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Kidney TransplantationCJASN ePress. Published on April 2, 2021 as doi: 10.2215/CJN.15070920 Long-Term Management Challenges

Thinking Outside the Box: Novel Protective Strategies in Kidney Transplantation

Hassan N. Ibrahim,1 Dina N. Murad,1 and Greg A. Knoll2

Abstract Despite the reduction in the incidence of acute rejection, a major risk factor for loss, there has been only modest improvement in long-term graft survival. Most cases of kidney graft loss have an identifiable cause that is not 1 idiopathic fibrosis/atrophy or calcineurin inhibitor . Distinct immunologic and nonimmunologic Division of Renal Diseases and factors conspire to lead to a common pathway of allograft fibrosis. It remains plausible that mitigating Hypertension, nonimmunologic damage using strategies proven effective in native may yield benefit in kidney Department of transplantation. In this review, we will focus on nonimmunologic aspects of kidney transplant care that may prove Medicine, Houston to be valuable adjuncts to a well-managed regimen. Topics to be addressed include the roles of Methodist Hospital, Houston, Texas hypertension and agents used to treat it, lipid lowering, sodium and water intake, elevated uric acid, metabolic 2Division of acidosis, and the use of sodium-glucose cotransporter 2 inhibitors on long-term kidney transplant health. , CJASN 17: ccc–ccc, 2022. doi: https://doi.org/10.2215/CJN.15070920 Department of Medicine, Ottawa Hospital and Ottawa Hospital Research Introduction nonimmunologic strategies, often explored and used Institute, Ottawa, Avoidance of premature graft failure remains a key first in the nontransplant setting, remain important Ontario, goal in the management of kidney transplant recip- options for the management of kidney transplant ients. Graft loss is associated with a nearly four-fold recipients. In this review, we will focus on nonimmu- Correspondence: higherriskofdeathcomparedwiththosewitha nologic aspects of kidney transplant care that may be Dr.HassanN.Ibrahim, 6550 Fannin Street, functioning graft (1,2). The Standardized Outcomes in overlooked and perhaps overshadowed by the focus Suite 1001, Houston, Nephrology—Kidney Transplantation group has on immunosuppression-based interventions. TX 77030. Email: identified kidney transplant survival as the most hnibrahim@ important priority for both patients and health care houstonmethodist.org providers (3). Preventing graft loss was the top Hypertension and Allograft Outcome priority, even over death, as transplant recipients BP lowering in both the general and CKD popula- were more concerned with quality rather than quan- tions has been associated with many beneficial effects, tity of life. Kidney transplant outcomes vary by including reduction in cardiovascular events and program and region. Registry data from 1988 to death. Data from the Systolic Blood Pressure Inter- 2014 on over 350,000 kidney transplant recipients vention Trial (SPRINT) suggest that even lower BP from the , the , Aus- targets (i.e., ,120 mm Hg) may be associated with tralia, and New Zealand are instructive (4). Long-term improved clinical outcomes, even for those with CKD ‐ adjusted graft failure risk (conditional on 1 year (5). Although the supportive data for BP lowering are fi function) was signi cantly higher in the United States more consistent for cardiovascular events and death, compared with , New Zealand, and the there are also beneficial effects of BP lowering on ‐ United Kingdom. Long term kidney graft outcomes kidney outcomes. In the nontransplant CKD popula- were, however, approximately 25% worse in the tion, a meta-analysis of 11 randomized trials found United States compared with the three other devel- that more intensive BP lowering was associated with a oped nations, perhaps due to major differences in significant reduction in events (defined health care delivery systems and extent of immuno- as either a composite of doubling of serum suppressive medications coverage. If the reasons level and 50% decline in GFR or kidney failure) (6). In behind these inferior outcomes in the United States the kidney transplant population, unfortunately, we can be firmly determined, appropriate changes may do not have similar supportivedata.Thereare result in substantial benefits to both patients and the observational data showing that a lower BP 1 year health care system in the United States. after transplantation is associated with an improve- Many strategies have been used with the intended ment in long-term graft survival, but perhaps the best goal of preserving kidney function and prolonging available evidence comes from the Folic Acid for graft survival. These include adjustments in immu- Vascular Outcome Reduction study, which showed a nosuppression to prevent and treat rejection as well as direct graded relation between systolic BP and future prevent the development of donor-specificantibody. risk of and all-cause mortality In addition to these immunologic approaches, (7,8). Unfortunately, there have been no interventional

www.cjasn.org Vol 17 January, 2022 Copyright © 2022 by the American Society of Nephrology 1 2 CJASN

trials evaluating whether lowering BP, to a specific target, 0.49 to 1.18) or doubling of serum creatinine (RR, 0.84; is associated with improvement in any clinically important 95% CI, 0.51 to 1.39) compared with controls. The major outcomes, such as allograft survival. Despite the lack of limitations of this systematic review are the relatively strong evidence from randomized trials in transplant short follow-up of the included trials (five trials with recipients, it seems reasonable to target a BP level similar ,2-year follow-up and overall range of follow-up of to other high-risk patients. A target BP of ,130/80 mm Hg 1–10 years), low death events (n571), and a low number has been recommended in the Kidney Disease Improving of transplant failure events (n572). KDIGO is currently Global Outcomes (KDIGO) guideline on post-transplant updating its BP guidelines for CKD. In a draft that was management (9). A similar target for kidney transplant circulated for public comment, an updated systematic recipients was suggested in the 2012 KDIGO clinical review suggested that ARB use, but not ACEi, is asso- practice guideline for the management of BP in CKD as ciated with a reduction in kidney allograft loss. This well as in the recently published American College of finding suggests that in addition to CCBs, ARB use for Cardiology/American Heart Association BP guidelines the management of hypertension may be preferred over (10,11). Until further evidence accumulates, a lower other agents given this salutary effect on graft survival. “SPRINT-like” target of ,120 mm Hg may not be an Attheendoftheday,however,atrialwith.10,000 appropriate goal given the higher risk of AKI and GFR recipients would be needed to prove superiority of - decline seen with more intensive BP control (12,13). These angiotensin-aldosterone system (RAAS) blockade in trans- concerns may conceivably be more serious in the setting of plant recipients. lack of robust autoregulation of renal blood flow in the Although RAAS blockade has been shown to prevent denervated allograft. 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 Choice of Antihypertensive Agent newly transplanted kidney. In fact, neither losartan nor Although there is no direct randomized trial–driven enalapril prevented expansion of the mesangial glomerular evidence to support a certain BP target in kidney transplant volume in normoalbuminuric, normotensive, normal, or recipients, there are data suggesting that calcium channel high GFR type 1 diabetic subjects who were treated for blockers (CCBs) may be the preferred antihypertensive in 5 years (19). The failure of RAAS blockade to show benefit this population (14). In a systematic review of 60 trials in transplantation similar to that observed in native kidney (n53802 patients), with 29 trials (n52262 recipients) com- disease may reflect the small sizes of the trials conducted paring CCBs with placebo or no treatment, ten trials and the low overall event rate, but it is also conceivable that involving 445 recipients comparing angiotensin- RAAS is not overly activated in kidney transplantation converting enzyme inhibitors (ACEis) with placebo or no (20–22). In the 5-year-long randomized trial of losartan treatment, and seven trials (n5405) comparing ACEis with versus placebo, we measured plasma renin activity (PRA) CCBs, Cross et al. (14) found that CCBs compared with and plasma aldosterone annually in 153 kidney transplant placebo or no treatment were associated with a 25% lower recipients. PRA and aldosterone were in the normal range risk of graft loss (relative risk [RR], 0.75; 95% confidence the entire duration of the trial; those on losartan exhibited interval [95% CI], 0.57 to 0.99) and an improvement in GFR higher PRA but similar plasma aldosterone levels (16,22). (mean difference, 4.5 ml/min per 1.73 m2;95%CI,2.2to Furthermore, PRA and plasma aldosterone levels did not 6.7). Although this supports the notion that CCBs are the vary by immunosuppressive agents used, and neither preferred antihypertensive agents in preventing allograft baseline nor serial PRA or aldosterone were associated failure, it is worth noting that ,900 recipients in these trials with GFR decline, , or cortical interstitial ex- received a non-CCB, which possibly limits the robustness pansion. A higher serial aldosterone level, however, was of this conclusion. associated with higher risk of kidney failure (hazard ratio, 1.01; 95% CI, 1.00 to 1.02; P50.02).

Renin-Angiotensin-Aldosterone System Blockade in Kidney Transplantation Blood Pressure Measurement: Role of Ambulatory In the nontransplant setting, ACEis and angiotensin Blood Pressure Monitoring receptor blockers (ARBs) have been shown to prolong Of relevance to the discussion of hypertension manage- kidney survival in patients with proteinuric kidney dis- ment in transplant recipients is the current dependence on eases. In the transplant setting, three relatively contempo- office BP measurement to diagnose and make treatment rary, well-done randomized trials in kidney decisions regarding hypertension. In an elegant study transplantation have been published (15–17). Collectively, by Mallamaci et al. (23), 260 stable kidney transplant these placebo-controlled trials randomized 867 recipients recipients underwent both routine office BP measure- to candesartan (for 1.7 years), losartan (for 5 years), or ment and 24-hour ambulatory BP monitoring (ABPM). ramipril (for 4 years). None of these trials demonstrated a Over a median follow-up of 3.9 years, 25% of recipients’ favorable effect on all-cause mortality, graft failure, or the visits triggered initiation or modification of their anti- conventional end point of creatinine doubling. Further- hypertensive regimen for office BP .140/90 mm Hg, more, in a systematic review of eight randomized trials whereas ambulatory BP was actually normal. In contrast, (n51502 patients) examining ACEi or ARB use in the 12% of visits revealed normal office BP, whereas ABPM kidney transplant population, Hiremath et al. (18) found no was in the hypertensive range. Collectively, 37% of beneficial effect on kidney transplant loss (RR, 0.76; 95% CI, office BP measurements triggered inappropriate therapeutic CJASN 17: ccc–ccc, January, 2022 Long-Term Allograft Protection, Ibrahim et al. 3

interventions. These data suggest that white coat hyper- fewer than three HLA matches, and receipt of a kidney tension and masked hypertension are prevalent in kidney from a woman donor were associated with lower levels. In transplant recipients and that perhaps wider use of ABPM is multivariable analysis adjusted for baseline GFR, uric acid needed to guide diagnosis and treatment in this popu- was associated with doubling of cortical interstitial volume lation. In the KDIGO CKD BP guideline recently sent out on biopsy or kidney failure from interstitial fibrosis/ for public review, the use of out of office BP measure- tubular atrophy at 5 years (odds ratio [OR], 1.83; 95% ments (ABPM and home BP monitoring) is suggested to CI, 1.06 to 3.17; P50.03). A 1-mg/dl higher time-varying complement office BP readings in both nontransplant and uric acid was associated with a 2.39-ml/min-lower iotha- transplant populations. The feasibility of a wider adoption lamate GFR (P,0.001) at 5 years but not with the secondary of ABPM remains a challenge for most, if not all, providers outcome of creatinine doubling, kidney failure, or death. and clinic personnel. 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 Sodium Intake and Allograft Function graft failure with increasing uric acid level after accounting There have been relatively few randomized trials exam- for kidney function as a time-varying confounder that is ining the role of salt restriction in CKD and kidney affected by prior uric acid levels. Collectively, these data transplantation (24–26). Collectively, nontransplant trials suggest a possible opportunity to study uric acid lowering have noted a favorable effect of sodium restriction on BP, as a potential intervention in kidney transplant recipients. but the effect on proteinuria and GFR change is not However, the prevalence of hyperuricemia is lower today consistent. In kidney transplant recipients, van den Berg with the more widespread use of compared et al. (27) compared sodium intake in 660 recipients with with the earlier days of cyclosporin predominance, and the that of 201 healthy controls. The average daily urinary negative trials of uric acid lowering in native kidney sodium excretion was 156 mmol/d compared with 195 disease certainly dampen enthusiasm regarding uric acid mmol/d in controls, and the association between sodium lowering being a reasonable target for future trials in intake and both systolic BP and diastolic BP was modest. kidney transplant recipients. Interestingly, Moeller et al. (28) noted no relationship between 24-hour urinary sodium excretion and antihyper- tensive medications use in 129 kidney transplant recipients Metabolic Acidosis and Allograft Function with stable kidney function. Two trials randomized 55 Kidney transplant recipients frequently have a mild kidney transplant recipients to daily sodium intake of metabolic acidosis that stems from defective acid handling 50–80 versus 100–150 mmol/d demonstrated an 11- to 30- as a result of reduced nephron mass and persistence of mm Hg reduction in systolic BP and a roughly 10 mm Hg in hyperparathyroidism early after transplantation (38). Fur- diastolic BP after 1.5–3 months on the low-sodium diet thermore, calcineurin inhibitors impair tubular acid secre- (29,30). On the basis of the available data, there seems to be tion and cause a type 4 renal tubular acidosis. The no distinct advantage of salt restriction in kidney trans- prevalence of metabolic acidosis following kidney trans- plant recipients or known benefit regarding allograft out- plantation can be as high as 50%, particularly in those with come. Clinical considerations such as volume overload and aGFR,30 ml/min per 1.73 m2 (39). Metabolic acidosis can BP control, however, would be logical indications for lead to enhanced ammonia genesis, which through com- sodium restriction. plement 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 Uric Acid and Allograft Outcome function decline. Studies in non-transplant settings seem to Uric acid has been implicated in endothelial dysfunction, suggest benefit from alkali supplementation, but a critical vascular smooth muscle proliferation, and stimulation of appraisal of 14 studies (1394 study subjects) suggests that profibrotic and inflammatory cytokines (31). Moreover, a the strength of the evidence linking alkali supplementation higher serum uric acid level has been linked to incident to slowing GFR decline is of moderate certainty and the hypertension, cardiovascular disease, incident CKD, and effect on urinary albumin lower as very low certainty (41). accelerating established CKD (32). Two randomized, Importantly, there have been no large-scale randomized placebo-controlled trials in diabetic and nondiabetic pa- trials that demonstrated less kidney failure with alkali tients with CKD, however, found that allopurinol did not supplementation. Whether acidosis can lead to kidney slow the decline in eGFR compared with placebo (33,34). In allograft dysfunction is uncertain, and the evidence has the transplant setting, the evidence linking elevation in uric generally been mixed. In one multicenter, retrospective acid to allograft survival is mixed. Meier-Kriesche et al. (35) cohort study of 2318 adult kidney transplant recipients, reported no difference in GFR decline between high, serum bicarbonate ,22 mEq/L at 3 months was associated medium, and low levels of uric acid obtained at the time with a 74% higher risk of allograft loss (hazard ratio, 1.74; of transplantation in 852 participants of the Symphony 95% CI, 1.26 to 2.42) (38). More recently, Gojowy et al. (42) trial. The Angiotensin II Blockade in Chronic Allograft showed that metabolic acidosis was present in 12% of 486 , Nephropathy trial assessed both baseline and time-varying recipients and that those with HCO3 22 mEq/L had a 3- uric acid level on iothalamate GFR change, proteinuria year graft survival of 74% compared with 93% for those development, and histologic changes (36). Men, higher without metabolic acidosis after adjusting for baseline body mass index, use, and lower GFR were eGFR. The Preserve-Transplant study is an ongoing pro- associated with a higher uric acid, whereas older age, spective, single-blind, multicenter, randomized controlled CJASN 4

Table 1. Clinical studies of sodium-glucose cotransporter 2 inhibitors in transplant recipients

Body Mass Systolic Diastolic No. of Participants/ eGFR, ml/min Index, Authors (Reference) Design/Duration Timepoint Hemoglobin A1c BP, BP, Agent Used per 1.73 m2 kg/m2,or mm Hg mm Hg Weight, kg

Rajasekeran et al. (47) Patient series 6 KT, 4 SPK; canagliflozin SPK KT SPK KT 23 mo Baseline 7.461.1 8.661.4 NA NA 60614 78618.2 NA Mean 20.84 26.5 24.8 24.3 22.14 change P value 0.07 0.13 0.30 0.30 0.07 AlKindi et al. (48) Patient series 8 KT: type 2 mellitus: Baseline 9.3%61.3 13569.59 80.6610.1 76613 32.767.2 24 mo 2, PTDM: 6; empagliflozin: 12 mo 7.4%61.4 126611.46 74.767.2 70615 27.464.2 6, dapagliflozin: 2 Mahling et al. (49) Prospective 10 KT with Baseline 7.3% 135 80 57 75 observational study mellitus; empagliflozin 12 mo 7.1% 132.5 79.5 67 73.1 12 mo Schwaiger et al. (50) Prospective, interventional 14 KT with PTDM; Baseline 6.7% 150 86 54 29.3 pilot study empagliflozin 12 mo 7.1 145 12 mo P value 0.03 0.36 0.02 0.93 0.04 Attallah and Patient series 8 KT: type 2 diabetes mellitus: ↓0.85 NA NA NA ↓2.4 Yassine (51) 12 mo 4, PTDM: 4; empagliflozin Halden et al. (52) Double-blind, placebo- 44 KT, all with PTDM; EPEPEPEPEP controlled, empagliflozin: 22, Baseline 6.9% 6.6% 136 135 76 78 66 59 28.8 27.5 randomized trial placebo: 22 24 wk 6.7% 6.9% 142 137 76 80 61 59 28.1 28.1 6mo P value 0.03 .0.99 .0.99 .0.99 0.01

KT, kidney transplant; SPK, simultaneous kidney-; NA, not available; PTDM, post-transplant diabetes mellitus; E, empagliflozin; P, placebo. CJASN 17: ccc–ccc, January, 2022 Long-Term Allograft Protection, Ibrahim et al. 5

trial of sodium bicarbonate versus placebo in 240 kidney primary prevention strategy for post-transplant diabe- transplant recipients (43). The primary end point is GFR tes mellitus. 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 Water Intake and Allograft Function suggested for native CKD, should perhaps be the goal in The general public is inundated with messages to drink kidney transplantation not only for its potential positive eight glasses of water daily for good health. The rationale effect on kidney function but also for preservation of for the need for higher water intake has included aug- bone health. mented 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 Sodium-Glucose Cotransporter 2 Inhibitors in Kidney trace, but some raised the possibility that Jane Brody of the Transplantation New York Times may have been responsible for promoting In patients with type 2 diabetes, sodium-glucose co- this concept (53). This has been propagated further, and a transporter 2 (SGLT-2) inhibitors reduce the risk of hospi- prime example is the “Drink-Up” campaign sponsored by talization for and the risk of serious adverse the Partnership for a Healthier America in collaboration kidney events (reviewed in ref. 44). The role of SGLT-2 with former First Lady Michelle Obama (54). inhibitors in nondiabetic kidney disease was addressed in It is thought that high fluid intake may confer a kidney two trials (45,46). In a 6-week randomized, double-blind, protective effect on kidney function in disease states. Work crossover trial of 53 nondiabetic subjects with a mean GFR supporting this notion has been primarily on the basis of rat of 58.3 ml/min and median proteinuria of 1110 mg/24 h, models that attribute the beneficial effects of generous fluid dapagliflozin 10 mg daily did not reduce proteinuria and intake on suppressing antidiuretic hormone, which has resulted in an acute 6.6-ml/min decline in GFR that was been linked to hyperfiltration-mediated injury. Hebert et al. reversible after discontinuation of the drug (45). The (55) reported accelerated GFR decline in those with CKD Dapagliflozin in Patients with CKD (DAPA-CKD) trial stages 3 and 4, with increasing urine volume potentially randomized 4304 patients (approximately one third were explained by pressure-induced glomerulosclerosis. In con- not diabetic) with a GFR between 25 and 75 ml/min and trast, Clark et al. (56) demonstrated a beneficial effect of proteinuria to dapagliflozin or placebo (46). After a median urine volume above 3 L on the rate of change in GFR in an follow-up of 2.4 years, participants assigned to dapagli- observational study of patients with CKD. His group later flozin were 39% less likely to experience the primary went on to perform the Water outcome of declining kidney function, kidney failure, or Intake Trial, which enrolled 631 subjects with a mean GFR death. Important cardiovascular end points were simi- of 43 ml/min per 1.73 m2, the majority of whom had micro- larly reduced. or macroalbuminuria (57). The group randomized to The experience with SGLT-2 inhibitors in kidney higher water intake was able to increase water intake by transplantation is limited to a few patient series and 0.6 L/d, but that did not translate into any positive effect on one randomized trial, summarized in Table 1 (47–52). the 1-year change in GFR when compared with the usual Halden et al. (52) reported the results of their single- hydration group. center, prospective, double-blind study of empagliflozin The issue of water intake has also been studied in kidney versus placebo in 49 kidney transplant recipients transplant recipients. Gordon et al. (58) interviewed 88 who developed post-transplant diabetes mellitus, had recipients 2 months after receiving a kidney transplant an eGFR.30 ml/min per 1.73 m2,andwereatleast regarding adherence to the center-recommended .3 L/d fluid 1 year post-transplantation. Empagliflozin resulted in a intake. The cohort was followed prospectively for 12 months, significantreductioninhemoglobinA1c,bodyweight, and multivariable regression models were used to determine anduricacidcomparedwithplacebo.Therewasno the effect of adherence to recommended fluid intake on eGFR difference between the groups with respect to GFR, but change. This study found no relationship between high fluid data on proteinuria were not reported. Importantly, it intake and eGFR at 6 or 12 months. Similar observations were does not seem that these agents interfere with calci- made by Magpantay et al. (59), who randomized 62 kidney neurin inhibitor levels. transplant recipients to .4or2L/dfor12monthsandfound In all, SGLT-2 inhibitors have emerged as major thera- that higher fluid intake resulted in no improvement. Lastly, peutic options for both diabetic and nondiabetic kidney Weber et al. (60) studied the relationship between urinary disease. Their use in the setting of kidney transplantation is volume and functional and structural kidney end points in the minimal, but it appears that they are safe to use in those previously mentioned Angiotensin Blockade in Chronic Allo- with preserved GFR. Certainly, the possibility that these graft Nephropathy trial. The highest urinary volume tertile agents may make urinary tract more common in (.2.56 L/d) was not associated with the development of transplant recipients needs to be considered carefully. cortical interstitial volume doubling on biopsy or kidney Interestingly, the incidence of urinary tract was failure from interstitial fibrosis/tubular atrophy (OR, 3.5; 95% similar in dapagliflozin- and placebo-treated participants CI, 0.4 to 38.1; P50.26); interstitial volume doubling or all- in the DAPA-CKD trial (46). Considering that cardiovas- cause kidney failure (OR, 7.04; 95% CI, 0.66 to 74.8; P50.10); or cular disease is the leading cause of death after kidney doubling of serum creatinine, all cause kidney failure, or death. transplantation, a large trial of SGLT-2 inhibitors in kidney Collectively, data from patients with native CKD and the small transplant recipients would be greatly welcomed. A con- observational studies in kidney transplantation do not support sideration should also be given to test these agents as a the need for high fluid intake in these populations. 6 CJASN

Hyperlipidemia References Perhaps as many as 50%–80% of kidney transplant 1. Kabani R, Quinn RR, Palmer S, Lewin AM, Yilmaz S, Tibbles LA, recipients have dyslipidemia (61). Interest in lipid lowering Lorenzetti DL, Strippoli GFM, McLaughlin K, Ravani P; Alberta Kidney Disease Network: Risk of death following kidney allograft with the intention of reducing cardiovascular deaths, failure: A systematic review and meta-analysis of cohort studies. which account for the majority of deaths in kidney trans- Nephrol Dial Transplant 29: 1778–1786, 2014 plant recipients, is long-standing. The Assessment Lescol in 2. Lam NN, Boyne DJ, Quinn RR, Austin PC, Hemmelgarn BR, Renal Transplantation Trial (ALERT) is the only prospec- Campbell P, Knoll GA, Tibbles LA, Yilmaz S, Quan H, Ravani P: tive randomized trial in transplant recipients comparing Mortality and morbidity in kidney transplant recipients with a fl fi failing graft: A matched cohort study [published online ahead of uvastatin with placebo and demonstrated a signi cant print April 14, 2020]. Can J Kidney Health Dis 10.1177/ 35% reduction in the incidence of nonfatal myocardial 2054358120908677 infarction or cardiac deaths in fluvastatin-treated recipients 3. Tong A, Sautenet B, Poggio ED, Lentine KL, Oberbauer R, Mannon but a nonsignificant reduction in the primary end point of R, Murphy B, Padilla B, Chow KM, Marson L, Chadban S, Craig JC, cardiac death, nonfatal myocardial infarction, or coronary Ju A, Manera KE, Hanson CS, Josephson MA, Knoll G; SONG-Tx P5 Graft HealthWorkshop Investigators: Establishing acoreoutcome intervention (RR, 0.83; 95% CI, 0.64 to 1.06; 0.14) (62). measure for graft health: A Standardized Outcomes in An extension of ALERT with 1652 patients from the Nephrology-Kidney Transplantation (SONG-Tx) consensus original study also demonstrated a 21% reduction of major workshop report. Transplantation 102: 1358–1366, 2018 cardiac events (P50.01) (63). However, there was no 4. Merion RM, Goodrich NP, Johnson RJ, McDonald SP, Russ GR, Gillespie BW, Collett D: Kidney transplant graft outcomes in difference in graft survival between groups. 379 257 recipients on 3 continents. Am J Transplant 18: Amlodipine is the most commonly used antihyperten- 1914–1923, 2018 sive agent in kidney transplant recipients, and its concom- 5. Cheung AK, Rahman M, Reboussin DM, Craven TE, Greene T, itant use with simvastatin at .20 mg daily for the latter Kimmel PL, Cushman WC, Hawfield AT, Johnson KC, Lewis CE, should be avoided to avoid myositis. Rosuvastatin at Oparil S, Rocco MV, Sink KM, Whelton PK, Wright JT Jr., Basile J, Beddhu S, Bhatt U, Chang TI, Chertow GM, Chonchol M, higher doses has been associated with increased protein- Freedman BI, Haley W, Ix JH, Katz LA, Killeen AA, Papademetriou uria and kidney failure in postmarketing studies. The V, Ricardo AC, Servilla K, Wall B, Wolfgram D, Yee J; SPRINT Prospective Evaluation of Proteinuria and Renal Function Research Group: Effects of intensive BP control in CKD. JAmSoc in Diabetic and Non-Diabetic Patients with Progressive Nephrol 28: 2812–2823, 2017 Renal Disease trials demonstrated a decline in urinary 6. Lv J, Ehteshami P, Sarnak MJ, Tighiouart H, Jun M, Ninomiya T, Foote C, Rodgers A, Zhang H, Wang H, Strippoli GF, Perkovic V: protein-creatinine ratio by 12.6% with atorvastatin 80 mg Effects of intensive blood pressure lowering on the progression of (P50.03) and a nonsignificant ,5%reductioninthe chronic kidney disease: A systematic review and meta-analysis. rosuvastatin 10 and 40 mg in diabetic subjects with baseline CMAJ 185: 949–957, 2013 proteinuria between 0.5 and 5 g/d (64). In nonpatients with 7. Mange KC, Cizman B, Joffe M, Feldman HI: Arterial hypertension and renal allograft survival. JAMA 283: 633–638, 2000 diabetes, there was a 24.1% reduction in urinary protein P5 fi 8. Carpenter MA, John A, Weir MR, Smith SR, Hunsicker L, Kasiske with atorvastatin 80 mg ( 0.003) and a nonsigni cant BL, Kusek JW, Bostom A, Ivanova A, Levey AS, Solomon S, ,10% reduction with 10 and 40 mg rosuvastatin (65). In all, Pesavento T, Weiner DE: BP, cardiovascular disease, and death in there is no evidence that lipid lowering is associated with the folic acid for vascular outcome reduction in transplantation improvement in allograft survival, but their use for car- trial. J Am Soc Nephrol 25: 1554–1562, 2014 9. Kidney Disease: Improving Global Outcomes (KDIGO) Trans- diovascular disease reduction should follow national plant Work Group: Living kidney donor. Available at: https:// guidelines. The choice of a specific agent in transplant kdigo.org/guidelines/living-kidney-donor/. Accessed December recipients should be highly individualized considering 2020 pharmacologic interactions and possible advantage of 10. Whelton PK, Carey RM, Aronow WS, Casey DE Jr., Collins KJ, atorvastatin over others in terms of reducing proteinuria. Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, fi Jones DW, MacLaughlin EJ, Muntner P, Ovbiagele B, Smith SC Jr., Strategies proven bene cial in native kidney disease, Spencer CC, Stafford RS, Taler SJ, Thomas RJ, Williams KA Sr., such as a lower BP target and RAAS blockade, have not Williamson JD, Wright JT Jr.: 2017 ACC/AHA/AAPA/ABC/ACPM/ been studied extensively, and neither yielded similar AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, results in transplant recipients. At this time, a BP target detection, evaluation, and management of high blood pressure in adults: A report of the American College of Cardiology/American of 130/80 mm Hg is recommended, and CCBs followed by Heart Association Task Force on Clinical Practice Guidelines ARBs are the preferred agents. The future research agenda [published correction appears in J Am Coll Cardiol 71: should include trials targeting acidosis treatment and 2275–2279, 2018 10.1016/j.jacc.2018.03.016]. J Am Coll Car- studying SGLT-2 inhibitors for reducing death from car- diol 71: e127–e248, 2018 diovascular disease and possibly prevention of post- 11. Becker GJ, Wheeler DC, De Zeeuw D, Fujita T, Furth SL, Holdaas H, Mendis S, Oparil S, Perkovic V, Rodrigues CIS, Sarnak MJ, transplant diabetes. Schernthaner G, Tomson CRV, Zoccali C: Kidney Disease: Im- proving Global Outcomes (KDIGO) blood pressure work group. Disclosures KDIGO clinical practice guideline for the management of blood H.N. Ibrahim reports employment with Houston Methodist pressure in chronic kidney disease. Kidney Int Suppl 2: 337–414, 2012 Hospital; consultancy agreements with Novartis; receiving research 12. Beddhu S, Shen J, Cheung AK, Kimmel PL, Chertow GM, Wei G, funding from National Institutes of Health; and honoraria from Boucher RE, Chonchol M, Arman F, Campbell RC, Contreras G, Relypsa. G.A. Knoll reports employment with Ottawa Hospital; and Dwyer JP,Freedman BI, Ix JH, Kirchner K, Papademetriou V,Pisoni serving on the editorial board of Canadian Journal of Kidney Health and R, Rocco MV,Whelton PK, Greene T:Implications of early decline Disease. The remaining author has nothing to disclose. in eGFR due to intensive BP control for cardiovascular outcomes in SPRINT. J Am Soc Nephrol 30: 1523–1533, 2019 13. Rocco MV, Sink KM, Lovato LC, Wolfgram DF, Wiegmann TB, Funding Wall BM, Umanath K, Rahbari-Oskoui F, Porter AC, Pisoni R, None. Lewis CE, Lewis JB, Lash JP, Katz LA, Hawfield AT, Haley WE, CJASN 17: ccc–ccc, January, 2022 Long-Term Allograft Protection, Ibrahim et al. 7

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