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OBJECTIVE To determine long-term outcomes for islet-alone and islet-after-kidney transplantation in adults with type 1 diabetes complicated by impaired awareness of hypoglycemia. RESEARCH DESIGN AND METHODS This was a prospective interventional and observational cohort study of islet-alone (n = 48) and islet-after-kidney (n = 24) transplant recipients followed for up to 8 years after intraportal infusion of one or more purified human pancreatic islet products under standardized immunosuppression. Outcomes included duration of islet graft survival (stimulated C-peptide ≥0.3 ng/mL), on-target glycemic control (HbA1c RESULTS Of the 48 islet-alone and 24 islet-after-kidney transplantation recipients, 26 and 8 completed long-term follow-up with islet graft function, 15 and 7 withdrew from follow-up with islet graft function, and 7 and 9 experienced islet graft failure, respectively. Actuarial islet graft survival at median and final follow-up was 84% and 56% for islet-alone and 69% and 49% for islet-after-kidney (P = 0.007) with 77% and 49% of islet-alone and 57% and 35% of islet-after-kidney transplantation recipients maintaining posttransplant HbA1c 90% in both cohorts. Insulin independence was achieved by 74% of islet-alone and islet-after-kidney transplantation recipients, with more than one-half maintaining insulin independence during long-term follow-up. Kidney function remained stable during long-term follow-up in both cohorts, and rates of sensitization against HLA were low. Severe adverse events occurred at 0.31 per patient-year for islet-alone and 0.43 per patient-year for islet-after-kidney transplantation. CONCLUSIONS Islet transplantation results in durable islet graft survival permitting achievement of glycemic targets in the absence of severe hypoglycemia for most appropriately indicated recipients having impaired awareness of hypoglycemia, with acceptable safety of added immunosuppression for both islet-alone and islet-after-kidney transplantation.

OBJECTIVE To determine long-term outcomes for islet-alone and islet-after-kidney transplantation in adults with type 1 diabetes complicated by impaired awareness of hypoglycemia. RESEARCH DESIGN AND METHODS Prospective interventional and observational cohort study of islet-alone (n =48) and islet-after-kidney (n =24) transplant recipients followed for up to 8-years after intraportal infusion of one or more Purified Human Pancreatic Islet products under standardized immunosuppression. Outcomes included duration of islet graft survival (stimulated C-peptide ≥0.3 ng/mL), on-target glycemic control (HbA1c RESULTS Of the 48 islet-alone and 24 islet-after-kidney recipients, 26 and 8 completed long-term follow-up with islet graft function, 15 and 7 withdrew from follow-up with islet graft function, and 7 and 9 experienced islet graft failure, respectively. Actuarial islet graft survival at median and final follow-up was 84 and 56% for islet-alone and 69 and 49% for islet-after-kidney (P =0.007) with 77 and 49% of islet-alone and 57 and 35% of islet-after-kidney recipients maintaining post-transplant HbA1c P =0.0017); freedom from severe hypoglycemia was maintained at >90% in both cohorts. Insulin-independence was achieved by 74% of islet-alone and islet-after-kidney recipients with more than half maintaining insulin-independence during long-term follow-up. Kidney function remained stable during long-term follow-up in both cohorts and rates of sensitization against human leukocyte antigens were low. Severe adverse events occurred at 0.31 per patient-year for islet-alone and 0.43 per patient-year for islet-after-kidney. CONCLUSIONS Islet transplantation results in durable islet graft survival permitting achievement of glycemic targets in the absence of severe hypoglycemia for most appropriately indicated recipients having impaired awareness of hypoglycemia with acceptable safety of added immunosuppression for both islet-alone and islet-after-kidney transplantation.

Allogeneic islet transplant offers a minimally invasive option for β cell replacement in the treatment of type 1 diabetes (T1D). The CIT consortium trial of purified human pancreatic islets (PHPI) in patients with T1D after kidney transplant (CIT06), a National Institutes of Health-sponsored phase 3, prospective, open-label, single-arm pivotal trial of PHPI, was conducted in 24 patients with impaired awareness of hypoglycemia while receiving intensive insulin therapy. PHPI were manufactured using standardized processes. PHPI transplantation was effective with 62.5% of patients achieving the primary endpoint of freedom from severe hypoglycemic events and HbA1c ≤ 6.5% or reduced by ≥ 1 percentage point at 1 year posttransplant. Median HbA1c declined from 8.1% before to 6.0% at 1 year and 6.3% at 2 and 3 years following transplant (P

Background About half of late kidney allograft losses are attributed to death with function (DWF), a poorly characterized outcome. An ongoing question is whether DWF is a consequence of chronic allograft dysfunction. Using the prospective Long-term Deterioration of Kidney Allograft Function study database, we sought to better define the impact, phenotype, and clinical course of DWF in the current era. Methods Three thousand five hundred eighty-seven kidney recipients with functional grafts at 90 days post-transplant were followed prospectively for a median of 5.2 years. Results Characteristics at transplantation in those with DWF (N = 350, 9.8%) differed from those who otherwise lost their grafts (death-censored graft failure [DC-GF], N = 295, 8.2%) or maintained function (N = 2942, 82.0%); DWF patients were older, sicker, and had been on dialysis longer, with more preexisting cardiovascular disease, whereas DC-GF patients experienced more early rejection, more acute rejection after 90 days, and a clinically significant decrease in kidney function before graft failure. In contrast, the clinical course after transplantation in DWF patients did not differ before death from those who maintained function throughout. Conclusions DWF and DC-GF in kidney transplant recipients represent differing clinical phenotypes occurring in distinct patient populations. Reducing the impact of DWF requires better definition of causes and clinical course and then trials of therapies to improve outcomes. Composite endpoints in clinical trials that group DWF and DC-GF together may obscure important clinical findings.

Inflammation in areas of fibrosis (i-IFTA) in posttransplant biopsies is part of the diagnostic criteria for chronic active TCMR (CA TCMR -- i-IFTA ≥ 2, ti ≥ 2, t ≥ 2). We evaluated i-IFTA and CA TCMR in the DeKAF indication biopsy cohorts: prospective (n = 585, mean time to biopsy = 1.7 years); cross-sectional (n = 458, mean time to biopsy = 7.8 years). Grouped by i-IFTA scores, the 3-year postbiopsy DC-GS is similar across cohorts. Although a previous acute rejection episode (AR) was more common in those with i-IFTA on biopsy, the majority of those with i-IFTA had not had previous AR. There was no association between type of previous AR (AMR, TCMR) and presence of i-IFTA. In both cohorts, i-IFTA was associated with markers of both cellular (increased Banff i, t, ti) and humoral (increased g, ptc, C4d, DSA) activity. Biopsies with i-IFTA = 1 and i-IFTA ≥ 2 with concurrent t ≥ 2 and ti ≥ 2 had similar DC-GS. These results suggest that (a) i-IFTA≥1 should be considered a threshold for diagnoses incorporating i-IFTA, ti, and t; (b) given that i-IFTA ≥ 2,t ≥ 2, ti ≥ 2 can occur in the absence of preceding TCMR and that the component histologic scores (i-IFTA,t,ti) each indicate an acute change (albeit i-IFTA on the nonspecific background of IFTA), the diagnostic category "CA TCMR" should be reconsidered.

The safety and efficacy of islet transplant for type 1 diabetes complicated by severe hypoglycemia was tested in a series of trials by the Clinical Islet Transplant (CIT) consortium. We sought to validate BETA-2 score and its utility to track change in graft function over time. 128 subjects (age 48.2 ± 10.9 years, 61.3% female) participated in 7 trials testing different approaches to immunosuppression, with 58 subjects enrolled in a follow-up observational study for up to 8 years. All subjects received 1-3 islet infusions of >4000 IE/kg at least 75 days apart. BETA-2 was calculated at 2.5, 6, 9, 12 months and then annually. Mean follow up was 45.0 months. Graft failure was defined as stimulated C-peptide < 0.3 ng/ml. The effect of time dependent BETA-2 on hazard of subsequent graft loss was estimated by joint analysis. In 120/128 subjects with graft function at day 75, CIT led to a rapid increase in BETA-2 to 24.3 ± 16.4 and remained stable for up to 8 years. 21 subjects who lost graft function after day 75 had lower BETA-2 than subjects who maintained graft function (D75: 14.5 ± 10.0 vs. 21.8 ± 11.1, p = 0.006). Joint analysis showed time dependent BETA-2 was highly predictive of graft loss (a 1 point drop in BETA-2 increased hazard of subsequent graft loss by 17% (eta = -0.19 ± 0.05, p = 0.0001). BETA-2 is a simple, yet powerful tool to describe and predict clinically important changes in graft function. Disclosure P.A. Senior: None. M.R. Rickels: Consultant; Self; Semma Therapeutics, Inc. Research Support; Self; Xeris Pharmaceuticals, Inc. T. Eggerman: None. L. Bayman: None. J. Qidwai: None. R. Alejandro: None. J.F. Markmann: None. L.G. Hunsicker: Advisory Panel; Self; Allergan plc., Bristol-Myers Squibb.

Phase 3 studies of islet transplant alone (ITA) and islet-after-kidney (IAK) transplantation in type 1 diabetes were completed by the CIT Consortium using the same procedures for islet manufacturing and induction immunosuppression but differing in maintenance immunosuppression. Both studies met their criteria for safety and efficacy over 2 and 3 year planned follow-up, respectively. The insulin sensitivity index, SI, was derived from an insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test using the minimal model approach before (repeated annually) and after islet transplantation, with post-transplant tests also used to assess β-cell function from the acute insulin response to glucose (AIRg) and the disposition index (DI = AIRg SI). Seventy subjects (48 ITA and 22 IAK) completed 79 tests before and 203 tests between 75 days and 3 years after islet transplantation. SI increased post-transplant in both groups and displayed an apparent hyperbolic relationship with post-transplant AIRg. Post-transplant SI was greater in ITA vs. IAK (P < 0.001). Log-transformed AIRg and SI indicate that SI is ∼24% lower at any given AIRg for IAK than ITA. Neither AIRg nor DI was significantly different between ITA and IAK post-transplant. Log-transformed AIRg and DI demonstrate significant prediction of islet graft failure (defined by mixed-meal tolerance test stimulated C-peptide < 0.3 ng/mL) such that each log increase of AIRg and DI reduces the hazard of islet graft failure by 45% and 42%, respectively. These results indicate that while insulin sensitivity improved after islet transplantation, post-transplant measures of β-cell function may better predict islet graft survival. Whether the differences in maintenance immunosuppression (low-dose tacrolimus and sirolimus, ITA; tacrolimus and mycophenolic acid, IAK) may explain the greater insulin sensitivity in ITA vs. IAK requires further study. Disclosure M.R. Rickels: Consultant; Self; Semma Therapeutics, Inc. Research Support; Self; Xeris Pharmaceuticals, Inc. T. Eggerman: None. L. Bayman: None. J. Qidwai: None. J. Naji: None. H.T. Nguyen: None. R. Alejandro: None. M. Bellin: Research Support; Self; Dexcom, Inc., Viacyte, Inc. Other Relationship; Self; Insulet Corporation. P. Senior: Research Support; Self; Allergan, Novo Nordisk. L.G. Hunsicker: Advisory Panel; Self; Allergan plc., Bristol-Myers Squibb. Funding National Institutes of Health; JDRF (1-SRA-2019-728-A-N)

Beyond the first posttransplant year, 3% of kidney transplants fail annually. In a prospective, multicenter cohort study, we tested the relative impact of early versus late events on risk of long-term death-censored graft failure (DCGF). In grafts surviving at least 90 days, early events (acute rejection [AR] and delayed graft function [DGF] before day 90) were recorded; serum creatinine (Cr) at day 90 was defined as baseline. Thereafter, a 25% rise in serum Cr or new-onset proteinuria triggered graft biopsy (index biopsy, IBx), allowing comparison of risk of DCGF associated with early events (AR, DGF, baseline serum Cr >2.0 mg/dL) to that associated with later events (IBx). Among 3678 patients followed for 4.7 ± 1.9 years, 753 (20%) had IBx at a median of 15.3 months posttransplant. Early AR (HR = 1.77, P

OBJECTIVE Attaining glycemic targets without severe hypoglycemic events (SHEs) is a challenging treatment goal for patients with type 1 diabetes complicated by impaired awareness of hypoglycemia (IAH). The CIT Consortium Protocol 07 (CIT-07) trial showed islet transplantation to be an effective treatment for subjects with IAH and intractable SHEs. We evaluated health-related quality of life (HRQOL), functional health status, and health utility before and after pancreatic islet transplantation in CIT-07 trial participants. RESEARCH DESIGN AND METHODS Four surveys, the Diabetes Distress Scale (DDS), the Hypoglycemic Fear Survey (HFS), the Short Form 36 Health Survey (SF-36), and the EuroQoL 5 Dimensions (EQ-5D), were administered repeatedly before and after islet transplantation. Summary statistics and longitudinal modeling were used to describe changes in survey scores from baseline and to characterize change in relation to a minimally important difference (MID) threshold of half an SD. RESULTS Improvements in condition-specific HRQOL met the MID threshold. Reductions from baseline in the DDS total score and its four DDS subscales (all P ≤ 0.0013) and in the HFS total score and its two subscales (all P < 0.0001) were observed across all time points. Improvements were observed after both 1 and 2 years for the EQ-5D visual analog scale (both P < 0.0001). CONCLUSIONS In CIT-07, 87.5% of the subjects achieved the primary end point of freedom from SHE along with glycemic control (HbA1c

Iron stores assuring optimal efficacy/safety for erythropoiesis are unknown in the dialysis population. Using multicenter trial data, we related safety profiles, erythropoiesis-stimulating agent (ESA), and intravenous iron dosing to achieved iron stores in 441 subjects randomized 2 : 1 to ferric citrate or active control as their phosphate binder over 52 weeks. Intravenous iron was given at each site's discretion if ferritin ≤ 1,000 ng/mL and transferrin saturation ≤ 30%. Multivariable time-dependent Cox regression jointly related the primary safety outcome (composite of cardiac, infection, gastrointestinal, and hepatobiliary serious adverse events) to moving averages of ferritin and transferrin saturation over the preceding 90 days with covariate adjustment. Multivariable generalized estimating equations related elevated ESA and intravenous iron doses to trailing 90-day averages of ferritin and transferrin saturation with covariate adjustment. The adjusted hazard ratio for the safety composite per 10% increase in transferrin saturation was 0.84 (95% confidence interval 0.68 - 1.02, p = 0.08) and 1.09 (0.86 - 1.35, p = 0.48) per 400 ng/mL increase in ferritin. The adjusted hazard ratio for the safety composite was 0.50 (0.29 - 0.88, p = 0.016) for the highest transferrin saturation tertile vs. the lowest. Adjusted odds ratios for higher intravenous iron dose were lower in the highest (0.23 [0.16 - 0.35], p 0.001) and middle transferrin saturation tertile (0.42 [0.31 - 0.57], p 0.001) vs. lowest. Incidence of elevated ESA dose was lower in the highest transferrin saturation tertile (p = 0.01). Ferritin did not predict clinical events or ESA dose. Transferrin saturation may be a better marker than serum ferritin to judge optimal iron stores in dialysis patients. Transferrin saturations 34% are safe and provide maximal efficacy. .

Inflammation in areas of fibrosis (i-IFTA) in posttransplant biopsy specimens has been associated with decreased death-censored graft survival (DC-GS). Additionally, an i-IFTA score ≥ 2 is part of the diagnostic criteria for chronic active TCMR (CA TCMR). We examined the impact of i-IFTA and t-IFTA (tubulitis in areas of atrophy) in the first biopsy for cause after 90 days posttransplant (n = 598); mean (SD) 1.7 ± 1.4 years posttransplant. I-IFTA, present in 196 biopsy specimens, was strongly correlated with t-IFTA, and Banff i. Of the 196, 37 (18.9%) had a previous acute rejection episode; 96 (49%) had concurrent i score = 0. Unlike previous studies, i-IFTA = 1 (vs 0) was associated with worse 3-year DC-GS: (i-IFTA = 0, 81.7%, [95% CI 77.7 to 85.9%]); i-IFTA = 1, 68.1%, [95% CI 59.7 to 77.6%]; i-IFTA = 2, 56.1%, [95% CI 43.2 to 72.8%], i-IFTA = 3, 48.5%, [95% CI 31.8 to 74.0%]). The association of i-IFTA with decreased DC-GS remained significant when adjusted for serum creatinine at the time of the biopsy, Banff i, ci and ct, C4d and DSA. T-IFTA was similarly associated with decreased DC-GS. Of these indication biopsies, those with i-IFTA ≥ 2, without meeting other criteria for CA TCMR had similar postbiopsy DC-GS as those with CA TCMR. Those with i-IFTA = 1 and t ≥ 2, ti ≥ 2 had postbiopsy DC-GS similar to CA TCMR. Biopsies with i-IFTA = 1 had similar survival as CA TCMR when biopsy specimens also met Banff criteria for TCMR and/or AMR. Studies of i-IFTA and t-IFTA in additional cohorts, integrating analyses of Banff scores meeting criteria for other Banff diagnoses, are needed.

Increased use of pediatric deceased donor kidneys could enlarge the deceased donor kidney pool. Kidney transplant outcomes from small pediatric donors were compared with those from ideal kidney (IK) and expanded criteria kidney (ECK) donors to understand the optimal use of pediatric donor kidneys.Kaplan-Meier analyses compared long-term patient and death-censored graft survival of en bloc kidney (EBK) and split kidney (SpK) transplants from small pediatric donors (aged ≤8 y and weight30 kg) with those from IK and ECK. Posttransplant serum creatinine) was compared among these cohorts. Deceased donor kidney disposition was determined from small pediatric donors with ≥1 organ transplanted.Patient and death-censored graft survival were similar among recipients of IK, EBK, and SpK transplants, and were superior to those of recipients of ECK. EBK and SpK transplants from donors 5-30 kg had first-year graft loss similar to ECK. Long-term graft survival and serum creatinine with kidneys from SpK donors10 kg were better than that with ECK donors. About 3901 transplants were performed from 3660 pediatric donors (53% yield).Pediatric kidneys can augment the kidney donor pool and should not be considered ECK. If 90% of kidneys from donors (aged ≤8 y and weight30 kg) with ≥1 organ transplanted been used (as SpK when10 kg) an additional 159 kidney transplants per year could have been performed. Expanding the use of pediatric kidneys should be further explored by the transplant community.

OBJECTIVE Impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50–80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment. RESEARCH DESIGN AND METHODS This multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA1c RESULTS The primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA1c level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients. CONCLUSIONS Transplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.

Background Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials.Methods In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including "chronic kidney disease", "chronic renal insufficiency", "albuminuria", "proteinuria", and "randomized controlled trial"; key inclusion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1.73 m(2), or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on albuminuria.Findings We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71%] with diabetes). Over a median follow-up of 3.4 years (IQR 2.3-4.2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0.89 (95% Bayesian credible interval [BCI] 0.13-1.70), each 30% decrease in geometric mean albuminuria by the treatment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5-45%; median R-2 0.47, 95% BCI 0.02-0.96). The association strengthened after restricting analyses to patients with baseline albuminuria of more than 30 mg/g (ie, 3.4 mg/mmol; R-2 0.72, 0.05-0.99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0.7 (ie, 30% decrease in albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0.68, and 95% of sufficiently large studies would have HRs between 0.47 and 0.95.Interpretation Our results support a role for change in albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain. Copyright (c) 2019 Elsevier Ltd. All rights reserved.

Item does not contain fulltext BACKGROUND: Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to support its validity in epidemiological studies is lacking. We aimed to assess the consistency of the association between change in albuminuria and risk of end-stage kidney disease in a large individual participant-level meta-analysis of observational studies. METHODS: In this meta-analysis, we collected individual-level data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC) with data on serum creatinine and change in albuminuria and more than 50 events on outcomes of interest. Cohort data were eligible if participants were aged 18 years or older, they had a repeated measure of albuminuria during an elapsed period of 8 months to 4 years, subsequent end-stage kidney disease or mortality follow-up data, and the cohort was active during this consortium phase. We extracted participant-level data and quantified percentage change in albuminuria, measured as change in urine albumin-to-creatinine ratio (ACR) or urine protein-to-creatinine ratio (PCR), during baseline periods of 1, 2, and 3 years. Our primary outcome of interest was development of end-stage kidney disease after a baseline period of 2 years. We defined an end-stage kidney disease event as initiation of kidney replacement therapy. We quantified associations of percentage change in albuminuria with subsequent end-stage kidney disease using Cox regression in each cohort, followed by random-effects meta-analysis. We further adjusted for regression dilution to account for imprecision in the estimation of albuminuria at the participant level. We did multiple subgroup analyses, and also repeated our analyses using participant-level data from 14 clinical trials, including nine clinical trials not in CKD-PC. FINDINGS: Between July, 2015, and June, 2018, we transferred and analysed data from 28 cohorts in the CKD-PC, which included 693 816 individuals (557 583 [80%] with diabetes). Data for 675 904 individuals and 7461 end-stage kidney disease events were available for our primary outcome analysis. Change in ACR was consistently associated with subsequent risk of end-stage kidney disease. The adjusted hazard ratio (HR) for end-stage kidney disease after a 30% decrease in ACR during a baseline period of 2 years was 0.83 (95% CI 0.74-0.94), decreasing to 0.78 (0.66-0.92) after further adjustment for regression dilution. Adjusted HRs were fairly consistent across cohorts and subgroups (ie, estimated glomerular filtration rate, diabetes, and sex), but the association was somewhat stronger among participants with higher baseline ACR than among those with lower baseline ACR (pinteraction

The DeKAF study was developed to better understand the causes of late allograft loss. Preliminary findings from the DeKAF cross-sectional cohort (with follow-up < 20 months) have been published. Herein, we present long-term outcomes in those recipients (mean follow-up ± SD, 6.6 ± 0.7 years). Eligibility included being transplanted prior to October 1, 2005; serum creatinine ≤ 2.0 mg/dL on January 1, 2006; and subsequently developing new-onset graft dysfunction leading to a biopsy. Mean time from transplant to biopsy was 7.5 ± 6.1 years. Histologic findings and DSA were studied in relation to postbiopsy outcomes. Long-term follow-up confirms and expands the preliminary results of each of 3 studies: (1) increasing inflammation in area of atrophy (irrespective of inflammation in nonscarred areas [Banff i]) was associated with increasingly worse postbiopsy death-censored graft survival; (2) hierarchical analysis based on Banff scores defined clusters (entities) that differed in long-term death-censored graft survival; and (3) C4d-/DSA- recipients had significantly better (and C4d+/DSA+ worse) death-censored graft survival than other groups. C4d+/DSA- and C4d-/DSA+ had similar intermediate death-censored graft survival. Clinical and histologic findings at the time of new-onset graft dysfunction define high- vs low-risk groups for long-term death-censored graft survival, even years posttransplant. These findings can help differentiate groups for potential intervention studies.

Recipients of kidney transplants (KTR) are at increased risk for cardiovascular events, graft failure, and death. It is unknown whether urine kidney injury biomarkers are associated with poor outcomes among KTRs. We conducted a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial using a case-cohort study design, selecting participants with adjudicated cardiovascular events, graft failure, or death. Urine neutrophil gelatinase–associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), IL-18, and liver–type fatty acid binding protein (L-FABP) were measured in spot urine samples and standardized to urine creatinine concentration. We adjusted for demographics, cardiovascular risk factors, eGFR, and urine albumin-to-creatinine ratio. Patients had 291 cardiovascular events, 257 graft failure events, and 359 deaths. Each log increase in urine NGAL/creatinine independently associated with a 24% greater risk of cardiovascular events (adjusted hazard ratio [aHR], 1.24; 95% confidence interval [95% CI], 1.06 to 1.45), a 40% greater risk of graft failure (aHR, 1.40; 95% CI, 1.16 to 1.68), and a 44% greater risk of death (aHR, 1.44; 95% CI, 1.26 to 1.65). Urine KIM-1/creatinine and IL-18/creatinine independently associated with greater risk of death (aHR, 1.29; 95% CI, 1.03 to 1.61 and aHR, 1.25; 95% CI, 1.04 to 1.49 per log increase, respectively) but not with risk of cardiovascular events or graft failure. Urine L-FABP did not associate with any study outcomes. In conclusion, among prevalent KTRs, higher urine NGAL, KIM-1, and IL-18 levels independently and differentially associated with greater risk of adverse outcomes.

Objective This study evaluated whether worsened outcomes in sex mismatch are related to mismatch of organ size in heart transplantation. Background Sizing for organ allocation in heart transplantation currently incorporates only body weight differences between the donor and recipient. Weight correlates poorly to cardiac size, and donor–recipient weight differences are not associated with differential survival. Heart size correlates with sex, and donor–recipient sex mismatch conveys worse-than-expected outcomes. Methods We performed a retrospective cohort study of 31,634 donor–recipient adult heart transplant pairings from the United Network for Organ Sharing transplantation registry. We used predictive models to calculate the predicted total heart mass (pHM) for recipient and donor pairs. We assessed organ size mismatch by calculating the percent difference between the donor and recipient pHM as [(pHMrecipient – pHMdonor)/(pHMrecipient)]*100. Results The most-undersized pHM septile demonstrated higher mortality during the first year post-transplantation (hazard ratio [HR]: 1.27; p l 0.001), which remained robust in adjusted models (HR: 1.25; p = 0.03). Survival did not vary across septiles of weight differences. On univariate analysis, sex mismatch was associated with higher mortality in male patients, but not in female patients. Controlling for differences in pHM reversed these associations. Adjusted models demonstrated worse survival associated with sex mismatch in female patients (1-year HR: 1.28; p = 0.02) but no difference in male patients (1-year HR, 1.00; p = 1.0). Conclusions Differences in donor–recipient pHM modulated the survival associated with donor–recipient sex mismatch and identified donor heart undersizing as an otherwise occult and potentially preventable cause of mortality following orthotopic heart transplantation.

Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are widely recognized subtypes of C3 glomerulopathy. These ultra-rare renal diseases are characterized by fluid-phase dysregulation of the alternative complement pathway that leads to deposition of complement proteins in the renal glomerulus. Disease triggers are unknown and because targeted treatments are lacking, progress to end stage renal failure is a common final outcome. We studied soluble CR1, a potent regulator of complement activity, to test whether it restores complement regulation in C3 glomerulopathy. In vitro studies using sera from patients with DDD showed that soluble CR1 prevents dysregulation of the alternative pathway C3 convertase, even in the presence of C3 nephritic factors. In mice deficient in complement factor H and transgenic for human CR1, soluble CR1 therapy stopped alternative pathway activation, resulting in normalization of serum C3 levels and clearance of iC3b from glomerular basement membranes. Short-term use of soluble CR1 in a pediatric patient with end stage renal failure demonstrated its safety and ability to normalize activity of the terminal complement pathway. Overall, these data indicate that soluble CR1 re-establishes regulation of the alternative complement pathway and provide support for a limited trial to evaluate soluble CR1 as a treatment for DDD and C3GN.

Background Elevated uric acid concentration is associated with higher rates of cardiovascular (CV) morbidity and mortality in the general population. It is not known whether hyperuricemia increases the risk for CV death or transplant failure in kidney transplant recipients. Study Design Post hoc cohort analysis of the FAVORIT Study, a randomized controlled trial that examined the effect of homocysteine-lowering vitamins on CV disease in kidney transplantation. Setting & Participants Adult recipients of kidney transplants in the United States, Canada, or Brazil participating in the FAVORIT Study, with hyperhomocysteinemia, stable kidney function, and no known history of CV disease. Predictor Uric acid concentration. Outcomes The primary end point was a composite of CV events. Secondary end points were all-cause mortality and transplant failure. Risk factors included in statistical models were age, sex, race, country, treatment assignment, smoking history, body mass index, presence of diabetes mellitus, history of CV disease, blood pressure, estimated glomerular filtration rate (eGFR), donor type, transplant vintage, lipid concentrations, albumin-creatinine ratio, and uric acid concentration. Cox proportional hazards models were fit to examine the association of uric acid concentration with study end points after risk adjustment. Results 3,512 of 4,110 FAVORIT participants with baseline uric acid concentrations were studied. Median follow-up was 3.9 (IQR, 3.0-5.3) years. 503 patients had a primary CV event, 401 died, and 287 had transplant failure. In unadjusted analyses, uric acid concentration was significantly related to each outcome. Uric acid concentration was also strongly associated with eGFR. The relationship between uric acid concentration and study end points was no longer significant in fully adjusted multivariable models ( P =0.5 for CV events; P =0.09 for death, and P =0.1 for transplant failure). Limitations Unknown use of uric acid–lowering agents among study participants. Conclusions Following kidney transplantation, uric acid concentrations are not independently associated with CV events, mortality, or transplant failure. The strong association between uric acid concentrations with traditional risk factors and eGFR is a possible explanation.

Background Cardiovascular disease (CVD) is the leading cause of death in kidney transplant recipients. Whether aspirin may reduce the risk for CVD, death, and kidney failure outcomes is uncertain. Study Design Post hoc cohort analysis of FAVORIT, a randomized trial examining the effect of homocysteine-lowering vitamins on CVD in kidney transplant recipients. Setting & Participants Prevalent adult kidney transplant recipients with hyperhomocysteinemia and stable kidney function from the United States, Canada, and Brazil participating in FAVORIT, with no known history of CVD. Predictor Aspirin use, with aspirin users matched to nonusers using a propensity score. Outcomes Incident CVD events, kidney failure, all-cause mortality, a composite of CVD events or mortality, and a composite of kidney failure or mortality. Cox proportional hazards models with a robust variance to account for the correlation in outcomes within matched pairs were sequentially adjusted for demographic, clinical, and laboratory characteristics to assess the association between aspirin use and events. Results 981 aspirin users were matched to 981 nonusers. During a 4-year mean follow up, there were 225 CVD events, 200 deaths, 126 kidney failure events, 301 composite kidney failure or mortality events, and 324 composite CVD or mortality events. Adjusted models showed no significant difference associated with aspirin use in risk for CVD events, all-cause mortality, kidney failure, composite of kidney failure or mortality, or composite of primary CVD events or mortality (HRs of 1.20 [95% CI, 0.92-1.58], 0.92 [95% CI, 0.69-1.23], 1.19 [95% CI, 0.81-1.74], 1.03 [0.82-1.31], and 1.11 [95% CI, 0.88-1.38], respectively). Limitations We did not examine dose or continued use of aspirin after randomization. CVD history is dependent on participant report at baseline. Aspirin use was non–randomly assigned. Conclusions Aspirin use is not associated with reduced risk for incident CVD, all-cause mortality, or kidney failure in stable kidney transplant recipients with no history of CVD.

In kidney transplant recipients, cardiovascular disease (CVD) is the leading cause of death. The relationship of kidney function with CVD outcomes in transplant recipients remains uncertain. We performed a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial to assess risk factors for CVD and mortality in kidney transplant recipients. Following adjustment for demographic, clinical and transplant characteristics, and traditional CVD risk factors, proportional hazards models were used to explore the association of estimated GFR with incident CVD and all-cause mortality. In 4016 participants, mean age was 52 years and 20% had prior CVD. Mean eGFR was 49 ± 18 mL/min/1.73 m(2) . In 3676 participants with complete data, there were 527 CVD events over a median of 3.8 years. Following adjustment, each 5 mL/min/1.73 m(2) higher eGFR at levels below 45 mL/min/1.73 m(2) was associated with a 15% lower risk of both CVD [HR = 0.85 (0.80, 0.90)] and death [HR = 0.85 (0.79, 0.90)], while there was no association between eGFR and outcomes at levels above 45 mL/min/1.73 m(2) . In conclusion, in stable kidney transplant recipients, lower eGFR is independently associated with adverse events, suggesting that reduced kidney function itself rather than preexisting comorbidity may lead to CVD.

Pyridoxamine dihydrochloride (Pyridorin, NephroGenex) inhibits formation of advanced glycation end products and scavenges reactive oxygen species and toxic carbonyls, but whether these actions translate into renoprotective effects is unknown. In this double-blind, randomized, placebo-controlled trial, we randomly assigned 317 patients with proteinuric type 2 diabetic nephropathy to twice-daily placebo; Pyridorin, 150 mg twice daily; or Pyridorin, 300 mg twice daily, for 52 weeks. At baseline, the mean age ± SD was 63.9±9.5 years, and the mean duration of diabetes was 17.6±8.5 years; the mean serum creatinine level was 2.2±0.6 mg/dl, and the mean protein-to-creatinine ratio was 2973±1932 mg/g. Regarding the primary end point, a statistically significant change in serum creatinine from baseline to 52 weeks was not evident in either Pyridorin group compared with placebo. However, analysis of covariance suggested that the magnitude of the treatment effect differed by baseline renal function. Among patients in the lowest tertile of baseline serum creatinine concentration, treatment with Pyridorin associated with a lower average change in serum creatinine concentration at 52 weeks (0.28, 0.07, and 0.14 mg/dl for placebo, Pyridorin 150 mg, and Pyridorin 300 mg, respectively; P=0.05 for either Pyridorin dose versus placebo); there was no evidence of a significant treatment effect in the middle or upper tertiles. In conclusion, this trial failed to detect an effect of Pyridorin on the progression of serum creatinine at 1 year, although it suggests that patients with less renal impairment might benefit.

Background: Sulodexide, a heterogenous group of sulfated glycosaminoglycans, includes low-molecular-weight heparin (similar to 80% +/- 8%), high-molecular-weight heparin (similar to 5% +/- 3%), and dermatan (similar to 20% +/- 8%), with a mean molecular weight of similar to 9 kDa. The drug is absorbed orally and has no anticoagulant effect in the doses used. Small preliminary studies consistently showed sulodexide to be associated with decreased albuminuria in patients with diabetes.Study Design: We conducted a multicenter placebo-controlled double-blinded study to determine the effect of sulodexide on urine albumin excretion in patients with type 2 diabetic nephropathy.Setting & Participants: Patients with type 2 diabetes and urine albumin-creatinine ratios (ACRs) of 35-200 mg/g in men and 45-200 mg/g in women were enrolled. Serum creatinine level wasIntervention: The study drug was sulodexide, 200 mg/d.Outcome & Measurements: The primary end point was normoalbuminuria (ACR 25%) or 50% decrease in baseline ACR.Results: In 1,056 randomly assigned patients with a mean baseline ACR of 107.8 +/- 83.7 mg/g, comparing the sulodexide versus placebo groups, the primary end point was achieved in 16.5% versus 18.4%; normoalbuminuria, in 7.9% versus 6.1%; and a 50% decrease in albuminuria, in 15.4% versus 17.6%. The relative probability of any given change in albuminuria was identical in both groups.Limitations: We were unable to determine whether the administered sulodexide was absorbed from the gastrointestinal tract.Conclusion: Sulodexide failed to decrease urine albumin excretion in patients with type 2 diabetic nephropathy and microalbuminuria. Am J Kidney Dis. 58(5):729-736. (C) 2011 by the National Kidney Foundation, Inc.

Background. Urinary albumin excretion frequently persists in diabetic patients who are treated with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Sulodexide, a glycosaminoglycan mixture of 80% heparan sulfate and 20% dermatan sulfate, has been hypothesized to reduce persistent albuminuria. We have conducted a multi-center randomized double-blind pilot study in order to determine the effect of 6 months' therapy with sulodexide on urinary albumin excretion and to address logistical issues for a full-scale trial.Methods. A total of 149 patients with type 2 diabetes and an albumin:creatinine ratio (ACR) between 20 and 300 mg/g were randomized with equal allocation to either placebo, 200 mg of sulodexide or 400 mg of sulodexide. The primary endpoint was the achievement, at 6 months, of either 3(1) return to normoalbuminuria (ACR Results. The primary efficacy endpoint was achieved in 25.3% of the patients in the two sulodexide groups combined versus 15.4% of the placebo-treated patients (P = 0.26). The primary endpoint was achieved in 33.3% (P = 0.075 for the comparison to placebo) in the sulodexide 200 mg group and 18.4% (P = 0.781) in the sulodexide 400 mg group. (No consistent patterns of side effects were observed.Conclusion. Based on the experience gained in this pilot study, one full-scale trial is currently being conducted to evaluate the effects of sulodexide on change in ACR in patients with persistent microalbuminuria, and a longer-term trial is underway to evaluate the effects of sulodexide on long-term renal disease progression in patients with overt proteinuria.

Background Approximately 200 000 kidney transplant recipients are living in the United States; they are at increased risk for cardiovascular and other adverse outcomes. Biomarkers predicting these outcomes are needed. Using specimens collected during the Folic Acid for Vascular Outcome Reduction in Transplantation trial, we determined whether plasma levels of B-type natriuretic peptide (BNP) and cardiac troponin I are associated with adverse outcomes in stable kidney transplant recipients. Methods Five hundred ten subjects were selected randomly from the 4110 Folic Acid for Vascular Outcome Reduction in Transplantation participants. This cohort was then enriched for all additional subjects with adverse outcomes (death, dialysis-dependent kidney failure (DDKF), and cardiovascular outcomes) for a total of 1131 participants studied. Quartiles of BNP and high-sensitivity cardiac troponin I (hs-cTnI) were included in adjusted models. Combinations of normal and elevated hs-cTnI (>26.2 ng/L) and BNP (>100 pg/mL) were also studied. Results Median concentrations (interquartile ranges) were 5.6 (3.3-10.5) ng/L for hs-cTnI and 39 (15, 94) pg/mL for BNP. Hazard ratios for each adverse outcome were higher with higher quartiles of BNP after adjustment and remained statistically significant after adding hs-cTnI to the model. The highest quartile hazard ratio for DDKF was 2.47 (95% confidence interval [95% CI], 1.21-5.05). Simultaneous elevations of BNP and hs-cTnI over clinical cutoffs were strongly associated with adverse outcomes with hazard ratios 8.8 (95% CI, 3.4-23.1) for DDKF and 6.3 (95% CI, 2.7-15.0) for cardiovascular outcomes. Conclusions Higher BNP is associated with mortality and cardiovascular and kidney outcomes in stable kidney transplant recipients. Elevated BNP and hs-cTnI identify candidates for targeted risk reduction.

The shortage of deceased donor kidneys and livers for transplantation has prompted the use of organs from donors deceased after cardiac death (DCD). We used the UNOS database to examine patient and graft survival following transplantation of DCD organs compared to those following grafts from donors deceased after brain death (DBD; for livers, grafts from donors < 60 years old were labeled ‘< 60 yrs’). Of 44035 deceased donor kidney transplant recipients, 1177 (3%) received a DCD kidney. There was no difference in patient or graft survival at 5 years (DCD vs. DBD: 81.3% vs. 80.8% and 66.9% vs. 66.5%; p = 0.70 and p = 0.52 respectively). Of 24688-deceased donor liver transplant recipients, 345 (1.4%) were from DCD donors and 20289 (82%) were from ‘< 60 yrs’ DBD donors. Three-year patient and graft survival were inferior in the DCD group (DCD vs. ‘< 60 yrs’ DBD: 77% vs. 80% and 65% vs. 75%; p = 0.016 and p < 0.0001 respectively) but were comparable to current alternatives, ‘≥ 60 yrs’ DBD livers (donor age ≥ 60) and split livers. DCD livers are a reasonable option when death is imminent. Our study demonstrates good outcomes using DCD kidneys and livers and encourages their use.

Advanced glycation end products (AGEs) are implicated in the pathogenesis of vascular damage, especially in patients with diabetes and renal insufficiency. The oxidatively formed AGE N(epsilon)-carboxymethyllysine (CML) is thought to be a marker of oxidative stress.Four hundred fifty patients with type 2 diabetes and nephropathy from the Irbesartan in Diabetic Nephropathy Trial cohort (mean age, 58 +/- 8.2 years; 137 women, 313 men) with a mean glomerular filtration rate of 48.2 mL/min (0.80 mL/s; Modification of Diet in Renal Disease formula) were followed up for 2.6 years. Serum CML was measured by using an enzyme-linked immunosorbent assay. Relationships between CML levels, traditional risk factors, and cardiovascular and renal events were tested in Cox proportional hazards models.Mean serum CML level was 599.9 +/- 276.0 ng/mL, and mean hemoglobin A1c level was 7.5% +/- 1.6%. One hundred forty-three first cardiovascular events occurred during follow-up; 74 patients died, 44 of cardiovascular causes. Final multivariate analysis showed age (relative risk [RR], 1.87; confidence interval [CI], 1.13 to 3.11; P = 0.016 for the highest compared with lowest quartile), history of prior cardiovascular events (RR, 1.96; CI, 1.35 to 2.85; P0.0005), and 24-hour urinary albumin-creatinine ratio (RR, 1.29; CI, 1.11 to 1.50 per doubling; P0.0005) to be independent risk factors for a first cardiovascular event, but not CML level. CML level also did not correlate significantly with renal outcome.Serum CML level could not be identified as an independent risk factor for cardiovascular or renal outcomes in the examined population. This suggests that traditional risk factors might have a more important role for these end points or that other AGE compounds, as well as tissue AGE levels, might be of greater relevance compared with serum levels, which remains open to further study.

We described the characteristics in a referred cohort of type II diabetic patients in the Developing Education on Microalbuminuria for Awareness of renal and cardiovascular risk in Diabetes study evaluating the global prevalence and determinants of microalbuminuria (MA). A cross-sectional study evaluating 32,208 type II diabetic patients without known albuminuria from 33 countries was performed. Overall, 8057 patients were excluded, either because of prior known proteinuria or non-diabetic nephropathy (3670), or because of invalid urine collections (4387). One single random urinary albumin/creatinine ratio was obtained in 24,151 patients (75%). The overall global prevalence of normo-, micro-, and macroalbuminuria was 51, 39, and 10%, respectively. The Asian and Hispanic patients had the highest prevalence of a raised urinary albumin/creatinine ratio (55%) and Caucasians the lowest (40.6), P0.0001. HbA1c, systolic blood pressure (BP), ethnicity, retinopathy, duration of diabetes, kidney function, body height, and smoking were all independent risk factors of MA, P0.0001. Estimated glomerular filtration rate was below 60 ml/min/1.73 m(2) in 22% of the 11,573 patients with available data. Systolic BP below 130 mmHg was found in 33 and 43% had an HbA1c below 7%. The frequency of patients receiving aspirin was 32%, statins 29%, and BP-lowering therapy 63%. A high prevalence globally of MA and reduced kidney function, both conditions associated with enhanced renal and cardiovascular risk, was detected in type II diabetic patients without prior known nephropathy. Early detection, monitoring of vascular complications, and more aggressive multifactorial treatment aiming at renal and vascular protection are urgently needed.

Background Surgically created arteriovenous (AV) grafts are the most common type of hemodialysis vascular access in the United States, but fail frequently due to the development of venous stenosis. The Dialysis Access Consortium (DAC) Aggrenox Prevention of Access Stenosis Trial tests the hypothesis that Aggrenox (containing dipyridamole and aspirin) can prevent stenosis and prolong survival of arteriovenous grafts.Methods This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1056 subjects over four years with one-half year follow-up. Subjects undergoing placement of a new AV graft for hemodialysis are randomized to treatment with Aggrenox or placebo immediately following access surgery. The primary outcome is primary unassisted patency defined as the time from access placement until thrombosis or an access procedure carried out to maintain or restore patency. The major secondary outcome is cumulative access patency. Monthly access flow monitoring is incorporated in the study design to enhance detection of a hemodynamically significant access stenosis before it leads to thrombosis.Results This paper describes the key issues in trial design, broadly including: 1) ethical issues surrounding the study of a clinical procedure that, although common, is no longer the clinical intervention of choice; 2) acceptable risk (bleeding) from the primary intervention; 3) inclusion of subjects already receiving a portion of the study intervention; 4) inclusion of subjects with incident rather than prevalent qualifying clinical conditions; 5) timing of the study intervention to balance safety and efficacy concerns; and 6) the selection of primary and secondary study endpoints.Conclusions This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent AV graft stenosis and failure, an important and costly problem in this patient population. Numerous design issues were addressed in implementing the trial and these will form a roadmap for future trials in this area.

Elevated arterial pressure is a major risk factor for progression to ESRD in diabetic nephropathy. However, the component of arterial pressure and level of BP control for optimal renal outcomes are disputed. Data from 1590 hypertensive patients with type 2 diabetes in the Irbesartan Diabetic Nephropathy Trial (IDNT), a randomized, double-blind, placebo-controlled trial performed in 209 clinics worldwide, were examined, and the effects of baseline and mean follow-up systolic BP (SBP) and diastolic BP and the interaction of assigned study medications (irbesartan, amlodipine, and placebo) on progressive renal failure and all-cause mortality were assessed. Other antihypertensive agents were added to achieve predetermined BP goals. Entry criteria included elevated baseline serum creatinine concentration up to 266 micromol/L (3.0 mg/dl) and urine protein excretion >900 mg/d. Baseline BP averaged 159/87 +/- 20/11 mmHg. Median patient follow-up was 2.6 yr. Follow-up achieved SBP most strongly predicted renal outcomes. SBP >149 mmHg was associated with a 2.2-fold increase in the risk for doubling serum creatinine or ESRD compared with SBP

Background The Dialysis Access Consortium (DAC) was developed to investigate interventions to improve hemodialysis vascular access outcomes. The autogenous arteriovenous fistula created by direct connection of native artery to vein is the recommended vascular access for hemodialysis. However, it fails frequently due to clotting after surgery.Purpose The DAC Early AV Fistula Thrombosis Trial tests the hypothesis that clopidogrel can prevent early fistula failure and increase the number of fistulas that ultimately become usable for hemodialysis access. This is one of two initial and concurrent trials being performed by the DAC. The companion trial investigates pharmacologic approaches to prevent venous stenosis leading to AV graft failure.Methods This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1284 patients over four years. Patients undergoing creation of a new native arteriovenous (AV) fistula are randomized to treatment with clopidogrel or placebo for six weeks following fistula creation surgery. The primary outcome is fistula patency at six weeks. The major secondary outcome is fistula suitability for dialysis.Results This paper examines key aspects of this study that have broad relevance to trial design including: 1) the selection of an intermediate event as the primary outcome, 2) timing of the intervention to balance efficacy and safety concerns, 3) ethical considerations arising from required modifications of concomitant drug therapy, and 4) choosing an efficacy or effectiveness evaluation of the intervention.Conclusions This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent early AV fistula failure and promote more usable fistulas for hemodialysis. The methodologic challenges identified and addressed during the development of this trial should help to inform the design of future vascular access trials, and are relevant to clinical trials addressing a wide range of questions.

C-reactive protein as a predictor of total arteriosclerotic outcomes in type 2 diabetic nephropathy.BackgroundThe inflammatory marker C-reactive protein (CRP) has been found in most, but not all, prospective studies to be associated with future cardiovascular outcomes. However, CRP has not been tested in the high-cardiovascular risk population of type 2 diabetic nephropathy.MethodsWe studied the independent relationship between CRP and the subsequent development of incident or recurrent arteriosclerotic outcomes (primary) and congestive heart failure events (secondary) in 1560 individuals with diabetic nephropathy, overt proteinuria, and hypertension enrolled in the prospective Irbesartan Diabetic Nephropathy Trial.ResultsTraditional cardiac risk factors were highly prevalent, CRP levels were high overall [quintiles (mg/L) 1st, 0 to 1.2; 2nd, 1.3 to 2.5; 3rd, 2.6 to 5.0; 4th, 5.1 to 10.0; and 5th, >10), and subsequent cardiovascular events were very common. A univariate relationship existed between CRP and total arteriosclerotic outcomes (P < 0.0001). However, after adjusting for study intervention and traditional risk factors, the relationship no longer remained. In fact, controlling for previous cardiovascular disease alone caused the association to become nonsignificant. The secondary analysis found a significant univariate relationship between CRP and congestive heart failure events (P = 0.007) that persisted in multivariate analyses (P = 0.006). However, this relationship was confined to the highest CRP quintile [RR (95% CI) 2.0 (1.27, 3.16)].ConclusionIn diabetic patients with nephropathy, CRP does not add predictive information above and beyond that provided by traditional established risk factors. Whether this holds true for other populations with similar risk burdens is an important public health question that should be addressed. A secondary finding of a link between CRP and congestive heart failure requires further confirmation.

Elevated arterial pressure enhances the risk for cardiovascular (CV) events in patients with diabetic nephropathy. The optimal BP and the component of the elevated BP that affect the risk have not been defined. A post hoc analysis was performed to assess the impact of achieved systolic, diastolic, and pulse pressures on CV outcomes in 1590 adults who had overt diabetic nephropathy and were enrolled in the Irbesartan Diabetic Nephropathy Trial (IDNT) and had a baseline serum creatinine above the normal range, up to 266 micromol/L (3.0 mg/dL), 24-h urine protein >900 mg/d, and at least 6 mo of follow-up. Patients were randomized to irbesartan, amlodipine, or placebo, with other antihypertensive agents to a BP goal of < or =135/85 mmHg. Progressively lower achieved systolic BP (SBP) to 120 mmHg predicted a decrease in CV mortality and congestive heart failure (CHF) but not myocardial infarctions (MI). A SBP below this threshold was associated with increased risk for CV deaths and CHF events. Achieved diastolic BP

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD), and it affects 30% of patients with type 1 diabetes mellitus (DM) and 20% of patients with type 2 DM. Clinical features in both types of DM are similar and are characterized by an underlying abnormality of the microcirculation, manifested by both retinopathy and nephropathy. Clinical hallmarks of DN include elevated blood pressure (BP) and elevated urinary protein excretion. Treatment consists of maintaining BP at

Patients with diabetic nephropathy are at elevated cardiovascular risk. C-reactive protein (CRP) has been used to successfully predict cardiovascular events.We identified clinical and biochemical characteristics that correlate with CRP levels in diabetic nephropathy patients.Baseline data obtained from 722 patients in the Irbesartan Diabetic Nephropathy Trial included age, sex, body mass index (BMI), systolic blood pressure (BP), serum creatinine, plasma low- and high-density cholesterol, triacylglycerol, serum albumin, hemoglobin A1C, 24h urinary protein excretion, plasma total homocysteine (tHcy), folate, B12, pyridoxal 5'-phosphate (PLP, active form of Vitamin B(6)), and plasma CRP levels.In univariate analyses CRP was positively associated with female sex (r=0.08; P=0.04), BMI (r=0.34; P0.01), serum creatinine (r=0.21; P0.01), hemoglobin A1C (r=0.08; 0.04), and inversely associated with PLP (r=-0.17; P0.01) and folate (r=-0.09; P=0.02). A stepwise multiple regression model found CRP directly correlated with BMI (P0.01) and serum creatinine (P0.01), and inversely correlated with PLP (P0.01). The final model explained 16% of the total variance of CRP.These results extend previous findings of an inverse relationship between Vitamin B(6) and CRP. The lack of association between CRP and certain established or emerging cardiovascular risk factors offers novel information regarding cardiovascular risk in this population.

The 6-mo function and the stability of function posttransplantation in 429 cadaver renal transplants was investigated from 1990 to 2000. The 6-mo creatinine clearance (CrCl) and the rate of change of CrCl beyond 6 mo posttransplantation were calculated. The mean 6-mo CrCl was 64.6 ± 1.1 ml/min and was stable between 1990 and 2000. The net slope of CrCl was −1.4 ± 0.5 ml/min per yr. The slope has improved in recent years, such that the mean slopes in the period after 1997 are actually positive (+3.5 ml/min per yr). The slope of CrCl beyond 6 mo was not related to the actual value of the 6 mo CrCl, i.e. , there was no accelerated loss of function at low CrCl levels. The 6-mo CrCl was independently determined by donor factors (age, gender), recipient factors (age, gender), and immune factors (rejection episodes, regraft status). The slope of the CrCl correlated independently with the transplant year, recipient gender, rejection episodes, diastolic BP, and the choice of immunosuppressive drugs. Cytomegalovirus infection and mismatch status and lipid levels and treatment were not independently associated with slope or 6-mo CrCl. Thus, the most striking change in the course of renal transplants over the past decade is the new stability of function, correlating with reduced rejection and probably due at least in part to the new immunosuppressive agents. Despite continued calcineurin inhibitor use, late improvement in function now occurs in many cadaver kidney transplants, suggesting a previously unappreciated capacity for functional adaptation. E-mail: phil.halloran@ualberta.ca

background As the need for transplantable organs increases, waiting lists of patients become longer. We studied the size and composition of the national pool of brain-dead organ donors during a three-year period and, on the basis of these data, considered ways to increase the rate of donation. methods We reviewed hospital medical records of deaths occurring in the intensive care unit from 1997 through 1999 in the service areas of 36 organ-procurement organizations to identify brain-dead potential organ donors. We examined data on characteristics of the potential donors, the processes of referral to organ-procurement organizations and of requesting donations, and the hospitals. results We identified a total of 18,524 brain-dead potential organ donors during the study period. The predicted annual number of brain-dead potential organ donors is between 10,500 and 13,800. The overall consent rate (the number of families agreeing to donate divided by the number of families asked to donate) for 1997 through 1999 was 54 percent, and the overall conversion rate (the number of actual donors divided by the number of potential donors) was 42 percent. Hospitals with 150 or more beds were more likely than smaller hospitals to have potential donors and actual donors (P

The arteriovenous graft (AVG) is most often used in hemodialysis patients when an autogenous fistula is not feasible. The optimal location (forearm or upper arm) and configuration (loop or straight) of AVGs are not known. To evaluate relationships of AVG location and configuration with patency, we conducted a secondary analysis using data from a randomized, placebo-controlled trial of dipyridamole plus aspirin for newly placed AVG.Participants of the Dialysis Access Consortium (DAC) Graft Study with newly placed upper extremity prosthetic grafts involving the brachial artery were studied. Multivariable analyses adjusting for trial treatment group, center, gender, race, body mass index, diabetes, current treatment with chronic dialysis, and prior arteriovenous vascular access or central venous catheter were performed to compare outcomes of forearm (fAVG) and upper arm (uAVG) grafts, including loss of primary unassisted patency (LPUP) and cumulative primary graft failure (CGF). Subgroup analyses of graft configuration and outflow vein used were also conducted.A total of 508 of the 649 participants (78%) enrolled in the trial had an upper extremity brachial artery graft placed, 255 with fAVG and 253 with uAVG. Participants with fAVG were less often male (33% vs 43%; P = .03), African American (62% vs 78%; P .001), and receiving dialysis at the time of surgery (62% vs 80%; P .001). Participants with fAVG had a higher mean body mass index (33 vs 29; P .001). The LPUP (fAVG 70% vs uAVG 78%; P = .07) and CGF (33% vs 36%; P = .91) were similar between fAVG and uAVG at 1-year follow-up. In multivariable analysis, AVG location (uAVG vs fAVG) was not associated with LPUP (hazard ratio, 1.21; 95% confidence interval, 0.90-1.63; P = .20) or CGF (hazard ratio, 1.36; 95% confidence interval, 0.94-1.97; P = .10). LPUP did not differ significantly between fAVG and uAVG among subgroups based on AVG configuration (P = 1.00) or outflow vein used (P = .16).Patency was comparable between fAVG and uAVG despite the larger caliber veins often encountered in the upper arm in carefully selected patients. Our findings support the traditional view that, in order to preserve a maximal number of access sites, the forearm location should be considered first before resorting to an upper arm graft.

Background: The safety and immune tolerance potential of donor marrow infusion with cadaveric source renal transplants was evaluated in a series of non-randomized multicenter pilot trials by the NIH Cooperative Clinical Trials in Transplantation (CCTT) Group. Patients and methods: Three strategies were tested: (1) immunosuppression with cyclosporin, azathioprine and prednisone with a single post-transplant day 1 infusion of 5 × 107 viable cells/kg, (2) OKT3 induction with triple drug therapy and marrow transfusion on day 1, or (3) same therapy as (2) but with an additional marrow transfusion on day 10–12. Results: Thirty-eight marrow recipients and 35 contemporaneous controls were entered with a mean follow-up of over 5 yr. Graft survival was initially better in the marrow recipients than the controls but was similar after 5 yr. Microchimerism rates were similar for the marrow infusion and control groups throughout the follow-up period, regardless of the immunosuppression strategies. Discussion: Bone marrow infusions were well tolerated by a group of cadaver renal allograft recipients. There were no complications from the infusion(s), no episodes of graft-vs.-host disease (GVHD) and no increase in infections or other complications. There was a trend toward early improved graft survival in marrow recipients. Decreased rejection rates were observed in black recipients.

Eight manufacturing facilities participating in the National Institutes of Health-sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed.

Cardiac troponins and natriuretic peptides are becoming established as predictors of clinical outcomes (CO) in patients with cardiovascular (CV) disease; however their value in renal transplant recipients has not been established. Using a case-control design, we tested baseline specimens from 1114

The optimal BP level in kidney transplant recipients remains uncertain. This post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial cohort assessed associations of BP with a pooled cardiovascular disease (CVD) outcome and with all-cause mortality. In 3474 prevalent kidney transplant patients, mean age was 52±9 years, 63% were men, 76% were white, 20% had a history of CVD, 40% had a history of diabetes mellitus, and the median time since transplant was 4.1 years (25th to 75th percentiles, 1.7-7.4); mean systolic BP was 136±20 mmHg and mean diastolic BP was 79±12 mmHg. There were 497 CVD events and 406 deaths. After adjustment for demographic and transplant characteristics and CVD risk factors, each 20-mmHg increase in baseline systolic BP associated with a 32% increase in subsequent CVD risk (hazard ratio [HR], 1.32; 95% confidence interval [95% CI], 1.19 to 1.46) and a 13% increase in mortality risk (HR, 1.13; 95% CI, 1.01 to 1.27). Similarly, after adjustment, at diastolic BP levels70 mmHg, each 10-mmHg decrease in diastolic BP level associated with a 31% increase in CVD risk (HR, 1.31; 95% CI, 1.06 to 1.62) and a 31% increase in mortality risk (HR, 1.31; 95% CI, 1.03 to 1.66). However, at diastolic BP levels70 mmHg, there was no significant relationship between diastolic BP and outcomes. Higher systolic BP strongly and independently associated with increased risk of CVD and all-cause mortality, without evidence of a J shape, whereas only lower levels of diastolic BP associated with increased risk of CVD and death in this trial.

A prospective, randomized, three-armed, double-blind, placebo-controlled clinical trial has been completed in 210 sites worldwide to determine whether the angiotensin II receptor blocker irbesartan or the calcium channel blocker amlodipine has a renoprotective effect in patients with overt type 2 diabetic nephropathy. A total of 1,715 subjects randomized during a 3-year period were followed a minimum of 2 years. The goal for all treatment groups was to achieve equivalent blood pressure control, with the blinded study drug (irbesartan, amlodipine, or placebo) as primary therapy with additional antihypertensive drugs, excluding angiotensin-converting enzyme inhibitors, calcium antagonists, and angiotensin II receptor antagonists, to achieve seated systolic blood pressure less than 135 mm Hg and diastolic blood pressure less than 85 mm Hg. The primary outcome was the combined endpoint of time to doubling of entry serum creatinine, end-stage renal disease, or death. Secondary outcomes included fatal and nonfatal cardiovascular events. A Clinical Management Committee monitored the conduct of the study. An Outcome Confirmation Committee classified all study outcome events in blinded fashion. An external Data Safety Monitoring Committee monitored unblinded data for interim safety and efficacy analyses of the study. Eligibility criteria included informed consent, age 30 to 70 years, adult-onset diabetes, hypertension, urine protein excretion greater than 900 mg/24 hours, and serum creatinine values of 90 to 265 micromol/L in women and 110 to 265 micromol/L in men. Baseline characteristics were age, 59 +/- 8 years; body mass index, 31 +/- 7 kg/m(2); 67% male; 73% white, 14% black, and 13% other; duration of diabetes, 15 +/- 9 years; retinopathy, 66%; neuropathy, 48%; congestive heart failure, 7.5%; screening seated systolic blood pressure, 156 +/- 18 mm Hg, and diastolic blood pressure, 85 +/- 11 mm Hg; urine protein excretion, 4.0 +/- 3.5 g/24 hours; serum creatinine, 150 +/- 53 micromol/L; serum potassium, 4.6 +/- 0.5 mEq/L; total cholesterol, 229 +/- 58 mg/dL; and hemoglobin A(1c), 8.1 +/- 1.7%. This large-scale international trial should help define the clinical course and standards of care for hypertensive adults with type 2 diabetes mellitus and nephropathy. Results available on May 19, 2001, will help in defining the current controversy of the risks and benefits of blockade of the renin-angiotensin system versus calcium channel blockade versus standard antihypertensive therapy in this large patient population.

Cyclosporine in patients with steroid-resistant membranous nephropathy: A randomized trial.BackgroundA clinical trial of cyclosporine in patients with steroid-resistant membranous nephropathy (MGN) was conducted. Although MGN remains the most common cause of adult-onset nephrotic syndrome, its management is still controversial. Cyclosporine has been shown to be effective in cases of progressive MGN, but it has not been used in controlled studies at an early stage of the disease.MethodsWe conducted a randomized trial in 51 biopsy-proven idiopathic MGN patients with nephrotic-range proteinuria comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo plus prednisone. All patients were followed for an average of 78 weeks, and the short- and long-term effects on renal function were assessed.ResultsSeventy-five percent of the treatment group versus 22% of the control group (P < 0.001) had a partial or complete remission of their proteinuria by 26 weeks. Relapse occurred in 43% (N = 9) of the cyclosporine remission group and 40% (N = 2) of the placebo group by week 52. The fraction of the total population in remission then remained almost unchanged and significant different between the groups until the end of the study (cyclosporine 39%, placebo 13%, P = 0.007). Renal function was unchanged and equal in the two groups over the test medication period. In the subsequent follow-up, renal insufficiency, defined as doubling of baseline creatinine, was seen in two patients in each group, but remained equal and stable in all of the other patients.ConclusionThis study suggests that cyclosporine is an effective therapeutic agent in the treatment of steroid-resistant cases of MGN. Although a high relapse does occur, 39% of the treated patients remained in remission and were subnephrotic for at least one-year post-treatment, with no adverse effect on filtration function.

mmHg/85±11 mmHg, serum creatinine 150±53 mmol/l (1.7±0.6 mg/dl ), creatinine clearance Background. Diabetic nephropathy is the most common cause of end-stage renal disease in the 66±34 ml/min and 24 h urine protein 4.0±3.5 g/day. developed world. Angiotensin-converting enzyme Keywords: angiotensin II receptor antagonist; diabetic inhibitors have been demonstrated to be renoprotective nephropathy; renoprotection; type II diabetes in type I diabetes and are now the standard of care for both hypertensive and non-hypertensive type I diabetic patients with any level of proteinuria. The role of blockade of the renin-angiotensin system in type II Introduction diabetic patients is not defined. The Collaborative Study Group has initiated the Irbesartan Type II Diabetic nephropathy is the most common end-stage Diabetic Nephropathy Trial (IDNT ), studying the renal disease ( ESRD) diagnosis in most of the eVect of the angiotensin II receptor antagonist irbesar- developed world, and is responsible for 43% of all new tan on progression of renal disease and mortality in patients requiring renal replacement therapy in the type II diabetic patients with overt nephropathy and USA (1). The incidence rate of diabetic ESRD is hypertension. Here we report the study design and increasing by 10% a year (1). This near epidemic baseline patient characteristics. growth occurs despite recent advances in the under- Methods. To qualify, hypertensive type II patients, age standing of the roles that glycaemic, blood pressure 30-70 years, must have a 24 h urinary protein excretion and dietary control, and angiotensin-converting of >900 mg and a serum creatinine 90-265 mmol/l enzyme inhibitors (ACEIs) play in the development (1.0-3.0 mg/dl ) in women and 110-265 mmol/l and progression of this disorder (2). The majority of (1.2-3.0 mg/dl ) in men. Three treatment arms include research to date has focused on type I diabetes, despite irbesartan, placebo and amlodipine, with every attempt the fact that the majority of patients with diabetes and made to achieve similar blood pressure levels in all ESRD have type II diabetes (3). treatment arms. A total of 1650 patients will be enrolled ACEIs play a unique role because of the 'renoprotec- utilizing ~225 clinics worldwide. The primary outcome tion' that they aVord: the property of slowing progres- measure is time to event to the composite end-point sion of renal disease independently of their eVect on of doubling of serum creatinine, end-stage renal disease blood pressure (4-8). They are now considered the or death. The secondary outcome measure is time to standard of care for type I patients with both incipient composite end-point of fatal or non-fatal cardiovas- (microalbuminuria) and overt nephropathy. Their role cular events. The average length of patient follow-up in patients with type II diabetes and nephropathy is is expected to be ~36 months. undefined (9). The present trial is being undertaken Results. The baseline characteristics of the study sub- predominantly in order to evaluate in a high risk jects are: age 59±8 years, duration of diabetes 15±9 hypertensive population whether blockade of the renin- years, height 168±11 cm (5 ft 6 in), weight 87±19 kg -angiotensin system with the angiotensin II receptor (192 lb), body mass index 31± 7k g/m2, blood pressure antagonist (AIIRA) irbesartan aVords similar renopro

For many complex surgical procedures there is an association between a low volume of procedures and an increased risk of death for the patients who undergo the procedures. We examined the effect of the volume of procedures at transplantation centers on the risk of death after liver transplantation. We analyzed all liver transplantations performed in the United States between October 1, 1987, and April 30, 1994. Because the results for 1987 to 1991 were largely similar to those from 1992 to 1994, we focused on the more recent period.Between January 1, 1992, and April 30, 1994, 47 centers performed 20 or fewer liver transplantations each per year (total, 837 transplantations) and were designated low-volume centers, and 52 centers performed more than 20 transplantations each per year (total, 6526) and were designated high-volume centers. The one-year mortality rate for the low-volume centers was 25.9 percent, as compared with 20.0 percent for the high-volume centers. Thirteen centers, all of which had low volumes, had one-year mortality rates of more than 40 percent. Low-volume centers that were affiliated with high-volume centers, such as pediatric transplantation programs, had results similar to those of the high-volume centers. The one-year mortality rate at unaffiliated low-volume centers was 28.3 percent, as compared with a rate of 20.1 percent for the group of all high-volume centers plus affiliated low-volume centers (P0.001).As a group, liver-transplantation centers in the United States that perform 20 or fewer transplantations per year have mortality rates that are significantly higher than those at centers that perform more than 20 transplantations per year. Information regarding the outcome of liver transplantation at transplantation centers should be made widely available to the public in a timely manner.

A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis.BackgroundA clinical trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis (FSGS) was conducted. Despite the fact that it is the most common primary glomerulonephritis to progress to renal failure, treatment trials have been very limited.MethodsWe conducted a randomized controlled trial in 49 cases of steroid-resistant FSGS comparing 26 weeks of cyclosporine treatment plus low-dose prednisone to placebo plus prednisone. All patients were followed for an average of 200 weeks, and the short- and long-term effects on renal function were assessed.ResultsSeventy percent of the treatment group versus 4% of the placebo group (P < 0.001) had a partial or complete remission of their proteinuria by 26 weeks. Relapse occurred in 40% of the remitters by 52 weeks and 60% by week 78, but the remainder stayed in remission to the end of the observation period. Renal function was better preserved in the cyclosporine group. There was a decrease of 50% in baseline creatinine clearance in 25% of the treated group compared with 52% of controls (P < 0.05). This was a reduction in risk of 70% (95% CI, 9 to 93) independent of other baseline demographic and laboratory variables.ConclusionsThese results suggest that cyclosporine is an effective therapeutic agent in the treatment of steroid-resistant cases of FSGS. Although a high relapse rate does occur, a long-term decrease in proteinuria and preservation of filtration function were observed in a significant proportion of treated patients.