Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes.

Allogeneic islet transplant offers a minimally invasive option for ß 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 < .001 for all vs baseline), with related improvements in hypoglycemia awareness and glucose variability. The improved metabolic control was associated with better health-related and diabetes-related quality of life. The procedure was safe and kidney allograft function remained stable after 3 years. These results add to evidence establishing allogeneic islet transplant as a safe and effective treatment for patients with T1D and unstable glucose control despite intensive insulin treatment, supporting the indication for PHPI in the post-renal transplant setting.

Impact of Hyperuricemia on Long-term Outcomes of Kidney Transplantation: Analysis of the FAVORIT Study.

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.

The safety of achieved iron stores and their effect on IV iron and ESA use: post-hoc results from a randomized trial of ferric citrate as a phosphate binder in dialysis
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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.
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Urine Injury Biomarkers and Risk of Adverse Outcomes in Recipients of Prevalent Kidney Transplants: The Folic Acid for Vascular Outcome Reduction in Transplantation Trial.

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.

Soluble CR1 therapy improves complement regulation in C3 glomerulopathy.

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.

Pyridorin in type 2 diabetic nephropathy.

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.

Long-term Outcomes With Islet-Alone and Islet-After-Kidney Transplantation for Type 1 Diabetes in the Clinical Islet Transplantation Consortium: The CIT-08 Study.

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 <7.0%), freedom from severe hypoglycemia, and insulin independence. 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 <7.0% (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 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.

Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: a randomized controlled trial.

BACKGROUND: Sulodexide, a heterogenous group of sulfated glycosaminoglycans, includes low-molecular-weight heparin (~80% ± 8%), high-molecular-weight heparin (~5% ± 3%), and dermatan (~20% ± 8%), with a mean molecular weight of ~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 was <1.5 mg/dL. Blood pressure goal was 130/80 mm Hg. A maximum US Food and Drug Administration-approved dose of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for a minimum of 4 months before randomization was required. INTERVENTION: The study drug was sulodexide, 200 mg/d. OUTCOME & MEASUREMENTS: The primary end point was normoalbuminuria (ACR <20 mg/g and a decrease >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.

Physician access and early nephrology care in elderly patients with end-stage renal disease.

Early nephrology care may improve treatment outcomes of patients with end-stage renal disease. We sought to examine if physician access affects early nephrology care defined as visiting a nephrologist 12 to 4 months before initiating dialysis. The study population consisted of elderly patients starting hemodialysis whose demographic characteristics and initial dialysis therapy were derived from form 2728 files of the Centers for Medicare & Medicaid Services. Early nephrology care, chronic kidney disease and co-morbidities along with access to local non-nephrologist physicians and nephrologists were identified based on Medicare claims and/or United States 2000 Census data. About one-third of elderly patients received early nephrology care prior to initiating dialysis. Patients living in an area with a large number of non-nephrologist physicians or living relatively far away from a nephrologist had a lower likelihood of getting early nephrology care prior to initiating dialysis while those in an area with more practicing nephrologists were more likely to get early nephrology care. The study shows that physician access significantly influences the use of early nephrology care among elderly patients progressing to end-stage renal disease in the United States.

Effects of sulodexide in patients with type 2 diabetes and persistent albuminuria.

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 < 20 mg/g with a decrease of at least 25%) or (2) a decrease in ACR of at least 50% from the baseline value. All patients used a maximum tolerated recommended FDA approved dose of an ACEI or ARB for at least 60 days and had stable blood pressure prior to randomization. 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.

Improved Health-Related Quality of Life in a Phase 3 Islet Transplantation Trial in Type 1 Diabetes Complicated by Severe Hypoglycemia.

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 <7% [<53 mmol/mol]) at 1 year post-initial islet transplantation. The same subjects reported consistent, statistically significant, and clinically meaningful improvements in condition-specific HRQOL as well as self-assessments of overall health.

Transjugular intrahepatic portosystemic shunt does not independently increase risk of death in high model for end stage liver disease patients.

Physicians often exclude patients with a model for end-stage liver disease (MELD) score ≥ 18 from a transjugular intrahepatic portosystemic shunt (TIPS) procedure due to the concern for higher risk of death. We aimed to determine if TIPS increased the risk of death in these patients. We analyzed the interaction between TIPS and MELD in 106 patients with TIPS and 79 with intractable ascites without TIPS. We performed Cox proportional hazard regression, including both TIPS and MELD as time-dependent covariates together with their interaction, to calculate the impact of TIPS on the risk of death associated with a high MELD score. We found a negative interaction between a high MELD score and a history of TIPS, with potentially important effect sizes. Patients with MELD scores ≥18 had a 51% lower incremental risk of death (lower risk than would be expected from the combined independent risks of MELD and needing/receiving TIPS) associated with TIPS than patients with MELD scores <18 (hazard ratio for TIPS, 0.49; 95% confidence interval, 0.10-2.45) in the first 6 months following TIPS. There was an 80% lower incremental risk of death among patients with a MELD score ≥18 (hazard ratio for TIPS, 0.20; 95% confidence interval, 0.03-1.23) 6 months after the TIPS procedure. Conclusion: Risk of death is associated with underlying disease severity as shown by the MELD score and the need for TIPS, and both history of TIPS and high MELD score independently increased the risk of mortality. However, the risk of death after TIPS was progressively lower than expected as the MELD score increased. (Hepatology Communications 2017;1:460-468).

B-Type Natriuretic Peptide and Cardiac Troponin I Are Associated With Adverse Outcomes in Stable Kidney Transplant Recipients.

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.

Rationale and design of the Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) trial.

BACKGROUND: Patients with chronic kidney disease, including kidney transplant recipients, are at high risk for cardiovascular disease (CVD). In addition to the constellation of traditional CVD risk factors in chronic kidney disease, elevated total homocysteine (tHcy) is notably more prevalent among the general population. The Folic Acid for Vascular Outcome Reduction In Transplantation (FAVORIT) trial is designed to evaluate whether lowering tHcy using vitamin supplementation reduces CVD events in renal transplant recipients. METHODS: FAVORIT is a multicenter double-blind randomized controlled clinical trial. Participants are clinically stable renal transplant recipients who are 6 months or longer posttransplant with elevated tHcy. Patients are randomized to a multivitamin that includes either a high-dose or low-dose of folic acid (5 or 0 mg), vitamin B6 (50 or 1.4 mg), and vitamin B12 (1000 or 2 microg). The primary end point is a composite of incident or recurrent CVD outcomes, that is, coronary heart, cerebrovascular, or abdominal aortic/lower extremity arterial events. A sample size of 4000 is estimated to provide 87% power to detect a 20% treatment effect. Recruitment is expected to continue until July 2006, with follow-up through June 2010. RESULTS: From August 2002 through December 2004, 2234 of the target 4000 patients were enrolled. In accordance with trial design, mean (SD) screening tHcy was elevated (17.4 +/- 6.2 micromol/L), and mean (SD) estimated creatinine clearance was consistent with stable renal function (58.0 +/- 18.6 mL/min). Evaluating baseline results to date, 42% of the randomized participants had a history of diabetes mellitus, and 21% had prevalent CVD. CONCLUSIONS: The FAVORIT trial is designed with sufficient power and follow-up time to detect a clinically relevant change in CVD risk between renal transplant recipients receiving a high or low tHcy-lowering folic acid multivitamin. Preliminary screening and baseline data support the trial's objectives.

The advanced glycation end product N(epsilon)-carboxymethyllysine is not a predictor of cardiovascular events and renal outcomes in patients with type 2 diabetic kidney disease and hypertension.

BACKGROUND: 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. METHODS: 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. RESULTS: 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; P < 0.0005), and 24-hour urinary albumin-creatinine ratio (RR, 1.29; CI, 1.11 to 1.50 per doubling; P < 0.0005) to be independent risk factors for a first cardiovascular event, but not CML level. CML level also did not correlate significantly with renal outcome. CONCLUSION: 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.

Effect of dialysis center profit-status on patient survival: a comparison of risk-adjustment and instrumental variable approaches.

OBJECTIVE: To compare the estimated effects of dialysis center profit status on patient survival using alternative estimation strategies with retrospective data. DATA SOURCES/STUDY SETTING: Patient and provider-level retrospective data from the United States Renal Data System (USRDS), 1996-1999. STUDY DESIGN: Observational risk adjustment and instrumental variable methods. DATA COLLECTION/EXTRACTION METHODS: Study collected measures from various USRDS files describing clinical characteristics, survival, and the profit status of the initial dialysis center for incident end-stage renal disease (ESRD) patients aged 67+. USRDS facility files were used to assess dialysis center profit status and measure patient distances to dialysis centers. PRINCIPAL FINDINGS: Found survival effect related to profit status in the range of previous research using risk-adjusting covariates similar to those used in previous models. Adding further risk-adjusting covariates halved this effect. The relative proximity of for-profit and nonprofit dialysis centers to the patient residence was the strongest determinant of the profit status of the patient's initial dialysis center. The effect of profit status on survival was eliminated using the two-stage least squares variant of instrumental variable estimation with the relative proximity of for-profit and nonprofit dialysis centers to the patient's residence as the instrument. CONCLUSIONS: Using only the variation in initial dialysis center profit status that was related to the relative proximity of for-profit and nonprofit dialysis centers to the patient, we found no relationship between dialysis center profit status and patient survival. These results are in contrast to results obtained using risk-adjustment methods with a limited set of risk-adjusting covariates.

Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia.

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 <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant. 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.

National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities.

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.

Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy.

BACKGROUND: Little is known of the effects of blood pressure reduction by specific classes of antihypertensive drugs on the association between proteinuria reduction and progression of kidney insufficiency and development of end-stage kidney disease in patients with overt diabetic nephropathy in type 2 diabetes mellitus. METHODS: Associations between baseline proteinuria and proteinuria reduction by either irbesartan, amlodipine, or control for similar decrements in blood pressure and the cumulative incidence of renal end points were examined using the Kaplan-Meier method in patients enrolled in the Irbesartan Diabetic Nephropathy Trial. RESULTS: Risk for kidney failure doubled for each doubling of baseline proteinuria level (hazard ratio, 2.04; 95% confidence interval, 1.87 to 2.22; P < 0.001). For each halving of proteinuria level between baseline and 12 months with treatment, risk for kidney failure was reduced by more than half (hazard ratio, 0.44; 95% confidence interval, 0.40 to 0.49; P < 0.001). For the same proportional change in proteinuria, the reduction in risk for kidney failure was significantly greater for irbesartan compared with amlodipine ( P = 0.048), but not control ( P = 0.245). Proteinuria reduction in the first 12 months of therapy with irbesartan is associated with 36% of the total renoprotective effect observed. CONCLUSION: Baseline proteinuria is an important risk factor for kidney failure and provides a means to identify patients at greatest risk. Halving proteinuria halves the kidney risk. Proteinuria reduction using an angiotensin receptor-blocking agent, such as irbesartan, should be regarded as an important therapeutic goal in renoprotective strategies.

Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy.

BACKGROUND: Patients with diabetes have increased risk for adverse cardiovascular events. Angiotensin-converting enzyme inhibitors are protective in type 1 diabetes. However, no definitive studies have examined the use of angiotensin-receptor blockers in patients with type 2 diabetes and overt nephropathy. The primary outcomes of the Irbesartan Diabetic Nephropathy Trial were doubling of serum creatinine levels, end-stage renal disease, and death from any cause. OBJECTIVE: To compare rates of cardiovascular events among patients with type 2 diabetic nephropathy who received conventional antihypertensive therapy with an angiotensin-receptor blocker (irbesartan) or a calcium-channel blocker (amlodipine), or placebo. DESIGN: Randomized double-blind, placebo-controlled trial with a median follow-up of 2.6 years. A time event analysis was used. SETTING: 209 centers in the Americas, Europe, Israel, and Australasia. PARTICIPANTS: 1715 adults with type 2 diabetic nephropathy and hypertension; serum creatinine levels of 89 micromol/L (1.0 mg/dL) to 266 micromol/L (3.0 mg/dL) in women and 106 micromol/L (1.2 mg/dL) to 266 micromol/L (3.0 mg/dL) in men; and urinary protein excretion rates of at least 900 mg/d. INTERVENTION: Treatment with irbesartan, amlodipine, or placebo. MEASUREMENTS: Time to cardiovascular death, myocardial infarction, congestive heart failure, strokes, and coronary revascularization. RESULTS: The three groups were not statistically different in the composite of cardiovascular events. Among the components of the composite, there was a trend toward a decrease in strokes in patients receiving amlodipine versus those receiving placebo (hazard ratio, 0.65 [95% CI, 0.35 to 1.22]; P = 0.18). Likewise, patients receiving amlodipine had a significantly lower rate of myocardial infarction when compared with placebo recipients (hazard ratio, 0.58 [CI, 0.37 to 0.92]; P = 0.02). In contrast, patients receiving irbesartan had a significantly lower incidence of congestive heart failure when compared with placebo recipients (hazard ratio, 0.72 [CI, 0.52 to 1.00]; P = 0.048) or amlodipine recipients (hazard ratio, 0.65 [CI, 0.48 to 0.87]; P = 0.004). CONCLUSION: The composite cardiovascular event rate did not differ in patients with type 2 diabetes and overt nephropathy treated with irbesartan, amlodipine, or placebo in addition to conventional antihypertensive therapy.