Background: Diabetes mellitus and hypertension are the leading causes of cardiovascular disease in the renal transplant recipients. This review looks at the potential role of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and reviews the management strategies for hypertension in this population. Summary: Large-scale clinical trials are needed to study the potential cardiorenal benefits and risks of complications in renal transplant recipients. Future clinical trials are also needed to define optimal blood pressure treatment goals and therapies and how they influence graft and patient survival. Key Messages: Multiple recent prospective randomized clinical trials have shown the benefits of using SGLT2is to improve the cardiorenal outcomes in patients with chronic kidney disease with or without diabetes mellitus. Renal transplant recipients were not included in these trials due to concerns about genitourinary complications; hence, the role of these agents in this population is unclear. A number of small studies have highlighted the safety of using these agents in renal transplant recipients. Posttransplant hypertension is a complex problem requiring individualized management. Recent guidelines recommend using a calcium channel blocker or angiotensin receptor blocker as the first-line antihypertensive agents in adult renal transplant recipients.

Cardiovascular disease (CVD) is a major cause of graft loss and the leading cause of death in renal transplant recipients (RTRs), accounting for 30% of all deaths with a functioning graft [1]. Diabetes mellitus and hypertension are the biggest contributors to the increased cardiovascular risk seen in RTRs [2]. This has led to great interest in developing newer strategies to mitigate this risk to improve cardiovascular outcomes in RTRs. The advent of the newer classes of antidiabetic agents, including sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RA), has changed the landscape of therapeutic options for patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). But the role of these medications in the kidney transplant population remains unclear. This review aimed to discuss the current evidence in the cardiorenal protective effects of SGLT2is and the potential role they can play in the kidney transplant population to mitigate cardiovascular risk. We also aimed to summarize the current management strategies for hypertension in kidney transplant recipients.

In 2008, the US Food and Drug Administration (FDA) issued guidance mandating cardiovascular outcome trials (CVOTs) for novel antihyperglycemic medications to demonstrate that the new drugs would not increase risk of myocardial infarction (MI), stroke, or cardiovascular death [3]. Various CVOTs designed to demonstrate the safety of the SGLT2is, including EMPA-REG OUTCOME [4], CANVAS [5], DECLARE-TIMI 58 [6], and SCORED [7] have reported the cardiovascular benefits of empagliflozin, canagliflozin, dapagliflozin, and sotagliflozin, respectively, in T2DM patients with CVD. Table 1 summarizes the baseline characteristics, and Table 2 summarizes the major cardiorenal outcomes of these trials. These safety trials showed that SGLT2is significantly reduced 3-point major adverse CV events (MACE: death from CV causes, nonfatal MI, or nonfatal stroke), all-cause mortality, and heart failure hospitalizations in those with CV risk factors, or established CVD. Post hoc subgroup analyses of these studies have shown that the relative effects on most cardiovascular and kidney disease outcomes were similar across estimated glomerular filtration rate (eGFR) and albuminuria subgroups [8, 10].

Table 1.

Baseline study characteristics of CVOTs of SGLT2is

EMPA-REGCANVASDECLARE-TIMI 58SCOREDCREDENCEDAPA-CKD
Drug Empagliflozin Canagliflozin Dapagliflozin Sotagliflozin Canagliflozin Dapagliflozin 
Total participants 7,020 10,142 17,160 10,584 4,401 4,304 
Median follow-up, year 3.1 2.4 4.2 1.33 2.6 2.4 
eGFR criteria for enrollment, mL/min/1.73 m2 =30 =30 =60 25–60 30–90 25–75 
Mean eGFR at enrollment, mL/min/1.73 m2 74 76 85 44.5 56 43.1 
ACR, mg/g No criteria<30: 60%30–300: 30%; >300: 10% No criteriaMedian ACR: 12.3 No criteria No criteriaMedian ACR: 74 Criteria: ACR >300–5,000Median ACR: 927 Criteria: ACR >200–5,000Median ACR949 
N (%) with CVD 7,020 (100) 6,656 (66) 6,974 (41) 3,054 (29) 2,220 (50) 1,610 (37) 
ACEi/ARB use, n (%) 5,666 (81) 8,116 (80) 13,950 (81) 9,229 (87) 4,395 (100) 4,224 (98) 
Statin use, n (%) 5,403 (77) 7,599 (75) 12,868 (75) – 3,036 (69) 2,794 (65) 
Metformin use, n (%) 5,193 (74) 7,825 (77) 14,068 (82) 5,862 (55) 2,545 (58) – 
EMPA-REGCANVASDECLARE-TIMI 58SCOREDCREDENCEDAPA-CKD
Drug Empagliflozin Canagliflozin Dapagliflozin Sotagliflozin Canagliflozin Dapagliflozin 
Total participants 7,020 10,142 17,160 10,584 4,401 4,304 
Median follow-up, year 3.1 2.4 4.2 1.33 2.6 2.4 
eGFR criteria for enrollment, mL/min/1.73 m2 =30 =30 =60 25–60 30–90 25–75 
Mean eGFR at enrollment, mL/min/1.73 m2 74 76 85 44.5 56 43.1 
ACR, mg/g No criteria<30: 60%30–300: 30%; >300: 10% No criteriaMedian ACR: 12.3 No criteria No criteriaMedian ACR: 74 Criteria: ACR >300–5,000Median ACR: 927 Criteria: ACR >200–5,000Median ACR949 
N (%) with CVD 7,020 (100) 6,656 (66) 6,974 (41) 3,054 (29) 2,220 (50) 1,610 (37) 
ACEi/ARB use, n (%) 5,666 (81) 8,116 (80) 13,950 (81) 9,229 (87) 4,395 (100) 4,224 (98) 
Statin use, n (%) 5,403 (77) 7,599 (75) 12,868 (75) – 3,036 (69) 2,794 (65) 
Metformin use, n (%) 5,193 (74) 7,825 (77) 14,068 (82) 5,862 (55) 2,545 (58) – 

eGFR, estimated glomerular filtration rate; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; CVD, cardiovascular disease; EMPA-REG, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose; CANVAS, Canagliflozin Cardiovascular Assessment Study Program; DECLARE-TIMI 58, Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; SCORED, Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease; CREDENCE, Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin in Patients with Chronic Kidney Disease.

Table 2.

Major cardiovascular and renal outcomes of CVOTs of SGLT2is

OutcomesEMPA-REG, empagliflozin, HR (95% CI)CANVAS, canagliflozin, HR (95% CI)DECLARE-TIMI 58, dapagliflozin, HR (95% CI)SCORED, sotagliflozin, HR (95% CI)CREDENCE, canagliflozin, HR (95% CI)DAPA-CKD, dapagliflozin, HR (95% CI)
MACE 0.86 (0.74–0.99) 0.86 (0.75–0.97) 0.93 (0.84–1.03) 0.77 (0.65–0.91) 0.80 (0.67–0.95) – 
CV death 0.62 (0.49–0.77) 0.87 (0.72–1.06) 0.98 (0.82–1.17) 0.90 (0.73–1.12) 0.78 (0.61–1.00) 0.81 (0.58–1.12) 
Nonfatal MI 0.87 (0.70–1.09) 0.85 (0.69–1.05) 0.89 (0.77–1.01) – – – 
Nonfatal stroke 1.24 (0.92–1.67) 0.90 (0.71–1.15) 1.01 (0.84–1.21) – – – 
HHF 0.65 (0.50–0.85) 0.67 (0.52–0.87) 0.73 (0.61–0.88) 0.67 (0.55–0.82) 0.61 (0.47–0.80) – 
CV death or HHF 0.66 (0.55–0.79) 0.78 (0.67–0.91) 0.83 (0.73–0.95) 0.74 (0.63–0.88) 0.69 (0.57–0.83) 0.71 (0.55–0.92) 
All-cause mortality 0.68 (0.57–0.82) 0.87 (0.74–1.01) 0.93 (0.82–1.04) 0.99 (0.83–1.18) 0.83 (0.68–1.02) 0.69 (0.53–0.88) 
Kidney composite outcome Doubling of SCr, initiation of RRT, or death from renal cause >40% decrease in eGFR, initiation of RRT or death from renal cause =40% decrease in eGFR to <60 mL/min/1.73 m2, ESRD, or death from renal cause =50% decrease in eGFR for =30 days, ESRD or sustained eGFR of <15 mL/min/1.73 m2 for =30 days ESRD, doubling of SCr or death from renal cause Sustained decline in eGFR of =50%, ESRD, or death from renal or CV causes 
Kidney composite outcome 0.54 (0.40–0.75) 0.60 (0.47–0.77) 0.53 (0.43–0.66) 0.71 (0.46–1.08) 0.66 (0.53–0.81) 0.61 (0.51–0.72) 
OutcomesEMPA-REG, empagliflozin, HR (95% CI)CANVAS, canagliflozin, HR (95% CI)DECLARE-TIMI 58, dapagliflozin, HR (95% CI)SCORED, sotagliflozin, HR (95% CI)CREDENCE, canagliflozin, HR (95% CI)DAPA-CKD, dapagliflozin, HR (95% CI)
MACE 0.86 (0.74–0.99) 0.86 (0.75–0.97) 0.93 (0.84–1.03) 0.77 (0.65–0.91) 0.80 (0.67–0.95) – 
CV death 0.62 (0.49–0.77) 0.87 (0.72–1.06) 0.98 (0.82–1.17) 0.90 (0.73–1.12) 0.78 (0.61–1.00) 0.81 (0.58–1.12) 
Nonfatal MI 0.87 (0.70–1.09) 0.85 (0.69–1.05) 0.89 (0.77–1.01) – – – 
Nonfatal stroke 1.24 (0.92–1.67) 0.90 (0.71–1.15) 1.01 (0.84–1.21) – – – 
HHF 0.65 (0.50–0.85) 0.67 (0.52–0.87) 0.73 (0.61–0.88) 0.67 (0.55–0.82) 0.61 (0.47–0.80) – 
CV death or HHF 0.66 (0.55–0.79) 0.78 (0.67–0.91) 0.83 (0.73–0.95) 0.74 (0.63–0.88) 0.69 (0.57–0.83) 0.71 (0.55–0.92) 
All-cause mortality 0.68 (0.57–0.82) 0.87 (0.74–1.01) 0.93 (0.82–1.04) 0.99 (0.83–1.18) 0.83 (0.68–1.02) 0.69 (0.53–0.88) 
Kidney composite outcome Doubling of SCr, initiation of RRT, or death from renal cause >40% decrease in eGFR, initiation of RRT or death from renal cause =40% decrease in eGFR to <60 mL/min/1.73 m2, ESRD, or death from renal cause =50% decrease in eGFR for =30 days, ESRD or sustained eGFR of <15 mL/min/1.73 m2 for =30 days ESRD, doubling of SCr or death from renal cause Sustained decline in eGFR of =50%, ESRD, or death from renal or CV causes 
Kidney composite outcome 0.54 (0.40–0.75) 0.60 (0.47–0.77) 0.53 (0.43–0.66) 0.71 (0.46–1.08) 0.66 (0.53–0.81) 0.61 (0.51–0.72) 

MACE, major adverse cardiac event (cardiovascular death, nonfatal MI or nonfatal stroke); CV, cardiovascular; MI, myocardial infarction; HHF, hospitalization for heart failure; SCr, serum creatinine; eGFR, estimated glomerular filtration rate; RRT, renal replacement therapy; ESRD, end-stage renal disease.

The renal outcomes data in the above trials showed strong potential evidence for nephroprotection with these agents. In the 2016 analysis of renal outcomes data in the EMPA-REG OUTCOME trial, patients treated with empagliflozin showed large reductions in the prespecified composite outcome of progression to macroalbuminuria, doubling of serum creatinine (SCr), initiation of renal replacement therapy, or death from renal disease (hazard ratio, 0.61; 95% confidence interval [CI]: 0.53–0.70). The post hoc renal composite of doubling of SCr, initiation of renal replacement therapy, or death from renal disease was also reduced by the drug (hazard ratio, 0.54; 95% CI: 0.40–0.75) (Table 2). Importantly, 80% of the trial participants were already receiving an ACE inhibitor or an ARB. Similar reductions in the composite outcomes were seen in the CANVAS and DECLARE-TIMI 58 trials (Table 2).

Despite the strong suggested benefits for nephroprotection, these trials were primarily geared toward evaluation of cardiovascular efficacy and safety. As such, they had a small number of patients with higher stages of CKD and proteinuria; therefore, it was difficult to assess the actual event rates of end-stage renal disease (ESRD). This issue was overcome by CREDENCE [11] and DAPA-CKD [12] studies. CREDENCE study randomized 4,401 patients with T2DM, CKD, and severely increased albuminuria (UACR from 300 to 5,000 mg/g) already treated with ACEIs or ARBs into canagliflozin or placebo. The study was prematurely terminated (median follow-up of 2.62 vs. a projected duration of 5.5 years) because of clear benefit of canagliflozin. The relative risk of the renal-specific composite of ESRD, doubling of SCr, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI: 0.53–0.81), and ESRD was lower by 32% (hazard ratio, 0.68; 95% CI: 0.54–0.86) (Table 2). Based on these results, KDIGO 2020 guidelines and American Diabetic Association guidelines suggest use of SGLT2is for patients with T2DM and CKD following metformin treatment for optimal nephroprotection [13]. DAPA-CKD included patients with an eGFR from 25 to 75 mL/min per 1.73 m2 and a UACR from 200 to 5,000 mg/g; 67.5% had a diagnosis of T2DM, while 32.5% had CKD due to causes other than diabetes mellitus (Table 1). The primary outcome (composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes) event occurred in 197 of 2,152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group (hazard ratio, 0.61; 95% CI: 0.51–0.72; p < 0.001) (Table 2). The effects of dapagliflozin were similar in participants with T2D and in those without T2D.

Recent CVOTs DAPA-HF [14] and EMPEROR [15] have looked specifically at heart failure as primary outcomes in patients with and without T2DM. Both these studies looked at composite of worsening heart failure or cardiovascular death in patients with ejection fraction <40%. They reported significant reduction in primary outcome with the addition of dapagliflozin or empagliflozin, respectively, to the standard treatment (DAPA-HF: hazard ratio, 0.74; 95% CI, 0.65–0.85; p < 0.001 and EMPEROR: hazard ratio, 0.75; 95% CI, 0.65–0.86; p < 0.001). Findings in patients with diabetes were similar to those in patients without diabetes in both these studies.

Several have been proposed to explain the cardiorenal benefits of SGLT2is. The CV benefits are beyond what could be explained solely by the modest improvements in blood sugar and blood pressure in these patients.

SGLT2is promote osmotic diuresis and natriuresis in patients with and without diabetes and thus reduce preload and decrease blood pressure [16, 17]. SGLT2is interfere with both SGLT2 and NHE3 (sodium-hydrogen exchanger isoform 3) in the proximal tubule, and this action yields short-term increases in the fractional excretion of sodium [18, 20]. This increase in sodium and chloride delivery to the distal tubule results in increased tubulo-glomerular feedback via chloride sensing by the macula densa that causes vasoconstriction of the afferent arterioles resulting in reduction of intraglomerular pressure. The SGLT2is are also reported to improve glomerular hyperfiltration of diabetic kidney via dilation of the efferent arteriole [21]. But the effects of tubulo-glomerular feedback often reset quickly and are not sustained. Furthermore, the magnitude of the early decline in glomerular filtration is decreased in patients with renal impairment [22]; however, the ability of SGLT2is to slow the progression of renal disease is not diminished [23]. It is also noteworthy that experimental knockout of SGLT2 is sufficient to attenuate glomerular hyperfiltration, but it does not prevent renal injury, inflammation, or fibrosis in experimental diabetes or ischemia [24, 26]. Hence, the reduction of intraglomerular pressures by SGLT2is does not entirely explain their renal protective effects [26].

SGLT2 inhibition has been shown to promote erythrocytosis and ketogenesis while at the same time reduce serum uric acid, an indicator of oxidative stress in patients with HF [27, 28]. These effects are thought to be a response to enhanced nutrient and oxygen deprivation. Many studies have reported that SGLT2is induces fasting-like and hypoxia-like transcriptional changes [29], which promote autophagic flux in multiple organs such as the kidney and the heart. At least three signaling pathways are involved in SGLT2i’s effect on autophagy flux in overnutrition diseases: mammalian target of rapamycin (mTOR), sirtuin-1 (SIRT1), and hypoxia-inducible factors pathways. These three pathways are affected by fasting-like state induced by SGLT2is and interact with each other [30]. Akt/mTOR signaling is hyperactivated in the kidney in nutrient surplus states, thus triggering proinflammatory pathways and promoting renal injury, whereas inhibition of mTOR can ameliorate fibrosis and the development of CKD [31, 34]. The molecular mechanisms that stimulate autophagy include the activation of energy deprivation sensors, SIRT1, and adenosine monophosphate-activated protein kinase (AMPK). These enzymes not only promote organellar integrity directly, but they also enhance autophagic flux, which leads to the removal of dysfunctional mitochondria and peroxisomes [26]. The effect of SGLT2is to reduce oxidative and endoplasmic reticulum stress, enhance mitochondrial health, suppress proinflammatory and profibrotic pathways, and preserve cell viability is paralleled by an increase in activity of AMPK, SIRT1, SIRT3, SIRT6, and PGC-1a and decreased activation of mTOR in diverse tissues under stress. Furthermore, when the effects of SGLT2is to promote activation of AMPK, SIRT1, SIRT3, and SIRT6 were attenuated by specific pharmacologic inhibition or knockdown of nutrient deprivation signaling pathways, the beneficial effects of SGLT2is to reduce oxidative stress, promote mitochondrial health, attenuate inflammation and fibrosis, and maintain cell viability and organ integrity were abolished [26].

From a mechanistic perspective, SGLT2i could portend a number of potential benefits in RTRs. First, SGLT2i-induced reduction in glomerular capillary hypertension and hyperfiltration decreases proteinuria, metabolic demand for tubular reabsorption, and subsequently oxygen consumption. This diminished workload may play an important role in preserving tubular function and glomerular filtration rate [35]. This may be of particular advantage to RTRs where ischemic tubular injury is common and detrimental to allograft longevity, especially in the setting of deceased donor transplantation and long-term immunosuppression. Second, SGT2i-induced glycosuria can lead to beneficial metabolic alterations including shifting substrate utilization from carbohydrate to lipid metabolism leading to reduced body fat and body weight along with increased ketogenesis, which serves as a more oxygen-efficient fuel and could lead to improved pancreatic function [35]. Several studies have shown that SGLT2is improve beta cell functionality and insulin secretion in patients with type 2 diabetes [36, 37]. These metabolic effects of SGLT2is may portend benefits in RTRs, who are prone to numerous metabolic complications and development of posttransplant diabetes mellitus secondary to immunosuppression medications. Third, the antihypertensive action of SGLT2i is most likely due to a combination of osmotic diuresis, weight loss, natriuresis, and an indirect effect on nitric oxide release secondary to better glycemic control [38, 39]. Posttransplant hypertension is prevalent in 50–80% of RTRs and is known to be associated with higher rates of allograft failure [39, 40]. Immunosuppressive agents like calcineurin inhibitor (CNIs) and steroids can induce hypertension through multiple mechanisms such as salt retention, vasoconstriction, and upregulation of RAAS. Improved blood pressure and volume control with SGLT2is can therefore play a beneficial role in RTRs [39].

RTRs have been largely excluded from large clinical trials for SGLT2is. Due to concerns for higher potential for genitourinary tract infections, KDIGO 2020 guidelines do not currently recommend using SGLT2is in RTRs. Despite that, there has been great interest in potential benefits of using SGLT2is in this population, given that RTRs have high prevalence of diabetes and CVD, and CVD is the leading cause of death in RTRs. As will be discussed later, patients with GFR below 60 mL/min, like RTR, are less likely to have genitourinary infections because of diminished glucosuric response to SGLT2i.

A prospective, double-blind, randomized trial, EMPA-Renal Tx, involving 44 patients, was done by Halden et al. [41] in Oslo, Norway, to assess the safety and efficacy of empagliflozin in RTRs. They included patients who were >1 year post kidney transplant, diagnosed with posttransplant diabetes mellitus, with stable renal function (eGFR >30 mL/mt), and on stable immunosuppressive therapy. They found weak antihyperglycemic action of empagliflozin, which reduced HbA1c by 0.2% at week 24, compared to a slight HbA1c increase (+0.1%) in the placebo group. The HbA1c decrease depended on kidney function, based on the fact that the increase in renal glucose excretion by SGLT2 inhibition is strongly GFR dependent: at an eGFR <50 mL/min/1.73 m2, empagliflozin-induced glucosuria and HbA1c reduction were virtually absent. Empagliflozin led to a decrease in body weight (3.5 kg compared to placebo in week 24), without a significant change in body composition at study termination. UTIs occurred in 3 patients on empagliflozin, two of whom had to withdraw from the study, but also in 3 patients in the placebo group. Overall, there was no significant difference between the groups in adverse events including infections, immunosuppressive drug levels, or eGFR.

A small pilot study in Vienna, Austria, converted 14 patients with stable kidney transplants who were on insulin and other antidiabetic drugs to empagliflozin [42]. There was an increase in HbA1c (+0.4% at 52 weeks) and weight loss (-5 kg median) with empagliflozin. 5 patients developed UTI (vs. 9 of 24 matched reference patients, p = 0.81), 1 developed balanitis, and there were no episodes of ketoacidosis.

In addition, several case series have also shown modest changes in HbA1c with SGLT2i use in RTRs [43, 47]. A meta-analysis of 8 SGLT2is studies with 132 RTR patients [48] showed significantly lower HbA1c (WMD = 0.56%; 95% CI: 0.97, 0.16; p = 0.007) and body weight (WMD = 2.16 kg; 95% CI: 3.08, 1.24; p < 0.001) at the end of the study compared to baseline (Table 3). There were no significant changes in eGFR, SCr, urine protein creatinine ratio, and blood pressure. In terms of safety profiles, 14 patients had urinary tract infection, one had genital mycosis, one had acute kidney injury, and one had cellulitis. The incidence of urinary tract infection was 43.8% in this study versus 38.0% among kidney transplant recipients who are not on SGLT2is [49], which was not significantly different (p = 0.13). There were no reported cases of euglycemic ketoacidosis or acute rejection during the treatment. Of note, inclusion criteria for most of these studies included patients at least 1-year posttransplantation with well-controlled diabetes and stable kidney function (baseline mean eGFR range: 54–86 mL/min/1.73 m2) who did not have a significant history of UTI or genital mycotic infections.

Table 3.

Summary effects of SGLT2 inhibitors on outcomes of interest among kidney transplant recipients with posttransplant diabetes mellitus, comparing levels at baseline and end of study

ParametersNumber of studySample sizeWMD95% CIp valueI2
eGFR 124 -2.51 mL/min/1.73 m2 (-5.03, 0.02) 0.06 
SCr 58 -0.05 mg/dL (-0.13, 0.03) 0.21 
UPCR 38 -211 mg/g (-655, 232) 0.35 93.2 
HbA1C 132 -0.57% (-0.97, -0.16) 0.006 85.2 
SBP 82 -3.24 mm Hg (-7.92, 1.45) 0.18 21.3 
DBP 82 -1.49 mm Hg (-3.81, 0.83) 0.21 
BMI 38 -1.20 kg/m2 (-2.67, 0.27) 0.11 21.4 
Weight 132 -2.15 kg (-3.07, -1.23) <0.001 
ParametersNumber of studySample sizeWMD95% CIp valueI2
eGFR 124 -2.51 mL/min/1.73 m2 (-5.03, 0.02) 0.06 
SCr 58 -0.05 mg/dL (-0.13, 0.03) 0.21 
UPCR 38 -211 mg/g (-655, 232) 0.35 93.2 
HbA1C 132 -0.57% (-0.97, -0.16) 0.006 85.2 
SBP 82 -3.24 mm Hg (-7.92, 1.45) 0.18 21.3 
DBP 82 -1.49 mm Hg (-3.81, 0.83) 0.21 
BMI 38 -1.20 kg/m2 (-2.67, 0.27) 0.11 21.4 
Weight 132 -2.15 kg (-3.07, -1.23) <0.001 

eGFR, estimated glomerular filtration rate; UPCR, urine protein-creatinine ratio; HbA1C, glycated hemoglobin; SBP, systolic blood pressure; DBP, diastolic blood pressure; BMI, body mass index; WMD, weighted mean difference; CI, confidence interval.

Previously published by Chewcharat et al. [48].

Based on the above studies in RTRs, the SGLT2is only seem to effectively reduce serum glucose in patients with eGFR >60, promote weight loss, and are best used selectively as add-on therapy for diabetes control in RTRs. With regards to safety of using SGLT2is in RTRs, current studies show rates of UTIs and other infections are comparable to transplant patients not on SGLT2is when they are used in carefully selected transplant patients. The potential risk of genitourinary complications is likely lower than in the general population because of the lower eGFR in RTR, and less glucosuria. Current studies do not show a significant reduction in blood pressure (BP) or proteinuria, as has been shown in studies in non-transplant population. This effect is likely due to small sample size and short follow-up of these studies to demonstrate these effects. Other considerations could be additional pathogenetic mechanisms such as arterial hypertension related to immunosuppressants [50]. Large-scale randomized clinical trials are needed in RTRs to prove the cardiovascular and renal benefits of SGLT2is in this population as observed in non-transplant population.

Hypertension in RTRs is a common clinical problem ranging from 50% to 80% and is associated with shortened allograft survival as well as with increased cardiovascular morbidity and mortality. The pathogenesis of posttransplant hypertension is complex and is a result of the interplay between immunological and non-immunological factors, with various donor and recipient factors playing a role.

Numerous studies have attempted to examine the relationship between BP and graft survival independent of allograft function [40, 51, 53]. The Collaborative Transplant Study, a large cohort study of nearly 30,000 kidney transplant recipients followed over 7 years, showed a graded association between systolic and diastolic BP and progressively decreased renal allograft function and death-censored chronic graft failure [40]. Another study from the same cohort database examined the association between changes in BP levels at 1- and 3-year posttransplantation and long-term graft outcomes up to 10 years following transplantation. They found that patients with a SBP >140 mm Hg at 1 year who were controlled to a SBP =140 mm Hg at 3-year posttransplantation had improved renal allograft outcomes and reduced CV death compared to those with persistent SBP of >140 mm Hg both at 1- and 3-year posttransplantation [53]. Unfortunately, there are no randomized controlled trials to determine the optimal BP goals and the value of intensive antihypertensive therapy on outcomes such as graft or patient survival in RTRs. There are also no data to define optimal treatment strategies. KDIGO 2021 guidelines [54] suggest a BP goal of <130/80 mm Hg in adult RTRs, regardless of the degree of proteinuria. However, this recommendation is based on expert opinion based on evidence from randomized controlled trials demonstrating survival and CV benefits of targeting SBP <130 mm Hg in the general population [55, 56].

The choice of antihypertensive medication should be on the basis of efficacy, tolerability, lack of known drug-drug interactions, and medical comorbidity. In the early posttransplant period, blood pressure may be influenced by postsurgical pain, volume overload, higher doses of corticosteroids and CNI levels, and slow or delayed allograft function. Dihydropyridine calcium channel blockers (CCB) are usually the first-line medications because of their efficacy, lack of major drug interactions, and their potential ability to counteract the vasoconstrictive effects of CNIs. Other agents including beta-blockers or diuretics can also be used, based on the clinical indications. ACE-inhibitors and ARBs should generally be avoided early posttransplantation because of their hemodynamic effect on GFR and potassium homeostasis [57, 58].

KDIGO 2021 guidelines [54] recommend using a CCB or ARB as the first-line antihypertensive agents in adult RTRs. A meta-analysis conducted by the Cochrane Kidney and Transplant Evidence Review Team [59] as part of the guideline evidence review showed that dihydropyridine CCB group led to a 38% reduction in graft loss (RR: 0.62; 95% CI: 0.43–0.90) over a mean of 25 months compared to placebo. In contrast, the reduction in graft loss by the non-dihydropyridine CCB group was not statistically significant (RR: 0.91; 95% CI: 0.61–1.34) compared to placebo. The evidence review has also found that ARB use compared to placebo led to a 65% reduction in graft loss (RR: 0.35; 95% CI: 0.15–0.84). They found no benefit of CCB or ARB use on all-cause mortality or CV events such as MI or stroke. They further reported that compared to placebo or no treatment, ACEi, alpha-blockers, beta-blockers, and MRAs had no significant effect on mortality, graft loss, or CV events. With regard to ACEi, there was trial evidence showing that these agents were effective at reducing BP and proteinuria in kidney transplant recipients. However, there was no significant effect of ACEi on all-cause mortality or graft loss, and their use was associated with a significant increase in adverse events in the kidney transplant population, including angioedema, cough, hyperkalemia, and anemia.

Most RTRs with hypertension require more than one antihypertensive medication to control the BP, and the choice should be based on the clinical indication. Patients with evidence of volume overload should be treated with diuretics prior to adding other medications. In patients with proteinuria and high BP, ARBs should be considered first-line medications. In women trying to conceive or who are pregnant, ACEi or ARBs are contraindicated, and CCBs are generally the agent of choice. Secondary causes of hypertension like transplant renal artery stenosis, primary hyperaldosteronism, and obstructive sleep apnea should also be considered in cases of resistant hypertension.

Both diabetes mellitus and hypertension are major risk factors for CVD, graft loss, and death in RTRs. Newer therapeutic approaches include SGLT2is, which have been shown to reduce cardiorenal risk in CKD population, irrespective of whether they have diabetes mellitus or not. These agents could potentially play an important role in decreasing the CV risk and improving renal outcomes in renal transplant patients, even though they should not be expected to significantly improve the glycemic control. Unfortunately, due to lack of clinical trials in this population, their role is unclear, and there is lingering concern regarding the potential increased risk of genitourinary infections in this population. Small-scale studies and meta-analyses indicate that these agents are well tolerated in carefully selected transplant patients. Large-scale randomized clinical trials are needed to further study the cardiovascular and renal benefits and safety of SGLT2is in transplant population.

Blood pressure management in RTRs should be individualized based on patient characteristics, timing after transplant, and clinical indications. BP goal of <130/80 mm Hg has been recommended by various guidelines based on expert opinion. CCBs and ARBs have been shown to decrease the incidence of graft loss compared to placebo and are recommended as first-line antihypertensive agents in adult RTRs. Future clinical trials are needed to define optimal BP treatment goals and therapies and how they influence graft and patient survival.

  • Various cardiovascular outcomes trials of sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown significant improvement in cardiovascular and renal outcomes in patients with chronic kidney disease with or without diabetes mellitus.

  • These clinical trials excluded renal transplant patients, but small studies suggest these agents may be safe to use in appropriately selected transplant patients.

  • KDIGO recommends targeting blood pressure <130/80 while using calcium channel blockers or angiotensin receptor blockers as first-line antihypertensive agents in renal transplant patients.

  • Large-scale clinical trials are needed in renal transplant patients to define the role of SGLT2is and the goals and management strategies for hypertension in this population.

The following articles, published within the annual period of review, are of particular interest:

Special interest [7, 12, 48]:

  • This study [7] presents the cardiorenal safety and efficacy of sotagliflozin in patients with DM and CKD. Sotagliflozin is both SGLT1 and SGLT2i.

  • This study [12] showed the cardiorenal benefits of dapagliflozin in patients with higher stages of CKD (eGFR as low as 25 mL/mt) and higher degrees of proteinuria with or without DM.

  • Meta-analysis [48] of 8 studies of SGLT2is use in kidney transplant recipients demonstrating safety of these agents in carefully selected patients.

Outstanding interest [13, 54]:

  • KDIGO guidelines [13] for diabetes management in kidney transplant recipients do not recommend the use of SGLT2is given the lack of large-scale trials in this population.

  • Recently published KDIGO guidelines [54] recommend using a CCB or ARB as the first-line antihypertensive agent in kidney transplant recipients based on the results of meta-analysis conducted by the Cochrane Kidney and Transplant Evidence Review Team.

Dr. Matthew Weir has served as a scientific consultant to AstraZeneca, Boehringer-Ingelheim, Merck, Bayer, Novo Nordisk, and Janssen. Drs. Amit Singh and Roberto Kalil report no conflicts and declare that they have no relevant financial interests.

No funding was received.

Drs. Matthew Weir, Amit Singh, and Roberto Kalil have contributed to the design, writing, and review of the paper.

1.
Saran
R
,
Li
Y
,
Robinson
B
,
Ayanian
J
,
Balkrishnan
R
,
Bragg-Gresham
J
.
US renal data system 2014 annual data report: epidemiology of kidney disease in the United States
.
Am J Kidney Dis
.
2015
66
1 Suppl 1
Svii, S1
305
.
2.
Matas
AJ
,
Smith
JM
,
Skeans
MA
,
Thompson
B
,
Gustafson
SK
,
Stewart
DE
.
OPTN/SRTR 2013 annual data report: kidney
.
Am J Transplant
.
2015
15
Suppl 2
1
34
.
3.
Smith
RJ
,
Goldfine
AB
,
Hiatt
WR
.
Evaluating the cardiovascular safety of new medications for type 2 diabetes: time to reassess
.
Diabetes Care
.
2016
;
39
(
5
):
738
42
.
4.
Zinman
B
,
Wanner
C
,
Lachin
JM
,
Fitchett
D
,
Bluhmki
E
,
Hantel
S
.
Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes
.
N Engl J Med
.
2015
;
373
(
22
):
2117
28
.
5.
Neal
B
,
Perkovic
V
,
Mahaffey
KW
,
de Zeeuw
D
CANVAS Program Collaborative Group
.
Canagliflozin and cardiovascular and renal events in type 2 diabetes
.
N Engl J Med
.
2017
;
377
(
7
):
644
57
.
6.
Wiviott
SD
,
Raz
I
,
Bonaca
MP
,
Mosenzon
O
,
Kato
ET
,
Cahn
A
.
Dapagliflozin and cardiovascular outcomes in type 2 diabetes
.
N Engl J Med
.
2019
;
380
(
4
):
347
57
.
7.
Bhatt
D
,
Szarek
M
,
Pitt
B
,
Cannon
CP
,
Leiter
LA
,
McGuire
DK
.
SCORED Investigators. Sotagliflozin in Patients with Diabetes and chronic kidney disease
.
N Engl J Med
.
2021
;
384
:
129
39
.
8.
Neuen
BL
,
Ohkuma
T
,
Neal
B
,
Matthews
DR
,
de Zeeuw
D
,
Mahaffey
KW
.
Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function
.
Circulation
.
2018
;
138
(
15
):
1537
50
.
9.
Mahaffey
KW
,
Jardine
MJ
,
Bompoint
S
,
Cannon
CP
,
Neal
B
,
Heerspink
HJL
.
Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups
.
Circulation
.
2019
;
140
(
9
):
739
50
.
10.
Wanner
C
,
Zinman
B
,
George
JT
,
Mattheus
M
,
von Eynatten
M
,
Inzucchi
SE
Empaglifflozin and cardiorenal outcomes in patients with non proteinuric kidney disease in the EMPAREG-OUTCOME trial
European Association for the Study of Diabetes
2019
. Abstract 5.
11.
Perkovic
V
,
Jardine
MJ
,
Neal
B
,
Bompoint
S
,
Heerspink
HJL
,
Charytan
DM
.
Canagliflozin and renal outcomes in type 2 diabetes and nephropathy
.
N Engl J Med
.
2019
;
380
(
24
):
2295
306
.
12.
Heerspink
HJL
,
Stefansson
BV
,
Correa-Rotter
R
,
Chertow
GM
,
Greene
T
,
Hou
FF
.
DAPA-CKD trial committees and investigators. Dapagliflozin in patients with chronic kidney disease
.
N Engl J Med
.
2020 Oct 8
383
1436
46
.
13.
Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group
.
KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease
.
Kidney Int
.
2020
98
S1
S115
.
14.
McMurray
JJV
,
Solomon
SD
,
Inzucchi
SE
,
Kober
L
,
Kosiborod
MN
,
Martinez
FA
.
Dapagliflozin in patients with heart failure and reduced ejection fraction
.
N Engl J Med
.
2019
;
381
(
21
):
1995
2008
.
15.
Packer
M
,
Anker
SD
,
Butler
J
,
Filippatos
G
,
Pocock
SJ
,
Carson
P
.
Cardiovascular and renal outcomes with empagliflozin in heart failure
.
N Engl J Med
.
2020
;
383
(
15
):
1413
24
.
16.
Al-Jobori
H
,
Daniele
G
,
Cersosimo
E
,
Triplitt
C
,
Mehta
R
,
Norton
L
.
Empagliflozin and kinetics of renal glucose transport in healthy individuals and individuals with type 2 diabetes
.
Diabetes
.
2017
;
66
(
7
):
1999
2006
.
17.
Seman
L
,
Macha
S
,
Nehmiz
G
,
Simons
G
,
Ren
B
,
Pinnetti
S
.
Empagliflozin (BI 10773), a potent and selective SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects
.
Clin Pharmacol Drug Dev
.
2013
;
2
(
2
):
152
61
.
18.
Borges-Júnior
FA
,
Silva Dos Santos
D
,
Benetti
A
,
Polidoro
JZ
,
Wisnivesky
ACT
,
Crajoinas
RO
.
Empagliflozin inhibits proximal tubule NHE3 activity, preserves GFR, and restores euvolemia in nondiabetic rats with induced heart failure
.
J Am Soc Nephrol
.
2021
;
32
(
7
):
1616
29
.
19.
Onishi
A
,
Fu
Y
,
Patel
R
,
Darshi
M
,
Crespo-Masip
M
,
Huang
W
.
A role for tubular Na+/H+ exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin
.
Am J Physiol Renal Physiol
.
2020
319
4
F712
28
.
20.
Griffin
M
,
Rao
VS
,
Ivey-Miranda
J
,
Fleming
J
,
Mahoney
D
,
Maulion
C
.
Empagliflozin in heart failure: diuretic and cardiorenal effects
.
Circulation
.
2020
;
142
(
11
):
1028
39
.
21.
van Bommel
EJM
,
Muskiet
MHA
,
van Baar
MJB
,
Tonneijck
L
,
Smits
MM
,
Emanuel
AL
.
The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial
.
Kidney Int
.
2020
;
97
(
1
):
202
12
.
22.
Adamson
C
,
Docherty
KF
,
Heerspink
HJL
,
de Boer
RA
,
Damman
K
,
Inzucchi
SE
.
Initial decline (dip) in estimated glomerular filtration rate after initiation of dapagliflozin in patients with heart failure and reduced ejection fraction: insights from DAPA-HF
.
Circulation
.
2022
;
146
(
6
):
438
49
.
23.
Zannad
F
,
Ferreira
JP
,
Pocock
SJ
,
Zeller
C
,
Anker
SD
,
Butler
J
.
Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: insights from EMPEROR-Reduced
.
Circulation
.
2021
;
143
(
4
):
310
21
.
24.
Vallon
V
,
Rose
M
,
Gerasimova
M
,
Satriano
J
,
Platt
KA
,
Koepsell
H
.
Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus
.
Am J Physiol Renal Physiol
.
2013
304
2
F156
67
.
25.
Nespoux
J
,
Patel
R
,
Zhang
H
,
Huang
W
,
Freeman
B
,
Sanders
PW
.
Gene knockout of the Na+-glucose cotransporter SGLT2 in a murine model of acute kidney injury induced by ischemia-reperfusion
.
Am J Physiol Renal Physiol
.
2020
318
5
F1100
12
.
26.
Packer
M
.
Critical reanalysis of the mechanisms underlying the cardiorenal benefits of SGLT2 inhibitors and reaffirmation of the nutrient deprivation signaling/autophagy hypothesis
.
Circulation
.
2022
;
146
(
18
):
1383
405
.
27.
Packer
M
.
Role of deranged energy deprivation signaling in the pathogenesis of cardiac and renal disease in states of perceived nutrient overabundance
.
Circulation
.
2020
;
141
(
25
):
2095
105
.
28.
Packer
M
.
Uric acid is a biomarker of oxidative stress in the failing heart: lessons learned from trials with allopurinol and SGLT2 inhibitors
.
J Card Fail
.
2020
;
26
(
11
):
977
84
.
29.
Osataphan
S
,
Macchi
C
,
Singhal
G
,
Chimene-Weiss
J
,
Sales
V
,
Kozuka
C
.
SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms
.
JCI Insight
.
2019
;
4
(
5
):
e123130
.
30.
Fukushima
K
,
Kitamura
S
,
Tsuji
K
,
Wada
J
,
Wada
J
.
Sodium–glucose cotransporter 2 inhibitors work as a “regulator” of autophagic activity in overnutrition diseases
.
Front Pharmacol
.
2021
;
12
:
761842
.
31.
Yamahara
K
,
Kume
S
,
Koya
D
,
Tanaka
Y
,
Morita
Y
,
Chin-Kanasaki
M
.
Obesity-mediated autophagy insufficiency exacerbates proteinuria-induced tubulointerstitial lesions
.
J Am Soc Nephrol
.
2013
;
24
(
11
):
1769
81
.
32.
Inoki
K
,
Mori
H
,
Wang
J
,
Suzuki
T
,
Hong
S
,
Yoshida
S
.
mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice
.
J Clin Invest
.
2011
;
121
(
6
):
2181
96
.
33.
Mori
H
,
Inoki
K
,
Masutani
K
,
Wakabayashi
Y
,
Komai
K
,
Nakagawa
R
.
The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential
.
Biochem Biophys Res Commun
.
2009
;
384
(
4
):
471
5
.
34.
Kogot-Levin
A
,
Hinden
L
,
Riahi
Y
,
Israeli
T
,
Tirosh
B
,
Cerasi
E
.
Proximal tubule mTORC1 is a central player in the pathophysiology of diabetic nephropathy and its correction by SGLT2 inhibitors
.
Cell Rep
.
2020
;
32
(
4
):
107954
.
35.
Vallon
V
,
Verma
S
.
Effects of SGLT2 inhibitors on kidney and cardiovascular function
.
Annu Rev Physiol
.
2021
;
83
:
503
28
.
36.
Asahara
S
,
Ogawa
W
.
SGLT2 inhibitors and protection against pancreatic beta cell failure
.
Diabetol Int
.
2019
;
10
:
1
2
.
37.
Shyr
ZA
,
Yan
Z
,
Ustione
A
,
Egan
EM
,
Remedi
MS
.
SGLT2 inhibitors therapy protects glucotoxicity-induced β-cell failure in a mouse model of human KATP-induced diabetes through mitigation of oxidative and ER stress
.
PLoS One
.
2022
;
17
(
2
):
e0258054
.
38.
Majewski
C
,
Bakris
GL
.
Blood pressure reduction: an added benefit of sodium–glucose cotransporter 2 inhibitors in patients with type 2 diabetes
.
Diabetes Care
.
2015
;
38
(
3
):
429
30
.
39.
Ujjawal
A
,
Schreiber
B
,
Verma
A
.
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) in kidney transplant recipients: what is the evidence
.
Ther Adv Endocrinol Metab
.
2022 Apr 13
13
20420188221090001
.
40.
Opelz
G
,
Wujciak
T
,
Ritz
E
.
Association of chronic kidney graft failure with recipient blood pressure. Collaborative transplant study
.
Kidney Int
.
1998
;
53
(
1
):
217
22
.
41.
Halden
TAS
,
Kvitne
KE
,
Midtvedt
K
,
Rajakumar
L
,
Robertsen
I
,
Brox
J
.
Efficacy and safety of empagliflozin in renal transplant recipients with posttransplant diabetes mellitus
.
Diabetes Care
.
2019
;
42
(
6
):
1067
74
.
42.
Schwaiger
E
,
Burghart
L
,
Signorini
L
,
Ristl
R
,
Kopecky
C
,
Tura
A
.
Empagliflozin in post transplantation diabetes mellitus: a prospective, interventional pilot study on glucose metabolism, fluid volume, and patient safety
.
Am J Transplant
.
2019
;
19
(
3
):
907
19
.
43.
Shah
M
,
Virani
Z
,
Rajput
P
,
Shah
B
.
Efficacy and safety of canagliflozin in kidney transplant patients
.
Indian J Nephrol
.
2019
;
29
(
4
):
278
81
.
44.
Rajasekeran
H
,
Kim
SJ
,
Cardella
CJ
,
Schiff
J
,
Cattral
M
,
Cherney
DZI
.
Use of canagliflozin in kidney transplant recipients for the treatment of type 2 diabetes: a case series
.
Diabetes Care
.
2017
;
40
(
7
):
e75
6
.
45.
Mahling
M
,
Schork
A
,
Nadalin
S
,
Fritsche
A
,
Heyne
N
,
Guthoff
M
.
Sodium-glucose cotransporter 2 (SGLT2) inhibition in kidney transplant recipients with diabetes mellitus
.
Kidney Blood Press Res
.
2019
;
44
(
5
):
984
92
.
46.
Attallah
N
,
Yassine
L
.
Use of empagliflozin in recipients of kidney transplant: a report of 8 cases
.
Transplant Proc
.
2019
;
51
(
10
):
3275
80
.
47.
AlKindi
F
,
Al-Omary
HL
,
Hussain
Q
,
Al Hakim
M
,
Chaaban
A
,
Boobes
Y
.
Outcomes of SGLT2 inhibitors use in diabetic renal transplant patients
.
Transplant Proc
.
2020
;
52
(
1
):
175
8
.
48.
Chewcharat
A
,
Prasitlumkum
N
,
Thongprayoon
C
,
Bathini
T
,
Medaura
J
,
Vallabhajosyula
S
.
Efficacy and safety of SGLT-2 inhibitors for treatment of diabetes mellitus among kidney transplant patients: a systematic review and meta-analysis
.
Med Sci
.
2020
;
8
(
4
):
47
.
49.
Wu
X
,
Dong
Y
,
Liu
Y
,
Li
Y
,
Sun
Y
,
Wang
J
.
The prevalence and predictive factors of urinary tract infection in patients undergoing renal transplantation: a meta-analysis
.
Am J Infect Control
.
2016
;
44
(
11
):
1261
8
.
50.
Morales
JM
,
Andres
A
,
Rengel
M
,
Rodicio
JL
.
Influence of cyclosporin, tacrolimus and rapamycin on renal function and arterial hypertension after renal transplantation
.
Nephrol Dial Transplant
.
2001
16
Suppl 1
121
4
.
51.
Mange
KC
,
Cizman
B
,
Joffe
M
,
Feldman
HI
.
Arterial hypertension and renal allograft survival
.
JAMA
.
2000
;
283
(
5
):
633
8
.
52.
Mange
KC
,
Feldman
HI
,
Joffe
MM
,
Fa
K
,
Bloom
RD
.
Blood pressure and the survival of renal allografts from living donors
.
J Am Soc Nephrol
.
2004
;
15
(
1
):
187
93
.
53.
Opelz
G
,
Dohler
B
Collaborative Transplant Study
.
Improved long-term outcomes after renal transplantation associated with blood pressure control
.
Am J Transplant
.
2005
;
5
(
11
):
2725
31
.
54.
Cheung
AK
,
Chang
TI
,
Cushman
WC
.
KDIGO 2021 clinical practice guideline for the management of blood pressure in chronic kidney disease
.
Kidney Int
.
2021
99
S1
87
.
55.
Carpenter
MA
,
John
A
,
Weir
MR
,
Smith
SR
,
Hunsicker
L
,
Kasiske
BL
.
BP, cardiovascular disease, and death in the folic acid for vascular outcome reduction in transplantation trial
.
J Am Soc Nephrol
.
2014
;
25
(
7
):
1554
62
.
56.
Pagonas
N
,
Bauer
F
,
Seibert
FS
,
Seidel
M
,
Schenker
P
,
Kykalos
S
.
Intensive blood pressure control is associated with improved patient and graft survival after renal transplantation
.
Sci Rep
.
2019
;
9
(
1
):
10507
.
57.
Wadei
HM
,
Textor
SC
.
Hypertension in the kidney transplant recipient
.
Transplant Rev (Orlando)
.
2010
;
24
(
3
):
105
20
.
58.
Weir
MR
,
Burgess
ED
,
Cooper
JE
,
Fenves
AZ
,
Goldsmith
D
,
McKay
D
.
Assessment and management of hypertension in transplant patients
.
J Am Soc Nephrol
.
2015
;
26
(
6
):
1248
60
.
59.
Cross
NB
,
Webster
AC
,
Masson
P
,
O’Connell
PJ
,
Craig
JC
.
Antihypertensive treatment for kidney transplant recipients
.
Cochrane Database Syst Rev
.
2009
2009
3
CD003598
.