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Literature review current through: Oct 2013. | This topic last updated: Jan 9, 2013.

INTRODUCTION — Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in Western societies and accounts for approximately 40 to 45 percent of cases of ESRD in the United States. Diabetic nephropathy was the etiology of ESRD in approximately 23 percent of kidney transplant recipients transplanted in the United States in 2008 [ 1 ].

Diabetes presents particular challenges both in the pretransplant evaluation and after transplantation. These challenges are related to the high incidence of cardiovascular disease among diabetic patients, and the increased risk of bacterial and fungal infections compared with nondiabetic transplant recipients.

In addition, glycemic control is often more difficult after transplantation. This is because 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 [ 2 ].

The major issues related to renal transplantation in diabetic patients with ESRD are discussed in this topic review. The role of combined kidney-pancreas transplantation is discussed separately. New onset diabetes that occurs after renal transplantation is also discussed separately. (See "Benefits and complications associated with kidney-pancreas transplantation in diabetes mellitus" and "Patient selection for and immunologic issues relating to kidney-pancreas transplantation in diabetes mellitus" and "New onset diabetes after transplant (NODAT) in renal transplant recipients" .)

BENEFITS OF TRANSPLANTATION — Kidney transplantation is the preferred renal replacement therapy for diabetic patients with ESRD, since it generally results in better survival and quality of life than dialysis. We recommend that diabetic patients who are eligible receive a kidney transplant rather than continue dialysis. Preemptive kidney transplantation rather than initiation of dialysis followed by transplantation is preferred, and if possible, a living donor kidney is preferred to a deceased donor kidney. We also suggest that all wait-listed diabetic patients register on both the standard-donor wait list and the expanded-criteria donor (ECD) wait list. Although ECD kidneys do not meet the criteria for standard donor kidneys, diabetic patients who receive them are likely to live longer than if they remained on dialysis.

Transplantation versus dialysis — For eligible candidates, we recommend kidney transplantation rather than dialysis. Compared with dialysis, transplantation is associated with a much better survival among all patients with ESRD [ 3-10 ]. 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 dialysis patients [ 6 ]; 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 wait-list patients (relative risk of 0.32).

Diabetes was the cause of ESRD 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 post-transplantation, the subset of 7200 diabetic transplant recipients had a 73 percent reduced risk of death compared with the approximately 15,000 diabetic wait-listed patients (relative risk 0.27, 95% CI, 0.24-0.30). The projected increase in life was 11 years among diabetic patients who undergo transplantation compared with diabetics who remain on the waiting list.

Another study from Scotland reported the survival of 1732 patients wait-listed for a first kidney transplant in 1999 [ 9 ]. Among approximately 250 diabetic patients, at 12 months after transplantation, the risk of death was lower with renal transplantation compared with dialysis (relative risk 0.33, 95% CI 0.15-0.74). Projected life expectancy was significantly higher in those who underwent transplantation (17.2 versus 5.8 years).

The reduction in mortality among transplant recipients compared with dialysis patients is due in part to a decrease in cardiovascular events especially among diabetic patients. Transplantation reduces the risk of fatal and non-fatal cardiovascular complications compared with long-term dialysis among patients selected to be suitable transplant candidates [ 11-15 ].

Preemptive transplantation and living donor versus deceased kidneys — 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 [ 16-19 ]. (See"Dialysis issues prior to and after renal transplantation", section on 'Preemptive transplantation and outcomes' .)

Limited evidence also suggests that diabetic patients with CKD have a survival advantage with preemptive transplantation. In an analysis of 73,103 patients registered in the USRDS database including almost 20,000 diabetic patients, 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 months, 12 to 24 months, 24 to 36, 36 to 48, and over 48 months, respectively [ 17 ].

Similarly, relative to preemptive transplants, waiting times of 0 to 6 months, 6 to 12 months, 12 to 24 months, 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 ESRD, including patients with diabetes.

It is not clear whether the benefits of preemptive transplantation among diabetic patients 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 kidney and deceased donor recipients [ 17 ]. 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 diabetic patients a lower mortality was observed among recipients of preemptive kidney transplants from living donors (with relative risks of 0.57 and 0.65 for recipients with type 1 and type 2 diabetes, respectively) but this association was NOT observed among either type 1 or type 2 diabetic recipients of cadaveric donor kidneys [ 20 ]. In practice, preemptive transplantation with a deceased donor kidney is rarely performed because of prolonged waiting-list times. (See "The kidney transplant waiting list", section on 'Access to the waiting list' .)

Living donor kidney transplantation provides better outcomes including graft and patient survival compared with simultaneous kidney-pancreas transplantation. Issues surrounding patient survival relating to kidney-pancreas transplantation are discussed separately. (See "Benefits and complications associated with kidney-pancreas transplantation in diabetes mellitus" .)

Expanded criteria kidneys — We suggest that all wait-listed diabetic patients register on both the standard-donor wait list and the expanded-criteria donor (ECD) wait list.

ECD kidneys are those from either a brain-dead donor older than 60 years, or a donor older than 50 years with at least two of the following: hypertension, serum creatinine greater than 1.5 mg/dL (133 µmol/L) or cerebrovascular cause of death [ 21 ]. Among all dialysis patients, transplantation of an ECD kidney is associated with a higher risk of allograft failure compared with transplantation of a standard donor kidney, but with a lower mortality compared with remaining on dialysis [ 21 ]. Upon registering on the deceased donor waiting list, potential recipients must state whether they will accept offers of an ECD kidney.

The potential benefit gained by all ECD-transplant recipients depends upon the patient’s age and on the anticipated waiting time for a deceased donor kidney; in general, older patients incur a survival benefit with ECD kidneys, whereas patients younger than 40 years are better off waiting for a standard kidney. This was shown in an in-depth analysis of the Scientific Registry of Transplant Recipients [ 21 ]. Although transplantation of an ECD kidney was associated with a survival benefit overall, subgroup analysis demonstrated a significant benefit for older than but not younger than 40 years. In addition, the survival benefit among patients older than 40 was not observed among those who were wait-listed at organ procurement organizations with short or medium wait-list times. (See "The kidney transplant waiting list", section on 'Expanded donor kidneys' .)

However, among diabetic patients of any age, there may be a survival advantage gained from accepting an ECD kidney [ 21,22 ]. In the study cited above, among all diabetic patients, there was a 23 percent reduction in mortality among recipients of an ECD transplantation [ 21 ]. By contrast to non-diabetic patients older than 40, a survival benefit was even observed among diabetic patients older than 40 who were wait-listed at organ procurement organizations with short or medium wait-list times (relative risk, 0.77, 95% CI 0.64 -0.94). In addition, among 2016 diabetic patients who were younger than 40 years and in an organ procurement organization with a short or medium waiting time, transplantation of an ECD kidney was associated with a 41 percent reduction in mortality (relative risk 0.59, 95% CI 0.30–1.16).

Similarly, diabetic patients benefit from transplantation of kidneys donated after cardiac death, which are generally perceived to have worse outcomes compared with standard criteria kidneys donated after non cardiac death. This was shown in an observational cohort study of 2575 ESRD 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 [ 23 ]. Approximately 29 percent of patients had diabetes and/or hypertension. Compared to those who remained on dialysis, mortality was significantly lower among patients who received a kidney donated after cardiac death (hazard ratio 0.44, 95% CI 0.24-0.80).

Thus survival of diabetic patients, especially those over age 40, is generally improved following transplantation of ECD kidneys compared with remaining on dialysis while awaiting a standard kidney.

PRETRANSPLANT EVALUATION — General issues related to pretransplant evaluation of all patients with chronic kidney disease are presented separately. (See"Evaluation of the potential renal transplant recipient" .) The following section reviews several issues of particular concern among patients with diabetes.

Timing of referral — We agree with the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines that recommend referral of chronic kidney disease (CKD) patients to transplant centers when estimated glomerular filtration rate (GFR) is less than 30 mL/min [ 24 ].

Cardiac evaluation — Cardiovascular disease remains the most common cause of death following kidney transplantation among diabetic patients, and the highest rates of adverse cardiac events are observed in the early post-transplant period. Diabetic transplant candidates are screened for coronary heart disease in order to identify modifiable cardiac conditions and potentially reduce morbidity and/or mortality on the waitlist and following transplantation. Additionally, the evaluation may identify patients who have limited expected survival due to severe cardiac disease; such patients should not undergo transplantation.

Prevalence of cardiovascular disease — Among all kidney transplant candidates, the incidence of coronary heart disease varies based on the specific population studied and the screening method utilized. (See "Evaluation of the potential renal transplant recipient" .)

The reported incidence of significant cardiac disease among asymptomatic diabetic patients who are evaluated for transplantation is approximately 33 to 50 percent [ 25-28 ]. As examples:

Among 155 consecutive diabetic patients evaluated for transplant between 1999 and 2004, angiographic evidence of significant coronary heart disease (>50 percent luminal diameter stenosis) was found in 69 patients (45 percent), with only 26 (17 percent) having history of angina [ 25 ]. The only risk factor of significance was age, with no patient under the age of 35 (n = 11) with significant coronary heart disease. The degree of hypercholesterolemia, hypertension, and smoking history did not differ between those with and without documented coronary disease.
Among 97 asymptomatic diabetic transplant candidates, 33 and 48 percent of type 1 and 2 diabetes patients had coronary heart disease, respectively, as defined by >70 percent stenosis in one or more coronary arteries [ 26 ]. Factors that predicted significant coronary heart disease included obesity (BMI >25, relative risk (RR) of 4.8), increased age (>47 years, RR of 3.0), and smoking history (2 percent increase in risk per pack-year of smoking).

In light of the high prevalence of asymptomatic cardiovascular disease, preoperative screening is routine at most transplant centers, although there have been attempts to develop clinical algorithms to identify high risk candidates. As an example, one such algorithm was developed and validated in a retrospective study of type 1 diabetic patients who were being evaluated for either solitary kidney or combined kidney pancreas transplantation between 1991 and 2001 [ 27,28 ]. Patients were characterized as high risk based upon the presence of any of the following risk factors: age ≥45 years, smoking history ≥5 pack-years, diabetes duration ≥25 years, or ST-T segment abnormalities on resting electrocardiogram.

Among 84 high risk patients who underwent angiography, significant coronary heart disease was detected in 31 (37 percent). At a median follow up of 47 months, six cardiac deaths occurred in the high risk group and no deaths occurred in the low risk group, although survival among the high risk patients was not different among those with or without significant disease detected by angiography.

Approach to evaluation — The optimal approach to the diabetic kidney transplant recipient is not clear and there are no reliable comparative studies in this cohort to guide the evaluation. Some clinicians base their approach on the age of the patient, duration of diabetes mellitus and smoking history, and presence or absence of electrocardiographic changes [ 29 ].

We perform noninvasive cardiac testing in all diabetic patients regardless of age. We do not routinely perform cardiac catheterization in all diabetic patients, unless they have symptoms and/or signs consistent with coronary heart disease, history of myocardial infarction and/or unstable angina. The data on patient survival does not unequivocally support the use of routine pretransplant cardiac catheterization, especially given the potential adverse effects of cardiac catheterization, including contrast nephropathy which could result in the earlier initiation of dialysis than may have occurred otherwise. Some clinicians, however, use routine cardiac catheterization among all diabetic patients older than 45 years of age.

The accuracy and predictive value of noninvasive testing is only fair in the ESRD population. We generally use dobutamine stress echocardiography rather than other noninvasive tests since data have suggested that this modality is most accurate among ESRD patients. (See "Clinical manifestations and diagnosis of coronary heart disease in end-stage renal disease (dialysis)", section on 'Stress tests' .)

We suggest the following approach:

All diabetic transplant candidates are evaluated with a history, physical examination, electrocardiogram, and chest radiograph.
Diabetic patients who have symptoms and/or signs consistent with coronary heart disease or a history of myocardial infarction undergo cardiac catheterization unless they recently underwent successful revascularization. As in the non-ESRD population, patients with unstable angina should undergo cardiac catheterization. (See "Overview of the acute management of unstable angina and non-ST elevation myocardial infarction", section on 'Immediate angiography and revascularization' .)
A screening dobutamine stress echocardiography is performed among all diabetic patients who do not undergo initial screening coronary angiography. If positive, the decision to proceed with angiography and possible angioplasty or surgery is usually made in conjunction with the patients' cardiologist.

As noted above, the overall accuracy and predictive value of noninvasive testing is only fair in the ESRD population, with accuracy of the different non-invasive imaging tests being center-specific and dependent upon the expertise of the examiner [ 30,31 ]. There are also problems associated with advanced kidney disease, including baseline abnormalities on the electrocardiogram and thallium scintigraphy and a frequent inability of patients to perform adequately during an exercise test [ 32 ]. Thus, exercise electrocardiography and exercise echocardiography are not generally recommended because of poor exercise capabilities in the dialysis population [ 30 ]. The optimal approach to non-invasive imaging in dialysis patients is discussed elsewhere. (See "Clinical manifestations and diagnosis of coronary heart disease in end-stage renal disease (dialysis)", section on 'Stress tests' .)

Among transplantation candidates, dobutamine -induced stress echocardiography appears to be more sensitive than other non-invasive tests, including vasodilator-induced stress nuclear scintigraphy. In one study of 125 candidates (39 percent diabetic patients), all patients underwent coronary angiography, dobutamine stress echocardiography, and resting and exercise electrocardiography [ 33 ]. Independent predictors of severe coronary artery disease (defined as luminal stenosis >70 percent by visual estimation in at least one epicardial artery) were a positive stress echo result (odds ratio of 23, 95% CI 6-88) or an abnormal resting electrocardiogram (odds ratio 7, 95% CI 2-34). Overall, the sensitivity and specificity of dobutamine stress echocardiography was approximately 75 percent.

Dobutamine -induced stress echocardiography may also be used to stratify cardiovascular risk [ 34,35 ]. This was assessed in a meta-analysis that evaluated the prognostic value of dobutamine stress echocardiography (four trials) and thallium scintigraphy (four studies with pharmacologic stress and four with exercise stress) in dialysis patients undergoing assessment for kidney or kidney-pancreas transplantation [ 34 ]. Overall, positive tests, compared with negative tests, resulted in a significantly increased risk of myocardial infarction (RR of 2.73, 95% CI 1.25-5.97) and coronary death (RR of 2.92, 95% CI 1.66-5.12). Among diabetic patients, subgroup analyses found that positive tests were also associated with a higher risk of coronary death (RR of 3.95, 95% CI 1.48-10.5) and myocardial infarction (RR of 2.68, 95% CI 0.95-7.57). Both reversible and fixed detects were associated with poor prognosis in diabetic patients with ESRD.

Intervention following positive screening test — Implicit in the rationale for screening is that intervention will improve outcomes. The optimal intervention for diabetic transplant candidates who have asymptomatic coronary heart disease is not known. In one study, published in 1992, 151 consecutive asymptomatic type 1 diabetic patients were screened prior to transplantation with cardiac catheterization [ 36 ]. Significant disease as defined by stenosis >75 percent in one or more coronary arteries was identified in 31 patients, of which 26 agreed to be randomized to either medical therapy (calcium channel blocker plus aspirin ) or intervention (angioplasty or bypass). Ten of 13 medically managed patients had an adverse coronary event versus 2 out of 13 revascularized patients in a median follow up of 8.4 months. In addition, 4 out of 13 medically managed patients died of myocardial infarction during the two-year follow-up [ 36 ]. However this study has never been validated in a larger prospective study with long-term follow-up. Randomized trials are needed to determine the optimal therapeutic approach to asymptomatic transplant candidates with coronary heart disease.

Issues related to reevaluation among diabetic patients on the waitlist for a kidney transplant are presented separately. (See "The kidney transplant waiting list" .)

Evaluation of peripheral vascular disease — To identify patients with iliac calcifications, we screen all diabetic patients older than 45 years of age, or those with poor femoral pulses or evidence of vascular disease elsewhere (eg, coronary heart disease or cerebrovascular disease), with a noncontrast abdominopelvic CT scan. Peripheral vascular disease is common among diabetic patients with ESRD and may prevent a successful anastomosis to the kidney allograft. (See "Peripheral artery disease in chronic kidney disease", section on 'Epidemiology' .)

The diagnosis is difficult to establish in such patients because of the presence of medial artery calcifications that render vessels non compressible for a standard ankle brachial index and or toe brachial index. (See "Peripheral artery disease in chronic kidney disease", section on 'Diagnosis' .)

Patients with symptoms of peripheral vascular disease (eg, claudication) are referred to a vascular specialist for further assessment and testing.

POSTTRANSPLANTION 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 "Development of malignancy following solid organ transplantation" and "Infection in the solid organ transplant recipient" and "Clinical manifestations and diagnosis of acute renal allograft rejection" and "Chronic renal allograft nephropathy" .)

The following is a focused discussion on some of these issues as they related to the diabetic patient with a kidney transplant.

Additional issues that may affect all diabetic patients, such as gastroparesis, autonomic neuropathy, peripheral neuropathy, and foot ulcers, are presented separately.

Allograft rejection — The incidence of rejection in diabetics has not been well-studied. In small studies, the risk of acute rejection was found to be similar between diabetic and nondiabetic patients [ 37,38 ]. This issue in all kidney transplant recipients is discussed in detail separately. (See "Clinical manifestations and diagnosis of acute renal allograft rejection" and "Acute renal allograft rejection: Treatment" .)

Malignancies — Although a paucity of data exists, the incidence of malignancies appears to be similar in kidney transplant recipients with and without diabetes [ 39 ]. However, one study reported a greater incidence of malignancies in patients who receive simultaneous pancreas-kidney transplant compared with kidney transplantation [ 40 ]. 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 "Development of malignancy following solid organ transplantation" and "Treatment and prevention of post-transplant lymphoproliferative disorders" .)

Viral infection — Issues surrounding viral infection and diabetes post-transplant are discussed separately. (See "New onset diabetes after transplant (NODAT) in renal transplant recipients" .)

Urinary tract infection — Despite the widespread use of prophylactic antibiotics, urinary tract infections (UTIs) remain common post-transplantation among kidney transplant recipients.

Post-transplant UTIs are more common in diabetic versus nondiabetic transplant recipients [ 41,42 ]. This is in part due to the high incidence of neurogenic bladders among diabetic patients. (See "Urinary tract infection in renal transplant recipients" .)

Our approach to prophylactic therapy among diabetic recipients is the same as that for nondiabetic recipients. Among diabetic and nondiabetic recipients, we recommend the administration of an antibiotic agent for prophylaxis therapy against UTIs. (See "Urinary tract infection in renal transplant recipients" .)

Recurrent diabetic nephropathy — Historically, the vast majority of diabetic transplant recipients have developed histological changes of recurrent diabetic nephropathy, in some cases within one year post-transplantation [ 43 ]. However, the incidence of diabetic nephropathy as a cause of graft failure is thought to be rare [ 44 ].

Recurrent disease in the allograft can theoretically be prevented by optimal glycemic control. A single randomized trial of type 1 diabetic patients showed that, compared with standard therapy, intensive insulin therapy at the time of transplantation was associated with fewer pathological changes of diabetic nephropathy on five-year kidney allograft biopsies [ 45 ]. Recurrent diabetic nephropathy is prevented by a successful kidney pancreas transplant. (See "Benefits and complications associated with kidney-pancreas transplantation in diabetes mellitus", section on 'Diabetic nephropathy' .)

Glycemic control — Glycemic control may become acutely worse in the immediate post-transplant period, in part due to increased insulin resistance and impaired insulin secretion associated with steroids and other immunosuppressant medications. Issues surrounding glycemic control among post-transplant diabetics are discussed separately. (See "New onset diabetes after transplant (NODAT) in renal transplant recipients" .)

SUMMARY AND RECOMMENDATIONS

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in Western societies. Diabetic nephropathy is the etiology of ESRD in approximately 23 percent of kidney transplant recipients transplanted in the United States. (See 'Introduction' above.)
Kidney transplantation is generally the optimal renal replacement therapy for diabetic patients with ESRD. Among all diabetic patients with ESRD who are eligible for transplantation, we recommend a kidney transplant rather than dialysis ( Grade 1B ). (See 'Transplantation versus dialysis' above.)
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. Among predialysis diabetic patients with chronic kidney disease 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 kidneys' above.)
The wait time for an expanded criteria donor (ECD) kidney may be less than that for a standard donor kidneys. Diabetic patients who receive expanded criteria donor (ECD) kidneys appear to be likely to live longer than if they remained on dialysis, although the ECD kidney may not be of the same quality as a standard donor kidney. We suggest that all wait-listed diabetic patients register on both the standard-donor wait list and the ECD wait list ( Grade 2C ). (See 'Expanded criteria kidneys' above.)
Given the goal of preemptive transplantation, diabetics should be referred to a transplant center when the glomerular filtration rate is less than 30 mL/min.(See 'Timing of referral' above.)
To help detect coronary heart disease and perhaps lower the risk of adverse effects with transplantation, diabetic patients with ESRD are evaluated for the presence and/or absence of coronary heart disease. The optimal approach is unclear. We suggest the following approach ( Grade 2C ) (see 'Approach to evaluation' above):

All diabetic transplant candidates are evaluated with a history, physical examination, electrocardiogram, and chest radiograph.
Diabetic patients who have symptoms and/or signs consistent with coronary heart disease or a history of myocardial infarction undergo cardiac catheterization unless they recently underwent successful revascularization.
Diabetic patients who do not undergo initial screening coronary angiography have a screening dobutamine stress echocardiography. If positive, the decision to proceed with angiography and possible angioplasty or surgery is usually made in conjunction with the patients' cardiologist. (See 'Cardiac evaluation' above.)

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Thursday, 30 March 2017

Renal transplantation in diabetic nephropathy

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