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Patients with end-stage renal disease treated with dialysis are often prescribed complex medication regimens, placing them at risk for drug-drug interactions and other medication-related problems. Particularly in the context of a broader interest in more patient-centered value-based care, improving medication management is an increasingly important focus area. However, current medication management metrics, designed for the broader patient population, may not be well suited to the specific needs of patients with kidney disease, especially given the complexity of medication regimens used by dialysis patients. We propose a kidney pharmacy-focused quality pyramid that is intended to provide a framework to guide dialysis organizations, health care providers, and/or clinicians with respect to an optimal medication management approach for dialysis patients. Incorporation of core programs in medication management, including medication reconciliation, safety programs, and medication therapy management for patients at high risk for medication-related problems, may result in improved outcomes. Although a growing body of evidence supports the concept that active medication management can improve medication adherence and reduce medication-related problems, these strategies are viewed as costly and are not widely deployed. However, if done effectively, pharmacy-led medication management has the potential to be one of the more cost-effective disease management strategies and may greatly improve outcomes for these complex patients. Index Words: end-stage renal disease, medication management, pharmacy

Advancing American Kidney Health (AAKH) ([1][1]) has the potential to transform kidney care in America and outlines what the kidney care community has been striving to achieve for decades, as described in the recently released Kidney Care Partners Kidney Care First initiative ([2][2]). This includes

Key Points Question Is enrollment in a chronic condition special needs plan (C-SNP) associated with improved outcomes in patients with end-stage kidney disease (ESKD)? Findings In this cohort study of 2545 C-SNP enrollees matched at the facility level to patients not enrolled in C-SNP and 1986 C-SNP enrollees matched at the county level to patients not enrolled in C-SNP, C-SNP enrollees had significantly lower hospitalization rates and mortality risk than matched patients who were not enrolled in a C-SNP. Meaning The findings of this study suggest that enrollment in a C-SNP may improve outcomes compared with standard care for patients with ESKD., This cohort study examines whether enrollment in a chronic condition special needs plan is associated with improved clinical outcomes and quality of life among patients with end-stage kidney disease (ESKD)., Importance While several studies have demonstrated the benefit of enrollment in chronic condition special needs plans (C-SNPs) for other chronic diseases (eg, diabetes), there is no evaluation of the association of C-SNPs with outcomes among patients with end-stage kidney disease (ESKD). Objective To examine whether and to what degree C-SNP enrollment was associated with improved clinical outcomes and quality of life in patients with ESKD. Design, Setting, and Participants This multicenter cohort study included 2718 patients who were newly enrolled in an ESKD C-SNP between January 1, 2013, and September 30, 2017, and receiving dialysis from DaVita Kidney Care. Patients were followed up until death, loss to follow-up, or end of study (ie, December 31, 2018). Enrollees in C-SNP were matched via multiple clinical and demographic characteristics with 2 different control populations, as follows: (1) those in the same facilities (n = 2545) or (2) those in similar counties (n = 1986). Patients enrolled in CareMore C-SNPs (n = 206) were excluded from the study. Data analysis was conducted June to December 2019. Exposures Standard ESKD care with dialysis plus access to an integrated care team who worked with the patient and the dialysis team, comprehensive health assessments done by the integrated care team, and access to select benefits (such as vision and dental care) as a C-SNP enrollee. Main Outcomes and Measures Hospitalizations, mortality, laboratory values indicative of metabolic control, and Kidney Disease Quality of Life 36-item (KDQOL-36) survey scores. Results The 2545 C-SNP enrollees in the facility-matched analysis had a mean (SD) age of 57.2 (12.9) years, and included 968 (38.0%) women, 1328 (52.2%) Hispanic individuals, and 553 (21.7%) African American individuals. The 1986 C-SNP enrollees in the county-matched analysis had a mean (SD) age of 57.8 (12.2) years, with 705 (35.5%) women, 1085 (54.6%) Hispanic individuals, and 472 (23.8%) African American individuals. Compared with patients not enrolled in C-SNP, enrollees had lower hospitalization rates, with incidence rate ratios of 0.90 (95% CI, 0.84-0.97; P = .006) in the facility-matched analysis and 0.76 (95% CI, 0.70-0.83; P

Fragmentation of care has been cited as a rationale toward moving to new care models with care coordination and a focus on value-based care delivery. This trend is gathering momentum in end-stage renal disease (ESRD) care given evident care gaps and the variety of healthcare entities that touch patients with ESRD in the course of their treatment. Although care models supported by chronic condition special needs plans and ESRD seamless care organizations (ESCOs) have advanced care and cost-effectiveness, their shortcomings limit their ability to support larger patient populations. New care models and potential organizational structures, such as those proposed in the Dialysis Patient Access To Integrated-care, Empowerment, Nephrologists, Treatments, and Services (PATIENTS) Demonstration Act, provide another approach toward reducing fragmentation of care, increasing patient health, and helping define better approaches to care for patients with ESRD so that they have the opportunity to be better transplant candidates. We recognize that this type of innovation represents change without certainty. We also believe that multiple levels of accountability, ongoing support for transplantation, and continued freedom of access to transplant professionals who participate in Medicare would prioritize patient health, quality of life, and choice with regard to transplantation with this care model.

Epidemiological data indicate that 20-50% of patients on dialysis for end-stage renal disease (ESRD) are obese (body mass index [BMI] ≥30 kg/m2) (1). Obese patients with chronic renal failure have longer wait times until kidney transplantation (2) and inferior patient outcomes (3-7). In the US, for example, patients with a BMI 40 kg/m2 (2). Higher BMIs in kidney transplant recipients are associated with excess risk of surgical site infections (SSIs), which negatively impact graft survival (8). Obesity is also associated with comorbidities such as diabetes, although data on whether obesity increases mortality in kidney transplanted patients remains unclear (8,9). Provider perceptions of these risks accompanied by the expectation of some centers to give obese patients time to lose weight are the main reasons why a number of transplant centers are reluctant to list obese patients for transplantation (2,10). Unfortunately, many of these obese patients have diabetes and hypertension likely secondary to their obesity (11) and such patients who remain on dialysis have a very high mortality rate. The 5-year mortality rate for diabetic and hypertensive dialysis patients is 75 and 70%, respectively (1). A recent study demonstrated that obese patients who did not present with any SSIs had the same kidney transplant success rate as patients with a normal BMI (8). If surgical procedures could be developed that prevent SSIs and demonstrate successful outcomes, transplant centers may become less reluctant to list obese patients for kidney transplantation. Although any benefit would still have to be weighed against potential increased risks from obesity-related comorbidities. The prevalence of obesity and ESRD is higher among racial and ethnic minority populations, including African-Americans and Hispanics, compared to Non-Hispanic whites (12-15). These observations suggest developing kidney transplantation options for obese patients with ESRD may also help to reduce health disparities in racial and ethnic minorities. We therefore developed a new, minimally invasive, robotic-assisted kidney transplantation method using a short epigastric incision. This method avoids any incision in the infection prone lower quadrants of the abdomen. We hypothesized a priori that the robotic approach would reduce SSIs and improve outcomes in obese kidney transplant patients. Herein, we present our experience and outcomes of the patients undergoing minimal invasive, robotic kidney transplantation at a single institution compared to patients who underwent the conventional open procedure.

MicroRNAs (miRNA) are short, noncoding RNA sequences that regulate gene expression by blocking protein translation or inducing messenger RNA (mRNA) degradation. miRNA is found in various tissues with variable expression, and changes in expression are related to various disease processes. Evidence suggests that changes in miRNA expression are critical for the normal development of kidney tissue. Alternatively, in diseases such as diabetic nephropathy, polycystic kidney disease, and lupus nephritis, specific miRNAs may enhance disease manifestations in a myriad of ways, ranging from activation of fibrotic pathways to anatomic changes that abet proteinuria. The variable expression of miRNA in kidney tissue, whether in the context of normal development or disease processes, makes miRNAs a valuable new tool for understanding, diagnosing, and discovering therapeutic options for pathologic processes that affect the kidney.

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Given limited resources, adding another chronic illness to the panoply of chronic disease care is problematic. Nevertheless, chronic kidney disease (CKD) is increasing in recognition and prevalence across the world, and a management strategy for this growing population is necessary. A diverse group of health care professionals interacts with patients with CKD and their family members, including nurses, nurse practitioners, dieticians, social workers, pharmacists, physicians, physical therapists, physician assistants, and public health workers. All these individuals have the opportunity to reinforce CKD management. This potentially would bring a broader health care workforce to bear on CKD, reducing the impact of the nephrology workforce shortage. To realize such a strategy, it is necessary to bolster CKD awareness and knowledge in the diverse health care workforce. A faculty development program that extends CKD awareness to existing health care workers also has the possibility of migrating into the learner curriculum in health professional schools. This approach would expand CKD education, creating a skilled diverse health care workforce.

Background—Chemokines and their receptors play a critical role in leukocyte trafficking, and inhibition of select chemokines has been shown to attenuate kidney disease and allograft rejection in animal models. We therefore evaluated chemokine and chemokine receptor transcripts in human renal allograft biopsies, correlating transcript levels with clinical course and immunohistochemical analysis to relate chemokine expression to relevant clinical human disease phenotypes. Methods—Renal biopsies were grouped as post-reperfusion (n=10), stable function (n=10), subclinical (n=10) or acute rejection (n=17), or calcineurin inhibitor nephrotoxicity (n=9) based on clinical presentation and histopathological assessment. Using quantitative real-time polymerase chain reaction analysis, chemokine transcripts were assessed relative to transcript levels in preprocurement biopsies from live donor kidneys (n=15). Results—Transcripts from several inflammatory chemokines (CCL3, CCL5, CXCL9, CXCL10 and CXCL11) and chemokine receptors (CCR5, CCR7 and CXCR3) were significantly elevated in allografts with subclinical and clinical acute rejection, indicating a strong polarization toward a TH1 effector phenotype during rejection. These transcripts also distinguished acutely rejecting allografts from allografts with non-rejection causes of renal dysfunction. Biopsies from patients with stable function without histological evidence of rejection had increased chemokine transcript levels that were qualitatively similar but quantitatively reduced compared to rejecting allografts. Conclusions—This comprehensive evaluation of chemokines and their receptors in human renal transplantation defines associations between chemokine expression and clinical phenotypes, may have diagnostic utility, and highlights relevant pathways for therapeutic intervention.

Once thought to be a minor player in hemodialysis (HD) access dysfunction relative to outflow stenosis, inflow stenosis has recently come to be viewed as a major cause of access failure. Indeed, recent literature has shown that up to 40% of all accesses referred for dysfunction have an inflow lesion. Imaging of the inflow segment has been traditionally performed by interventional nephrologists via retrograde occlusive arteriography (ROA). Recent advances in our understanding of ROA have cast the technique in a negative light, with the possibility of vascular complications and poor diagnostic yield coming to the fore. Using a prospectively collected, vascular access database, we identified 18 consecutive patients who received imaging of inflow lesions by ROA and direct arteriogram (DA). The mean percent luminal stenoses were found to be 59.89 ± 24 and 79.06 ± 17.8 (p = 0.009) for the ROA vs. DA groups, respectively. Using multiple regression analysis, DA was found to be associated with detecting higher degree of luminal stenosis (β = 19.17, 95% CI 6.28-32.05, p = 0.006). This small case series provides evidence on the theoretical concern that ROA does not adequately evaluate inflow lesions. We may conclude that by relying solely on ROA, interventional nephrologists may be failing to detect a subset of hemodynamically significant inflow lesions.

The asymptomatic nature of chronic kidney disease (CKD) makes explicit screening strategies for individuals at risk as the only means of early detection. This will allow more time for interventions to alter the natural history of the disease by delaying or preventing kidney disease progression and its complications. Patient awareness of CKD remains low. Utilization of CKD tests for patients at risk and interpretation of those tests to detect CKD by primary care physicians remain suboptimal. There is insufficient evidence to support general population screening. Diabetes, hypertension, and age 60 or greater are the primary CKD screening target conditions, based on assessments representative of the general populations in America and Norway. Although cardiovascular disease, family history of CKD, and ethnic and racial minorities are important predictors of CKD risk, they do not contribute significantly beyond the scope of diabetes, hypertension, and older age. Challenges remain to define the roles in the community of the primary physician and nephrologist to implement intensive blood pressure control, use of renin-angiotensin system blockers for proteinuric patients and nephrology referral as indicated. The electronic medical record holds the most promise in CKD screening through improvements in the flow of information and application of clinical decision support.

Health care delivery at academic health centers (AHCs) can be viewed as dinosaur-like. Both are large and complex entities that consume many resources and are slow to adapt to competitive predatory forces. The potential for severe climate shifts, with changes in payer mix, competition from the private sector, and health care reform all occurring in the current health care system, could precipitate either the beginning of extinction for the AHC dinosaur or, hopefully, stimulate its evolution and development into a new model of health care delivery.Given the importance of clinical revenue to the entirety of the AHC enterprise, there is incentive for AHCs to maintain and indeed expand their clinical care delivery mechanisms. Yet, AHCs are institutions of investigation and inquiry. New models of care delivery and their impact on the current clinical care system must be developed through local demonstration projects and experimental clinical models. These models must be studied, and the findings should be shared with the community.The authors argue that this course of action will be challenging because traditional workflows must be restricted to improve care coordination and a changing workforce demographic. It will also require thoughtful approaches to reward innovative clinical work and new directions in strategic management by institution leaders. This commentary outlines recommendations to stave off extinction and enhance the next generation of clinical care delivery at AHCs.

The waiting list for kidney transplantation continued to grow between 1999 and 2008, from 41 177 to 76 089 candidates. However, active candidates represented the minority of this increase (36 951-50 624, a 37% change), while inactive candidates increased over 500% (4226-25 465). There were 5966 living donor (LD) and 10 551 deceased donor (DD) kidney transplants performed in 2008. The total number of pancreas transplants peaked at 1484 in 2004 and has declined to 1273. Although the number of LD transplants increased by 26% from 1999 to 2008, the total number peaked in 2004 at 6647 before declining 10% by 2008. The rate of LD transplantation continues to vary significantly as a function of demographic and geographic factors, including waiting time for DD transplant. Posttransplant survival remains excellent, and there appears to be greater use of induction agents and reduced use of corticosteroids in LD recipients. Significant changes occurred in the pediatric population, with a dramatic reduction in the use of LD organs after passage of the Share 35 rule. Many strategies have been adopted to reverse the decline in LD transplant rates for all age groups, including expansion of kidney paired donation, adoption of laparoscopic donor nephrectomy and use of incompatible LD.

Functional magnetic resonance imaging (fMRI) is a powerful tool for examining kidney function, including organ blood flow and oxygen bioavailability. We have used contrast enhanced perfusion and blood oxygen level-dependent (BOLD) MRI to assess kidney transplants with normal function, acute tubular necrosis (ATN) and acute rejection. BOLD and MR-perfusion imaging were performed on 17 subjects with recently transplanted kidneys. There was a significant difference between medullary R2⁎ values in the group with acute rejection (R2⁎=16.2/s) compared to allografts with ATN (R2⁎=19.8/s; P=.047) and normal-functioning allografts (R2⁎=24.3/s;P=.0003). There was a significant difference between medullary perfusion measurements in the group with acute rejection (124.4±41.1 ml/100 g per minute) compared to those in patients with ATN (246.9±123.5 ml/100 g per minute; P=.02) and normal-functioning allografts (220.8±95.8 ml/100 g per minute; P=.02). This study highlights the utility of combining perfusion and BOLD MRI to assess renal function. We have demonstrated a decrease in medullary R2⁎ (decrease deoxyhemoglobin) on BOLD MRI and a decrease in medullary blood flow by MR perfusion imaging in those allografts with acute rejection, which indicates an increase in medullary oxygen bioavailability in allografts with rejection, despite a decrease in blood flow.

Rationale and Objectives The purpose of this study was to evaluate prospectively a gadolinium-based perfusion technique for intrarenal blood flow in transplanted kidneys and to determine if magnetic resonance imaging (MRI) measurements of intrarenal perfusion could be used to differentiate between normal-functioning kidney allografts and allografts with acute tubular necrosis (ATN) or acute rejection. Materials and Methods Twenty-one subjects were enrolled within 4 months of receiving a kidney transplant. A biopsy was performed on subjects to diagnose each allograft as having either ATN or acute rejection. A group of subjects with normal functioning transplants was also enrolled in our study. MRI perfusion images were acquired on a 1.5 T MRI system within 48 hours after biopsy using an echo planar, T2∗-weighted sequence, and an injection of gadodiamide contrast agent administered at a dose of 0.1 mmol/kg. Scan parameters were: repetition time/echo time/flip = 1000 ms/30 ms/60°, field of view = 340 × 340 mm, matrix = 128 × 64, slice thickness = 10 mm, and temporal resolution = 1.0 seconds. Cortical and medullary blood flow values were calculated. Results Medullary blood flow values were significantly ( P = .02) lower in allografts undergoing acute rejection (121 ± 41 mL/100 g/min) compared to normal-functioning allografts (221 ± 96 mL/100 g/min) and those with ATN (247 ± 124 mL/100 g/min). Cortical blood flow values were also significantly ( P = .03) reduced in allografts with acute rejection (243 ± 116 mL/100 g/min) compared to those with normal function (413 ± 116 mL/100 g/min). Conclusions Preliminary results indicate that MRI perfusion techniques may provide a means of determining noninvasively the viability of renal allografts, potentially alleviating the need for biopsy in some patients.

KDIGO (Kidney Disease: Improving Global Outcomes) is an international initiative with a key mission of developing clinical practice guidelines in the area of chronic kidney disease (CKD). KDIGO recently published evidence-based clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C virus infection in individuals with CKD. The process of adaptation of international guidelines is an important task that, although guided by general principles, needs to be individualized for each region and country. Therefore, the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (KDOQI) convened a multidisciplinary group to comment on the application and implementation of the KDIGO guidelines for patients with CKD in the United States. This commentary summarizes the process undertaken by this group in considering the guidelines in the context of health care delivery in the United States. Guideline statements are presented, followed by a succinct discussion and annotation of the rationale for the statements. Research recommendations that are of particular interest to the United States are then summarized to highlight future areas of inquiry that would enable updating of the guidelines.

Individuals with kidney failure often elect to undergo kidney transplantation because they believe that they will be more active and return a sense of normality to their lives with a functioning transplant. Therefore it is important to assess whether these objectives are being met. To do so, we can examine health-related quality of life (HRQOL) in transplant recipients. A number of tools have been used for this purpose, including general HRQOL instruments such as the 36-item short-form health survey (SF-36) and transplant-specific surveys such as the Kidney Transplant Questionnaire. In general, HRQOL assessments improve with transplantation in functional and physical domains. However, many factors actually influence HRQOL in a negative way, including comorbid conditions, kidney function per se, rejection episodes and hospitalizations, employment status, and adverse effects of medications. Perceived physical appearance, issues related to sexuality, stress, anxiety, and even guilt complicate the emotional and psychological landscape after transplantation. This constellation of factors may be predictive of posttransplant life events, such as resumption of employment. Posttransplant HRQOL may be exceedingly important in understanding the issues related to adherence with treatment regimens, especially in the pediatric and adolescent transplant populations. HRQOL is now established as an important issue after transplantation. Nonetheless, shortcomings still exist in our ability to address HRQOL after transplantation. In particular, more study of patient-centered interventions is needed. The use of standardized methodologies for patient assessment could improve our ability to identify if such patient-centered interventions actually succeed across populations, and help us further address the panoply of factors encompassed within posttransplant HRQOL.

Background. Kidney half-life and inter-stage progression rates in native chronic kidney disease (CKD) and CKD-transplant (CKD-T) remain unknown. Methods. We examined stage-to-stage progression/ regression rates in patients with CKD (n ¼ 601) and CKD-T (n ¼ 431) between 1991 and 2001. Kidney function was estimated by Cockcroft–Gault and MDRD eGFR formulae. Kaplan–Meier analyses determined progression and regression half-lives, defined as the time required for 50% of kidneys to advance towards a higher or lower stage of CKD, respectively. Results. Most (67%) of the patients were in stage 3. Patients with native CKD were more likely to progress compared to CKD-T (inter-stage progression rates 12 vs 4 cases per 100 patient-years, P < 0.0001). Accordingly, estimated glomerular filtration rate (eGFR)-based progression half-lives were significantly shorter in CKD compared to CKD-T [6 vs 9.6 years, P < 0.0001, hazard ratio (HR) 3.1, 95% confidence interval (CI) ¼ 2.5–3.7]. Creatinine clearance (CCR)based stage half-lives were 7.2 months shorter in each group (5.4 and 9 years in CKD and CKD-T, respectively). Despite slower progression rates in patients with transplant kidney disease, adjusted patient survival rates were significantly decreased in CKD-T compared to CKD. Only Scr and CCR-based formulae were significantly associated with patient and allograft outcomes in the CKD-T group. Moreover, death rates were not different in stage 3 compared to stage 2 CKD-T, suggesting that eGFR and the current staging classification have a limited value to predict patient death in this cohort. Conclusion. Kidney half-lives per stage of CKD may be a novel tool to examine disease progression.

Background. An increase in the incidence of autoimmune diseases has been described in patients receiving alemtuzumab. Methods. To determine whether induction with alemtuzumab increases recurrence of glomerular disease, we performed a retrospective study in 443 patients with biopsy-proven glomerular diseases undergoing kidney transplantation. Patients receiving alemtuzumab (n=161) were compared with those receiving interleukin (IL)-2-receptor antagonists (n=217) or antithymocyte globulin (n=64). Results. Biopsy-proven glomerular disease recurrence was similar in patients induced with alemtuzumab or IL-2 receptor antagonists. Patients receiving antithymocyte antibody had a lower recurrence rate than patients treated with other induction agents, with borderline significance (hazard ratio [HR] 0.13, 95% confidence interval [95% CI] 0.02−0.98, P=0.047). Patients with systemic lupus treated with alemtuzumab had a similar re-emergence of autoreactive antibodies to patients treated with other agents. Recurrent disease increased the risk of allograft failure (HR 2.36, 95% CI 1.28−4.32, P=0.0056). The development of acute rejection and the use of deceased (vs. living) donor kidneys were also significant factors influencing graft survival. A greater risk of mortality was detected in those patients with recurrent glomerular disease (HR 3.76, 95% CI 1.37−10.35, P=0.01), whereas increased age at transplantation (HR 1.05) and the use of deceased (vs. living) donor kidneys (HR 3.20) also increased mortality. No specific induction agent significantly affected graft loss or mortality when using adjusted or unadjusted hazard ratios. Conclusions. In this retrospective analysis, induction with alemtuzumab did not increase the rate of re-emergence of autoantibodies or biopsy-proven recurrence of glomerular disease. A slight reduction in the incidence of recurrence was observed in patients treated with thymoglobulin, yet this observation can only be validated in a prospective randomized trial.

Background andobjectivesThecalcimimeticcinacalcet reduced therisk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older ($65 years, n=1005) and younger (,65 years, n=2878) patients. Design, setting, participants, & measurements Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified. ResultsOlderpatients hadhigher baselineprevalenceof diabetesmellitusandCV comorbidity. Annualizedrates of kidney transplantation and parathyroidectomy were .3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. Conclusions In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone. Clin J Am Soc Nephrol 10: ccc–ccc, 2015. doi: 10.2215/CJN.07730814

Several medications have been proposed to improve hemodialysis (HD) vascular access outcomes based on potentially favorable anticoagulant, antiplatelet, or pleiotropic properties. The purpose of this study was to evaluate the relationship between medication use and vascular access patency in a group of HD patients. We conducted a historical cohort study of the US Renal Data System Dialysis Mortality and Morbidity Wave II study to identify patients with an arteriovenous fistula (AVF), polytetrafluoroethylene (PTFE) graft, or a permanent catheter for vascular access. Cox regression analysis, adjusted for age, gender, race, history of coronary artery disease, peripheral vascular disease, or coronary artery bypass graft, was used to model the hazard ratio (HR) of permanent vascular access failure. Of the 2001 HD patients in the Wave II study, 901 (45%) were included in the analysis. PTFE graft patency was greater for males (HR, 0.73; 95% CI 0.53-1.00, p = 0.05) and for older individuals (HR, 0.99; 95% CI 0.98-1.00, p = 0.02). Treatment with antiplatelet medications, ticlopidine and dipyridamole (HR, 3.54; 95% CI 1.07-11.76; p = 0.04), or aspirin (HR, 2.49; 95% CI 1.31-4.73; p = 0.005) was associated with significantly worse AVF patency. Antiplatelet agents had a significant negative association with access patency in this cohort. In contrast to other published data, it was difficult to identify any beneficial effect of specific medications on access patency.

It is essential that community-based nephrologists and primary care physicians, who are increasingly involved in the management of stable renal allograft recipients, are familiar with new-generation immunosuppressive drugs. This comprehensive article by Arjang Djamali and colleagues is a guide to the pharmacokinetics, dosing, drug–drug interactions and adverse effects of the mainstays of modern immunosuppression; calcineurin inhibitors, antimetabolites, mTOR inhibitors and corticosteroids. Kidney transplantation is the treatment of choice for patients with end-stage renal disease, in part because of ongoing efforts towards improving immunosuppressive strategies. Although calcineurin inhibitors remain the mainstay of immunosuppression in kidney transplant recipients, within this class of drug there has been a shift from use of ciclosporin to use of tacrolimus. Mycophenolate mofetil and mycophenolate sodium are now the antimetabolites of choice. A new class of drugs (inhibitors of mammalian target of rapamycin) that includes sirolimus is being increasingly used in stable kidney transplant recipients. New data, however, indicate that a more cautious approach to the use of this drug is warranted. Many transplant centers are now using steroid avoidance, minimization and withdrawal protocols. The impact of these different drugs and therapeutic strategies on outcomes has to be weighed against their immunosuppressive benefit. As more and more community-based nephrologists and primary care physicians are becoming involved in the care of stable kidney transplant recipients, it is important for these clinicians to familiarize themselves with novel immunosuppressive drugs and their pharmacokinetic properties.

Campath-1H (alemtuzumab) induction was used for renal transplantation in combination with sirolimus as immunosuppression. We previously reported a high (28%) rate of early rejection with this regimen, and now report 3-year outcomes. Twenty-nine patients were recipients of either deceased donor or non-HLA (Human Leukocyte Antigen) identical living donor primary renal allografts. Clinical parameters including infection, malignancy, kidney function, and kidney histology were followed prospectively for 3 years. Three-year cumulative graft and patient survival were 96% and 100%, respectively. Twenty patients were maintained on steroid-free immunosuppressive regimens, and 15 patients were maintained on monotherapy for immunosuppression (12 on sirolimus). No serious infectious complications were observed and two patients developed basal cell skin cancer. The 3-year results of our initial pilot study demonstrate good graft (96%) and patient (100%) outcomes. Campath-1H induction has yielded a high proportion of patients maintained on immunosuppressive monotherapy (57%) without serious infectious- and no malignancy-related complications. The reported regimen yielded novel insights into both Campath-1H and sirolimus therapy in renal transplantation. Because of the higher incidence of early rejection, we recommend a modified strategy of immunosuppression including a brief course of a calcineurin inhibitor.

Kidney transplantation is the treatment of choice for patients with ESRD. Despite improvements in short-term patient and graft outcomes, there has been no major improvement in long-term outcomes. The use of kidney allografts from expanded-criteria donors, polyoma virus nephropathy, underimmunosuppression, and incomplete functional recovery after rejection episodes may play a role in the lack of improvement in long-term outcomes. Other factors, including cardiovascular disease, infections, and malignancies, also shorten patient survival and therefore reduce the functional life of an allograft. There is a need for interventions that improve long-term outcomes in kidney transplant recipients. These patients are a unique subset of patients with chronic kidney disease. Therefore, interventions need to address disease progression, comorbid conditions, and patient mortality through a multifaceted approach. The Kidney Disease Outcomes Quality Initiative from the National Kidney Foundation, the European Best Practice Guidelines, and the forthcoming Kidney Disease: Improving Global Outcomes clinical practice guidelines can serve as a cornerstone of this approach. The unique aspects of chronic kidney disease in the transplant recipient require the integration of specific transplant-oriented problems into this care schema and a concrete partnership among transplant centers, community nephrologists, and primary care physicians. This article reviews the contemporary aspects of care for these patients.

To prospectively assess the oxygenation state of renal transplants and determine the feasibility of using blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging to differentiate between acute tubular necrosis (ATN), acute rejection, and normal function.This HIPAA-compliant study had institutional human subjects review committee approval, and written informed consent was obtained from all patients. BOLD MR imaging was performed in 20 patients (age range, 21-70 years) who had recently received renal transplants. Six patients had clinically normal functioning transplants, eight had biopsy-proved rejection, and six had biopsy-proved ATN. R2* (1/sec) measurements were obtained in the medulla and cortex of transplanted kidneys. R2* is a measure of the rate of signal loss in a specific region and is related to the amount of deoxyhemoglobin present. Statistical analysis was performed by using a two-sample t test. Threshold R2* values were identified to discriminate between transplanted kidneys with ATN, those with acute rejection, and those with normal function.R2* values for the medulla were significantly lower in the acute rejection group (R2* = 15.8/sec +/- 1.5) than in normally functioning transplants (R2* = 23.9/sec +/- 3.2) and transplants with ATN (R2* = 21.3/sec +/- 1.9). The differences between the acute rejection and normal function groups (P = .001), as well as between the acute rejection and ATN groups (P.001), were significant. Acute rejection could be differentiated from normal function and ATN in all cases by using a threshold R2* value of 18/sec. R2* values for the cortex were higher in ATN (R2* = 14.2/sec +/- 1.4) than for normally functioning transplants (R2* = 12.7/sec +/- 1.6) and transplants with rejection (R2* = 12.4/sec +/- 1.2). The difference in R2* values in the cortex between ATN and rejection was statistically significant (P = .034), although there was no threshold value that enabled differentiation of all cases of ATN from cases of normal function or acute rejection.R2* measurements in the medullary regions of transplanted kidneys with acute rejection were significantly lower than those in normally functioning transplants or transplants with ATN. These results suggest that marked changes in intrarenal oxygenation occur during acute transplant rejection.

AT1R blockade reduces IFN-γ production in lymphocytes in vivo and in vitro.BackgroundType 1 angiotensin II (Ang II) receptor (AT1R) signaling induces proinflammatory responses. Recent studies suggest that T lymphocytes express AT1R; yet the effects of Ang II binding to AT1R on T cells are poorly understood. We examined the effect of AT1R blockade on release of the proinflammatory cytokine, interferon-gamma (IFN-γ) by human lymphocytes in vivo and in vitro.MethodsWe used an AT1R blocker losartan in a randomized clinical trial in kidney transplant recipients over a 12-month period [AT1R blocker (N = 11) and control (N = 10)]. Peripheral blood lymphocytes, isolated from both cohorts, were analyzed by enzyme-linked immunosorbent spot assays (ELISPOT) analyses and real-time reverse transcription-polymerase chain reaction (RT-PCR) to enumerate IFN-γ producing T cells and IFN-γ mRNA levels. The effects of AT1R blockade in vitro were assessed using human alloreactive T cells and an IFN-γ producing human cytotoxic T-lymphocyte line. Alloreactive T cells were treated with losartan or candesartan and enzyme-linked immunosorbant assay (ELISA) was used to measure IFN-γ protein release. The cytotoxic T-lymphocyte line also was AT1R blocker–treated prior to determining IFN-γ producing cells by intracellular cytokine staining.ResultsThe AT1R blocker cohort had a significant decrease in IFN-γ producing peripheral blood lymphocytes (P≤ 0.05 for each time point) and IFN-γ mRNA levels (P = 0.01 vs. control patients). Losartan also decreased IFN-γ production (P < 0.001) in purified alloreactive T cells in vitro as did candesartan. Moreover, Ang II amplified IFN-γ generation (P < 0.05) in alloreactive T cells while AT1R blocker treatment inhibited Ang II's effect (P < 0.04). AT1R blocker treatment furthermore also inhibited IFN-γ production in the cytotoxic T-lymphocyte line.ConclusionAT1R blockers may have a clinically relevant immunomodulatory role by blocking IFN-γ production in T cells.

BACKGROUND Heat shock protein (HSP) 27 plays a cytoprotective role through its antioxidant, antiapoptotic, and actin-stabilizing properties during cell stress. The authors hypothesized that HSP27 is involved in chronic allograft nephropathy (CAN), a chronic state of inflammation and stress. METHODS The authors used the Fisher 344-to-Lewis model of CAN. Transplants were performed in 3-month-old recipient rats. HSP27 mRNA and protein levels were determined using semiquantitative polymerase chain reaction, microarray (stress-toxicity, GEArray) analyses, gene sequencing, immunoblotting, and immunohistochemical analyses at 10 days and 6 months posttransplant. P38 mitogen-activated protein kinase (MAPK), manganese (Mn) superoxide dismutase (SOD), copper-zinc (CuZn) SOD, FasL, Bax, hypoxia-inducible factor (HIF)-1alpha, and CD3 lymphocytes were studied in parallel as selective biomarkers of oxidative stress (OS), apoptosis, hypoxia, and graft-infiltrating immune cells. RESULTS Six months after transplantation, kidney allografts displayed histologic and functional features of CAN, including tubular atrophy, interstitial fibrosis, glomerulosclerosis, and increased proteinuria and serum creatinine levels. HSP27 mRNA and protein levels in CAN were reduced by 50% and 85%, respectively (P=0.04). Immunohistochemical analyses revealed a "shift" in HSP27 from the medulla to the cortex in allografts with CAN. Bax, phosphorylated p38-MAPK, HIF-1alpha, and MnSOD followed a parallel relocation pattern. CD3 lymphocyte density and tubular FasL expression were also greater in the cortex of allografts with CAN. Time-course analyses revealed that most of these changes were present as early as 10 days posttransplant. CONCLUSIONS The shift of HSP27 from the medulla to the cortex, combined with greater CD3, p38-MAPK, Bax, FasL, HIF-1alpha, and MnSOD immunoreactivity in this area of the kidney, likely represents an allograft-level response to CAN-related OS-hypoxia.

Background. Hypomagnesaemia is a common side effect of cyclosporin A (CsA) therapy. Animal studies suggest that magnesium (Mg) supplementation inhibits chronic CsA nephropathy. Methods. To determine if low Mg levels correlate with true CsA-induced nephrotoxicity in humans, we examined kidney transplant biopsy records at our centre for all transplant biopsies performed between 1990 and 2002. We simultaneously reviewed the medical records to determine whether serum Mg levels were checked at the time of biopsy. Those individuals with histologically proven CsA nephrotoxicity were studied. Results. Serum total Mg levels were available for 320 patients, 60 of whom were diagnosed with chronic CsA-mediated nephropathy. Patients were divided in two groups, a low Mg [n ¼ 29, 1.8 (1.67–1.9) mg/dl or 0.74 (0.68–0.78) mmol/l] and a normal Mg group [n ¼ 31, 2.2 (2.0–2.4) mg/dl or 0.9 (0.82–0.98) mmol/l, P

Organ transplantation often depends on obtaining functioning organs from a donor who has recently died. This review presents a structured approach to management of the care of the brain-dead donor so as to achieve the greatest chance of a successful outcome in the recipient of the organs. Hypotension, hypothermia, diabetes insipidus, and cardiac dysfunction are common challenges to management. Brain death affects both hormone production and physiological responses in the donor.

The shortage of cadaveric donors for simultaneous pancreas-kidney transplantation has prompted the use of cadaveric organs from pediatric donors. The long-term outcome and its impact on overall long-term survival are unknown. A total of 680 recipients receiving cadaver Simultaneous pancreas-kidney (SPK) transplantation from pediatric and adult donors between July 1986 and September 2001 were analyzed and compared. Ten-year kidney and pancreas graft survival for SPK transplantation from donors aged18 years (n = 142) were 80% and 72%, respectively, compared to 61% pancreas and kidney graft survival from donorsor =18 years of age (n = 538; p = 0.03 and 0.05, respectively). Five years post-transplant, blood glucose, HbA1c and creatinine clearance were significantly better in recipients from pediatric donors (85.3 +/- 13 mg/dL, 5.5 +/- 3.5% and 65.6 +/- 16 mL/min, respectively), compared to recipients from adult donors (95.1 +/- 29 mg/dL, 5.9 +/- 3.5% and 58.3 +/- 17 mL/min; p = 0.001, 0.01 and 0.002, respectively). Causes of graft failure for kidney and pancreas transplants were similar between the two groups. No statistically significant difference was observed in patient survival between recipients from pediatric donors compared to adult donors (85% vs. 76%, p = 0.29). When recipients of SPK from pediatric donors were stratified according to age (3-11 years and 12-17 years) and compared, no difference in kidney or pancreas graft survival was observed (kidney 76.4% vs. 81.3%, p = 0.15; pancreas 75% vs. 76%, p = 0.10, respectively). Pediatric donors represent a valuable source of organs, providing excellent short- and long-term outcomes. Wide utilization of pediatric organs will substantially increase the donor pool.

Post-transplant hypertension remains a significant risk factor for graft loss, but whether or not specific blood pressure (BP) medications affect graft outcome is still unknown. We assessed the interaction between BP control and antihypertensive drugs on graft outcome. We retrospectively examined clinic BP data for 1662 renal transplant (RTx) patients, transplanted between 1994 and 2000 at our centre. The analysis examined all patients who received central alpha-agonists and peripheral alpha-antagonists, beta-blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibition (ACEI), angiotensin receptor blockers (ARBs). BP recordings during treatment were categorized for each agent. Thus, a particular BP could be categorized for multiple medications. A total of 1462 patients (pts) (88%) were Caucasian and 800 pts (46%) received cadaveric RTx. There were 10.6+/-6.8 BP measurements for each patient post-RTx. CCBs, alone among the classes of antihypertensive drugs evaluated, reduced the risk for graft loss (RR: 0.736; P=0.035) in the overall analysis. Interestingly, stratifying levels of BP control unmasked a beneficial effect on graft survival of ACEI/ARB therapy in individuals with higher levels of systolic (>152 mmHg) and diastolic blood pressure (>98 mmHg) treated with ACEI/ARBs compared to individuals treated with CCBs (P

Background:Chronic kidney disease (CKD) affects up to 19.2 million Americans, and untreated kidney disease can progress to kidney failure. Patient education is an important part of slowing disease progression, but the ability of health professionals to provide this education is limited by time constraints. To date, there have been no systematic evaluations of CKD eHealth Web sites. Methods:Seven nonproprietary and 4 proprietary Web sites geared toward educating patients with CKD were identified by using the Internet to search for the terms "chronic kidney disease," "kidney disease," and "chronic renal failure." Web sites were evaluated according to (1) compliance with the principles of the Health on the Net (HON) Foundation Code of Conduct and (2) reading grade level. Results:Nonproprietary sites were in compliance with an average of 5.2 principles, with a range of 3 to 8. Average compliance of proprietary Web sites with the HON Code of Conduct principles was 3.12, with a range of 2 to 4 ( P = 0.021). Of nonproprietary Web sites, average reading grade level assessed by the Fry Readability Scale was greater than grade 14, with a range from grade 11 through graduate school. Of proprietary sites, average readability was grade 11, with a range from grades 7 through 16 ( P = 0.575). Conclusion:The Internet has the potential to be a very powerful educational tool for patients with CKD. However, many easily accessed CKD public health Web sites do not comply with accepted standards for health Web sites and are written using language beyond the general public's reading comprehension.

Endocytosis modulates cell responses by removing and recycling receptors from the cell surface. Type I angiotensin II receptors (AT1R) are somewhat unique in that they are expressed at apical (AP) and basolateral (BL) membranes in proximal tubule cells and both receptor sites undergo endocytosis. We analyzed AT1R cytoplasmic (-COOH) tail deletion mutants to determine whether classic AT1R endocytosis motifs functioned similarly in polarized cells and simultaneously altered receptor properties. Serially truncating the AT1R tail had little effect on AP/BL AT1R distribution as determined by 125I-angiotensin II binding in LLCPK(Cl4) cells transfected with an AT1R transcript. AP AT1R expression required the proximal 12 amino acids in the AT1R-COOH tail. Deleting all but the proximal 12 aa of the AT1R-COOH tail (T316L mutant) decreased AP AT1R internalization at 20 min (17 +/- 6%; p < 0.05 versus full-length; n = 5) and inhibited AP AT1R-stimulated arachidonic acid release (counts released per milligram of protein at 20 min: full-length, 18,762 +/- 4018; T316L, 2430 +/- 1711; n = 4; p < 0.02). Endosomal fusion assays were performed using peptide sequences of regions in the AT1R tail involved in endocytosis (YFLQLLKYIPP [LL] and LSTKMSTLSY [STL]). Peptide STL significantly inhibited endosomal fusion (22 +/- 10% of control; n = 5; p < 0.05 versus positive control). Peptide LL had no significant inhibitory effect. AT(1)R in polarized cells contain dominant endocytosis signals but these motifs do not correlate with AP or BL AT1R expression. Moreover, peptide sequences within the AT1R-COOH tail necessary for endocytosis also modulate endosomal fusion properties.

Background Cardiovascular disease remains epidemic in transplant recipients, despite aggressive treatment of cardiovascular risk factors. Thus, novel risk factors could play a role in the genesis of cardiovascular events in this population. Methods We evaluated the impact of early posttransplant anemia on cardiovascular events. We examined rolling average hematocrit values at 30-day intervals and determined the effect of increasing hematocrit on the risk for cardiovascular (CV) events in a single-center population of 404 type 1 diabetic end-stage renal disease patients who underwent either cadaveric kidney transplantation alone or simultaneous pancreas-kidney transplantation. Results Greater than 60% of the individuals in the study cohort had hematocrit less than or equal to 30% at least once during the first 30 days posttransplant. Forty-two individuals (10.4% of the study population) had at least one 30-day rolling hematocrit less than or equal to 30% and a CV event (myocardial infarction, CV death, angina, congestive heart failure) during the first 26 weeks of the posttransplant course. Increasing hematocrit (>30%) led to a reduction in the risk ratio (RR) for a CV event compared with hematocrit less than or equal to 30% (RR, 0.237; P=0.015). The association between anemia and CV events remained statistically significant in a multivariate analysis (RR, 0.65; P=0.022) that also included age and a history of pretransplant ischemic heart disease. Conclusions These data suggest that anemia is an important risk factor for early posttransplant CV events in a high-risk population. Prospective studies of anemia management therapy in this setting are warranted to determine whether this will reduce early posttransplant CV risk.

Although the Kidney Disease Outcomes and Quality Initiative (K/DOQI) guidelines serve to integrate the multiple stages of chronic kidney disease (CKD), in practice, the treatment of kidney disease over its progressive course may be somewhat fragmented. Because the provision of integrated care across the stages of kidney disease, is likely to be advantageous for both patients and care providers, a conceptual framework which graphically depicts the complex and chronic nature of kidney disease may prove useful. The Life Options Rehabilitation Advisory Council (LORAC) proposes a cycle diagram to reflect the chronicity and complexity of kidney disease and to emphasize a holistic perception of kidney disease the notion that kidney disease, from its inception to the worst-case scenario outcome of kidney failure. The kidney disease cycle conceptualization can serve as a patient teaching aid and as a reminder of the communication, collaboration, and cooperation that are required among primary care physicians and practitioners in each of the specialty areas that address the spectrum of kidney disease.

Campath-1H, an anti-CD52 monoclonal antibody, was used as induction therapy (40 mg i.v. total dose) in 29 primary human renal transplants, and the patients were maintained on rapamycin monotherapy (levels 8-15 ng/mL) post-transplant. Campath-1H profoundly depletes lymphocytes long-term and more transiently depletes B cells and monocytes. All patients are alive and well at 3-29 months of follow up. One graft was lost because of rejection. There have been no systemic infections and no malignancies. Eight of 29 patients have experienced rejection, which was successfully treated in seven of eight patients. Five of these patients had pathological evidence of a humoral component of their rejection. Seven of the 29 patients were converted to standard triple therapy on account of rejection. Rapamycin was generally well tolerated in that there were no significant wound-healing problems; two lymphoceles required surgical drainage; and most patients were treated with a lipid-lowering agent. Flow crossmatch testing post-transplant revealed evidence of alloantibody in two patients tested with previous combined cellular and humoral rejection. Biopsies have shown no chronic allograft nephropathy to date. In view of the relatively high incidence of early humoral rejection, we plan to modify the immunosuppressive regimen in subsequent pilot studies. This clinical trial provides insight into the use of Campath-1H induction in combination with rapamycin maintenance monotherapy.

Background. Chronic allograft nephropathy (CAN) remains a major barrier to long-term allograft survival. The authors retrospectively compared the development of CAN in recipients of cadaveric (CAD), living-related donor (LRD), and living-unrelated donor (LURD) transplants at their center. Methods. The authors retrospectively examined the impact of various factors on the incidence of CAN using univariate and multivariate proportional hazards analysis in a single-center kidney transplant population. Results. Between 1 January 1990 and 31 May 2000, 2,140 kidney-alone transplants were performed at the authors' center. The overall 5-year incidence of biopsy-proven CAN was 12.2% (n=203). Risk factors for CAN included the number of transplants (P=0.0001), acute rejection (P=0.0001), panel reactive antibody (P=0.0001), discharge creatinine (P=0.0001), 1-year creatinine (P=0.0015), delayed graft function (P=0.007), total human leukocyte antigen (HLA)-B and -DR mismatches (P=0.0005), recipient age (P=0.003), black donor race (P=0.001), black recipient race (0.0457), donor age (P=0.0053), cold storage time (P=0.019), and cytomegalovirus infections (P=0.002). Interestingly, although the LRD HLA-identical recipients had a significantly lower incidence of CAN (P=0.0015), the incidence of CAN in CAD and HLA-nonidentical LRD recipients did not differ. Graft survival was significantly worse in CAD recipients compared with all other groups (P

Recombinant human erythropoietin (rHuEPO) and iron supplementation have had a profoundly positive impact on the anemia of patients with chronic kidney disease. However, a significant number of patients remain hyporesponsive to rHuEPO, with hemoglobin values less than target levels. A suboptimal response to rHuEPO is associated with complications that can reduce quality of life and increase morbidity, mortality, and costs. There are a number of other metabolic derangements associated with uremia that can impact on the production and survival of red blood cells. Dialysis-related carnitine disorder is a functional metabolic deficiency, common in chronic dialysis patients, that can have a negative impact on erythrocyte production and survival. This article reviews the role of L-carnitine in the pathogenesis and adjunctive treatment of anemia associated with kidney failure. After a comprehensive database search, primary and secondary reports were analyzed. Laboratory studies examining the influence of carnitine on red blood cell function and clinical trials of L-carnitine in dialysis patients support the use of L-carnitine in the setting of rHuEPO hyporesponsiveness. Consensus groups, including the National Kidney Foundation-Kidney Disease Outcome Quality Initiative (K/DOQI), consider the use of L-carnitine for hyporesponsive rHuEPO-dependent anemia a promising application of this therapy, recommending an empiric trial of L-carnitine in these patients.

Aims: Cardiovascular mortality has been reported to be 10- to 20-fold higher in chronic dialysis patients than in the age-matched general population. It has been suggested that increased oxidant stress and resulting vascular wall injury due to uremia and the hemodialysis procedure may be one of the mechanisms predisposing to these cardiovascular complications. Further, hemodialysis membrane bioincompatibility can contribute to increased oxidative stress and prevalence of inflammation. Materials: We studied 18 chronic hemodialysis (CHD) patients (age 62.8 ± 14.7 years, 39% male, 61% African-American, 44% insulin-dependent diabetic, 61% smokers, 61% with documented coronary artery disease) during hemodialysis with 2 membranes with different flux and complement activating properties. Methods: We have measured free and phospholipid-bound F 2 -isoprostane (F 2 -IsoP) levels, a sensitive marker of oxidative stress, in CHD patients and compared them to levels in healthy subjects. We have also examined the acute effects of the hemodialysis procedure using both biocompatible and bioincompatible membranes on F 2 -IsoP levels. Results: The results indicated that, compared to controls, both free (96.2 ± 48.8 pg/ml versus 37.6 ± 17.2 pg/ml) and bound F 2 -IsoP (220.4 ± 154.8 pg/ml versus 146.8 ± 58.4 pg/ml) levels were significantly higher (p < 0.05 for both). There was a statistically significant decrease in free F 2 -IsoP concentrations at 15 and 30 minutes of HD, which rebounded to baseline levels at the completion of the procedure. There were no significant differences in F 2 -IsoP concentrations between the 2 study dialyzers at any time point. Age, smoking status, diabetes mellitus and presence of cardiovascular disease were also not correlated with F 2 -IsoP levels in this patient population. There was a significant association between predialysis F 2 -IsoP and C-reactive protein concentrations. Conclusion: Using a sensitive and specific assay for the measurement of F 2 -IsoP, we demonstrated that CHD patients are under increased oxidative stress. During a single hemodialysis treatment, the hemodialysis membrane appears to have no discernable effect on oxidative stress status. Measurement of F 2 -isoprostanes may be a useful biomarker of oxidative stress status as well as in developing new therapeutic strategies to ameliorate inflammatory and oxidative injury in this patient population.

BACKGROUND: The demand for organs has increased exponentially with a new name added to the United States waiting list every 16 min. As such, kidneys from medically marginal donors are being considered for transplantation more frequently, including kidneys from individuals already at risk for renal disease, e.g., diabetic donors. METHODS: We compared outcomes when using kidneys from donors with type 1 diabetes mellitus (D1) or type 2 diabetes mellitus (D2) at our center as a function of time. All patients with available data who underwent renal transplantation were evaluated (n=2013). RESULTS: Forty-two individuals were recipients of D1 or D2 donor kidneys. Thirty of these individuals did not have diabetes (R0). All patients received quadruple sequential immunosuppression with cyclosporine (CsA) or tacrolimus (FK506). Donor serum creatinine (Scr) values were not significantly different. D2 kidneys came from older donors (mean age, 56+/-10.4 years; P< or =0.01 vs. D1 and D0 donors). Mean discharge Scr was greater in nondiabetic D2 recipients (D2/R0, 2.45+/-1.3 mg/dl; P=0.0016 vs. D0/R0), and transplantation of D1 or D2 kidneys was associated with a significantly increased frequency of posttransplant proteinuria (P=0.0089). Interestingly, R0 recipients of D1 or D2 kidneys were more likely to initiate oral hypoglycemic therapy after transplant (P=0.04). However, rejection episodes were not significantly different among groups, and long-term graft survival and patient survival were similar among groups. CONCLUSIONS: These data suggest that diabetic kidneys can be safely used without risk to patient or graft survival. Preexisting diabetic injury in the donor may increase the risk for proteinuria, compromised renal function, and posttransplant glucose intolerance.

Chronic allograft nephropathy (CAN) is a multifactorial lesion. There has been a gradu-ally increasing recognition of the importance of antigen-independent factors influencingthe development and progression of CAN. One important antigen-independent hor-mone in this setting is angiotensin II (AII), which is associated with progressive kidneydisease. Although the pathogenesis of native kidney disease may differ from CAN, thechronic progressive nature of both entities raises the hypothesis that AII also has a rolein CAN. However, AII also serves as a theoretical focal point, linking many of the factorsinvolved in CAN. Fortunately, we have therapies, angiotensin converting enzyme in-hibitors (ACE-I), and type 1 angiotensin II receptor (AT

New antiviral agents and practice guidelines have been implemented to address cytomegalovirus (CMV) infection in organ transplantation. We hypothesized that such measures would reduce rates of symptomatic CMV infection, CMV disease, and CMV seroconversion and associated complications in renal transplant and simultaneous pancreas-kidney transplant recipients. We analyzed the impact of CMV in 1,424 renal transplant and simultaneous pancreas-kidney transplant recipients, transplanted at our center between January 1, 1994 and June 30, 1999. Most patients received quadruple sequential immunosuppression with high-dose acyclovir (800 mg four times daily) for 12 weeks as prophylaxis. High-risk patients (donor CMV-positive/recipient CMV-negative) received ganciclovir (500 to 1,000 mg three times daily) beginning in 1998, again for 12 weeks. One hundred and one renal transplant (9.0%) and 40 simultaneous pancreas-kidney transplant (13.4%) recipients experienced symptomatic CMV infection or CMV disease. Donor CMV-positive/recipient CMV-negative patients had the greatest rates of CMV infection or CMV disease (25.2%; P = 0.0001 versus all other categories). The impact of CMV on outcomes was evaluated in a proportional hazards model. Symptomatic CMV infection or CMV disease increased the risk for subsequent rejection (relative risk, 2.11; P = 0.003) and non-CMV infection (relative risk, 2.24; P = 0.001). To determine if the effects of ganciclovir were masked by pre-1998 data, CMV infection and CMV disease rates for ganciclovir-treated patients (n = 62) were censored at 1 year and compared with acyclovir-treated patients (n = 287). Ganciclovir was associated with trends toward lower rates of infection and disease. It also delayed the time to infection or disease. Serologic testing in high-risk patients also showed late seroconversion, with 20% of patients seroconverting by 6 months, 12 weeks after the prophylaxis period. These data suggest that despite better prophylaxis strategies, CMV remains an important pathogen in renal transplant and simultaneous pancreas-kidney transplant recipients. This finding may require reassessment of prophylaxis strategies and the development of alternative or novel anti-CMV regimens.

Background/Aims: 1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) plays an important role in regulating immunologic responsiveness in addition to its effects on bone metabolism. This is potentially beneficial in the transplant setting. Animal studies have demonstrated the utility of 1,25-(OH)2D3 in prolonging allograft survival. Therefore, we evaluated the effects of 1,25-(OH)2D3 (oral calcitriol) in human renal transplant recipients. Methods: A case-control study was undertaken assessing the effects of calcitriol on transplant function. The effect of calcitriol on renal function was analyzed using general linear mixed modeling of the change in slope of serum creatinine (Scr) prior to and following the start of calcitriol therapy. Results: There was a significant increase in baseline Scr (p < 0.001) prior to starting calcitriol. Following initiation of calcitriol, there was a deceleration in the rate of loss of graft function (p = 0.031 at day 300 of therapy). Graft survival was also prolonged in calcitriol-treated patients compared to a control population with evidence of chronic allograft nephropathy but no calcitriol therapy (p < 0.03). Overall, there were no adverse or harmful effects related to calcitriol therapy. 1,25-(OH)2D3 therapy was associated with (1) a deceleration in the rate of loss of renal function in transplant recipients with more than one year of allograft function, and (2) no significant change in allograft function early after transplantation. Conclusion: These data suggest that short- and long-term prospective trials evaluating 1,25-(OH)2D3 or 1,25-(OH)2D3 analogs in human kidney transplantation are warranted. Such trials may help us elucidate mechanism and duration of action, as well as safety issues related to these novel immunomodulatory agents.

Readmission for acute conditions has become an important metric for health systems in looking at the success of their original treatment for a particular condition. Indeed, it is so important that there are specific financial penalties relating to readmissions for specific conditions. In general

Severity stratification and prediction models are important tools for gauging outcomes in critically ill patients. However, most severity scoring systems are inaccurate when attempting to predict mortality in individuals with acute renal failure (ARF), including the APACHE (Acute Physiology and Chronic Health Evaluation) II scoring system. APACHE III scoring encompasses a greater array of physiologic parameters that may better correlate with outcome in ARF. We evaluated APACHE II and APACHE III scoring in 27 individuals admitted to the intensive acre unit (ICU) with ARF requiring dialysis. We also evaluated the predictive value of serial APACHE III scoring on mortality. Sixteen of the study subjects were discharged alive from the ICU. APACHE II scores for ICU survivors versus nonsurvivors were not significantly different at the outset of dialysis treatment, though they did discriminate between survivors and nonsurvivors at 48 hours (survivors 15 ± 6.2; nonsurvivors 18.1 ± 6.9; p = 0.019). However, average APACHE III scores for survivors were significantly less than those for nonsurvivors on all days of score collection, including at the outset of dialysis (day 0 survivors 94.7 ± 22.1; nonsurvivors 106.8 ± 21.7; p = 0.03). APACHE III scores on day 2 also discriminated between those who recovered renal function (83.6 ± 16.7) compared to those who did not (105.6 ± 21.4) (p = 0.05). Serial APACHE III scoring provided rapid and reproducible scoring that differentiated between survivors and nonsurvivors in a group of critically ill patients with ARF. This study suggests that further investigations are warranted to confirm whether serial APACHE III scoring should be considered as an adjunct clinical tool in caring for individuals with ARF in the ICU.