An Apple a Day Keeps Dialysis Away

Kidney transplantation is the preferred treatment for kidney failure and improves both quality of life and mortality. There is a growing discrepancy between eligible recipients on the waiting list and the number of suitable donor kidneys. In the United States, the average waiting list time is about 4 years, and every year, about 5% of potential recipients die while waiting for a kidney transplant. Unfortunately, an increased number of kidney transplant recipients develop graft failure and return to dialysis (1). In patients who return to dialysis, they suffer from lower quality of life and higher mortality rates (1). Kidney graft loss also exacerbates the discrepancy between supply and demand, and it is thus imperative that each kidney transplant graft is as healthy as possible for as long as possible. Studies identifying modifiable factors that improve the health and longevity of kidney transplant grafts are warranted and are important to reduce the morbidity, mortality, and high health care costs associated with kidney graft loss.

A potential modifiable factor affecting kidney transplant graft health is the role of acid load, which has been well studied in CKD. Patients with CKD and decreased GFR have decreased capacity to eliminate the daily hydrogen load, which leads to chronic metabolic acidosis. Chronic metabolic acidosis in patients with CKD leads to a slew of adverse effects, including growth delay in children, exacerbation of bone disease and cardiovascular disease, worse inflammation, and an acceleration of progressive kidney disease (2).

Metabolic acidosis is also highly prevalent in kidney transplant recipients, with prevalence ranging from 12% to 58% (3). Lower serum bicarbonate levels (<22 mEq/L) are associated with a higher risk of graft loss and death-censored graft failure in kidney transplant recipients (3). The underlying mechanisms by which metabolic acidosis occurs in kidney transplant recipients are not well understood but may involve several mechanisms including a decrease in GFR, leading to decreased capacity to synthesize ammonia and excrete acid, and use of calcineurin inhibitors, leading to renal tubular acidosis. The effect of donor factors, such as donor age, donor kidney function, and type of transplant, and recipient factors, such as diet, on metabolic acidosis in kidney transplant recipients is still unclear. The mechanisms causing kidney disease progression and higher likelihood of graft loss are currently unknown but postulated to be due to alternative complement pathway activation, precipitation of calcium within the kidney, and/or increased endothelin production that mediates tubulointerstitium injury (2).

Diet contributes significantly to the net acid load. Patients with CKD who are treated with dietary modifications to reduce acid load (i.e., increased fruit and vegetable intake) have improved metabolic acidosis and delayed progression of their kidney disease (4). In fact, increasing fruits and vegetables improves metabolic acidosis and kidney injury to a similar degree as oral sodium bicarbonate supplementation (4). This leads to two questions: (1) Do kidney transplant recipients with high dietary acid load have a higher likelihood of progression to graft failure? (2) What intervenable factors could mitigate this progression to graft failure? These two questions are imperative to answer to potentially improve the health and life span of kidney grafts.

In this issue of CJASN, Yeung et al. (5) aim to answer this knowledge gap in their article “Net Endogenous Acid Excretion and Kidney Allograft Outcomes.” Yeung et al. (5) performed a prospective, observational, longitudinal study encompassing a moderately large cohort of >600 kidney transplant recipients at least 1 year post-transplant to examine the association between dietary acid load and risk of kidney function decline or graft failure. Dietary acid load was expressed as net endogenous acid production (NEAP). Food frequency questionnaires (FFQs) and 24-hour urine collections were used to estimate NEAP. The composite kidney end point was either graft failure (defined as return to dialysis or retransplantation) or doubling of plasma creatinine. Yeung et al. (5) followed these patients for a median time of over 5 years, during which almost 20% reached the kidney end point.

Kidney transplant recipient median NEAP_FFQ and NEAP_urine (40 [35–45] and 54 [44–66] mEq/d, respectively) values were similar to those of the general population in The Netherlands, where the study was conducted. However, higher NEAP_FFQ and NEAP_urine (per SD higher) were independently associated with higher risk of the composite kidney end point and were mediated by venous HCO₃ ⁻ levels. In other words, higher dietary acid load leading to metabolic acidosis may lead to progression of kidney transplant graft loss. Additionally, urine ammonium excretion was inversely associated with the composite kidney end point. Some observational studies in CKD have also found that higher urinary ammonium excretion is associated with a lower risk of kidney outcomes (6). These are intriguing results and suggest that dietary acid load is associated with kidney outcomes in kidney transplant recipients.

Similar to findings in patients with CKD, kidney transplant recipients with the highest NEAP had the lowest intake of fruits, vegetables, and potassium and the highest intake of animal protein and sodium on the basis of the FFQ. Fruits and vegetables are metabolized into HCO₃ ⁻ and may therefore act in a similar manner to supplementation with oral sodium bicarbonate to protect kidney function. High potassium intake has been associated with improved kidney outcomes in kidney transplant recipients (7). Thus, increasing fruit and vegetable intake in kidney transplant recipients may improve graft function. Currently, our nutritional guidelines for patients after kidney transplant only include general food hygiene and recommend low salt intake. This study provides some evidence to optimize nutritional counseling for patients: increase fruits and vegetables, decrease animal-based protein, decrease sodium intake, and increase potassium intake. It should be noted that diets high in fruits and vegetables have not been associated with significant hyperkalemia in patients with advanced CKD (stage 4) and, thus, should be able to be safely implemented in kidney transplant recipients. However, if nutritional guidance for kidney transplant recipients changes, food insecurity must also be addressed. Food insecurity is associated with greater odds of CKD, and people with food insecurity are more likely to be overweight/obese due to limited intake of fruits and vegetables and increased intake of energy-dense foods (8). The lack of dietary intake of fruits and vegetables may mediate this association by increasing NEAP in patients with kidney disease. As kidney professionals, we must advocate for equitable access to nutrient-rich foods, which may improve CKD progression and graft failure in our kidney transplant recipients.

Overall, this study adds to the evidence showing the association between higher dietary acid load and kidney disease progression. Metabolic acidosis hastens the decline of kidney function in both kidney transplant recipients and patients with CKD. It should be noted that the median time from kidney transplantation was 5.5 (1.8–12.1) years in this study. Whether higher dietary acid load earlier postkidney transplantation is associated with graft dysfunction remains unknown. Nonetheless, this study should guide research to determine whether dietary modifications may be a simple, effective way to improve long-term graft function. Currently, there are no interventional trials examining the effect of increasing fruits and vegetables on outcomes in kidney transplant recipients. However, there are studies examining the effect of sodium bicarbonate supplementation. A recent pilot, randomized, double-blinded, placebo-controlled, crossover study showed that sodium bicarbonate supplementation in 20 kidney transplant recipients was safe, was feasible, and trended toward improved vascular health (9). There is currently a large randomized controlled trial examining the effect of sodium bicarbonate supplementation versus placebo on kidney outcomes (NCT03102996) in kidney transplant recipients (10). Results from this study should be available in the next year.

Together, the data support the need for prospective, randomized trials evaluating the effect of lowering dietary acid load on kidney outcomes in patients with kidney transplants. Dietary-based approaches may have more favorable effects on BP due to less sodium load than supplement-based approaches. Studies with hard outcomes are needed to determine the benefits and risks of food-based approaches to reduce dietary acid load in kidney transplant recipients.

Disclosures

J. Kendrick reports receiving research funding from Fresenius Medical Care Renal Therapies Group and serving as a scientific advisor or member of the Amgen Medical Advisory Board, the AstraZenica Medical Advisory Committee, the Tricida Medical Advisory Board, and the Velphoro Medical Advisory Board. The remaining author has nothing to disclose.

Funding

Support for this study was provided by National Institutes of Health, National Heart, Lung, and Blood Institute grant R01HL132868 (to J. Kendrick).