Saul Nurko

Demographic and clinical characteristics associated with glomerular filtration rates in living kidney donors.

Due to the shortage of organs, living donor acceptance criteria are becoming less stringent. An accurate determination of the glomerular filtration rate (GFR) is critical in the evaluation of living kidney donors and a value exceeding 80 ml/min per 1.73 m(2) is usually considered suitable. To improve strategies for kidney donor screening, an understanding of factors that affect GFR is needed. Here we studied the relationships between donor GFR measured by (125)I-iothalamate clearances (mGFR) and age, gender, race, and decade of care in living kidney donors evaluated at the Cleveland Clinic from 1972 to 2005. We report the normal reference ranges for 1057 prospective donors (56% female, 11% African American). Females had slightly higher mGFR than males after adjustment for body surface area, but there were no differences due to race. The lower limit of normal for donors (5th percentile) was less than 80 ml/min per 1.73 m(2) for females over age 45 and for males over age 40. We found a significant doubling in the rate of GFR decline in donors over age 45 as compared to younger donors. The age of the donors and body mass index increased over time, but their mGFR, adjusted for body surface area, significantly declined by 1.49+/-0.61 ml/min per 1.73 m(2) per decade of testing. Our study shows that age and gender are important factors determining normal GFR in living kidney donors.

Evaluation of Creatinine-Based Estimates of Glomerular Filtration Rate in a Large Cohort of Living Kidney Donors

Background. Accurate determination of kidney function is critical in the evaluation of living kidney donors and higher donor glomerular filtration rate (GFR) is associated with better allograft outcomes. However, among transplant centers donor kidney function evaluation varies widely. Methods. The performance of creatinine clearance (CrCl), Modification of Diet in Renal Disease (MDRD), the re-expressed MDRD equations with standardized creatinine, and the Cockcroft-Gault (CG) formula as compared with 125I-iothalamate GFR (iGFR) was analyzed in 423 donors. All methods of GFR measurement were then evaluated for their association with graft function at 1 year. Results. The MDRD and re-expressed MDRD equations underestimated iGFR whereas CG showed minimal bias (median difference=−11.0, −16.3, and −0.5 mL/min/1.73 m2, respectively). CrCl overestimated iGFR (10 mL/min/1.73 m2). The MDRD, re-expressed MDRD, and CG formulas were more accurate (88%, 86%, and 88% of estimates within 30% of iGFR, respectively) than CrCl (80% within 30% of iGFR). Interestingly, low bias and high accuracy were achieved by averaging the MDRD estimation with the CrCl result; both methods available to the clinician in most transplant centers. We also showed that predonation GFR as measured by isotopic renal clearance or any of the creatinine-based estimation formulas may be associated with allograft function at 1 year, whereas the widely used CrCl was not. Conclusions. Variable performance was seen among different GFR estimations, with CrCl being the poorest. Recent recommendations to use the MDRD equation with standardized serum creatinine did not improve its performance. However, recognizing the limited availability of GFR laboratories, these methods are still clinically useful if used with caution and understanding their limitations.

Donor factors influencing graft outcomes in live donor kidney transplantation

Living donor renal allograft survival is superior to that achieved from deceased donors, although graft outcome is suboptimal in some of these patients. In an effort to identify the subset of patients at high risk for poor outcomes we studied donor risk factors in 248 living kidney donor–recipient pairs. Unadjusted donor 125I-iothalamate GFR (iGFR), donor age more than 45 years, donor total cholesterol level less than 200 mg/dL, and donor systolic blood pressure (SBP) less than 120 mm Hg were correlated with allograft estimated glomerular filtration rate (eGFR), and incidence of acute rejection (AR), delayed graft function and/or graft loss at 2 years posttransplantation. Donor iGFR less than 110 mL/min (slope=−7.40, P<0.01), donors more than 45 years (slope=−8.76, P<0.01), donor total cholesterol levels more than 200 mg/dL (slope=−10.03, P<0.01), and SBP more than 120 mm Hg (slope=−5.60, P=0.03) were associated with lower eGFR. By multivariable linear regression analysis these variables remained independently associated with lower eGFR, and poorer outcomes. The increasing number of donor factors (age, iGFR, cholesterol, and blood pressure) was directly associated with worse posttransplant eGFR (P<0.01). In conclusion, our data suggest that routine assessment of living donor parameters could supplement the consideration of recipient characteristics in predicting posttransplant risk of graft injury/dysfunction.

Association of Metabolic Syndrome With Kidney Function and Histology in Living Kidney Donors

The selection of living kidney donors is based on a formal evaluation of the state of health. However, this spectrum of health includes subtle metabolic derangements that can cluster as metabolic syndrome. We studied the association of metabolic syndrome with kidney function and histology in 410 donors from 2005 to 2012, of whom 178 donors were systematically followed after donation since 2009. Metabolic syndrome was defined as per the NCEP ATPIII criteria, but using a BMI > 25 kg/m2 instead of waist circumference. Following donation, donors received counseling on lifestyle modification. Metabolic syndrome was present in 50 (12.2%) donors. Donors with metabolic syndrome were more likely to have chronic histological changes on implant biopsies than donors with no metabolic syndrome (29.0% vs. 9.3%, p < 0.001). This finding was associated with impaired kidney function recovery following donation. At last follow‐up, reversal of metabolic syndrome was observed in 57.1% of donors with predonation metabolic syndrome, while only 10.8% of donors developed de novo metabolic syndrome (p < 0.001). In conclusion, metabolic syndrome in donors is associated with chronic histological changes, and nephrectomy in these donors was associated with subsequent protracted recovery of kidney function. Importantly, weight loss led to improvement of most abnormalities that define metabolic syndrome.

Malignant acanthosis nigricans and endometrioid adenocarcinoma of the parametrium: the search for malignancy

Malignant acanthosis nigricans is recognized as a cutaneous sign of internal malignancy, usually an adenocarcinoma. Although cases of malignant acanthosis nigricans have been associated with cervical, ovarian, and endometrial neoplasms, we describe a case with a rarely if ever reported association, endometrioid adenocarcinoma of the parametrium.

Beneficial Outcomes of a Steroid-Free Regimen With Thymoglobulin Induction in Pancreas-Kidney Transplantation

BACKGROUND Steroid-free immunosuppressive regimens are becoming more common in pancreas transplantation, with persistent concerns regarding its safety and efficacy. METHODS We performed a retrospective chart review of 87 pancreas transplant recipients-22 simultaneous pancreas-kidney transplants, 48 pancreas-after-kidney transplants, and 17 pancreas transplant alone-who underwent transplantation within the period of January 2000 to November 2006 and who received induction therapy with thymoglobulin followed by maintenance immunosuppression with tacrolimus and mycophenolate mofetil. We compared one group on a steroid-free regimen (n = 25) with another on a steroid-based regimen (n = 62). RESULTS At 6 months, there was no kidney graft loss and no significant difference between groups (steroid-free vs steroid-based groups) in patient survival (100% vs 96.8%), pancreas graft survival (96.0% vs 93.5%), acute rejection (4.0% vs 11.3%), hospitalization for any cause (60.0% vs 51.6%), infection requiring hospitalization (16.0% vs 32.3%), or incidence of BK viremia (0% vs 3.2%). CMV viremia occurred less in the steroid-free group (0% vs 17.7% in the steroid-based group, P = .024). The estimated glomerular filtration rate (eGFR) at 6 months was higher in the steroid-free group (74.8 vs 55.7 mL/min/1.73 m2 in the steroid-based group, P = .001), with fewer occurrences of a 25% decline in eGFR (33.3% among the steroid-free group vs 61.7% among steroid-based group, P = .019), despite similar average tacrolimus exposure (11.7 +/- 3.7 vs 12.2 +/- 2.7 ng/dL, P = .478). CONCLUSIONS A steroid-free regimen with thymoglobulin induction followed by tacrolimus and mycophenolate mofetil for maintenance in pancreas transplantation was safe and effective in preventing rejection, with reduced incidence of CMV infection and better-preserved kidney function.

Hyperhomocysteinemia: detection, risk assessment, and treatment.

Homocysteine is formed by the demethylation of methionine in the course of its normal metabolism. Hyperhomocysteinemia is an independent risk factor for vascular disease. It develops most commonly from folate deficiency, genetic abnormalities, and chronic renal failure. Current models favor direct angiotoxicity involving endothelial and vascular smooth muscle cells, and impaired thrombolysis. Folic acid reduces hyperhomocysteinemia and thus provides an opportunity for risk-factor modification.

The relative risk of overall graft loss and acute rejection among African American renal transplant recipients is attenuated with advancing age.

Schold JD, Srinivas TR, Braun WE, Shoskes DA, Nurko S, Poggio ED. The relative risk of overall graft loss and acute rejection among African American renal transplant recipients is attenuated with advancing age.
Clin Transplant 2011: 25: 721–730.

Patterns of Kidney Function Decline in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Analysis From the HALT-PKD Trials

BACKGROUND Previous clinical studies of autosomal dominant polycystic kidney disease (ADPKD) reported that loss of kidney function usually follows a steep and relentless course. A detailed examination of individual patterns of decline in estimated glomerular filtration rate (eGFR) has not been performed. STUDY DESIGN Longitudinal post hoc analysis of data collected during the Halt Progression of Polycystic Kidney Disease (HALT-PKD) trials. SETTING & PARTICIPANTS 494 HALT-PKD Study A participants (younger; preserved eGFR) and 435 Study B participants (older; reduced eGFR) who had more than 3 years of follow-up and 7 or more eGFR assessments. MEASUREMENTS Longitudinal eGFR assessments using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation. PREDICTORS Demographic, clinical, laboratory, and imaging features of participants. OUTCOMES Probability of linear and nonlinear decline patterns or of stable eGFR calculated for each participant from a Bayesian model of individual eGFR trajectories. RESULTS Most (62.5% in Study A and 81% in Study B) participants had a linear decline in eGFR during up to 8 years of follow-up. A proportion (22% in Study A and 13% in Study B) of progressors had a nonlinear pattern. 15.5% of participants in Study A and 6% in Study B had a prolonged (≥4.5 years) period of stable eGFRs. These individuals (Study A) had significantly smaller total kidney volumes, higher renal blood flows, lower urinary albumin excretion, and lower body mass index at baseline and study end. In Study B, participants with reduced but stable eGFRs were older than the progressors. Two-thirds of nonprogressors in both studies had PKD1 mutations, with enrichment for weak nontruncating mutations. LIMITATIONS Relatively short follow-up of a clinical trial population. CONCLUSIONS Although many individuals with ADPKD have a linear decline in eGFR, prolonged intervals of stable GFRs occur in a substantial fraction. Lower body mass index was associated with more stable kidney function in early ADPKD.

Immunosuppressive Therapy in Kidney and Pancreas Transplantation

This chapter provides a brief overview of the immunosuppressive drugs that are currently in use, the combination drug regimens that are commonly used in kidney and pancreas transplantation, the reported outcomes with these regimens, and some experimental immunosuppressive agents that are in advanced clinical development. Also discussed is the treatment of acute rejection episodes. The evidence that could help the transplant physician in regimen selection and design is then summarized.