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Several studies have demonstrated that angiotensin-converting enzyme inhibitors (ACEIs) blunt progression of renal disease in nondiabetic patients with chronic kidney disease (CKD).1–4 However, ACEIs can cause hyperkalemia by impairing renal potassium excretion through interference with production and/or secretion of aldosterone.5 Hyperkalemia from ACEI use has been frequently described,6–8 and ACEIs are often underprescribed in patients with CKD because of concerns of hyperkalemia.9 β-Blocker (BB) use has also been associated with hyperkalemia, most likely through redistribution of potassium from intracellular to extracellular compartments as a result of blockade of β2-adrenoreceptor–mediated cellular potassium uptake.10,11 The African American Study of Kidney Disease and Hypertension (AASK) was a randomized clinical trial in nondiabetic African Americans with hypertensive CKD. One primary goal was to determine the effects of 3 different classes of antihypertensive agents on progression of renal disease: a dihydropyridine calcium channel blocker (CCB), a BB, and an ACEI. The most beneficial drug therapy was with ACEIs.12 The other primary goal was to determine the effects of 2 different BP goals on progression of renal disease; the trial demonstrated that a target mean arterial BP (MAP) of 102 to 107 mm Hg was as effective as stricter BP goal of a MAP lower than 92 mm Hg.12 Participants had a glomerular filtration rate (GFR) between 20 and 65 mL/min/1.73 m2 and no identified causes of renal insufficiency other than hypertension. After the close of the trial phase of the AASK, the investigators were directed by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) appointed Data Safety Monitoring Board to use the AASK database to explore factors associated with development of hyperkalemia. In this report, we describe the incidence of hyperkalemia by class of antihypertensive drug in the AASK and report the independent associations of other clinically measured factors

New-onset diabetes after transplant (NODAT) is a serious complication after kidney transplantation. We studied the relationship between steroid-free maintenance regimens and NODAT in a national cohort of adult kidney transplant patients.A total of 25,837 previously nondiabetic kidney transplant patients, engrafted between January 1, 2004, and December 31, 2006, were included in the study. Logistic regression analysis was used to compare the risk of developing NODAT within 3 years after transplant for patients discharged with and without steroid-containing maintenance immunosuppression regimens. The effect of transplant program-level practice regarding steroid-free regimens on the risk of NODAT was studied as well.The cumulative incidence of NODAT within 3 years of transplant was 16.2% overall; 17.7% with maintenance steroids and 12.3% without (P0.001). Patients discharged with steroids had 42% greater odds of developing NODAT compared with those without steroids (adjusted odds ratio [AOR]=1.42, 95% confidence interval [CI]=1.27-1.58, P0.001). The maintenance regimen of tacrolimus and mycophenolate mofetil or mycophenolate sodium was associated with 25% greater odds of developing NODAT (AOR=1.25, 95% CI=1.08-1.45, P=0.003) than the regimen of cyclosporine and mycophenolate mofetil or mycophenolate sodium. Several induction therapies also were associated with lower odds of NODAT compared with no induction. Patients from programs that used steroid-free regimens for a majority of their patients had reduced odds of NODAT compared with patients from programs discharging almost all of their patients on steroid-containing regimens.The adoption of steroid-free maintenance immunosuppression at discharge from kidney transplantation in selected patients was associated with reduced odds of developing NODAT within 3 years.

Background. Malignancy is a dreaded complication of organ transplantation. Immunosuppressive drug therapy-induced impairment of the organ graft recipient's immune surveillance is considered to be the mechanism for the heightened incidence and metastatic progression. We identified a cell-autonomous and host-immunity independent mechanism for cyclosporine-associated tumor progression. In this study, we investigated the effect of rapamycin on tumor progression, in the presence and absence of cyclosporine. Methods. A spontaneously arising renal adenocarcinoma (renal cancer) of BALB/c origin was used as the model tumor. The effect of rapamycin on renal cancer cell phenotype, molecules (E-cadherin, p27 kipl, cyclin Dl) implicated in tumor progression, and the effect of rapamycin on in vivo tumor progression were explored in BALB/c mice and in T-cell, B-cell, and natural killer (NK) cell-deficient severe combined immune deficiency (SCID)-beige mice. In the SCID-beige mice, T24 human bladder transitional cell carcinoma also was used as the tumor inoculum. Results. Rapamycin conditioning of renal cancer cells upregulated E-cadherin expression and induced phenotypic transition from invasive spindle, or dome-shaped cells, with exploratory pseudopodia to noninvasive cuboidal cells that formed cell-to-cell adhesions. Rapamycin increased p27 kipl, reduced cyclinDl, and arrested the growth of renal cancer cells in G1/S phase. In vivo, rapamycin prevented tumor growth and metastatic progression in syngeneic BALB/c or SCID-beige mice, and in BALB/c or SCID-beige mice treated with cyclosporine. Rapamycin treatment alone, or with cyclosporine, prolonged the survival of mice inoculated with renal cancer cells or T24 human bladder cancer cells. Conclusions. Our findings, in addition to unlinking mechanisms of immunosuppression from that of tumor progression, suggest that rapamycin may be of value for the management of posttransplant malignancy.

Background. The economic merit of universal prophylaxis and preemptive therapy in the management of cytomegalovirus (CMV) infection for serology positive (R+) kidney transplant patients remains undefined. We performed cost effectiveness and cost utility modeling comparing these two approaches. Methods. The incidence of CMV infection under universal prophylaxis and preemptive therapy was determined among 653 R+ patients from our institution and 416 R+ patients from various clinic trials, respectively. Standardized decision tree analysis and Markov transitional models were used to calculate cost and quality-adjusted life years (QALYs) from the prototypical clinical data and published literature. Incremental cost effectiveness and cost utility were calculated as dollars for one case of infection avoided and one QALY gained over 10 years, respectively. One- and two-way sensitivity analyses were performed. Results. The incidence of CMV infection was 4.1% and 55.5% within the first year after transplant for universal prophylaxis and preemptive therapy, respectively. Compared with preemptive therapy, universal prophylaxis incurred $1464 more in direct cost while saving $7309 in indirect cost, and resulted in a net gain of 0.209 in QALYs per patient over a 10-year period. Thus, universal prophylaxis dominates over preemptive therapy with a cost saving of $27,967 for 1 QALY gained. This cost saving was sensitive to the variation in the rate of CMV infection and disease with each approach. Conclusion. Universal prophylaxis in CMV R+ kidney transplant patients is clinically effective and cost saving. It should be considered as the preferred approach.

Abnormal glucose metabolism (AGM) is common early after kidney transplantation and is a risk factor for new-onset diabetes after transplant (NODAT) (1, 2). The majority of NODAT occurs early after kidney transplantation, and it is associated with increased cardiovascular events and mortality (3–5). Metabolic syndrome (MS) is a constellation of metabolic and nonmetabolic disorders that occurs frequently in kidney transplant recipients as well, and it is associated with impaired long-term renal allograft function and poor patient survival (6, 7). In addition, various components of MS are shown to be risk factors for the development of AGM and NODAT (1, 8). It is unclear what relationship exists between AGM and MS early after kidney transplantation. Current guidelines recommend using fasting plasma glucose or oral glucose tolerance to diagnose AGM (9–11). However, in the kidney transplant population, it has been shown that the oral glucose tolerance test (OGTT) has a superior sensitivity in diagnosing AGM when compared with fasting glucose levels alone (12). Furthermore, the OGTT can clearly define a subgroup of patients who demonstrate an impaired glucose tolerance (IGT) that can be a precursor of type 2 diabetes mellitus and a predictor of mortality in the general population (13, 14). Thus, the early detection of AGM and MS after transplantation could be of great importance because it will allow for a more timely intervention to prevent or reduce the long-lasting deleterious effects of both conditions on patient and allograft survival. We performed a prospective observational study investigating the relationship between AGM and MS in de novo kidney transplant recipients. Here, we report the findings at 10 weeks after kidney transplantation.

Malignancy is a dreaded complication of organ transplantation. Immunosuppressive drug therapy-induced impairment of the organ graft recipient's immune surveillance is considered to be the mechanism for the heightened incidence and metastatic progression. We identified a cell-autonomous and host-immunity independent mechanism for cyclosporine-associated tumor progression. In this study, we investigated the effect of rapamycin on tumor progression, in the presence and absence of cyclosporine.A spontaneously arising renal adenocarcinoma (renal cancer) of BALB/c origin was used as the model tumor. The effect of rapamycin on renal cancer cell phenotype, molecules (E-cadherin, p27 kip1, cyclin D1) implicated in tumor progression, and the effect of rapamycin on in vivo tumor progression were explored in BALB/c mice and in T-cell, B-cell, and natural killer (NK) cell-deficient severe combined immune deficiency (SCID)-beige mice. In the SCID-beige mice, T24 human bladder transitional cell carcinoma also was used as the tumor inoculum.Rapamycin conditioning of renal cancer cells upregulated E-cadherin expression and induced phenotypic transition from invasive spindle, or dome-shaped cells, with exploratory pseudopodia to noninvasive cuboidal cells that formed cell-to-cell adhesions. Rapamycin increased p27 kip1, reduced cyclinD1, and arrested the growth of renal cancer cells in G1/S phase. In vivo, rapamycin prevented tumor growth and metastatic progression in syngeneic BALB/c or SCID-beige mice, and in BALB/c or SCID-beige mice treated with cyclosporine. Rapamycin treatment alone, or with cyclosporine, prolonged the survival of mice inoculated with renal cancer cells or T24 human bladder cancer cells.Our findings, in addition to unlinking mechanisms of immunosuppression from that of tumor progression, suggest that rapamycin may be of value for the management of posttransplant malignancy.