Metabolic Disorders with Kidney Transplant

Abstract

Metabolic disorders are highly prevalent in kidney transplant candidates and recipients and can adversely affect post-transplant graft outcomes. Management of diabetes, hyperparathyroidism, and obesity presents distinct opportunities to optimize patients both before and after transplant as well as the ability to track objective data over time to assess a patient’s ability to partner effectively with the health care team and adhere to complex treatment regimens. Optimization of these particular disorders can most dramatically decrease the risk of surgical and cardiovascular complications post-transplant. Approximately 60% of nondiabetic patients experience hyperglycemia in the immediate post-transplant phase. Multiple risk factors have been identified related to development of new onset diabetes after transplant, and it is estimated that upward of 7%–30% of patients will develop new onset diabetes within the first year post-transplant. There are a number of medications studied in the kidney transplant population for diabetes management, and recent data and the risks and benefits of each regimen should be optimized. Secondary hyperparathyroidism occurs in most patients with CKD and can persist after kidney transplant in up to 66% of patients, despite an initial decrease in parathyroid hormone levels. Parathyroidectomy and medical management are the options for treatment of secondary hyperparathyroidism, but there is no randomized, controlled trial providing clear recommendations for optimal management, and patient-specific factors should be considered. Obesity is the most common metabolic disorder affecting the transplant population in both the pre- and post-transplant phases of care. Not only does obesity have associations and interactions with comorbid illnesses, such as diabetes, dyslipidemia, and cardiovascular disease, all of which increase morbidity and mortality post-transplant, but it also is intimately inter-related with access to transplantation for patients with kidney failure. We review these metabolic disorders and their management, including data in patients with kidney transplants.

Introduction

Metabolic disorders are highly prevalent in kidney transplant candidates and recipients and can adversely affect post-transplant graft outcomes. Thoughtful management of diabetes, hyperparathyroidism, and obesity is critical to optimize the waitlisted population and the patient after transplant. Furthermore, the ability of a patient to comply with complex treatment regimens for aggressive management of their underlying metabolic disorders is an important consideration in assessing the future adherence with immunosuppressive (1,2).

Knowledge of the current literature and tools available to assist in the optimization of these complex patients is needed for success during all phases of transplant care. We provide an overview of the contemporary management of the most complicated metabolic disorders pre-, peri-, and post-transplant with an emphasis on the most pertinent and recent data.

Pretransplant Management of Metabolic Disorders

One of the challenges in managing patients prior to transplant is the degree of cardiovascular disease already present. This is compounded by metabolic disorders that may develop during this time. Data demonstrate that existing cardiovascular disease leads to increased rates of cardiovascular events post-transplant (3–6). In addition, diabetes and obesity both have significant overlap in their presentation and risk for poor outcomes post-transplantation.

Data from the US Renal Data System demonstrate that patients with elevated hemoglobin A1c prior to transplant have an increased risk of post-transplant diabetes mellitus, which in turn, is associated with increased rates of cardiovascular events and decreased patient and graft survival (7,8). Hemoglobin A1c is poorly correlated with fasting blood glucose in patients with kidney failure and those with severe anemia, likely underestimating patients at risk of post-transplant hyperglycemia (9).

The risk of post-transplant diabetes mellitus should be considered when evaluating patients for transplant candidacy, and patients should be counseled on expectations regarding hyperglycemia management post-transplant. Preexisting diabetes itself is a risk factor for increased rejection rates post-transplant (10). Chakkera et al. (11) found seven factors associated with increased risk of new onset diabetes after transplant in their patient population, including age, planned corticosteroid therapy post-transplant, prescription for gout medicine, body mass index (BMI), fasting glucose and triglycerides, and family history of type 2 diabetes, all of which are readily available when listing patients for transplant. Other factors that have been associated with new onset diabetes after transplant include race, hepatitis C, and use of tacrolimus over cyclosporin (12). At our center, a risk assessment has been built into our electronic medical record, and it is used by the pharmacist at the time of assessment for transplant so that risk of developing new onset diabetes after transplant is available to the team at the time of transplant.

Along with uncontrolled diabetes, elevated parathyroid hormone (PTH) may also be a marker of pretransplant nonadherence and could help indicate patients in whom targeted interventions pretransplant might improve post-transplant outcomes (13). There is an opportunity to ensure optimization of patients with elevated PTH prior to transplant because one of the most important risk factors for postkidney transplant hyperparathyroidism is elevated pretransplant PTH levels along with calcium, phosphate, dialysis vintage, and graft function post-transplant (14).

Data suggest that parathyroidectomy prior to transplant increases bone mineral density more effectively than parathyroidectomy after transplant (15). In a retrospective analysis at our center, patients who were transplanted with PTH≥6× normal experienced an increased risk of graft failure, but those who underwent pretransplant parathyroidectomy had a much lower risk of graft failure (odds ratio, 0.547; 95% confidence interval, 0.327 to 0.913) (16). This further adds to the data suggesting that patients who are poorly managed pretransplant have worse outcomes, and it suggests that parathyroidectomy pretransplant can improve post-transplant outcomes.

Obesity is a metabolic disorder that is intimately inter-related with access to transplantation for patients with kidney failure (6). Most transplant centers require that BMI criteria be met prior to listing; this is supported by a survey by the American Society of Transplant surgeons in which 66 of 67 centers used BMI of 35–45 kg/m² as the upper limit allowable to initiate an evaluation (17). Studies using United Network for Organ Sharing (UNOS) data have demonstrated decreased likelihood of receiving a transplant with increasing BMI >25 kg/m² as well as increased likelihood of being bypassed when an organ became available with a BMI>25 kg/m² (18). These UNOS data also demonstrated that 20% of all transplant centers have not listed a single morbidly obese patient with BMI>40 kg/m² and that only 15% of centers list severely obese patients with BMI>35 kg/m². This risk-averse listing criteria are driven by not only inferior outcomes demonstrated in the morbidly obese population but also, the increased technical challenges and costs associated with higher levels of care. This barrier to transplant access is compounded by the reluctance of bariatric surgeons to offer surgical weight loss strategies to patients with kidney failure to support them in the effort to meet the BMI goals (19).

Studies confirm that patients listed inactive because of obesity achieved their weight loss goals and were activated only half of the time. This was attributed to a variety of barriers to effective medically supervised weight loss, including comorbidities preventing activity, dietary restrictions associated with kidney disease management, fluid balance, and psychosocial challenges (20,21). New pharmacologic agents support weight loss through thermogenesis, supporting decreased caloric intake or directly interrupting the absorption of calories taken in (22). However, there are limited data on their safety in kidney disease. One promising study reporting 2-year follow-up of a medical weight loss program with orlistat (alli), nutrition education, diet, and exercise for kidney transplant candidates with BMI>28 kg/m² demonstrated a 5- to 6-kg weight loss benefit observed within the first 6 months that persisted (23). This study was nonrandomized and limited by potential bias, but it does support safety of this weight loss strategy in the kidney transplant candidate population. Bariatric surgery is an alternative option for durable weight loss in this population (19,21,24). The specific experience of bariatric surgery as a bridge to kidney transplantation has been explored with encouraging results, both with sleeve gastrectomy and with Roux-en-Y gastric bypass as surgical options (25–27). However, all weight loss programs are resource intensive, and broad feasibility remains limited for patients with activity restrictions, disability, and psychosocial barriers.

When considering a patient’s transplant candidacy, transplant centers should consider not only the burden of preexisting comorbid disease and the effect on graft survival but also, a patient’s ability to understand and comply with complex treatment regimens. The track record of their successful management of diabetes or hyperparathyroidism as well as demonstrating medically supervised weight loss can all be considered as surrogate markers for health care literacy and adherence.

Peritransplant Management of Metabolic Disorders

Data clearly demonstrate the advantages of transplantation over dialysis in patients with diabetes with decreased mortality and cardiovascular events, and this benefit is noted to strengthen over time (28). Management of metabolic disorders immediately post-transplant is critical to the long-term cardiovascular and graft outcomes of kidney transplantation as well as immediate surgical complications. Observational studies have demonstrated that perioperative hyperglycemia increases the risk for infection, adverse events, reoperative interventions, and mortality even in nonpatients with diabetes (29,30). Obesity also heavily influences surgical approach and expected complications at the time of transplantation, including post-transplant hyperglycemia.

It is estimated that upward of 7%–30% of patients will develop post-transplant diabetes mellitus within the first year post-transplant and will need to start blood glucose management in addition to a new transplant regimen (31). Additionally, hyperglycemia early post-transplant has been shown to increase the risk of rejection and infection post-transplant (32). Along with this, infections, such as hepatitis C and cytomegalovirus, also increase the risk for hyperglycemia post-transplant along with transplant from a deceased donor due to higher levels of proinflammatory markers (33). With all of these risk factors, continuous glucose monitoring (CGM) provides a much clearer picture as to a patient’s true glycemic control post-transplant and can be used in both patients with and without diabetes. In a small population of nondiabetic patients with CGM monitoring for 4 days post-transplant, patients who developed post-transplant diabetes mellitus 3 months after transplant tended to have higher fasting blood glucose on day 1 (34). In pediatric patients with kidney transplants, CGM helped to identify patients with impaired glucose tolerance, which also correlated with hypoglycemic events (35). Kidney transplant recipients have an ideal indication for CGM and perhaps broader availability, and data can aid in the diagnosis of post-transplant diabetes mellitus and long-term management.

Insulin should be used early after transplant to help protect the β-cells and prevent further damage; data suggest that insulin is the best medication for preventing new onset diabetes after transplant (36). Basal-bolus insulin regimens using a combination of short- and long-acting insulins have been validated in postsurgical patients as well as those in a critical care setting (37,38). The traditional oral antihyperglycemic agents metformin and sulfonylureas have limited utility in the early post-transplant population due to adverse effect profiles, but they may be appropriate in select patients. Lactic acidosis can occur in patients treated with metformin experiencing AKI, which is not predictable post-transplant, and it can lead to serious complications. Sulfonylureas are limited by challenges with hypoglycemia, drug interactions, and dosing.

Corticosteroids have also been well documented as a risk factor for developing post-transplant diabetes mellitus. An attempt at modulating this risk by comparing early corticosteroid withdrawal with chronic low-dose corticosteroid administration has failed to demonstrate significant differences in the incidence of post-transplant diabetes mellitus (39). Other induction agents, such as basiliximab and antithymocyte globulin, have not been found to be associated with post-transplant hyperglycemia. Corticosteroids are also used for the treatment of rejection; thus, monitoring after rejection treatment is crucial. It is also important to consider the mechanism of action of corticosteroids in inducing post-transplant dysglycemia with the mechanisms of other immunosuppressive drugs, like tacrolimus, which may raise concern for additive risks of post-transplant diabetes with coadministration of these drugs (Figure 1).

Figure 1.

Mechanism of immunosuppression effects on blood glucose. NFAT, nuclear factor of activated T-cells, a family of transcription factors shown to be integral to immune response.

There are many factors that affect a patient’s blood glucose control in the immediate post-transplant phase, including steroid dose, kidney function, and baseline glycemic control. Blood glucose levels can change rapidly on the basis of these different factors, and close follow-up is needed because patients with kidney transplants are discharged within days after transplant. The transplant pharmacist is uniquely positioned to help care for patients who require intense monitoring with frequent dose adjustments of their antihyperglycemic regimen. Studies show that pharmacists’ effect on diabetes management in kidney transplant results in significant reductions in hemoglobin A1c in patients diagnosed with post-transplant diabetes mellitus (40,41). At our center, we have adopted a model optimizing the use of the transplant pharmacist as a transition to the transplant endocrinologist when the patient is stable, about 3 months post-transplant. This has led to a reduction in readmissions and emergency department visits for hyperglycemia management within 90 days post-transplant without increased adverse effects or hypoglycemia. Management of post-transplant hyperglycemia is crucial to the short- and long-term outcomes of both diabetic and nondiabetic patients with transplants.

A recent systematic review and meta-analysis of the literature demonstrated a higher risk of acute rejection, patient death, graft loss, and delayed graft function in patients classified as obese with a BMI>30 kg/m² (42). Obesity and rapid weight gain post-transplant can also increase the risk for hyperglycemia. A subgroup analysis of children 6–12 years old in the North American Pediatric Renal Transplant Cooperative Study demonstrated an association between obesity and increased risk of death (43). The most definitive risk factor associated with a poor outcome in the obese kidney transplant population is the occurrence of wound infection, which is noted in up to 40% of patients (44). A modified surgical approach has been proposed in select morbidly obese patients to avoid these wound complications by using a robotic approach (45–47). Corticosteroid use has not been associated with weight gain post-transplant (48). Regardless of potentially inferior outcomes compared with nonobese patients undergoing transplantation, the evidence is clear that obese patients have far better outcomes with transplantation compared with dialysis (49).

Management of metabolic disorders during the pretransplant period is critical to the outcome of the transplant and post-transplant management.

Post-Transplant Management of Metabolic Disorders

Diabetes, hyperparathyroidism, and obesity are not metabolic disorders in silos unto themselves. It is important to highlight their long-term risks associated hypertension, proteinuria, and ultimately, cardiovascular disease in addition to their implications on the graft and patient survival. Diabetes itself accelerates atherosclerosis and increases arterial stiffness (50,51). Elevated PTH levels are also thought to be associated with structural changes in resistance vessels and changes in vasodilatory responses, and obesity leads to activation of the sympathetic nervous system and altered renin-angiotensin-aldosterone system responses (52,53). These situations lead to increased BP and other micro- and macrovascular complications, including proteinuria. Although outside the scope of this review, BP control post-transplant is critical to management of metabolic disorders in kidney transplant recipients.

New onset diabetes after transplant is associated with an increased risk of death with a functioning graft and an increased risk of acute rejection, thus making it critical to manage diabetes effectively (54). In addition to diet and exercise, there are over ten classes of medications currently Food and Drug Administration approved for management of patients with type 2 diabetes, but few of those have been studied in the post-transplant population. The most relevant data post-transplant is summarized in Table 1. It is important to note that the Kidney Disease Improving Global Outcomes guidelines recommend that all patients with transplants and diabetes receive cholesterol-lowering therapy with a statin as well to optimize cardiovascular risk.

Table 1.

Summary of studies of post-transplant diabetes medications

Agent	Study Year	Study Authors	Type of Study	Population Type	No. of Participants	Outcomes	PMID
Glipizide	1998	Sagedal et al. (55)	Prospective study	Kidney transplant recipients	11	Glipizide does not change cyclosporin metabolism	9850449
Rosiglitazone	2004	Baldwin et al. (56)	Prospective cohort study/observational study	Solid organ recipients	18	Rosiglitazone can be used as a well tolerated and safe alternative to insulin	15087762
Rosiglitazone	2005	Pietruck et al. (57)	Prospective cohort study/observational study	Kidney transplant recipients	22	Rosiglitazone improves fasting blood glucose without changing tacrolimus or cyclosporin levels	15773972
Repaglinide	2006	Türk et al. (58)	Observational study	Kidney transplant recipients	23	Repaglinide can be a safe option, specifically in white patients	16539642
Gliquidone	2008	Tuerk et al. (59)	Retrospective database study	Kidney transplant recipients	47	Gliquidone improves fasting blood glucose, similar efficacy as rosiglitazone	18793545
Metformin	2008	Kurian et al. (60)	Retrospective chart review	Kidney transplant recipients	32	Metformin is safe for an average of 16 mo after transplant	19095596
Metformin	2014	Stephen et al. (61)	Retrospective cohort study	Kidney transplant recipients	46,914	Metformin is not associated with negative allograft or patient survival effects	25613554
Thiazolidinediones	2008	Kurian et al. (60)	Retrospective chart review	Kidney transplant recipients	46	Thiazolidinediones are safe for an average of 37 mo after transplant	19095596
Sitagliptin	2011	Lane et al. (62)	Pilot study	Kidney transplant recipients	15	Sitagliptin can significantly reduce HbA1c without changes in tacrolimus, sirolimus, and eGFR	22067216
Sitagliptin	2014	Boerner et al. (63)	Retrospective analysis	Kidney transplant recipients	22	Sitagliptin is safe for treatment in kidney transplant recipients	24817885
Vildagliptin	2013	Werzowa et al. (64)	Randomized, placebo-controlled clinical trial	Kidney transplant recipients	48	Vildagliptin significantly decreases HbA1c and 3-mo 2-h plasma glucose	23380864
Vildagliptin	2013	Gueler et al. (65)	Retrospective study	Heart transplant recipients	30	Vildagliptin can significantly decrease average glucose levels and HbA1c	23630415
Pioglitazone	2013	Werzowa et al. (64)	Randomized, placebo-controlled clinical trial	Kidney transplant recipients	48	Pioglitazone significantly decreases HbA1c, improves fasting plasma glucose, and 3-mo 2-h plasma glucose	23380864
Liraglutide	2013	Pinelli et al. (66)	Patient series	Kidney transplant recipients	5	Liraglutide administered together with tacrolimus does not change tacrolimus levels	24065848
Liraglutide	2018	Liou et al. (67)	Retrospective analysis	Kidney transplant recipients	7	Liraglutide improved weight, glucose control, and eGFR	30316386
Empagliflozin	2019	Halden et al. (68)	Single-center, prospective, doubly blind study	Kidney transplant recipients	49	Empagliflozin decreases body weight and improves glycemic control	30862658
Empagliflozin	2019	Schwaiger et al. (69)	Prospective, interventional pilot study	Kidney transplant recipients	14	Empagliflozin improves β-cell sensitivity, decreases oral glucose insulin sensitivity, and decreases body weight	30585690

PMID, PubMed reference number; HbA1c, hemoglobin A1c.

Sodium glucose cotransporter 2 inhibitors are newer on the market and of interest in the kidney transplant population because of their cardiovascular benefits, including decreased macrovascular incidents in patients with established cardiovascular disease. However, because their mechanism of action is to concentrate glucose in the urine, there is increased risk of urinary tract infections, especially in patients with immunosuppression. A small study in which 49 patients >1 year post-transplant with stable immunosuppression and GFR were placed on empagliflozin demonstrated only a modest reduction in hemoglobin A1c (−0.2%), with only one withdrawal for urosepsis (68). Sodium glucose cotransporter 2 inhibitors are a reasonable medication to consider for post-transplant diabetes mellitus in stable patients with transplants a year out from transplant when immunosuppression has likely been reduced. Further studies are needed to determine cardiovascular benefit in this patient population.

Data support the use of dipeptidyl peptidase-4 inhibitors in post-transplant diabetes mellitus to avoid hypoglycemic events. Sitagliptin has demonstrated improved fasting blood glucose levels in patients with kidney transplant (70), but it does require dose adjustment on the basis of kidney function. Linagliptin may be more beneficial in this patient population because it is not cleared by the kidneys and should provide the same benefit. Other incretin therapies, like the glucagon-like peptide-1 receptor agonists, also could provide benefit in patients with transplants by improving insulin resistance with the additional benefit of weight lost (67).

Immunosuppressant medications have a role in inducing post-transplant hyperglycemia and post-transplant diabetes mellitus as summarized in Table 2. Often, these effects are dose dependent, such as with glucocorticoids and tacrolimus (74,79). Minimization of these immunosuppressive agents in select populations can be a reasonable strategy to aid in diabetes management; however, this confers a higher risk of graft rejection. To balance the risk of post-transplant hyperglycemia or diabetes with rejection, immunosuppressant regimens need to be individualized on the basis of past clinical trials demonstrating the effect of each immunosuppressant agent and patient characteristics.

Table 2.

Summary of studies of immunosuppressant medications’ post-transplant diabetes mellitus effects

Agent	Study Year	Study Authors	Type of Study	Population Type	No. of Participants	Outcomes	PMID
Tacrolimus	1990	Starzl et al. (71)	Experimental drug observational study	Kidney (with and without other organ[s]) transplant recipients	36	FK506 has similar side effects as cyclosporin but potentially to a lesser degree	1693970
Tacrolimus	1991	Shapiro et al. (72)	Observational study	Kidney transplant recipients	65	FK506 has similar profile as cyclosporin but may be superior to cyclosporin in its hyperuricemia, hypertension, and hypercholesterolemia side effects	1703352
Tacrolimus	2001	Duijnhoven et al. (73)	Prospective longitudinal study	Kidney transplant recipients	18	Insulin sensitivity index if abnormal or indeterminate can be a risk factor for future development of diabetes after transplant	11181807
Tacrolimus	2002	Boots et al. (74)	Prospective study	Kidney transplant recipients	15	Decreased tacrolimus trough results in improvement in β-cell secretion and withdrawing steroids results in decreased LDL, HDL, total lipid, triglycerides, and HbA1c	11752041
Tacrolimus	2008	Porrini et al. (75)	Multicenter, prospective study	Kidney transplant recipients	154	Within 1 yr of transplant, 20% of transplant recipients receiving tacrolimus develop diabetes	18431233
Tacrolimus versus cyclosporin	1997	Pirsch et al. (76)	Randomized, open label study	Kidney transplant recipients	412	Incidence of post-transplant diabetes much higher with tacrolimus (19.9%) than with cyclosporin (4.0%), but lower rate of rejection with tacrolimus compared with cyclosporin	9112351
Tacrolimus versus cyclosporin	2007	Vincenti et al. (77)	Open label, randomized, multicenter study	Kidney transplant recipients	682	Incidence of impaired fasting glucose significantly higher with tacrolimus than with cyclosporin at 6 mo	17359512
Tacrolimus versus cyclosporin	2008	Ghisdal et al. (78)	Single-center, retrospective analysis	Kidney transplant recipients	54	Conversion to cyclosporin from tacrolimus significantly decreases HbA1c and fasting plasma glucose, and it may lead to remission of diabetes after transplant	17971033
Early steroid withdrawal versus chronic low-dose steroid treatment	2008	Woodle et al. (79)	Prospective, multicenter, randomized, double-blind, placebo-controlled trial	Kidney transplant recipients	386	Early steroid withdrawal is associated with an increased rate of acute rejection but has comparable long-term graft function as chronic low-dose steroid treatment	18936569
Sirolimus	2008	Johnston et al. (80)	Retrospective data analysis	Kidney transplant recipients	20,124	Sirolimus is associated with diabetes after transplantation	18385422
Sirolimus versus tacrolimus/MMF	2011	Flechner et al. (81)	Randomized trial	Kidney transplant recipients	443	Sirolimus-based regimens were not found to be superior in outcomes to tacrolimus/MMF	21668635
Sirolimus versus cyclosporin versus steroids	2011	Gyurus et al. (82)	Retrospective analysis	Kidney transplant recipients	514	Sirolimus treatment can be a risk factor for development of diabetes	21693238
Sirolimus versus calcineurin inhibitors	2013	Veroux et al. (83)	Retrospective study	Kidney transplant recipients	344	After development of diabetes after transplantation, converting from calcineurin inhibitors to sirolimus significantly improves or resolves the diabetes without increased risk of graft rejection	23762090
Corticosteroids	2015	Pirsch et al. (39)	Double-blind, prospective, randomized, controlled trial	Kidney transplant recipients	277	Early corticosteroid withdrawal has limited benefits compared with chronic low-dose prednisone	25881802
Belatacept versus cyclosporin	2011	Rostaing et al. (84)	Post hoc analysis of randomized, controlled trial	Kidney transplant recipients	336	Numerically better graft and patient survival at 12 mo in patients with diabetes on belatacept versus cyclosporin	21921152

PMID, PubMed reference number; HbA1c, hemoglobin A1c; MMF, mycophenolate mofetil.

Tacrolimus has been shown to potentially confer a lower risk of rejection compared with cyclosporin; however, the incidence of post-transplant diabetes mellitus was shown to be significantly higher with tacrolimus (76). Decreasing tacrolimus trough levels and switching a patient from tacrolimus to cyclosporin have both been shown to improve or even remit post-transplant dysglycemia and diabetes (74,77). Additionally, sirolimus has been shown to confer an independent risk toward developing post-transplant diabetes mellitus (81). Similar to tacrolimus, switching patients from sirolimus to cyclosporin after development of post-transplant diabetes mellitus has been shown to improve or even resolve diabetes without compromising graft function (83). Belatacept is an alternative to calcineurin inhibitors that may be used as the backbone of immunosuppressive therapy to avoid the toxic effects of tacrolimus. Belatacept has been shown to improve glucose tolerance when withdrawing tacrolimus potentially through CD86 blockade, which may be involved in insulin resistance (85).

Secondary hyperparathyroidism occurs in most patients with CKD and can persist after kidney transplant in up to 66% of patients, despite an initial decrease in PTH levels (86). Maintaining normal PTH post-transplant is critical because it affects bone health; additionally, it is associated with graft loss and all-cause mortality. Pihlstrøm et al. (87) found that, after a follow-up time of approximately 7 years, patients with kidney transplants and hyperparathyroidism (intact PTH >65 pg/ml) had an increased risk of all-cause mortality (hazard ratio, 1.04) and graft loss (hazard ratio, 1.06), indicating the importance of maintaining PTH levels post-transplant.

PTH helps to maintain the calcium-phosphate balance along with the kidneys, bones, and gastrointestinal tract (Figure 2). Vitamin D, vitamin D analogs, and calcimimetics are most commonly used for the medical management of hyperparathyroidism. Cinicalcet, a calcimimetic, has the most data for use after transplantation. There is only one randomized, controlled trial comparing medical management with parathyroidectomy in the post-transplant setting (88). Delos Santos et al. (89) provide an excellent overview of medical management, including data in patients with transplants, and it will not be included here.

Figure 2.

Calcium (Ca)-phosphate (Phos) balance. PTH, parathyroid hormone.

In studies of parathyroidectomy post-transplant, the benefits on the graft are not as clear, and there is potential for allograft function impairment in the year postparathyroidectomy (90). In the only randomized, controlled trial of parathyroidectomy versus medical management with cinacalcet post-transplant, parathyroidectomy was found to be superior at controlling calcium and PTH levels and increasing femoral neck bone mineral density; however, the long-term clinical benefits are not known (88). However, hyperparathyroidism is a clear indicator of poor transplant outcomes, and effective treatment prior to transplant is critical for post-transplant success. The method of management is not well studied and still up for discussion with larger randomized, controlled trials.

Obesity is the most common metabolic disorder affecting the transplant, and it should not be ignored post-transplant because weight gain can be common (91,92). Multiple studies have corroborated that bariatric surgery in general is safe and feasible in patients having undergone previous kidney transplantation as well as those with ESKD, and it seems to be more efficacious than supervised medical weight loss strategies (19,27,93,94). A Markov decision analytic model was used in a recent study performed by Choudhury et al. (27) in assessing which option is the best suited for kidney transplant candidates in reaching a BMI goal of <35 kg/m² for listing. These analyses compared medically supervised weight loss with both sleeve gastrectomy and Roux-en-y gastric bypass arms, demonstrating both improved overall survival as well as transition to a transplanted state in the Roux-en-y gastric bypass arm (27). Clearly, more research is needed to fully identify the best strategies for weight loss in our kidney transplant population to support greater access to and improved results in obese candidates and recipients.

There are significant considerations when managing metabolic disorders after kidney transplantation given the crucial immunosuppressive balance with medications and the effect that procedures, such as parathyroidectomy and surgery, may have on graft outcomes. However, the close management of these metabolic disorders is necessary for long-term patient survival.

Metabolic disorders, including diabetes, hyperparathyroidism, and obesity, clearly have significant effect on the kidney transplant population during multiple phases of care—affecting patient access to the waitlist, the ability to successfully receive a transplant, and ultimately, the likelihood of experiencing a good outcome long term. Understanding the risks associated with these disorders and optimal management strategies is crucial to the ultimate successful outcome post-transplant.

Disclosures

Dr. Belfort de Aguiar, Dr. Callender, Dr. Cohen, Dr. Haakinson, and Dr. Korah have nothing to disclose.

Funding

None.