Version May 2024
INTRODUCTION — Diabetic kidney disease is the most common cause of end-stage kidney disease (ESKD) in Western societies and accounts for approximately 40 to 45 percent of cases of ESKD in the United States. Diabetic kidney disease is the etiology of ESKD in approximately 39 percent of patients on the kidney transplant waiting list in 2020. Approximately 33 percent of kidney transplant recipients transplanted in the United States in 2020 had ESKD secondary to diabetes, which remains the leading cause of ESKD among kidney transplant recipients [1,2].
Diabetes presents particular challenges both in the pretransplant evaluation and after transplantation. These challenges are related to the high incidence of cardiovascular disease among patients with diabetes and the increased risk of bacterial and fungal infections compared with nondiabetic transplant recipients despite equivalent immunosuppression.
In addition, glycemic control is often more difficult after transplantation. In addition to the increased clearance of insulin from the circulation with a newly functioning kidney transplant, immunosuppressive regimens used after transplantation have detrimental effects on pancreatic beta cell function and peripheral insulin action, which make it difficult to achieve target glucose levels and prevent the recurrence of the diabetic lesions in the transplanted kidney [3].
The major issues related to kidney transplantation in patients with diabetes and ESKD are discussed in this topic review. The role of combined kidney-pancreas transplantation is discussed separately. Posttransplantation diabetes mellitus in kidney transplant recipients is also discussed separately:
●(See "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications".)
●(See "Kidney transplantation in adults: Posttransplantation diabetes mellitus".)
EPIDEMIOLOGY — Diabetic kidney disease remains the leading cause of end-stage kidney disease (ESKD) among patients on the kidney transplant waiting list. Although overall rates of deceased-donor transplantation have increased since the new kidney allocation system (KAS) was implemented in 2014, patients with ESKD from diabetic kidney disease have a lower rate (approximately 15 percent) of receiving a deceased-donor kidney transplant compared with waitlisted patients with other causes of ESKD [2]. Patients with ESKD from diabetic kidney disease also have the highest pretransplant mortality rates while on the waitlist (8 deaths per 100 waitlist years) and higher mortality rates within six months after removal from a waitlist (approximately 14 percent), compared with patients with other causes of ESKD. In 2020, approximately 25 percent of living-donor kidney transplants were performed in patients with diabetes and ESKD, in what appears to be a rising trend [2]. These data put into perspective the unique challenges faced by this patient population.
A more detailed discussion of the kidney transplant waiting list in the United States is presented separately. (See "Kidney transplantation in adults: The kidney transplant waiting list in the United States".)
BENEFITS OF TRANSPLANTATION — Kidney transplantation is the preferred kidney replacement therapy for patients with diabetes and end-stage kidney disease (ESKD) since it results in better survival and quality of life than dialysis in the vast majority of patients.
Transplantation versus dialysis — For all patients with diabetic kidney disease and ESKD who are eligible for transplantation, we recommend kidney transplantation rather than dialysis. Compared with dialysis, transplantation is associated with much better survival among all patients with ESKD [4-11]. In one of the largest, most comprehensive studies to date, survival analysis using data from the United States Renal Data System (USRDS) was performed on nearly 230,000 patients on dialysis [7]; among the 46,000 placed on a waiting list for transplantation, 23,000 subsequently underwent a first cadaveric transplant. Despite a significantly increased short-term mortality following surgery, the long-term risk of death was much lower among transplant recipients compared with patients accepted for transplantation but who had not yet received an allograft. As an example, at three to four years, the mortality risk was nearly 70 percent lower among transplant recipients compared with waitlisted patients (relative risk [RR] 0.32).
Diabetes was the cause of ESKD among 33 percent of the 46,164 patients on the transplant waiting list and 31 percent of the 23,275 transplant recipients. At 18 months posttransplantation, the subset of 7200 transplant recipients with diabetes had a 73 percent reduced risk of death compared with the approximately 15,000 waitlisted patients with diabetes (RR 0.27, 95% CI 0.24-0.30). The projected increase in life was 11 years among patients with diabetes who undergo transplantation compared with patients with diabetes who remain on the waiting list.
Multiple other studies have confirmed the benefit of transplantation over dialysis and the gain in life years achieved through transplantation in both type 1 and type 2 diabetes mellitus patients with ESKD [10,12].
The reduction in mortality among transplant recipients compared with dialysis patients is due in part to a decrease in cardiovascular events, especially among patients with diabetes. Transplantation reduces the risk of fatal and nonfatal cardiovascular complications compared with long-term dialysis among patients selected to be suitable transplant candidates [13-17].
Preemptive transplantation and living-donor versus deceased-donor kidneys — For patients with diabetic kidney disease and ESKD who are eligible for transplantation, we recommend preemptive kidney transplantation if possible, rather than initiation of dialysis followed by transplantation. Among all patients with chronic kidney disease (CKD), evidence suggests that preemptive kidney transplantation (ie, before dialysis is required) leads to substantial improvements in patient survival when compared with transplantation after a period of dialysis therapy [18-21]. (See "Kidney transplantation in adults: Timing of transplantation and issues related to dialysis", section on 'Preemptive transplantation'.)
Limited evidence also suggests that patients with diabetes and CKD have a survival advantage with preemptive transplantation. In an analysis of 73,103 patients registered in the USRDS database including almost 20,000 patients with diabetes, compared with preemptive transplantation, there was a relative increase in mortality risk after transplantation of 21, 28, 41, 53, and 72 percent among those with waiting times of 6 to 12, 12 to 24, 24 to 36, 36 to 48, and over 48 months, respectively [19].
Similarly, relative to preemptive transplants, waiting times of 0 to 6, 6 to 12, 12 to 24, and over 24 months conferred a 17, 37, 55, and 68 percent relative increase in risk for death-censored graft loss after transplantation, respectively. The association between mortality risk and graft loss and increasing time on dialysis was observed for all subgroups defined by the cause of ESKD, including patients with diabetes.
It is not clear whether the benefits of preemptive transplantation among patients with diabetes are achieved when either living-donor or deceased-donor kidneys are used. In the study cited above, preemptive transplantation was associated with better patient and allograft survival among both living-donor and deceased-donor recipients [19]. However, another study has suggested that the benefit of preemptive transplantation is limited to living-donor recipients. In a retrospective study of over 20,000 patients with diabetes, a lower mortality was observed among recipients of preemptive kidney transplants from living donors (with RRs of 0.57 and 0.65 for recipients with type 1 and type 2 diabetes, respectively), but this association was not observed among recipients of cadaveric donor kidneys who had either type 1 or type 2 diabetes [22]. In practice, preemptive transplantation with a deceased-donor kidney rarely occurs because of prolonged waiting-list times. (See "Kidney transplantation in adults: The kidney transplant waiting list in the United States", section on 'Access to the waiting list'.)
Some studies have shown that living-donor kidney transplantation provides better outcomes, including graft and patient survival, compared with simultaneous pancreas-kidney (SPK) transplantation. Issues surrounding patient and graft survival relating to pancreas-kidney transplantation and selection of the optimal transplant procedure are discussed separately. (See "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications" and "Pancreas-kidney transplantation in diabetes mellitus: Patient selection and pretransplant evaluation", section on 'Selection of optimal procedure'.)
Higher-risk kidneys — In patients with diabetes who are waitlisted, the risk associated with accepting marginal donor kidneys, such as those with high kidney donor profile index (KDPI), those from patients at increased risk of infection, and those from deceased donors with diabetes, must be balanced with the risks of remaining on the transplant waitlist.
High-KDPI kidneys — We advise that, in general, waitlisted patients with diabetes consent for deceased-donor kidneys with a kidney donor profile index (KDPI) ≥85. However, the decision to recommend KDPI ≥85 consent for patients with diabetes may depend upon additional factors. Increased mortality and graft loss may be observed in high-KDPI candidates with risk factors including coronary artery disease, peripheral vascular disease, obesity, and hypotension [23].
KDPI is calculated using donor age, ethnicity, hypertension, diabetes, height, weight, creatinine, cause of death, hepatitis C virus (HCV) status, hepatitis B virus (HBV) status, and donation after cardiac death status (see "Kidney transplantation in adults: Organ sharing"). Kidneys with the highest KDPI have the lowest long-term projected allograft survival. In 2014, the use of KDPI replaced the designation of expanded-criteria donor (ECD) in organ allocation within the United States. Kidneys were previously designated as ECD if the donor was brain dead and older than 60 years or the donor was older than 50 years with at least two of the following: hypertension, serum creatinine greater than 1.5 mg/dL (133 micromol/L), or cerebrovascular cause of death [24].
Data on the use of high-KDPI kidneys in diabetic kidney transplant candidates have shown a survival benefit. As an example, a retrospective analysis of 184,277 patients added to the deceased-donor kidney waitlist in the United States between 2002 and 2011 assessed the survival benefit of transplantation with high-KDPI (KDPI >70) kidneys versus waiting for an offer with a lower-KDPI (KDPI <70) kidney [25]. Transplantation with high-KDPI kidneys was associated with increased short-term but decreased long-term mortality risk. All patients with diabetes aged >50 years and/or at centers with median wait time ≥33 months had greater five-year survival with high-KDPI kidney transplants compared with waiting for an offer of a lower-KDPI kidney.
Similarly, patients with diabetes benefit from transplantation of kidneys donated after cardiac death, which are generally perceived to have worse outcomes compared with standard-criteria kidneys donated after noncardiac death. This was shown in an observational cohort study of 2575 ESKD patients that evaluated the mortality risk of those who received a standard-criteria kidney donated after cardiac death versus patients who continued on dialysis and waited for a standard-criteria kidney donated after brain death [26]. Approximately 29 percent of patients had diabetes and/or hypertension. Compared with those who remained on dialysis, mortality was significantly lower among patients who received a kidney donated after cardiac death (hazard ratio [HR] 0.44, 95% CI 0.24-0.80).
Kidneys from donors meeting risk criteria — We advise that waitlisted patients with diabetes consent for kidneys from donors who fall under the 2002 United States Public Health Service Donor Risk Criteria; these kidneys were formerly referred to as Public Health Service Increased Risk kidneys. As of March 2021, there have been changes to this terminology and criteria to make them more aligned with the 2020 United States Public Health Service Guideline for assessing solid organ donors and monitoring transplant recipients for HIV, hepatitis B (HBV), and hepatitis C (HCV). Policy changes include refined criteria for determining if a deceased or living donor has risk for acute HIV, HBV, or HCV; removal of increased risk terminology; modified testing requirements and timeframes for deceased donors, living donors, candidates, and recipient; and substitution of providing information rather than requiring specific, separate informed consent. (See "Evaluation of the potential deceased organ donor (adult)", section on 'Medical and social history'.)
By definition, donors meeting the risk criteria are associated with a relatively increased risk of infection (approximately 1 in 1000 risk of HCV and 1 in 10,000 risk of HIV). In an analysis of data from the Scientific Registry of Transplant Recipients (SRTR), acceptance of a such kidneys was associated with a long-term survival benefit when compared with declining such an offer [27,28]. Candidates who accepted such kidney offers experienced a 48 percent lower risk of death that continued beyond six months after the decision to accept such a kidney.
Deceased diabetic donor kidneys — We also advise that waitlisted patients with diabetes consent for kidneys from deceased donors with diabetes although each case must be reviewed individually. In general, kidneys from deceased donors with diabetes are carefully selected to avoid those with severe damage from diabetic kidney disease. In an analysis of the Organ Procurement and Transplantation Network (OPTN) database, recipients with diabetes who received kidneys from deceased donors with diabetes had a decreased risk of all-cause mortality compared with those remaining on the waitlist or receiving a kidney from a donor without diabetes (HR 0.91, 95% CI 0.84-0.98). When taking KDPI into account, a lower mortality risk was observed in recipients of low-KDPI (KDPI ≤85 percent) diabetic donor kidneys or high-KDPI (KDPI >85 percent) nondiabetic donor kidneys but not in recipients transplanted with a high-KDPI diabetic donor kidney. In addition, diabetic transplant candidates aged <40 years at the time of waitlisting had no survival benefit from transplantation with a diabetic donor kidney, regardless of KDPI. Thus, based upon these findings, a comprehensive assessment of the diabetic donor, including possible donor kidney biopsy, should be performed, as well as careful recipient selection for such diabetic donor offers.
PRETRANSPLANT EVALUATION — Issues related to pretransplant evaluation of all patients with chronic kidney disease (CKD), including issues of particular concern among patients with diabetes, are presented separately:
POSTTRANSPLANTATION CARE — Many complications related to kidney transplantation may occur in all transplant recipients. These include allograft rejection and an increased risk of infection and malignancy:
●(See "Malignancy after solid organ transplantation".)
●(See "Infection in the solid organ transplant recipient".)
●(See "Kidney transplantation in adults: Chronic allograft nephropathy".)
The following is a focused discussion on some of these issues as they relate to the patient with diabetes with a kidney transplant.
Additional issues that may affect all patients with diabetes, such as gastroparesis, autonomic neuropathy, peripheral neuropathy, and foot ulcers, are presented separately.
Allograft rejection — The incidence of rejection in patients with diabetes compared with patients without diabetes has not been well studied. In small studies, the risk of acute rejection was found to be similar between patients with and without diabetes [29,30]. However, one retrospective analysis of 1140 kidney transplant recipients, of whom 10 percent were diabetic, reported a higher risk for acute T cell-mediated rejection among patients with diabetes compared with those without diabetes (19 versus 12 percent, respectively) [31]. In general, diabetic transplant recipients are not considered to be at increased risk of rejection and do not need an augmented level of immunosuppression or extra monitoring. This issue in all kidney transplant recipients is discussed in detail separately:
●(See "Kidney transplantation in adults: Treatment of acute T cell-mediated (cellular) rejection".)
Malignancies — Although a paucity of data exists, the incidence of malignancies appears to be similar in kidney transplant recipients with and without diabetes [32]. However, one study reported a greater incidence of malignancies in patients who receive simultaneous pancreas-kidney (SPK) transplant compared with kidney transplantation [33]. It is unclear whether this may have been secondary to differences in the intensity of immunosuppression among such patients.
This issue in all kidney transplant recipients is discussed in detail separately:
●(See "Malignancy after solid organ transplantation".)
●(See "Treatment and prevention of post-transplant lymphoproliferative disorders".)
Infections — Although the exact risk and incidence of infections attributed purely to a recipient's diabetic status are uncertain, diabetic kidney transplant recipients appear to have a higher risk of infection-related mortality and morbidity in the setting of immunosuppression:
●In one study that compared infection-related mortality among 19,103 kidney transplant recipients (2968 [15.5 percent] with preexisting diabetes before transplant), the risks of overall (16 versus 10 percent) and infection-related (3.3 versus 2.1 percent) mortality after transplantation were higher for recipients with diabetes than in those without diabetes [34].
●In an analysis of 29,966 kidney transplant recipients from the United States Renal Data System (USRDS), 42 percent of whom had diabetes before transplant, those with pretransplant diabetes had a 43 percent higher risk of developing infections requiring hospitalization compared with those without diabetes [35].
Urinary tract infection — Despite the widespread use of prophylactic antibiotics, urinary tract infections (UTIs) remain common posttransplantation among kidney transplant recipients.
Posttransplant UTIs are more common in recipients with diabetes versus those without diabetes [36,37]. This is in part due to the high incidence of neurogenic bladders among patients with diabetes. Other risks and causes of UTIs in transplant recipients with diabetes are similar to those in nontransplant patients with diabetes, including glucosuria, impaired host responses, and the use of sodium-glucose co-transporter 2 (SGLT-2) inhibitors.
Our approach to prophylactic therapy among recipients with diabetes is the same as that for recipients without diabetes. This is discussed in more detail elsewhere. (See "Urinary tract infection in kidney transplant recipients", section on 'Prevention'.)
Recurrent diabetic kidney disease — Historically, the vast majority of diabetic transplant recipients have developed histologic changes of recurrent diabetic kidney disease, in some cases within one year posttransplantation [38]. In the contemporary era of tacrolimus-based immunosuppression, up to 52 percent of diabetic transplant recipients have histologic evidence of diabetic kidney disease/mesangial sclerosis at 10 years after transplantation [39]. However, the incidence of diabetic kidney disease as a cause of graft failure is thought to be rare [40].
Recurrent disease in the allograft can theoretically be prevented by optimal glycemic control. A single randomized trial of patients with type 1 diabetes showed that, compared with standard therapy, intensive insulin therapy at the time of transplantation was associated with fewer pathological changes of diabetic kidney disease on five-year kidney allograft biopsies [41]. Recurrent diabetic kidney disease is prevented by a successful pancreas-kidney transplant. (See "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications", section on 'Benefits'.)
Glycemic control — Glycemic control may become acutely worse in the immediate posttransplant period, in part due to increased insulin resistance and impaired insulin secretion associated with glucocorticoids and other immunosuppressant medications (ie, tacrolimus), respectively. In addition, weight gain, which occurs commonly after kidney transplantation, may increase the risk for worsening glycemic control.
Patients with previously diagnosed diabetes will typically display worse glycemic control compared with patients diagnosed with posttransplant diabetes (PTDM) [42]. Continuous glucose monitoring may be a potential option in this setting [42-44], but there are no data showing that this approach is superior to noncontinuous glucose monitoring via capillary glucose testing. In patients testing with self-monitored capillary blood glucose, we advise monitoring not just fasting blood glucose but also postprandial blood glucose and blood glucose in the afternoon (ie, 4 PM) or early evening. A commonly seen glucose pattern consists of normal fasting glucose or mild fasting hyperglycemia with more pronounced hyperglycemia (usually exceeding ≥200 mg/dL) in the early afternoon [45]. In cases of PTDM, hemoglobin A1c may not be reliable for diagnosis early (within first 45 to 90 days) after transplantation due to several biases (ie, blood transfusions, anemia, etc). Thus, we advise caution with relying only on HbA1c or fasting blood glucose for the diagnosis of PTDM. (See "Kidney transplantation in adults: Posttransplantation diabetes mellitus", section on 'Establishing the diagnosis'.)
Close attention to nutrition both pre- and posttransplant may help mitigate posttransplant weight gain and improve glycemic control. Issues surrounding glycemic control among posttransplant patients with diabetes are discussed separately. (See "Kidney transplantation in adults: Posttransplantation diabetes mellitus".)
The importance of glycemic control on long-term outcomes was shown in a study of 486 patients with type 1 diabetes who underwent SPK (n = 256) or living-donor kidney (n = 230) transplantation between 1983 and 2012 [46]. With a median follow-up of 7.9 years, the adjusted hazard ratio (HR) for cardiovascular disease-related death in SPK compared with living-donor kidney transplantation was 0.63. This outcome was accentuated in those with a functioning SPK transplant.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)
SUMMARY AND RECOMMENDATIONS
●Overview – Diabetic kidney disease is the most common cause of end-stage kidney disease (ESKD) in Western societies. Diabetic kidney disease is the etiology of ESKD in approximately 25 to 27 percent of kidney transplant recipients transplanted in the United States. (See 'Introduction' above and 'Epidemiology' above.)
●Benefits of transplantation
•Transplantation versus dialysis – Kidney transplantation is generally the optimal kidney replacement therapy for patients with diabetes and ESKD. For all patients with diabetes and ESKD who are eligible for transplantation, we recommend a kidney transplant rather than dialysis (Grade 1B). (See 'Transplantation versus dialysis' above.)
•Timing of transplantation – The timing of transplantation influences patient survival; patients who undergo transplantation without ever starting dialysis have decreased mortality compared with those who are dialyzed prior to transplantation. For predialysis patients with diabetes and chronic kidney disease (CKD) who are eligible for transplantation, we recommend, whenever possible, preemptive kidney transplantation rather than initiation of dialysis followed by transplantation (Grade 1B). Living-donor kidneys are preferred to deceased-donor kidneys. (See 'Preemptive transplantation and living-donor versus deceased-donor kidneys' above.)
•Higher-risk kidneys – The wait time for a high-kidney donor profile index (KDPI) kidney may be less than that for a standard-donor kidney. Patients with diabetes who receive high-KDPI kidneys appear to be likely to live longer than if they remained on dialysis, although the high-KDPI kidney may not be of the same quality as a standard-donor kidney. We advise that, in general, waitlisted patients with diabetes register on the standard-donor waitlist as well as the waitlists for high-KDPI kidneys, kidneys from donors meeting risk criteria, and deceased diabetic donor kidneys. (See 'Higher-risk kidneys' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Garry S Tobin, MD, and Christina L Klein, MD, who contributed to earlier versions of this topic review.
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