Regional variability in liver waiting list removals causes false ascertainment of waiting list deaths.

Inconsistent identification of reasons for removal from the liver transplant waiting list by Organ Procurement and Transplantation Network (OPTN) regions may contribute to regional variability in wait-list death rates. We analyzed OPTN and Social Security Administration (SSA) reported deaths of 103 364 liver transplant candidates listed May 8, 2003-April 17, 2011, and determined regional variability in risk of death attributable to differences in use of OPTN removal codes. Only 26% of candidates removed as "too sick" died within 90 days of delisting; 6335 deaths after delisting were not reported to OPTN. The ratio of number of candidates removed as "too sick" to number who died on the waiting list varied by region from 0.23 to 0.94, indicating substantial variability in use of removal codes. Including SSA-reported deaths within 90 days of delisting reduced regional variability in risk of death by 48% compared with deaths on the list alone, and by 35% compared with deaths plus the "too sick" designation. Codes for delisting liver transplant candidates are inconsistently applied among OPTN regions, spuriously elevating estimated regional variability in risk of wait-list death. This variability is ameliorated by including SSA- reported deaths within 90 days of delisting.

OPTN policy regarding prioritization of patients with hepatopulmonary syndrome: does it provide equitable organ allocation?

United Network for Organ Transplantation (UNOS) policy 3.6.4.5.1 provides exception points to patients diagnosed with hepatopulmonary syndrome (HPS) to compensate for their reported increased mortality risk. We compared pre- and posttransplant and overall outcomes in 255 patients receiving exception points under this policy (HPS policy patients) with 32 358 nonexception control patients listed in the model for end-stage liver disease (MELD) era to determine whether the intent of the policy is being met. Overall, 92.5% of HPS policy patients versus 45.5% of controls had been transplanted, 5.1% versus 31.2% remained on waiting list and 1.5% versus 14.1% had died while awaiting transplant (p < 0.0001 for each comparison). Relative risk (RR) of death for HPS policy patients compared to controls was 0.158 (confidence interval [CI]: 0.059-0.420, p = 0.0002) pretransplant, and 0.827 (CI: 0.587-1.170, p = 0.28) posttransplant. Overall (combined waitlist and posttransplant) RR of death was 0.514 (CI: 0.374-0.707, p = 0.00004) compared with controls. After adjustment for laboratory MELD, overall RR was 0.807 (CI: 0.587-1.110, p = 0.19), indicating that HPS policy patients' mortality risk would be similar to that of controls had they been listed with their laboratory MELD score. HPS policy patients have a significant pretransplant survival advantage over standard liver transplant candidates because of the exception points awarded, and have similar posttransplant survival. Better criteria for diagnosing and grading of HPS are required.

Short- and long-term outcomes with the use of kidneys and livers donated after cardiac death.

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.

Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective.

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), P<0.0001. HbA1c, systolic blood pressure (BP), ethnicity, retinopathy, duration of diabetes, kidney function, body height, and smoking were all independent risk factors of MA, P<0.0001. 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.

A clinical trial in type 2 diabetic nephropathy.

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.

Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.

BACKGROUND: It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure. METHODS: We randomly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo. The target blood pressure was 135/85 mm Hg or less in all groups. We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration, the development of end-stage renal disease, or death from any cause. We also compared them with regard to the time to a secondary, cardiovascular composite end point. RESULTS: The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group (P=0.02) and 23 percent lower than that in the amlodipine group (P=0.006). The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group (P=0.003) and 37 percent lower in the irbesartan group than in the amlodipine group (P<0.001). Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups (P=0.07 for both comparisons). These differences were not explained by differences in the blood pressures that were achieved. The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group (P=0.008) and 21 percent more slowly than in the amlodipine group (P=0.02). There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point. CONCLUSIONS: The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.

Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial.

BACKGROUND: A 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. METHODS: We 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. RESULTS: Seventy-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. CONCLUSION: This 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.

Comparison of the serum and intracellular pharmacokinetics of azithromycin in healthy and diabetic volunteers.

STUDY OBJECTIVE: To compare serum and intracellular pharmacokinetics of azithromycin in healthy volunteers and patients with diabetes. DESIGN: Open-label, parallel study. SETTING: Clinical research center. SUBJECTS: Twelve patients with diabetes and 12 healthy volunteers. INTERVENTIONS: Subjects were given a single 500-mg dose of azithromycin followed by 250 mg/day for 2 days. Blood samples were obtained just before and after the third dose for up to 24 hours for serum and 168 hours for intracellular measurement of azithromycin. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic parameters were calculated by noncompartmental methods and compared with a t test. The groups did not differ in maximum concentration, time to maximum concentration, or area under the concentration-time curve in serum or polymorphonuclear cells (PMNs). Differences in the PMN:serum ratio were observed at the 24-hour time point (healthy 1209 +/- 432, diabetic 859 +/- 286, p=0.051). CONCLUSION: In general, the pharmacokinetics of azithromycin are comparable in diabetics and healthy volunteers. Accumulation of drug in macrophages was slightly lower in patients.

The Irbesartan type II diabetic nephropathy trial: study design and baseline patient characteristics. For the Collaborative Study Group.

BACKGROUND: Diabetic nephropathy is the most common cause of end-stage renal disease in the developed world. Angiotensin-converting enzyme inhibitors have been demonstrated to be renoprotective 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 diabetic patients is not defined. The Collaborative Study Group has initiated the Irbesartan Type II Diabetic Nephropathy Trial (IDNT), studying the effect of the angiotensin II receptor antagonist irbesartan on progression of renal disease and mortality in type II diabetic patients with overt nephropathy and hypertension. Here we report the study design and baseline patient characteristics. METHODS: To qualify, hypertensive type II patients, age 30-70 years, must have a 24 h urinary protein excretion of >900 mg and a serum creatinine 90-265 micromol/l (1.0-3. 0 mg/dl) in women and 110-265 micromol/l (1.2-3.0 mg/dl) in men. Three treatment arms include irbesartan, placebo and amlodipine, with every attempt made to achieve similar blood pressure levels in all treatment arms. A total of 1650 patients will be enrolled utilizing approximately 225 clinics worldwide. The primary outcome measure is time to event to the composite end-point of doubling of serum creatinine, end-stage renal disease or death. The secondary outcome measure is time to composite end-point of fatal or non-fatal cardiovascular events. The average length of patient follow-up is expected to be approximately 36 months. RESULTS: The baseline characteristics of the study subjects are: age 59+/-8 years, duration of diabetes 15+/-9 years, height 168+/-11 cm (5 ft 6 in), weight 87+/-19 kg (192 lb), body mass index 31+/-7 kg/m(2), blood pressure 156+/-18 mmHg/85+/-11 mmHg, serum creatinine 150+/-53 micromol/l (1.7+/-0.6 mg/dl), creatinine clearance 66+/-34 ml/min and 24 h urine protein 4.0+/-3.5 g/day.

A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group.

UNLABELLED: A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. BACKGROUND: A 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. METHODS: We 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. RESULTS: Seventy 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. CONCLUSIONS: These 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.

The effect of the volume of procedures at transplantation centers on mortality after liver transplantation.

BACKGROUND AND METHODS: 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. RESULTS: 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 (P<0.001). CONCLUSIONS: 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.

Dietary protein restriction and the progression of chronic renal disease: what have all of the results of the MDRD study shown? Modification of Diet in Renal Disease Study group.

The Modification of Diet in Renal Disease (MDRD) Study was the largest randomized clinical trial to test the hypothesis that protein restriction slows the progression of chronic renal disease. However, the primary results published in 1994 were not conclusive with regard to the efficacy of this intervention. Many physicians interpreted the failure of the MDRD Study to demonstrate a beneficial effect of protein restriction over a 2- to 3-yr period as proving that this therapy does not slow disease progression. The authors believe that this viewpoint is incorrect, and is the result of misinterpretation of inconclusive evidence as evidence in favor of the null hypothesis. Since then, numerous secondary analyses of the MDRD Study have been undertaken to clarify the effect of protein restriction on the rate of decline in GFR, urine protein excretion, and onset of end-stage renal disease. This review describes some of the principles of secondary analyses of randomized clinical trials, presents the results of these analyses from the MDRD Study, and compares them with results from other randomized clinical trials. Although these secondary results cannot be regarded as definitive, the authors conclude that the balance of evidence is more consistent with the hypothesis of a beneficial effect of protein restriction than with the contrary hypothesis of no beneficial effect. Until additional data become available, physicians must continue to make recommendations in the absence of conclusive results. The authors suggest that physicians incorporate the results of these secondary analyses into their interpretation of the findings of the MDRD Study.

Evaluation of pre- and posttransplant donor-specific transfusion/cyclosporine A in non-HLA identical living donor kidney transplant recipients. Cooperative Clinical Trials in Transplantation Research Group.

BACKGROUND: The beneficial effects of donor specific transfusion (DST) have become controversial in the cyclosporine era. This study was performed to evaluate the potential benefits of a new protocol for administering DSTs in the perioperative period. METHODS: Non-HLA identical living donor kidney transplant recipients were randomized prospectively to control or to receive a DST 24 hr before transplant and 7-10 days posttransplant. All patients received similar immunosuppression according to protocol. RESULTS: The protocol had 212 evaluable patients (115 transfused and 97 control). There were no differences in 1- and 2-year graft and patient survival, causes of graft failure, incidence and types of infection, repeat hospitalization, or the ability to withdraw steroids. Immunological hyporesponsiveness (by mixed lymphocyte culture) occurred more frequently in transfused patients (18%) than controls (3%) (P = 0.04). Blood stored for > or =3 days was associated with fewer early rejections than blood stored < or =2 days. Overall, class II antigen mismatches were associated with more rejection episodes than class I antigen mismatches. However, transfused patients, but not control patients, with more class I antigen mismatches were more likely to have rejections. CONCLUSIONS: Administration of DSTs by the method described had no practical influence on patient or graft survival for up to 2 years. However, donor-specific hyporesponsiveness was more common in transfused patients (18 vs. 3%). Longer follow-up will be needed to determine whether DST will be associated with long-term benefit.

Sudden hearing loss associated with tacrolimus in a kidney-pancreas allograft recipient.

A 38-year-old woman with type 1 diabetes underwent kidney-pancreas transplantation. Her postoperative course was complicated due to recurrent acute graft rejections and pancreatitis. After initial immunosuppression with microemulsion cyclosporine, mycophenolate mofetil, and prednisone with muromonab-CD3 induction, cyclosporine was switched to tacrolimus on day 44. The initial dosage was 5 mg twice/day, but it was gradually increased to 10 mg twice/day, aiming at 15-20 ng/ml. On day 17 of tacrolimus therapy the woman developed sudden hearing loss with tinnitus. The serum tacrolimus level was 28.3 ng/ml (therapeutic range 10-20 ng/ml) on day 20 of tacrolimus therapy, and peaked at 34.9 ng/ml on day 28. Two audiograms performed on days 28 and 29 confirmed bilateral hearing loss of 80% for speech perception, characterized as mild to moderate sensorineural hearing loss with speech reception threshold of 35 dB (normal < 20 dB) in both ears. The tacrolimus dosage was gradually reduced to 6 mg twice/day by day 36, with drug level 9.7 ng/ml, after which her hearing gradually recovered.

The Banff 97 working classification of renal allograft pathology.

BACKGROUND: Standardization of renal allograft biopsy interpretation is necessary to guide therapy and to establish an objective end point for clinical trials. This manuscript describes a classification, Banff 97, developed by investigators using the Banff Schema and the Collaborative Clinical Trials in Transplantation (CCTT) modification for diagnosis of renal allograft pathology. METHODS: Banff 97 grew from an international consensus discussion begun at Banff and continued via the Internet. This schema developed from (a) analysis of data using the Banff classification, (b) publication of and experience with the CCTT modification, (c) international conferences, and (d) data from recent studies on impact of vasculitis on transplant outcome. RESULTS: Semiquantitative lesion scoring continues to focus on tubulitis and arteritis but includes a minimum threshold for interstitial inflammation. Banff 97 defines "types" of acute/active rejection. Type I is tubulointerstitial rejection without arteritis. Type II is vascular rejection with intimal arteritis, and type III is severe rejection with transmural arterial changes. Biopsies with only mild inflammation are graded as "borderline/suspicious for rejection." Chronic/sclerosing allograft changes are graded based on severity of tubular atrophy and interstitial fibrosis. Antibody-mediated rejection, hyperacute or accelerated acute in presentation, is also categorized, as are other significant allograft findings. CONCLUSIONS: The Banff 97 working classification refines earlier schemas and represents input from two classifications most widely used in clinical rejection trials and in clinical practice worldwide. Major changes include the following: rejection with vasculitis is separated from tubulointerstitial rejection; severe rejection requires transmural changes in arteries; "borderline" rejection can only be interpreted in a clinical context; antibody-mediated rejection is further defined, and lesion scoring focuses on most severely involved structures. Criteria for specimen adequacy have also been modified. Banff 97 represents a significant refinement of allograft assessment, developed via international consensus discussions.

Center-specific graft and patient survival rates: 1997 United Network for Organ Sharing (UNOS) report.

CONTEXT: Multiple comprehensive, risk-adjusted studies evaluating short-term surgical mortality have been reported previously. This report analyzes short-term and long-term outcomes, both nationally and at each individual transplant program, for all solid organ transplantations performed in the United States. OBJECTIVES: To report graft and patient survival rates for all solid organ transplantations, both nationally and at each specific transplant program in the United States, and to compare the expected survival rate with the actual survival rate of each individual program. DESIGN AND SETTING: Multivariate regression analysis of donor and recipient factors affecting graft and patient survival of all kidney, liver, pancreas, heart, lung, and heart-lung transplants reported to the United Network for Organ Sharing from 742 separate transplant programs. PATIENTS: A cohort of 97587 solid organ transplantations performed on 92966 recipients in the United States from January 1988 through April 1994. MAIN OUTCOME MEASURES: Short-term and conditional 3-year national and individual transplant program graft and patient survival rates overall and from 2 separate eras (era 1, January 1988-April 1992; era 2, May 1992-April 1994); comparison of actual center-specific performance with risk-adjusted expected performance and identification of centers with better-than-expected or worse-than-expected survival rates. RESULTS: One-year graft follow-up exceeded 98% and conditional 3-year follow-up exceeded 91% for all organs. Graft and patient survival improved significantly in era 2 compared with era 1 for all cadaver organs except heart, which remained the same. One-year cadaveric graft survival ranged from 81.5% for heart to 61.9% for heart-lung and 3-year conditional graft survival ranged from 91.3% for pancreas to 74.7% for lung. The percentage of programs whose actual 1-year graft survival was not different from or was better than their risk-adjusted expected survival ranged from 98.3% for heart-lung to 75.7% for liver. Most kidney, liver, and heart programs whose actual survival was significantly less than expected performed small numbers (less than the national average) of transplantations per year. CONCLUSIONS: Graft and patient survival for solid organ transplantations showed improvement over time. Conditional 3-year graft and patient survival rates were approximately 90% for all organs except for lung and heart-lung. The conditional 3-year survival rates were better than 1-year survival rates, indicating the major risk after transplantation occurs in the first year. The majority of transplant programs achieved actual survival rates not significantly different from their expected survival rates. Center effects were most significant within the first year after transplantation and had much less influence on long-term survival outcomes.

Cyclosporine trough concentrations in predicting allograft rejection and renal toxicity up to 12 months after renal transplantation.

STUDY OBJECTIVE: To evaluate the utility of cyclosporine (CsA) trough concentrations as a monitoring tool for acute graft rejections and CsA nephrotoxicity. DESIGN: Retrospective chart review. SETTING: University-affiliated teaching hospital. PATIENTS: One hundred thirty-seven adults who had undergone kidney transplantation. MEASUREMENTS AND MAIN RESULTS: Clinical data extracted from the charts were CsA dosage, CsA trough levels (whole blood, HPLC method), biopsy findings to confirm acute rejections, and serum creatine to determine clearance by the Jelliffe method. Data were collected at up to 1 month, between 1 month and 3 months, and between 3 and 12 months after transplantation. For each time period, receiver's operating characteristics curves were generated to identify the optimum CsA concentration for avoiding acute rejection and CsA nephrotoxicity. At up to 1 month, the CsA therapeutic response threshold was 182 ng/ml (sensitivity 69%, specificity 84%, p<0.0001) and toxicity threshold for CsA nephrotoxicity was 204 ng/ml (sensitivity 89%, specificity 56%, p<0.0001). Between 1 month and 3 months, the respective figures were 175 ng/ml (sensitivity 58%, specificity 89%, p<0.0002) and 189 ng/ml (sensitivity 87%, specificity 65%, p<0.0001). Between 3 and 12 months, the CsA therapeutic response threshold decreased to 135 ng/ml (sensitivity 56%, specificity 40%, p>0.1) and the toxicity threshold for CsA nephrotoxicity remained relatively static at 204 ng/ml (sensitivity 100%, specificity 14%, p<0.0001). CONCLUSION: Early in CsA therapy it is essential to prevent graft rejection. Drug concentrations exceeding approximately 182 ng/ml threshold accomplish this goal. Later, successful therapy demands that CsA nephrotoxicity be avoided. This goal is accomplished by not exceeding a CsA concentration of 204 ng/ml.

Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study.

The Modification of Diet in Renal Disease (MDRD) Study examined the effects of dietary protein restriction and strict blood pressure control on the decline in glomerular filtration rate (GFR) in 840 patients with diverse renal diseases. We describe a systematic analysis to determine baseline factors that predict the decline in GFR, or which alter the efficacy of the diet or blood pressure interventions. Univariate analysis identified 18 of 41 investigated baseline factors as significant (P < 0.05) predictors of GFR decline. In multivariate analysis, six factors--greater urine protein excretion, diagnosis of polycystic kidney disease (PKD), lower serum transferrin, higher mean arterial pressure, black race, and lower serum HDL cholesterol--independently predicted a faster decline in GFR. Together with the study interventions, these six factors accounted for 34.5% and 33.9% of the variance between patients in GFR slopes in Studies A and B, respectively, with proteinuria and PKD playing the predominant role. The mean rate of GFR decline was not significantly related to baseline GFR, suggesting an approximately linear mean GFR decline as renal disease progresses. The 41 baseline predictors were also assessed for their interactions with the diet and blood pressure interventions. A greater benefit of the low blood pressure intervention was found in patients with higher baseline urine protein. None of the 41 baseline factors were shown to predict a greater or lesser effect of dietary protein restriction.