Pharmaceuticals that permits him to serve as an unpaid consultant for Gilead and that he has no financial relationship with Gilead. Dr. Kliger reports receiving personal fees from the ASN for chairing Nephrologists Transforming Dialysis Safety and from the National Institute of Diabetes and Digestive and Kidney Diseases for chairing the Hemodialysis Novel Therapies Consortium.