Back to the Future 2020−2021 The Nephrology Fellows Edition

COVID-19

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections have led to high rates of acute kidney injury (AKI; up to 60% of patients in ICU) (1). Moreover, patients with chronic kidney disease (CKD) or end-stage kidney disease (ESKD) and kidney transplant recipients are more vulnerable to COVID-19 and its associated complications. The surge of new patients requiring kidney replacement therapy (KRT) has led to inpatient shortages of staffing, hemodialysis (HD) machines, and dialysis fluid, whereas outpatient HD centers have had to grapple with strategies for infection control among vulnerable patients with routine exposure to healthcare settings. These challenges have been driving factors to increase the use of acute peritoneal dialysis (PD) and hybrid therapies, such as prolonged intermittent KRT (PIKRT), and to develop innovative protocols, such as the generation of on-site continuous renal replacement therapy (CRRT) fluid (2). Nephrologists have also led investigative conversations, as we look to answer if angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) increase or decrease the risk or clinical course of COVID-19 and to solve the conundrum of if the virus does actually “infect” the kidney.

SGLT2 inhibitors

Any article recapping 2020 without mentioning sodium glucose cotransporter-2 inhibitors (SGLT2i) would be incomplete. Nephrology has waited about two decades for an upgrade in the armamentarium to slow the progression of CKD. Canagliflozin started the revolution when it was featured in Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), which focused primarily on kidney outcomes in patients with type 2 diabetes, as opposed to prior studies centered on cardiovascular outcomes. The relative risk of the kidney-specific composite was lower by 34% with canagliflozin (3). SGLT- 2i did not stop there and in 2020, made their march toward non-diabetic kidney disease (non-DKD) with Dapagliflozin in CKD (DAPA-CKD). Even including patients without diabetes, dapagliflozin demonstrated a more than 40% reduction in a sustained decline in the estimated glomerular filtration rate (eGFR) of at least 50%, ESKD, or death from kidney causes (4). There is more to come in 2021, as we will discuss in the next section. For now, we can go beyond offering ACE inhibitors and ARBs to our patients.

Finerenone

Just when we thought we had enough to rejoice about regarding therapeutics in CKD, finerenone entered the fray. A NephJC commentary put it aptly: “Can finerenone fiddle the forgotten A of the [renin-angiotensin-aldosterone system] RAAS string?” Finerenone, a non-steroidal mineralocorticoid antagonist that is more potent and selective in nature than spironolactone and eplerenone, has previously demonstrated greater protection from kidney and cardiac events, along with improved structural cardiac remodeling in animal studies (5). Mechanistically, it decreases macrophage expression of the pro-fibrotic genes—tumor growth factor-β1 and plasminogen activator inhibitor-1—and increases the expression of anti-fibrotic genes (6). This translated into the success of the Finerenone in Reducing Kidney Failure and Disease Progression in DKD (FIDELIO-DKD) trial, which demonstrated an 18% reduction in primary composite outcome (decrease of at least 40% in the eGFR from baseline or death from kidney causes). One of the primary concerns of hyperkalemia associated with use will remain and hopefully can be further addressed in 2021.

PEXIVAS

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) continued to see advances in 2020. Induction and maintenance regimens have attained a nuanced approach as a result of multiple trials, but optimal use of steroids and plasmapheresis [plasma exchange (PLEX)] still required further nuance in practice (7). PEXIVAS (PLEX and Glucocorticoids for Treatment of AAV) partially solved this quandary by showing non-inferiority with a lower-dose steroid regimen. However, PLEX did not demonstrate benefit with respect to the development of ESKD, but a few caveats need to be discussed:

1. Kidney biopsy was not an entry criterion for the study. Therefore, we cannot truly assess acuity vs. chronicity of disease to ascertain who would benefit from PLEX.

2. A subgroup of patients with non-severe and severe pulmonary hemorrhage did benefit from PLEX, albeit the benefit was not statistically significant. This was likely because relatively few patients with severe pulmonary hemorrhage were enrolled, a population for which many physicians traditionally opt to use PLEX.

Although an argument could be made not to use PLEX in most patients with mild to moderate AAV disease, it may still be prudent to use it with severe disease and/or those with pulmonary hemorrhage. The jury is still out on the latter population and will need more research.

Transplantation

Given that our attention was crowded by so much in 2020, a few good pivotal developments did fly under the radar, especially in the realm of transplantation. Generation of immune tolerance continues to be the Holy Grail in transplantation. Since the discovery of tolerance in 1945 in the freemartin cattle (8), various strategies for tolerance induction have been attempted with no clinically translatable success and frequently associated with graft-versus-host disease (GVHD). In 2020, a phase 1 trial (n = 10) was successful in demonstrating not only safety but also efficacy with the injection of modified immune cells (leukapheresis-derived donor monocytes treated with mitomycin C). These cells developed features of immature dendritic cells and resulted in profound suppression of the T cell response, with ensuing development of durable immune tolerance (9). It remains to be seen how phase 2 trials (n = 200) of this strategy will progress, but one thing is for sure: the search for the Holy Grail could be getting closer.

Race and eGFR

We learned in medical school that there were various creatinine-based formulas used to estimate GFR and that some of them [namely, the Modification of Diet in Renal Disease (MDRD) (10) and CKD-Epidemiology Collaboration (CKD-EPI) (11) equations] included a race coefficient. With the use of this coefficient, Black and White patients with otherwise similar characteristics would receive different eGFR results, with Black patients having up to a 20% higher eGFR.

But if race is a cultural, not scientific, construct, based largely on phenotypic features rather than genetic differences, how can we in the nephrology community base some of our most important equations on it? Furthermore, where does this equation stand in an increasingly multi-racial world, where our patients are diverse and often cannot be placed into a binary “Black or White” category? Is it possible that these equations have been underestimating the severity of kidney disease in our Black patients, thus delaying valuable care and possibly even preventing patients from getting listed on the kidney transplant list? It was only over the past few years that medical students and other trainees from around the country started to ask these questions, forcing us all to think critically about this important issue. This has led to a number of institutions removing the coefficient, in addition to the National Kidney Foundation (NKF) and American Society of Nephrology (ASN) forming a joint task force (12) to address the issue of race in eGFR equations. The task force aims to issue initial recommendations by January 2021, and we look forward to continued discussions both from the task force and within our own institutions from around the country on this critically important topic.

SGLT2I

2020 was an incredibly exciting year for SGLT2i, with the publication of DAPA-CKD in October opening the door for use of this medication class to improve outcomes in patients with CKD and importantly without diabetes (4). We now eagerly await the results of the EMPA-KIDNEY (The Study of Heart and Kidney Protection with Empagliflozin) trial, which will be the largest trial to date to look at the use of SGLT2i in an entirely non-diabetic population of patients with CKD and albuminuria at risk of progression. Importantly, this trial is enrolling patients with eGFR as low as 20 mL/min/1.73 m², which is the lowest eGFR to be included in an SGLT2i trial to date (13). Although the trial is not scheduled to be completed until October 2022, we look forward to seeing what promising results may be presented in 2021. Furthermore, we are excited to incorporate SGLT2i into our clinical practices, providing the most impactful, new therapeutic option to our patients with CKD since RAAS inhibitors.

Finerenone

Because we’re on the topic of novel therapeutics, it seems only appropriate to discuss finerenone, the selective, non-steroidal mineralocorticoid antagonist that resulted in lower risk of DKD progression (albeit with a nearly twofold increase in risk of hyperkalemia) when compared to placebo in adult patients with type 2 diabetes, CKD, and proteinuria in the recently published FIDELIO-DKD trial (14). In February 2021, we expect the completion of the long-awaited Finerenone in Reducing Cardiovascular Mortality and Morbidity in DKD (FIGARO-DKD) trial, also comparing finerenone to placebo in patients with DKD. Having enrolled >7000 participants to date, this multi-center, international trial will be larger than FIDELIO-DKD. Although the trial will look primarily at cardiovascular endpoints, important kidney secondary outcomes will be examined as well (15). We look forward to comparing and contrasting the results of this important trial to FIDELIO-DKD and making evidence-based decisions as to whether we may have yet another valuable medication in our arsenal to delay the progression of DKD.

Home dialysis modalities

As nephrologists, we all recognize the importance of our patients maintaining their quality of life once they have to begin dialysis. Unfortunately, >85% of patients in the United States still initiate dialysis in-center (16), meaning they often have to go on disability, potentially lose their job, and are forced to commute at least thrice weekly for their life-saving therapy. Contrast this to peritoneal dialysis (PD) and home HD, in which patients are trained to safely perform dialysis in the comfort of their own home, allowing for a more normal lifestyle. It is no surprise then that in a 2010 survey on the topic, >90% of nephrologists stated they would choose either home HD or PD as their initial KRT modality while awaiting a transplant (17). Perhaps the only shocking thing is that it took until 2019 and the issuance of an executive order to get the ball rolling in prioritizing home dialysis modalities for our patients and making sure that payment models would reflect the importance of this order (18). Now with the Centers for Medicare & Medicaid Services (CMS) set to begin reimbursing more for Medicare beneficiaries using home modalities in January 2021 (19), we hope to see many more conversations between nephrologists and patients needing to start dialysis, emphasizing the benefits of home modalities and reflecting the reality of what most nephrologists would want for themselves.

COVID-19

How could we finish an “anticipated topics” list without talking about COVID-19? The pandemic has had profound effects in both our personal and professional lives. Conflicting information has come out about the potential interaction between inhibitors of the renin-angiotensin system and whether they may be harmful or helpful in patients with COVID-19 (20). We have seen high rates of AKI among patients with COVID-19 and higher rates of comorbidity and death among those patients (21). Of those patients with AKI and COVID-19 who survived their illness but were discharged from the hospital requiring KRT, it is still unknown how many of these patients will end up developing ESKD. In patients with ESKD who are hospitalized with COVID-19, adjusted rates of in-hospital death and prolonged length of stay are significantly higher than in patients without ESKD (22). Furthermore, adjustments have had to be made to outpatient dialysis facilities, often opening up separate shifts dedicated to patients with COVID-19.

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In addition to the impact of COVID-19 on our patients and clinical practice, nephrology fellows have quickly adapted to changes in academic medicine. Telemedicine has been incorporated in outpatient dialysis rounds, inpatient rounds, clinics, as well as teleconferences held within institutions and internationally. How we interact with our patients as well as our colleagues, mentors, and nephrology community has changed and so too will our clinical practice and academic discourse. Meanwhile, many of us remain on the front lines and face continued fears of infectious exposure or the threat that a community’s medical resources may be overwhelmed during a surge of cases. Needless to say, we are all ready for some glimmer of hope with the recent news of encouraging results in multiple phase III SARS-CoV-2 vaccine trials. In the meantime, we look forward to the ASN COVID-19 Fellows Only Roundtable to be held virtually on January 13, which will give fellows the chance to share our fears, uncertainties, and stressors, as well as anything else we want to discuss surrounding COVID-19, in a safe environment.

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So many important things happened in 2020 in the world of nephrology, and we are excited to see what 2021 will bring us. One thing is for sure: as fellows, we will be intricately involved in many of the things that will shape the future of nephrology. As we begin a new year at Kidney News, we can’t wait to put “fellows first” as we listen to feedback, glean valuable insight, and highlight stories from nephrology trainees around the world.