Harini A. Chakkera

Diminishing significance of HLA matching in kidney transplantation

To determine trends in the significance of HLA matching and other risk factors in kidney transplantation, we analyzed data on graft survival in a consecutive sample of 33 443 transplant recipients who received deceased donor kidneys from December 1994 to December 1998 with a mean follow‐up time of 2.2 years. HLA matching and other risk factors (peak panel reactive antibody, donor age, sex and cause of death, cold ischemia time, donor and recipient body size) were examined. Mean likelihood ratios of models, fit with and without each variable of interest, were calculated by generating bootstrapped samples from each single year cohort. Pooled censored and uncensored graft survival rates were 90.6% and 89.9% at 1 year, 85.8% and 84.5% at 2 years, and 80.7% and 78.6% at 3 years. HLA matching declined in significance while other factors retained similar levels of statistical significance over the four yearly cohorts. With evolving clinical practice, including the provision of safer and more potent immunosuppressive therapy, the significance of HLA matching has diminished. Non‐immunologic factors continue to impede more marked improvements in long‐term graft survival. Recognizing these trends, organ allocation algorithms may need to be revised.

Influence of Race on Kidney Transplant Outcomes within and outside the Department of Veterans Affairs

Inferior outcomes after kidney transplantation among African Americans are poorly understood. It was hypothesized that unequal access to medical care among transplant recipients might contribute to worse posttransplantation outcomes among African Americans and that racial disparities in kidney transplant outcomes would be less pronounced among patients who receive health care within versus outside the Department of Veterans Affairs (VA), because eligible veterans who receive care within the VA are entitled to receive universal access to care, including coverage of prescription drugs. A study cohort of 79,361 patients who were undergoing their first kidney transplant in the United States between October 1, 1991, and October 31, 2000, was assembled, with follow-up data on graft survival obtained through October 31, 2001. After multivariable proportional hazards adjustment for a wide range of recipient and donor characteristics, African-American patients were at increased risk for graft failure compared with non-African-American patients (relative risk [RR] 1.31; 95% confidence interval [CI] 1.26 to 1.36). African-American race was associated with a similarly increased risk for graft failure among patients who were VA users (RR 1.31; 95% CI 1.11 to 1.54) and non-VA users (RR 1.31; 95% CI 1.26 to 1.36). In conclusion, racial disparities in kidney transplant outcomes seem to persist even in a universal access-to-care system such as the VA. Reasons for worse outcomes among African Americans require further investigation.

Impact of Subclinical Inflammation on the Development of Interstitial Fibrosis and Tubular Atrophy in Kidney Transplant Recipients

Our aim was to study the impact of subclinical inflammation on the development of interstitial fibrosis and tubular atrophy (IF/TA) on a 1‐year protocol biopsy in patients on rapid steroid withdrawal (RSW). A total of 256 patients were classified based on protocol biopsy findings at months 1 or 4. Group 1 is 172 patients with no inflammation, group 2 is 50 patients with subclinical inflammation (SCI), group 3 is 19 patients with subclinical acute rejection (SAR) and group 4 is 15 patients with clinical acute rejection (CAR). On the 1‐year biopsy, more patients in group 2 (SCI) (34%, p = 0.004) and group 3 (SAR) (53%, p = 0.0002), had an IF/TA score > 2 compared to group 1 (control) (15%). IF/TA was not increased in group 4 (CAR) (20%). The percent with IF/TA score > 2 and interstitial inflammation (Banff i score > 0) was higher in group 2 (16%, p = 0.004) and group 3 (37%, p < 0.0001) compared to group 1 (3%). In a multivariate analysis, patients in groups 2 or 3 had a higher risk of IF/TA score > 2 on the 1‐year biopsy (OR 6.62, 95% CI 2.68–16.3). We conclude that SCI and SAR increase the risk of developing IF/TA in patient on RSW.

Relationship between Inpatient Hyperglycemia and Insulin Treatment after Kidney Transplantation and Future New Onset Diabetes Mellitus

BACKGROUND AND OBJECTIVES Approximately two-thirds of kidney transplant recipients with no previous history of diabetes experience inpatient hyperglycemia immediately after kidney transplant surgery; whether inpatient hyperglycemia predicts future new onset diabetes after transplant (NODAT) is not established. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A retrospective study was conducted to determine the risk conferred by inpatient hyperglycemia on development of NODAT within 1 year posttransplant. All adult nondiabetic kidney transplant recipients between June 1999 and January 2008 were included. Posttransplant inpatient hyperglycemia was defined as any bedside capillary blood glucose > or = 200 mg/dl or insulin therapy during hospitalization. NODAT was defined as HbA1C > or = 6.5%, fasting venous serum glucose > or = 126 mg/dl, or prescribed diet or medical therapy for diabetes mellitus. RESULTS The study cohort included 377 patients. NODAT developed in 1 (4%) of the 28 patients without inpatient hyperglycemia, 4 (18%) of the 22 patients with inpatient hyperglycemia but not treated with insulin, and in 98 (30%) of the 327 of the patients who were diagnosed with inpatient hyperglycemia and were treated with insulin. In adjusted analyses, requirement of insulin therapy during hospitalization posttransplant was associated with a 4-fold increase in NODAT (relative risk 4.01; confidence interval, 1.49 to 10.7; P = 0.006). CONCLUSION Development of inpatient hyperglycemia after kidney transplantation in nondiabetic patients significantly increased the risk of NODAT. Additionally, we observed a significantly increased risk of cardiovascular events in patients who developed NODAT.

Hyperglycemia during the Immediate Period after Kidney Transplantation

BACKGROUND AND OBJECTIVES Hyperglycemia and new-onset diabetes occurs frequently after kidney transplantation. The stress of surgery and exposure to immunosuppression medications have metabolic effects and can cause or worsen preexisting hyperglycemia. To our knowledge, hyperglycemia in the immediate posttransplantation period has not been studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a retrospective, observational study to characterize the prevalence and assess the pharmacologic management of hyperglycemia in kidney transplant recipients who underwent transplantation at our center between June 1999 and December 2006. Data were abstracted from electronic and pharmacy databases. RESULTS The study cohort included 424 patients (mean age 51 yr; 58% men; 25% with pretransplantation diabetes). All patients with and 87% without pretransplantation diabetes had evidence of hyperglycemia (bedside glucose >or=200 mg/dl or physician-instituted insulin therapy), whereas the prevalence of hypoglycemia was low (4.5%). Hyperglycemia was sustained throughout hospitalization. All patients with and 66% without pretransplantation diabetes required insulin at hospital discharge. Patients with pretransplantation diabetes were treated primarily with short-acting insulin during the first 24 h after transplantation but were transitioned to long-acting insulin as the hospital stay progressed. CONCLUSIONS Investigators have historically attempted to identify hyperglycemia after hospital discharge. Our data indicate that a substantial number of patients without pretransplantation diabetes develop hyperglycemia and require insulin during the hospital phase of their care immediately after kidney transplantation. Prospective studies are needed to delineate factors that contribute to development of new-onset diabetes after transplantation among patients with transient hyperglycemia.

Calcineurin inhibition and new-onset diabetes mellitus after transplantation.

New-onset diabetes after transplantation independently increases the risk of cardiovascular disease, infections, and graft loss and decreases patient survival. The required balance between insulin sensitivity/resistance and insulin secretion is necessary to maintain normal glucose metabolism. Calcineurin inhibitors are standard immunosuppression drugs used after transplantation and have been implicated in the development of new-onset diabetes after transplantation partially by pancreatic β-cell apoptosis and resultant decrease in insulin secretion. The ability of muscle to take up glucose is critical to blood glucose homeostasis. Skeletal muscle is quantitatively the most important tissue in the body for insulin-stimulated glucose disposal and is composed of diverse myofibers that vary in their properties between healthy and insulin-resistant muscle. Various signaling pathways are responsible for remodeling of skeletal muscle, and among these is the calcineurin/nuclear factor of activated T-cell pathway. The mechanism of action of the calcineurin inhibitors is to bind in a complex with a binding protein to calcineurin and inhibit its dephosphorylation and activation of nuclear factor of activated T cells. In this review, we will provide a detailed discussion of the hypothesis that inhibition of calcineurin in tissues involved in insulin sensitivity/resistance could be at least partially responsible for the diabetogenicity seen with the use of calcineurin inhibitors.

Age, kidney function, and risk factors associate differently with cortical and medullary volumes of the kidney

The kidney atrophies in patients with advanced chronic kidney disease (CKD) but factors influencing kidney size in normal adults are less clear. To help define this we measured kidney volumes on contrast-enhanced CT images from 1344 potential kidney donors (ages 18 to 75 years). Cortical volume per body surface area progressively declined in both genders with increased age. Statistically, this was primarily dependent on the age-related decline in glomerular filtration rate (GFR). Independent predictors of increased cortical volume per body surface area were male gender, increased GFR, increased 24-hour urine albumin, current smoker, and decreased high-density lipid cholesterol. Medullary volume per body surface area increased with age in men while it increased with age in women until age 50 followed by a subsequent decline. Independent predictors of increased medullary volume per body surface area were older age, male gender, increased GFR, increased 24-hour urine albumin, increased serum glucose, and decreased serum uric acid. Thus, while cortical volume declines with age along the same biological pathway as the age-related decline in GFR and albuminuria some CKD risk factors are actually associated with increased cortical or medullary volume among relatively healthy adults. Underlying hypertrophy or atrophy of different nephron regions may explain these findings.

Pretransplant risk score for new-onset diabetes after kidney transplantation

OBJECTIVE New-onset diabetes after kidney transplantation (NODAT) has adverse clinical and economic implications. A risk score for NODAT could help identify research subjects for intervention studies. RESEARCH DESIGN AND METHODS We conducted a single-center retrospective cohort study using pretransplant clinical and laboratory measurements to construct a risk score for NODAT. NODAT was defined by hemoglobin A1c (HbA1c) ≥6.5%, fasting serum glucose ≥126 mg/dL, or prescribed therapy for diabetes within 1 year posttransplant. Three multivariate logistic regression models were constructed: 1) standard model, with both continuous and discrete variables; 2) dichotomous model, with continuous variables dichotomized at clinically relevant cut points; and 3) summary score defined as the sum of the points accrued using the terms from the dichotomous model. RESULTS A total of 316 subjects had seven pretransplant variables with P < 0.10 in univariate logistic regression analyses (age, planned corticosteroid therapy posttransplant, prescription for gout medicine, BMI, fasting glucose and triglycerides, and family history of type 2 diabetes) that were selected for multivariate models. Areas under receiver operating curves for all three models were similar (0.72, 0.71, and 0.70). A simple risk score calculated as the sum of points from the seven variables performed as well as the other two models in identifying risk of NODAT. CONCLUSIONS A risk score computed from seven simple pretransplant variables can identify risk of NODAT.

The Substantial Loss of Nephrons in Healthy Human Kidneys with Aging

Nephron number may be an important determinant of kidney health but has been difficult to study in living humans. We evaluated 1638 living kidney donors at Mayo Clinic (MN and AZ sites) and Cleveland Clinic. We obtained cortical volumes of both kidneys from predonation computed tomography scans. At the time of kidney transplant, we obtained and analyzed the sections of a biopsy specimen of the cortex to determine the density of both nonsclerotic and globally sclerotic glomeruli; the total number of glomeruli was estimated from cortical volume×glomerular density. Donors 18-29 years old had a mean 990,661 nonsclerotic glomeruli and 16,614 globally sclerotic glomeruli per kidney, which progressively decreased to 520,410 nonsclerotic glomeruli per kidney and increased to 141,714 globally sclerotic glomeruli per kidney in donors 70-75 years old. Between the youngest and oldest age groups, the number of nonsclerotic glomeruli decreased by 48%, whereas cortical volume decreased by only 16% and the proportion of globally sclerotic glomeruli on biopsy increased by only 15%. Clinical characteristics that independently associated with fewer nonsclerotic glomeruli were older age, shorter height, family history of ESRD, higher serum uric acid level, and lower measured GFR. The incomplete representation of nephron loss with aging by either increased glomerulosclerosis or by cortical volume decline is consistent with atrophy and reabsorption of globally sclerotic glomeruli and hypertrophy of remaining nephrons. In conclusion, lower nephron number in healthy adults associates with characteristics reflective of both lower nephron endowment at birth and subsequent loss of nephrons.

De novo donor-specific human leukocyte antigen antibodies early after kidney transplantation

Background Our aim was to determine the incidence of de novo donor-specific human leukocyte antigen (HLA) antibody (dnDSA) during the first year after kidney transplantation and the impact of early dnDSA on acute rejection and protocol biopsy findings. Methods We selected all patients who received a kidney transplant at our center between July 2010 and March 2012. Single antigen bead assay was performed at 1, 4 and 12 months after transplantation. Only DSAs with a mean fluorescence intensity (MFI) of greater 999 were included. Results We included 245 kidney transplant recipients who did not have a DSA before transplantation. At 12 months, 8.2% of the patients developed dnDSA; 2.4% of them were to HLA class I and 6.5% to HLA class II. Of the 32 patients with a dnDSA at 1 or 4 months, only 8 (25%) persisted at 12 months. The risk of antibody-mediated rejection (AMR) was higher in the dnDSA group. For the dnDSA group with MFI of 3,000 or greater (compared with the group with MFI<3,000), the hazard ratio for AMR was 10.6 (95% confidence interval, 2.27–49.5). The cumulative incidence of AMR or mixed rejection at 1 year was 30% in the group with dnDSA MFI level of 3,000 or greater but only 4% for the group with dnDSA with MFI less than 3,000. On 1-year protocol biopsies, the dnDSA group showed more interstitial inflammation, tubulitis, and glomerulitis. Conclusion We conclude that dnDSA occurring during the first posttransplantation year may be transient, and the risk of AMR is higher in patients with a dnDSA MFI level that is greater than 3,000.