William M. Bennett

Immunosuppression and the Risk of Post-Transplant Malignancy Among Cadaveric First Kidney Transplant Recipients

The success of renal transplantation may be counterbalanced by serious adverse medical events. The effect of immunosuppression on the incidence of de novo neoplasms among kidney recipients should be monitored continuously. Using data from the Scientific Registry of Transplant Recipients, we studied the association of induction therapy by immunosuppression with antilymphocyte antibodies, with the development of de novo neoplasms. The study population included more than 41 000 recipients who received a cadaveric first kidney transplant after December 31, 1995, and were followed through February 28, 2002.

Magnetic Resonance Imaging Evaluation of Hepatic Cysts in Early Autosomal-Dominant Polycystic Kidney Disease: The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease Cohort

The objective of this study was to investigate the prevalence of hepatic cysts by age and gender in patients with early autosomal-dominant polycystic kidney disease (ADPKD) and to determine whether hepatic cyst volume is related to renal and renal cyst volumes by using magnetic resonance imaging (MRI). A total of 230 patients with ADPKD (94 men and 136 women) who were aged 15 to 46 yr and had relatively preserved renal function were studied. MRI images of the kidney and liver were obtained to measure renal, renal cyst, and hepatic cyst volumes. These volume measurements and hepatic cyst prevalence were compared in all patients and in subgroups on the basis of gender and age (15 to 24, 25 to 34, and 35 to 46 yr). The overall prevalence of hepatic cysts was 83%; the prevalence was 58, 85, and 94% in the sequential age groups and 85% in women and 79% in men. The prevalence was related directly to renal volume (chi2 = 4.30, P = 0.04) and to renal cyst volume (chi2 = 5.59, P = 0.02). The total hepatic cyst volume was significantly greater in women than in men (a logarithmic transformation mean of 5.27 versus 1.94 ml; P = 0.003). The average hepatic cyst volume was 0.25, 5.75, and 22.78 ml in sequential age groups. Hepatic cysts are evident in 94% of patients who are older than 35 yr and in 55% of individuals who are younger than 25 yr. Hepatic cysts are more prevalent and larger in total cyst volume in women than in men. Hepatic cyst prevalence and aggregate total hepatic cyst volume increased with age.

Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease

Data from serial renal magnetic resonance imaging of the Consortium of Radiologic Imaging Study of PKD (CRISP) autosomal dominant polycystic kidney disease (PKD) population showed that cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population, and that larger kidneys are associated with more rapid disease progression. The significance of gene type to disease progression is analyzed in this study of the CRISP cohort. Gene type was determined in 183 families (219 cases); 156 (85.2%) had PKD1, and 27 (14.8%) had PKD2. PKD1 kidneys were significantly larger, but the rate of cystic growth (PKD1 5.68%/yr; PKD2 4.82%/yr) was not different (P = 0.24). Cyst number increased with age, and more cysts were detected in PKD1 kidneys (P < 0.0001). PKD1 is more severe because more cysts develop earlier, not because they grow faster, implicating the disease gene in cyst initiation but not expansion. These insights will inform the development of targeted therapies in autosomal dominant PKD.

Analgesia in Patients With ESRD: A Review of Available Evidence

Moderate to severe pain frequently accompanies chronic diseases in general and end-stage renal disease (ESRD) in particular. Several analgesic agents and associated metabolites show altered pharmacokinetics in the presence of reduced glomerular filtration rate. Drug-related side effects may exacerbate symptoms frequently observed in persons with chronic kidney disease (CKD; eg, fatigue, nausea, vomiting, and constipation) or those often attributed to hemodialysis therapy (eg, orthostatic hypotension and impaired cognition). Persons with advanced CKD and ESRD are at increased risk for adverse effects of analgesic agents because of enhanced drug sensitivity, comorbid conditions, and concurrent medication use. Dose adjustment and avoidance of certain analgesics may be required in patients with advanced CKD and ESRD. We review the available evidence on pharmacokinetics and adverse drug effects of various analgesic agents commonly used in patients with advanced CKD and ESRD. Determining an optimal approach to the control of pain in patients with advanced CKD and ESRD will require additional research.

Morbid obesity does not preclude successful renal transplantation.

Abstract:u2002 Many renal transplantation centers arbitrarily deny transplantation to patients with morbid obesity usually defined as body mass index >35. We present a series of 173 primary renal transplant patients in a new transplant program that accepted all recipients with 3u2003yrs or greater life expectancy and no active malignancy or infection. When the patient outcomes are divided into groups by body mass index, it can be seen as expected that patients with body mass index >30 have an increased prevalence of wound infections (pu2003<u20030.05). However, aside from this complication there are no statistically significant outcome differences between the three groups realizing the possibility of type II statistical error because of small numbers. Graft survival, patient survival and other surgical complications are the same in all groups regardless of body mass index. At the end of the 3‐yr interval with a minimum transplant follow‐up of 3u2003months, 169 of 173 patients were alive and 163 of 173 transplants were functioning. Based on our experience, morbid obesity should not be used to exclude patients arbitrarily from transplantation anymore than advanced age or diabetes should.

Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) often results in ESRD but with a highly variable course. Mutations to PKD1 or PKD2 cause ADPKD; both loci have high levels of allelic heterogeneity. We evaluated genotype-phenotype correlations in 1119 patients (945 families) from the HALT Progression of PKD Study and the Consortium of Radiologic Imaging Study of PKD Study. The population was defined as: 77.7% PKD1, 14.7% PKD2, and 7.6% with no mutation detected (NMD). Phenotypic end points were sex, eGFR, height-adjusted total kidney volume (htTKV), and liver cyst volume. Analysis of the eGFR and htTKV measures showed that the PKD1 group had more severe disease than the PKD2 group, whereas the NMD group had a PKD2-like phenotype. In both the PKD1 and PKD2 populations, men had more severe renal disease, but women had larger liver cyst volumes. Compared with nontruncating PKD1 mutations, truncating PKD1 mutations associated with lower eGFR, but the mutation groups were not differentiated by htTKV. PKD1 nontruncating mutations were evaluated for conservation and chemical change and subdivided into strong (mutation strength group 2 [MSG2]) and weak (MSG3) mutation groups. Analysis of eGFR and htTKV measures showed that patients with MSG3 but not MSG2 mutations had significantly milder disease than patients with truncating cases (MSG1), an association especially evident in extreme decile populations. Overall, we have quantified the contribution of genic and PKD1 allelic effects and sex to the ADPKD phenotype. Intrafamilial correlation analysis showed that other factors shared by families influence htTKV, with these additional genetic/environmental factors significantly affecting the ADPKD phenotype.

Subclinical Renal Injury Induced by Transient Cyclosporine Exposure is Associated with Salt‐Sensitive Hypertension

Cyclosporine use is highly associated with the development of salt‐sensitive hypertension. We hypothesized that subtle renal injury induced by cyclosporine could lead to salt sensitivity. Cyclosporine nephropathy was induced by treatment for 4u2003weeks with cyclosporine (15u2003mg/kg/day) on a low sodium (0.05%) diet, followed by stopping cyclosporine and placement on a high sodium (4%) diet for 4u2003additional weeks. Control groups included a group treated with cyclosporine (15u2003mg/kg/day) on a normal salt diet in which nephropathy does not develop, and a vehicle‐treated group. A fourth group received half‐dose of cyclosporine (8u2003mg/kg/day) on a low sodium diet, which results in mild nephropathy. Biopsies were obtained at the end of the cyclosporine administration (4u2003week) and at sacrifice (8u2003week), and blood pressure and renal function were measured. Rats treated with cyclosporine for 4u2003weeks on a low sodium diet developed classic features of tubulointerstitial disease and arteriolopathy; these changes were absent in the cyclosporine/normal salt group and in the vehicle group. At 4u2003weeks, all groups were switched to a high salt diet; only the rats with nephropathy developed hypertension. The degree of hypertension correlated closely with the degree of tubulointerstitial injury (ru200a=u200a0.85) and with the severity of the arteriolopathy (ru200a=u200a0.9) (pu200a<u200a0.0.1). Importantly, renal function (creatinine clearance) was normal in all groups at 8u2003weeks, documenting that the hypertension could not be attributed to cyclosporine‐mediated alterations in glomerular filtration rate (GFR). One mechanism by which cyclosporine induces hypertension is the induction of subtle renal microvascular and tubulointerstitial disease. This mechanism is not dependent on GFR and may persist even after the cyclosporine is discontinued.

Drug Dosing in the Elderly Patients with Chronic Kidney Disease

Chronic kidney disease is a common disorder that affects many patients with a prevalence approaching 19 million people in the United States. Kidney failure and renal impairment is a common occurrence in the geriatric population. Most types of kidney diseases are chronic conditions and frequently manifest at the late stages of life. Epidemiologic studies suggest that older patients are at a greater risk for renal failure if the kidney experiences insults from ischemia or exposure to pharmacologic and diagnostic nephrotoxins. Pharmacologic management of most common diseases in elderly individuals is a difficult task, particularly in older individuals with chronic kidney disease. Thus, primary care providers must proceed with caution when prescribing drugs for elderly patients with kidney disease.

Kidney transplantation in the morbidly obese: complicated but still better than dialysis.

Bennett WM, McEvoy KM, Henell KR, Pidikiti S, Douzdjian V, Batiuk T. Kidney transplantation in the morbidly obese: complicated but still better than dialysis.u2028Clin Transplant 2011: 25: 401–405.

Segmentation of Individual Renal Cysts from MR Images in Patients with Autosomal Dominant Polycystic Kidney Disease

OBJECTIVEnTo evaluate the performance of a semi-automated method for the segmentation of individual renal cysts from magnetic resonance (MR) images in patients with autosomal dominant polycystic kidney disease (ADPKD).nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnThis semi-automated method was based on a morphologic watershed technique with shape-detection level set for segmentation of renal cysts from MR images. T2-weighted MR image sets of 40 kidneys were selected from 20 patients with mild to moderate renal cyst burden (kidney volume < 1500 ml) in the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP). The performance of the semi-automated method was assessed in terms of two reference metrics in each kidney: the total number of cysts measured by manual counting and the total volume of cysts measured with a region-based thresholding method. The proposed and reference measurements were compared using intraclass correlation coefficient (ICC) and Bland-Altman analysis.nnnRESULTSnIndividual renal cysts were successfully segmented with the semi-automated method in all 20 cases. The total number of cysts in each kidney measured with the two methods correlated well (ICC, 0.99), with a very small relative bias (0.3% increase with the semi-automated method; limits of agreement, 15.2% reduction to 17.2% increase). The total volume of cysts measured using both methods also correlated well (ICC, 1.00), with a small relative bias of <10% (9.0% decrease in the semi-automated method; limits of agreement, 17.1% increase to 43.3% decrease).nnnCONCLUSIONnThis semi-automated method to segment individual renal cysts in ADPKD kidneys provides a quantitative indicator of severity in early and moderate stages of the disease.