Thinking Outside the Box: Novel Kidney Protective Strategies in Kidney Transplantation : Clinical Journal of the American Society of Nephrology

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Kidney Transplantation Long-Term Management Challenges

Thinking Outside the Box: Novel Kidney Protective Strategies in Kidney Transplantation

Ibrahim, Hassan N.1; Murad, Dina N.1; Knoll, Greg A.2

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CJASN 16(12):p 1890-1897, December 2021. | DOI: 10.2215/CJN.15070920
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Avoidance of premature graft failure remains a key goal in the management of kidney transplant recipients. Graft loss is associated with a nearly four-fold higher risk of death compared with those with a functioning graft (1,2). The Standardized Outcomes in Nephrology—Kidney Transplantation group has identified kidney transplant survival as the most important priority for both patients and health care providers (3). Preventing graft loss was the top priority, even over death, as transplant recipients were more concerned with quality rather than quantity of life. Kidney transplant outcomes vary by program and region. Registry data from 1988 to 2014 on over 350,000 kidney transplant recipients from the United States, the United Kingdom, Australia, and New Zealand are instructive (4). Long-term adjusted graft failure risk (conditional on 1‐year function) was significantly higher in the United States compared with Australia, New Zealand, and the United Kingdom. Long‐term kidney graft outcomes were, however, approximately 25% worse in the United States compared with the three other developed nations, perhaps due to major differences in health care delivery systems and extent of immunosuppressive medications coverage. If the reasons behind these inferior outcomes in the United States can be firmly determined, appropriate changes may result in substantial benefits to both patients and the health care system in the United States.

Many strategies have been used with the intended goal of preserving kidney function and prolonging graft survival. These include adjustments in immunosuppression to prevent and treat rejection as well as prevent the development of donor-specific antibody. In addition to these immunologic approaches, nonimmunologic strategies, often explored and used first in the nontransplant setting, remain important options for the management of kidney transplant recipients. In this review, we will focus on nonimmunologic aspects of kidney transplant care that may be overlooked and perhaps overshadowed by the focus on immunosuppression-based interventions.

Hypertension and Allograft Outcome

BP lowering in both the general and CKD populations has been associated with many beneficial effects, including reduction in cardiovascular events and death. Data from the Systolic Blood Pressure Intervention Trial (SPRINT) suggest that even lower BP targets (i.e., <120 mm Hg) may be associated with improved clinical outcomes, even for those with CKD (5). Although the supportive data for BP lowering are more consistent for cardiovascular events and death, there are also beneficial effects of BP lowering on kidney outcomes. In the nontransplant CKD population, a meta-analysis of 11 randomized trials found that more intensive BP lowering was associated with a significant reduction in kidney failure events (defined as either a composite of doubling of serum creatinine level and 50% decline in GFR or kidney failure) (6). In the kidney transplant population, unfortunately, we do not have similar supportive data. There are observational data showing that a lower BP 1 year after transplantation is associated with an improvement in long-term graft survival, but perhaps the best available evidence comes from the Folic Acid for Vascular Outcome Reduction study, which showed a direct graded relation between systolic BP and future risk of cardiovascular disease and all-cause mortality (7,8). Unfortunately, there have been no interventional trials evaluating whether lowering BP, to a specific target, is associated with improvement in any clinically important outcomes, such as allograft survival. Despite the lack of strong evidence from randomized trials in transplant recipients, it seems reasonable to target a BP level similar to other high-risk patients. A target BP of <130/80 mm Hg has been recommended in the Kidney Disease Improving Global Outcomes (KDIGO) guideline on post-transplant management (9). A similar target for kidney transplant recipients was suggested in the 2012 KDIGO clinical practice guideline for the management of BP in CKD as well as in the recently published American College of Cardiology/American Heart Association BP guidelines (10,11). Until further evidence accumulates, a lower “SPRINT-like” target of <120 mm Hg may not be an appropriate goal given the higher risk of AKI and GFR decline seen with more intensive BP control (12,13). These concerns may conceivably be more serious in the setting of lack of robust autoregulation of renal blood flow in the denervated allograft.

Choice of Antihypertensive Agent

Although there is no direct randomized trial–driven evidence to support a certain BP target in kidney transplant recipients, there are data suggesting that calcium channel blockers (CCBs) may be the preferred antihypertensive in this population (14). In a systematic review of 60 trials (n=3802 patients), with 29 trials (n=2262 recipients) comparing CCBs with placebo or no treatment, ten trials involving 445 recipients comparing angiotensin-converting enzyme inhibitors (ACEis) with placebo or no treatment, and seven trials (n=405) comparing ACEis with CCBs, Cross et al. (14) found that CCBs compared with placebo or no treatment were associated with a 25% lower risk of graft loss (relative risk [RR], 0.75; 95% confidence interval [95% CI], 0.57 to 0.99) and an improvement in GFR (mean difference, 4.5 ml/min per 1.73 m2; 95% CI, 2.2 to 6.7). Although this supports the notion that CCBs are the preferred antihypertensive agents in preventing allograft failure, it is worth noting that <900 recipients in these trials received a non-CCB, which possibly limits the robustness of this conclusion.

Renin-Angiotensin-Aldosterone System Blockade in Kidney Transplantation

In the nontransplant setting, ACEis and angiotensin receptor blockers (ARBs) have been shown to prolong kidney survival in patients with proteinuric kidney diseases. In the transplant setting, three relatively contemporary, well-done randomized trials in kidney transplantation have been published (15–17). Collectively, these placebo-controlled trials randomized 867 recipients to candesartan (for 1.7 years), losartan (for 5 years), or ramipril (for 4 years). None of these trials demonstrated a favorable effect on all-cause mortality, graft failure, or the conventional end point of creatinine doubling. Furthermore, in a systematic review of eight randomized trials (n=1502 patients) examining ACEi or ARB use in the kidney transplant population, Hiremath et al. (18) found no beneficial effect on kidney transplant loss (RR, 0.76; 95% CI, 0.49 to 1.18) or doubling of serum creatinine (RR, 0.84; 95% CI, 0.51 to 1.39) compared with controls. The major limitations of this systematic review are the relatively short follow-up of the included trials (five trials with <2-year follow-up and overall range of follow-up of 1–10 years), low death events (n=71), and a low number of transplant failure events (n=72). KDIGO is currently updating its BP guidelines for CKD. In a draft that was circulated for public comment, an updated systematic review suggested that ARB use, but not ACEi, is associated with a reduction in kidney allograft loss. This finding suggests that in addition to CCBs, ARB use for the management of hypertension may be preferred over other agents given this salutary effect on graft survival. At the end of the day, however, a trial with >10,000 recipients would be needed to prove superiority of renin-angiotensin-aldosterone system (RAAS) blockade in transplant recipients.

Although RAAS blockade has been shown to prevent progression of proteinuric kidney disease, it has never been shown to reduce structural damage or kidney failure in patients with preserved kidney function akin to that of a newly transplanted kidney. In fact, neither losartan nor enalapril prevented expansion of the mesangial glomerular volume in normoalbuminuric, normotensive, normal, or high GFR type 1 diabetic subjects who were treated for 5 years (19). The failure of RAAS blockade to show benefit in transplantation similar to that observed in native kidney disease may reflect the small sizes of the trials conducted and the low overall event rate, but it is also conceivable that RAAS is not overly activated in kidney transplantation (20–22). In the 5-year-long randomized trial of losartan versus placebo, we measured plasma renin activity (PRA) and plasma aldosterone annually in 153 kidney transplant recipients. PRA and aldosterone were in the normal range the entire duration of the trial; those on losartan exhibited higher PRA but similar plasma aldosterone levels (16,22). Furthermore, PRA and plasma aldosterone levels did not vary by immunosuppressive agents used, and neither baseline nor serial PRA or aldosterone were associated with GFR decline, proteinuria, or cortical interstitial expansion. A higher serial aldosterone level, however, was associated with higher risk of kidney failure (hazard ratio, 1.01; 95% CI, 1.00 to 1.02; P=0.02).

Blood Pressure Measurement: Role of Ambulatory Blood Pressure Monitoring

Of relevance to the discussion of hypertension management in transplant recipients is the current dependence on office BP measurement to diagnose and make treatment decisions regarding hypertension. In an elegant study by Mallamaci et al. (23), 260 stable kidney transplant recipients underwent both routine office BP measurement and 24-hour ambulatory BP monitoring (ABPM). Over a median follow-up of 3.9 years, 25% of recipients’ visits triggered initiation or modification of their antihypertensive regimen for office BP >140/90 mm Hg, whereas ambulatory BP was actually normal. In contrast, 12% of visits revealed normal office BP, whereas ABPM was in the hypertensive range. Collectively, 37% of office BP measurements triggered inappropriate therapeutic interventions. These data suggest that white coat hypertension and masked hypertension are prevalent in kidney transplant recipients and that perhaps wider use of ABPM is needed to guide diagnosis and treatment in this population. In the KDIGO CKD BP guideline recently sent out for public review, the use of out of office BP measurements (ABPM and home BP monitoring) is suggested to complement office BP readings in both nontransplant and transplant populations. The feasibility of a wider adoption of ABPM remains a challenge for most, if not all, providers and clinic personnel.

Sodium Intake and Allograft Function

There have been relatively few randomized trials examining the role of salt restriction in CKD and kidney transplantation (24–26). Collectively, nontransplant trials have noted a favorable effect of sodium restriction on BP, but the effect on proteinuria and GFR change is not consistent. In kidney transplant recipients, van den Berg et al. (27) compared sodium intake in 660 recipients with that of 201 healthy controls. The average daily urinary sodium excretion was 156 mmol/d compared with 195 mmol/d in controls, and the association between sodium intake and both systolic BP and diastolic BP was modest. Interestingly, Moeller et al. (28) noted no relationship between 24-hour urinary sodium excretion and antihypertensive medications use in 129 kidney transplant recipients with stable kidney function. Two trials randomized 55 kidney transplant recipients to daily sodium intake of 50–80 versus 100–150 mmol/d demonstrated an 11- to 30-mm Hg reduction in systolic BP and a roughly 10 mm Hg in diastolic BP after 1.5–3 months on the low-sodium diet (29,30). On the basis of the available data, there seems to be no distinct advantage of salt restriction in kidney transplant recipients or known benefit regarding allograft outcome. Clinical considerations such as volume overload and BP control, however, would be logical indications for sodium restriction.

Uric Acid and Allograft Outcome

Uric acid has been implicated in endothelial dysfunction, vascular smooth muscle proliferation, and stimulation of profibrotic and inflammatory cytokines (31). Moreover, a higher serum uric acid level has been linked to incident hypertension, cardiovascular disease, incident CKD, and accelerating established CKD (32). Two randomized, placebo-controlled trials in diabetic and nondiabetic patients with CKD, however, found that allopurinol did not slow the decline in eGFR compared with placebo (33,34). In the transplant setting, the evidence linking elevation in uric acid to allograft survival is mixed. Meier-Kriesche et al. (35) reported no difference in GFR decline between high, medium, and low levels of uric acid obtained at the time of transplantation in 852 participants of the Symphony trial. The Angiotensin II Blockade in Chronic Allograft Nephropathy trial assessed both baseline and time-varying uric acid level on iothalamate GFR change, proteinuria development, and histologic changes (36). Men, higher body mass index, diuretic use, and lower GFR were associated with a higher uric acid, whereas older age, fewer than three HLA matches, and receipt of a kidney from a woman donor were associated with lower levels. In multivariable analysis adjusted for baseline GFR, uric acid was associated with doubling of cortical interstitial volume on biopsy or kidney failure from interstitial fibrosis/tubular atrophy at 5 years (odds ratio [OR], 1.83; 95% CI, 1.06 to 3.17; P=0.03). A 1-mg/dl higher time-varying uric acid was associated with a 2.39-ml/min-lower iothalamate GFR (P<0.001) at 5 years but not with the secondary outcome of creatinine doubling, kidney failure, or death. Uric acid level is highly influenced by GFR. In an elegant analysis addressing uric acid and graft failure in 1170 recipients, Kim et al. (37) demonstrated no higher risk of graft failure with increasing uric acid level after accounting for kidney function as a time-varying confounder that is affected by prior uric acid levels. Collectively, these data suggest a possible opportunity to study uric acid lowering as a potential intervention in kidney transplant recipients. However, the prevalence of hyperuricemia is lower today with the more widespread use of tacrolimus compared with the earlier days of cyclosporin predominance, and the negative trials of uric acid lowering in native kidney disease certainly dampen enthusiasm regarding uric acid lowering being a reasonable target for future trials in kidney transplant recipients.

Metabolic Acidosis and Allograft Function

Kidney transplant recipients frequently have a mild metabolic acidosis that stems from defective acid handling as a result of reduced nephron mass and persistence of hyperparathyroidism early after transplantation (38). Furthermore, calcineurin inhibitors impair tubular acid secretion and cause a type 4 renal tubular acidosis. The prevalence of metabolic acidosis following kidney transplantation can be as high as 50%, particularly in those with a GFR<30 ml/min per 1.73 m2 (39). Metabolic acidosis can lead to enhanced ammonia genesis, which through complement activation, can lead to tubulointerstitial injury (40). This has engendered a great deal of interest in whether alleviating acidosis in native CKD would slow kidney function decline. Studies in nontransplant settings seem to suggest benefit from alkali supplementation, but a critical appraisal of 14 studies (1394 study subjects) suggests that the strength of the evidence linking alkali supplementation to slowing GFR decline is of moderate certainty and the effect on urinary albumin lower as very low certainty (41). Importantly, there have been no large-scale randomized trials that demonstrated less kidney failure with alkali supplementation. Whether acidosis can lead to kidney allograft dysfunction is uncertain, and the evidence has generally been mixed. In one multicenter, retrospective cohort study of 2318 adult kidney transplant recipients, serum bicarbonate <22 mEq/L at 3 months was associated with a 74% higher risk of allograft loss (hazard ratio, 1.74; 95% CI, 1.26 to 2.42) (38). More recently, Gojowy et al. (42) showed that metabolic acidosis was present in 12% of 486 recipients and that those with HCO3<22 mEq/L had a 3-year graft survival of 74% compared with 93% for those without metabolic acidosis after adjusting for baseline eGFR. The Preserve-Transplant study is an ongoing prospective, single-blind, multicenter, randomized controlled trial of sodium bicarbonate versus placebo in 240 kidney transplant recipients (43). The primary end point is GFR change over 2 years, and the trial is expected to be completed in June 2021. Until these data are available, maintaining serum bicarbonate above 22 mmol/L, which is suggested for native CKD, should perhaps be the goal in kidney transplantation not only for its potential positive effect on kidney function but also for preservation of bone health.

Sodium-Glucose Cotransporter 2 Inhibitors in Kidney Transplantation

In patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT-2) inhibitors reduce the risk of hospitalization for heart failure and the risk of serious adverse kidney events (reviewed in ref. 44). The role of SGLT-2 inhibitors in nondiabetic kidney disease was addressed in two trials (45,46). In a 6-week randomized, double-blind, crossover trial of 53 nondiabetic subjects with a mean GFR of 58.3 ml/min and median proteinuria of 1110 mg/24 h, dapagliflozin 10 mg daily did not reduce proteinuria and resulted in an acute 6.6-ml/min decline in GFR that was reversible after discontinuation of the drug (45). The Dapagliflozin in Patients with CKD (DAPA-CKD) trial randomized 4304 patients (approximately one third were not diabetic) with a GFR between 25 and 75 ml/min and proteinuria to dapagliflozin or placebo (46). After a median follow-up of 2.4 years, participants assigned to dapagliflozin were 39% less likely to experience the primary outcome of declining kidney function, kidney failure, or death. Important cardiovascular end points were similarly reduced.

The experience with SGLT-2 inhibitors in kidney transplantation is limited to a few patient series and one randomized trial, summarized in Table 1 (47–52). Halden et al. (52) reported the results of their single-center, prospective, double-blind study of empagliflozin versus placebo in 49 kidney transplant recipients who developed post-transplant diabetes mellitus, had an eGFR>30 ml/min per 1.73 m2, and were at least 1 year post-transplantation. Empagliflozin resulted in a significant reduction in hemoglobin A1c, body weight, and uric acid compared with placebo. There was no difference between the groups with respect to GFR, but data on proteinuria were not reported. Importantly, it does not seem that these agents interfere with calcineurin inhibitor levels.

Table 1. - Clinical studies of sodium-glucose cotransporter 2 inhibitors in transplant recipients
Authors Design/Duration No. of Participants/Agent Used Timepoint Hemoglobin A1c Systolic BP, mm Hg Diastolic BP, mm Hg eGFR, ml/min per 1.73 m2 Body Mass Index, kg/m2, or Weight, kg
Rajasekeran et al. (47) Patient series
23 mo
6 KT, 4 SPK; canagliflozin SPK KT SPK KT
Baseline 7.4±1.1 8.6±1.4 NA NA 60±14 78±18.2 NA
Mean change −0.84 −6.5 −4.8 −4.3 −2.14
P value 0.07 0.13 0.30 0.30 0.07
AlKindi et al. (48) Patient series
24 mo
8 KT: type 2 diabetes mellitus: 2, PTDM: 6; empagliflozin: 6, dapagliflozin: 2 Baseline 9.3%±1.3 135±9.59 80.6±10.1 76±13 32.7±7.2
12 mo 7.4%±1.4 126±11.46 74.7±7.2 70±15 27.4±4.2
Mahling et al. (49) Prospective observational study
12 mo
10 KT with type 2 diabetes mellitus; empagliflozin Baseline 7.3% 135 80 57 75
112 mo 7.1% 132.5 79.5 67 73.1
Schwaiger et al. (50) Prospective, interventional pilot study
12 mo
14 KT with PTDM; empagliflozin Baseline 6.7% 150 86 54 29.3
12 mo 7.1 145
P value 0.03 0.36 0.02 0.93 0.04
Attallah and Yassine (51) Patient series
12 mo
8 KT: type 2 diabetes mellitus: 4, PTDM: 4; empagliflozin ↓0.85 NA NA NA ↓2.4
Halden et al. (52) Double-blind, placebo-controlled, randomized trial
6 mo
44 KT, all with PTDM; empagliflozin: 22, placebo: 22 E P E P E P E P E P
Baseline 6.9% 6.6% 136 135 76 78 66 59 28.8 27.5
24 wk 6.7% 6.9% 142 137 76 80 61 59 28.1 28.1
P value 0.03 >0.99 >0.99 >0.99 0.01
KT, kidney transplant; SPK, simultaneous kidney-pancreas; NA, not available; PTDM, post-transplant diabetes mellitus; E, empagliflozin; P, placebo.

In all, SGLT-2 inhibitors have emerged as major therapeutic options for both diabetic and nondiabetic kidney disease. Their use in the setting of kidney transplantation is minimal, but it appears that they are safe to use in those with preserved GFR. Certainly, the possibility that these agents may make urinary tract infections more common in transplant recipients needs to be considered carefully. Interestingly, the incidence of urinary tract infection was similar in dapagliflozin- and placebo-treated participants in the DAPA-CKD trial (46). Considering that cardiovascular disease is the leading cause of death after kidney transplantation, a large trial of SGLT-2 inhibitors in kidney transplant recipients would be greatly welcomed. A consideration should also be given to test these agents as a primary prevention strategy for post-transplant diabetes mellitus.

Water Intake and Allograft Function

The general public is inundated with messages to drink eight glasses of water daily for good health. The rationale for the need for higher water intake has included augmented clearance of toxins, better skin health, and possibly aiding in weight loss. Certainly, none of these have proven to be true. The origin of this recommendation is hard to trace, but some raised the possibility that Jane Brody of the New York Times may have been responsible for promoting this concept (53). This has been propagated further, and a prime example is the “Drink-Up” campaign sponsored by the Partnership for a Healthier America in collaboration with former First Lady Michelle Obama (54).

It is thought that high fluid intake may confer a kidney protective effect on kidney function in disease states. Work supporting this notion has been primarily on the basis of rat models that attribute the beneficial effects of generous fluid intake on suppressing antidiuretic hormone, which has been linked to hyperfiltration-mediated injury. Hebert et al. (55) reported accelerated GFR decline in those with CKD stages 3 and 4, with increasing urine volume potentially explained by pressure-induced glomerulosclerosis. In contrast, Clark et al. (56) demonstrated a beneficial effect of urine volume above 3 L on the rate of change in GFR in an observational study of patients with CKD. His group later went on to perform the Chronic Kidney Disease Water Intake Trial, which enrolled 631 subjects with a mean GFR of 43 ml/min per 1.73 m2, the majority of whom had micro- or macroalbuminuria (57). The group randomized to higher water intake was able to increase water intake by 0.6 L/d, but that did not translate into any positive effect on the 1-year change in GFR when compared with the usual hydration group.

The issue of water intake has also been studied in kidney transplant recipients. Gordon et al. (58) interviewed 88 recipients 2 months after receiving a kidney transplant regarding adherence to the center-recommended >3 L/d fluid intake. The cohort was followed prospectively for 12 months, and multivariable regression models were used to determine the effect of adherence to recommended fluid intake on eGFR change. This study found no relationship between high fluid intake and eGFR at 6 or 12 months. Similar observations were made by Magpantay et al. (59), who randomized 62 kidney transplant recipients to >4 or 2 L/d for 12 months and found that higher fluid intake resulted in no improvement. Lastly, Weber et al. (60) studied the relationship between urinary volume and functional and structural kidney end points in the previously mentioned Angiotensin Blockade in Chronic Allograft Nephropathy trial. The highest urinary volume tertile (>2.56 L/d) was not associated with the development of cortical interstitial volume doubling on biopsy or kidney failure from interstitial fibrosis/tubular atrophy (OR, 3.5; 95% CI, 0.4 to 38.1; P=0.26); interstitial volume doubling or all-cause kidney failure (OR, 7.04; 95% CI, 0.66 to 74.8; P=0.10); or doubling of serum creatinine, all cause kidney failure, or death. Collectively, data from patients with native CKD and the small observational studies in kidney transplantation do not support the need for high fluid intake in these populations.


Perhaps as many as 50%–80% of kidney transplant recipients have dyslipidemia (61). Interest in lipid lowering with the intention of reducing cardiovascular deaths, which account for the majority of deaths in kidney transplant recipients, is long-standing. The Assessment Lescol in Renal Transplantation Trial (ALERT) is the only prospective randomized trial in transplant recipients comparing fluvastatin with placebo and demonstrated a significant 35% reduction in the incidence of nonfatal myocardial infarction or cardiac deaths in fluvastatin-treated recipients but a nonsignificant reduction in the primary end point of cardiac death, nonfatal myocardial infarction, or coronary intervention (RR, 0.83; 95% CI, 0.64 to 1.06; P=0.14) (62). An extension of ALERT with 1652 patients from the original study also demonstrated a 21% reduction of major cardiac events (P=0.01) (63). However, there was no difference in graft survival between groups.

Amlodipine is the most commonly used antihypertensive agent in kidney transplant recipients, and its concomitant use with simvastatin at >20 mg daily for the latter should be avoided to avoid myositis. Rosuvastatin at higher doses has been associated with increased proteinuria and kidney failure in postmarketing studies. The Prospective Evaluation of Proteinuria and Renal Function in Diabetic and Non-Diabetic Patients with Progressive Renal Disease trials demonstrated a decline in urinary protein-creatinine ratio by 12.6% with atorvastatin 80 mg (P=0.03) and a nonsignificant <5% reduction in the rosuvastatin 10 and 40 mg in diabetic subjects with baseline proteinuria between 0.5 and 5 g/d (64). In nonpatients with diabetes, there was a 24.1% reduction in urinary protein with atorvastatin 80 mg (P=0.003) and a nonsignificant <10% reduction with 10 and 40 mg rosuvastatin (65). In all, there is no evidence that lipid lowering is associated with improvement in allograft survival, but their use for cardiovascular disease reduction should follow national guidelines. The choice of a specific agent in transplant recipients should be highly individualized considering pharmacologic interactions and possible advantage of atorvastatin over others in terms of reducing proteinuria.

Strategies proven beneficial in native kidney disease, such as a lower BP target and RAAS blockade, have not been studied extensively, and neither yielded similar results in transplant recipients. At this time, a BP target of 130/80 mm Hg is recommended, and CCBs followed by ARBs are the preferred agents. The future research agenda should include trials targeting acidosis treatment and studying SGLT-2 inhibitors for reducing death from cardiovascular disease and possibly prevention of post-transplant diabetes.


H.N. Ibrahim reports employment with Houston Methodist Hospital; consultancy agreements with Novartis; receiving research funding from National Institutes of Health; and honoraria from Relypsa. G.A. Knoll reports employment with Ottawa Hospital; and serving on the editorial board of Canadian Journal of Kidney Health and Disease. The remaining author has nothing to disclose.



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kidney transplantation; hypertension; outcomes

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