Diabetes & The Body

Diabetic Ketoacidosis And HHS After Renal Transplantation

The incidence and risk factors for diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome (previously called non-ketotic hyperosmolar coma) had not been reported in a population of renal transplant recipients. Researchers performed a historical cohort study of 39,628 renal transplantation recipients at a center the outcomes were hospitalizations for a primary diagnosis of diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome. Cox Regression analysis was used to calculate adjusted hazard ratios for time to hospitalization for diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome. The incidence of diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome were 33.2/1000 person years (PY) and 2.7/1000 PY respectively for recipients with a prior diagnosis of diabetes mellitus (DM), and 2.0/1000 PY and 1.1/1000 PY in patients without DM. In Cox Regression analysis, in a study of African Americans (AHR, 2.71, 95 %CI, 1.96–3.75), females, recipients of cadaver kidneys, patients age 33–44 (vs. >55), more recent year of transplant, and patients with maintenance TAC (tacrolimus, vs. cyclosporine) had significantly higher risk of diabetic ketoacidosis.

However, the rate of diabetic ketoacidosis decreased more over time in TAC users than overall. Risk factors for hyperglycemic hyperosmolar syndrome were similar except for the significance of positive recipient hepatitis C serology and non-significance of female gender. Both diabetic ketoacidosis (AHR, 2.44, 95% CI, 2.10–2.85, p < 0.0001) and hyperglycemic hyperosmolar syndrome (AHR 1.87, 95% CI, 1.22–2.88, p = 0.004)

There are even fewer reports on hyperglycemic hyperosmolar syndrome after renal transplantation. Recently, post-transplant diabetes mellitus has been associated with tacrolimus use in renal transplant recipients with hepatitis C antibody positivity. Tacrolimus was approved by the FDA for use in kidney transplantation in 1997. Researchers therefore performed a historical cohort study of the United States Renal Data System (USRDS) Renal transplant population. Their objectives were to determine the incidence, risk factors, and mortality associated with hospitalizations for diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome occurring after renal transplantation. This study used the data from the United States Renal Data System (USRDS), using standard analysis files (SAF's) as of May 2000. The USRDS, indirectly mandated by federal law, incorporates baseline and follow-up demographic and clinical data on all patients receiving end stage renal disease (ESRD) therapy in the United States. ESRD therapy includes hemodialysis, peritoneal dialysis, and renal transplantation.

Patient characteristics and treatment factors were those at the date of transplant. Recipients of organs other than kidneys were excluded.

The outcome was conduction of a historical cohort study of the incidence, risk factors and associated patient survival for hospitalized cases of diabetic ketoacidosis at hospital discharge for diabetic ketoacidosis and hyperosmotic hyperosmolar syndrome as a primary discharge diagnosis in renal transplant recipients. The first hospitalization for diabetic ketoacidosis after the first solitary renal transplant with follow-up time truncated at three years was counted in analysis. Hospitalizations were chosen because they were more accessible in the database and less subject to interpretation than outpatient cases of diabetic ketoacidosis.

Hospitalizations were chosen because they were more accessible in the database and less subject to interpretation than outpatient cases of diabetic ketoacidosis, especially since the USRDS database has no information on confirmatory studies. This data for transplant recipients may be unreliable after the patient has survived ³3 years post transplant. Hospitalizations for diabetic ketoacidosis occurring at any time after renal transplant, including after graft failure censored for patient death, were counted in analysis.

The independent associations between patient factors and hospitalizations for diabetic ketoacidosis were examined using multivariate analysis with stepwise Cox Regression including recipient and donor age, recipient race, gender, weight, pretransplant dialysis (yes/no), duration of dialysis prior to transplantation, total follow-up time, recipient hepatitis C serology, donor cytomegalovirus serology, pre-transplant dialysis (yes/no), rejection (either treatment or diagnosis) occurring at any time in the study period, induction antibody therapy, maintenance immunosuppressive medications at time of discharge after transplant surgery, graft loss, and cause of end stage renal disease (ESRD, either diabetes or other causes). The USRDS does not reliably distinguish between type I and type II diabetes.

Previous investigators have used the occurrence of diabetes in patients younger than age 40 as a surrogate for type I diabetes. However, given the growing frequency of type II diabetes in younger patients, researchers did not think this assumption would be valid in more recent years of the database. Researchers therefore chose to group all patients with ESRD due to diabetes together, diabetes as a comorbid condition at the time of listing for transplant was also used as a variable, although information on this variable was missing or unknown for 23.3% of patients. Information on insulin dependence was missing for 81% of patients, however, and was not considered reliable for analysis. Episodes of rejection were not restricted to those occurring in the first year, in contrast to studies of allograft function, since there is no evidence that late vs. early rejection has a different impact on diabetic ketoacidosis. However, only episodes of diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome occurring after the approximate date of rejection were used in assessing the association of rejection with diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome. The total cumulative dose of prednisone was not available in the USRDS. The number of days of prednisone administered prior to initial hospital discharge; however, values were missing for >90% of patients in both databases and could not be used as a covariate in the above analyses.

Maintenance immunosuppressive medication use, in particular cyclosporine and tacrolimus, at the time of discharge after transplantation was also analyzed as a preexisting covariate. Information on use of medications(other than immunosuppressive medications), alcohol, tobacco, or radiologic procedures was not available. The initial dialysis modality a patient used for at least 60 days after presentation to end stage renal disease and prior to renal transplantation was utilized in intention to treat fashion. For time to diabetic ketoacidosis, survival time was defined as the time from first renal transplant until hospitalization for diabetic ketoacidosis, with patients censored at death, loss to follow-up, or end of the study. Survival time was defined as the time from the date of transplant until the date of death, censored for loss to follow-up or the end of the study. The patient survival probabilities were estimated by using the Life Tables and Kaplan Meier method.

All analyses were performed using SPSS 9.0 TM (SPSS, Inc., Chicago, IL). Files were merged and converted to SPSS files using DBMS/Copy (Conceptual Software, Houston, TX). Univariate analysis was performed with Chi-square testing for categorical variables (Fisher's exact test was used for violations of Cochran's assumptions) and Student's two-sided t-test for continuous variables (the Wilcoxon signed rank test was used for variables without a Gaussian distribution). Linear regression analysis was used to assess trends over time, with adjusted residuals inspected to verify the appropriateness of the regression technique. Variables with p < 0.10 in univariate analysis for a relationship with development of hospitalization for diabetic ketoacidosis were entered into multivariate analysis as covariates. Kaplan-Meier analysis was used to construct survival plots of time to hospitalized diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome after renal transplantation. Log-log plots were inspected to assess for proportionality of hazards over time at the mean of each significant covariate. Because the majority of patients were censored that is they did not experience the primary outcome during the study period, stepwise Cox Regression likelihood ratio method was used to model factors associated with time to hospitalized diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome, controlling for covariates listed above.

For all the risk factor analysis reported in the present study, only the first hospitalization for diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome, respectively, occurring during the study period was analyzed (one hospitalization per patient). The association of hospitalized diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome was assessed using Cox non-proportional hazards regression, with times after hospitalization for diabetic ketoacidosis coded as 1 and all other times as 0, as previously reported.

Tacrolimus was introduced into clinical practice more recently than cyclosporine. This could have resulted similar to the linear risk of mortality after diabetic ketoacidosis, the risk of mortality after hyperglycemic hyperosmolar syndrome was constant over time. Hospitalization for hyperglycemic hyperosmolar syndrome was independently associated with increased mortality in Cox non-proportional hazards regression analysis, adjusted hazard ratio = 1.87, 95% CI, 1.22–2.88, p = 0.004. Causes of death were missing or unknown for 45.5% of patients with hyperglycemic hyperosmolar syndrome. The leading cause of death in patients hospitalized for hyperglycemic hyperosmolar syndrome was acute myocardial infarction (18%), cardiac arrest of unknown cause (13%), and sepsis (9%).

The present study showed that renal transplant recipients had a rate of diabetic ketoacidosis of 33.2/1000 person years in recipients a history of diabetes as a comorbid condition and 1.9/1000 person years in patients without a prior history of diabetes (measured as total hospitalizations for comparison with other reports). In contrast, the estimated annual incidence of diabetic ketoacidosis in the general population was 4.6–8 episodes per 1000 diabetic subjects. In the general population, the rate of diabetic ketoacidosis episodes as a primary hospitalization diagnosis was 0.3/1000 patients, and the rate of hyperglycemic hyperosmolar syndrome episodes was 0.04/1000 (rates stratified for patients with diabetes were not available). Although statistical comparison could not be performed due to the much higher rate of diabetes among renal transplant recipients than in the general population, the rates of diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome in renal transplant recipients appear to be substantially higher than for either diabetic patients or for the general population, after excluding patients with combined kidney-pancreas transplants. Certain risk factors were common to both the total risk of diabetic ketoacidosis and the risk of diabetic ketoacidosis occurring in patients without a prior known history of diabetes. Despite adjustment for body mass index, graft loss, rejection episodes or employment status these factors, socioeconomic factors could certainly not be excluded, and have been implicated in prior studies. Similarly, low body mass index was associated with diabetic ketoacidosis in either situation (in contrast to the association of high body mass with the increased risk of type II diabetes). However, differences in gender and graft loss were not associated with de novo diabetic ketoacidosis. Each of these may reflect risk factors for diabetes in the general population. Conversely, donor type and use of maintenance tacrolimus were only associated with de novo diabetic ketoacidosis. The increased risk of cadaver donor type could be related to medication use. The relatively high rate of "de novo" diabetic ketoacidosis (diabetic ketoacidosis occurring in patients who did not have a known diagnosis of diabetes at the time of transplant) could represent drug-associated diabetic ketoacidosis, which has infrequently been reported with the use of both tacrolimus and cyclosporine. Previous case series did not have sufficient sample size to determine competing risks between calcineurin inhibitors, but the present study would suggest the risk is greater with tacrolimus. Because of rapid changes in the use of tacrolimus during the study period, as indicated above, conclusions should be limited.

Therefore, reported risk factors such as obesity, cumulative prednisone use, and hepatitis C status would not be expected to affect the risk of diabetic ketoacidosis, consistent with reports in the general population. This is in contrast to hyperglycemic hyperosmolar syndrome, which would be expected to occur disproportionately in patients with type II diabetes. While older age and higher BMI were significant in univariate analysis, they were not significant in multivariate analysis, while the significance of positive recipient hepatitis C serology persisted. Use of diabetes as an aggregate outcome, combining either both type I and type II diabetes, or combining diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome, might obscure the relationship with certain risk factors if the associations were in different directions (as is the case with body mass index, for example: low body mass index being associated with type I diabetes, and high body mass being associated with type II diabetes). Use of such aggregate outcomes might also have missed an association between hyperglycemic hyperosmolar syndrome and hepatitis C.

The present study thus provides more indirect evidence that the post-transplant diabetes associated with hepatitis C infection is predominantly type II diabetes, as suggested in other reports. This is in contrast to a lack of association between hepatitis C seropositivity and diabetes as a cause of renal failure, as was previously reported. Nevertheless, the increasing rate of diabetic ketoacidosis noted during the study period (Figure 1, more marked for total diabetic ketoacidosis than de novo diabetic ketoacidosis) is in contrast to the decreasing rate of de novo diabetic ketoacidosis and stable rate of total diabetic ketoacidosis noted for users of tacrolimus (Figure 2). While this information is necessarily preliminary, it suggests the possibility that factors other than tacrolimus use may be responsible for the increasing rate of diabetic ketoacidosis noted during the study, which was independent of all other factors assessed. Researchers did not find an association between diabetic ketoacidosis and viral infections other than hepatitis C, notably cytomegalovirus, nor did they find an association between diabetic ketoacidosis and antibody induction therapy, which would be expected to decrease immunity but might also allow for a greater propensity to viral infections. It can only point to another recent report by Bhalla et al, which found that "de novo" post-transplant diabetes mellitus (confirmed by renal biopsy) was much more common and much more rapid in onset than previously suspected, and could not be explained by usual clinical predictors, which is quite similar to the findings. The authors implicated "novel mechanisms" as the reason for this rapid increase. Whether this represents a relationship with newly appreciated viral infections, such as polyomavirus, or other factors is presently unknown.

Both diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome were associated with an increased risk of mortality among renal transplant recipients, consistent with reports in the general population. If anything, the relative risk associated with diabetic ketoacidosis was greater than that for hyperglycemic hyperosmolar syndrome, somewhat in contrast to the general population. However, previous population based reports have not adjusted for the difference in age of presentation for this differing conditions. Given the limitations of the database, causes of death were primarily cardiovascular and not infectious, also consistent with the general population.

There are several limitations to this retrospective study. Findings are associative, not causative, and risk cannot be assigned without the ability to control for other variables prospectively during the course of the study. Researchers could not assess the causes for hospitalization for diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome, or how they were treated, including the use of insulin. This study could not independently verify the type of diabetes. It could not assess certain important risk factors, such as nutritional status, the use of alcohol or infection, with hospitalized diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome. The current study's limitation to hospitalized cases of diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome would tend to underestimate the frequency of these conditions in this population. However, these conditions are almost universally managed by hospitalization in the United States. Another limitation of the study is the inability to track whether the patients were subsequently switched from tacrolimus or cyclosporine during the course of the present study. However, reports of conversion from cyclosporine to tacrolimus, which are most commonly employed as a rescue agent for refractory acute or chronic rejection or cyclosporine toxicity, suggest that this number is very small. Similarly, conversion from tacrolimus to cyclosporine, most commonly due to tacrolimus induced diabetes, by published report appears to be even rarer. The short follow up duration of the study may also be a limitation. Strengths of the present analysis include its large size and population-based character, and relatively complete capture and follow up.

In conclusion, rates of diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome after renal transplantation were substantially higher than reported for the general population, whether in diabetic or non-diabetic populations. These rates appear to be increasing significantly over time, particularly for diabetic ketoacidosis, even as the risk for diabetic ketoacidosis in patients treated with tacrolimus is decreasing significantly. In addition, they have identified high-risk groups for diabetic ketoacidosis, de novo diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome after renal transplantation, and confirmed the association of both diabetic ketoacidosis and hyperglycemic hyperosmolar syndrome with increased mortality after renal transplantation.