Sean F. Leavey

Prognosis after primary renal transplant failure and the beneficial effects of repeat transplantation: Multivariate analyses from the United States renal data system

BACKGROUND Survival of transplant recipients after primary renal allograft failure has not been well studied. METHODS A cohort of 19,208 renal transplant recipients with primary allograft failure between 1985 and 1995 were followed from the date of allograft loss until death, repeat transplantation, or December 31, 1996. The mortality, wait-listing, and repeat transplantation rates were assessed. The mortality risks associated with repeat transplantation were estimated with a time-dependent survival model. RESULTS In total, 34.5% (n=6,631) of patients died during follow-up. Of these deaths, 82.9% (n=5,498) occurred in patients not wait-listed for repeat transplantation, 11.9% (n=789) occurred in wait-listed patients, and 5.2% (n=344) occurred in second transplant recipients. Before repeat transplantation, the adjusted 5-year patient survival was 36%, 49%, and 65% for type I diabetes mellitus (DM), type II DM, and nondiabetic end-stage renal disease, respectively (P<0.001; DM vs. nondiabetics). The adjusted 5-year patient survival was lower in Caucasians (57%, P<0.001) compared with African-Americans (67%) and other races (64%). The 5-yr repeat transplantation rate was 29%, 15%, and 19%, whereas the median waiting time for a second transplant was 32, 90, and 81 months for Caucasians, African-Americans, and other races, respectively (P<0.0001 each). Repeat transplantation was associated with 45% and 23% reduction in 5-year mortality for type I DM and nondiabetic end-stage renal disease, respectively, when compared with their wait-listed dialysis counterparts with prior transplant failure. CONCLUSIONS The loss of a primary renal allograft was associated with significant mortality, especially in recipients with type I DM. Repeat transplantation was associated with a substantial improvement in 5-year patient survival. Recipients with type I DM achieved the greatest proportional benefit from repeat transplantation.

Renal transplantation in end-stage sickle cell nephropathy

BACKGROUND The role of renal transplantation as treatment for end-stage sickle cell nephropathy (SCN) has not been well established. METHODS We performed a comparative investigation of patient and allograft outcomes among age-matched African-American kidney transplant recipients with ESRD as a result of SCN (n=82) and all other causes (Other-ESRD, n=22,565). RESULTS The incidence of delayed graft function and predischarge acute rejection in SCN group (24% and 26%) was similar to that observed in the Other-ESRD group (29% and 27%). The mean discharge serum creatinine (SCr) was 2.7 (+/-2.5) mg/dl in the SCN recipients compared to 3.0 (+/-2.5) mg/dl in the Other-ESRD recipients (P=0.42). There was no difference in the 1-year cadaveric graft survival (SCN: 78% vs. Other-ESRD: 77%), and the multivariable adjusted 1-year risk of graft loss indicated no significant effect of SCN (relative risk [RR]=1.39, P=0.149). However, the 3-year cadaveric graft survival tended to be lower in the SCN group (48% vs. 60%, P=0.055) and their adjusted 3-year risk of graft loss was significantly greater (RR= 1.60, P=0.003). There was a trend toward improved survival in the SCN transplant recipients compared to their dialysis-treated, wait-listed counterparts (RR=0.14, P=0.056). In comparison to the Other-ESRD (RR=1.00), the adjusted mortality risk in the SCN group was higher both at 1 year (RR=2.95, P=0.001) and at 3 years (RR=2.82, P=0.0001) after renal transplantation. CONCLUSIONS The short-term renal allograft result in recipients with end-stage SCN was similar to that obtained in other causes of ESRD, but the long-term outcome was comparatively diminished. There was a trend toward better patient survival with renal transplantation relative to dialysis in end-stage SCN.

Vascular access outcomes using the transposed basilic vein arteriovenous fistula

BACKGROUND Although the transposed basilic vein arteriovenous fistula (TBAVF) is increasingly performed for hemodialysis vascular access in patients lacking adequate superficial veins, little is known about the long-term patency or risk factors for failure. METHODS A retrospective analysis was conducted for 99 patients who had a TBAVF created between April 1997 and October 2001. Primary outcomes were unassisted and assisted patency rates and primary failure rates. RESULTS This was the first access procedure in 46% of patients, mean age was 55 years, and 46% were men. Unassisted and assisted patency rates were 47% and 64% at 1 year and 41% and 58% at 2 years, respectively. Primary access failure occurred in 23% of cases. Unassisted access patency was significantly worse in patients with a previous access (relative risk [RR], 2.04; confidence interval [CI], 1.09 to 3.85; P = 0.03) or an ipsilateral central venous catheter (RR, 2.92; CI, 1.34 to 6.38; P < 0.01). Primary access failure was affected by older age (RR, 2.0; CI, 1.20 to 3.38; P < 0.01), obesity (RR, 7.1; CI, 1.65 to 30.1; P < 0.05), and a previous vascular access (RR, 6.4; CI, 1.49 to 27.6; P = 0.01). Steal syndrome requiring intervention occurred in 5% of cases. CONCLUSION In summary, the TBAVF provides a viable option for vascular access; however, certain patient characteristics seem to affect long-term patency and should be considered when exploring access options.

Gender differences in the risk for chronic renal allograft failure.

Background. Despite the known differences in immunological reactivity between males and females, no differences in graft survival have been described among renal transplant recipients with regard to gender. To address this paradox, we analyzed data from 73,477 primary renal transplants collected in the US Renal Data System database. Methods. Logistic regression and Cox proportional hazard models were used to investigate the primary study end points, graft loss secondary to acute rejection (AR) or chronic allograft failure (CAF). CAF was defined as graft loss beyond 6 months, not attributable to death, recurrent disease, acute rejection, thrombosis, infection, noncompliance, or technical problems. The models adjusted for 15 covariates including immunosuppressive regimen, and donor and recipient characteristics. Results. The overall 8-year graft and patient survivals were significantly better in female renal transplant recipients compared with male recipients. However graft survival censored for death was not significantly different by gender. By multivariate analysis, females had a 10% increased odds of AR (OR=1.10, CI 1.02–1.12), but conversely a 10% lower risk of graft loss secondary to CAF (RR=0.9, CI 0.85–0.96). The risk for CAF increased significantly with increasing age for both males and females, but this effect was greater for males than for females (P <0.001). Conclusion. Although female renal transplant recipients have a similar death censored graft survival compared with males, there are important differences in immunological behavior. Females have a higher risk of AR while having a decreased risk of graft loss secondary to CAF.

Endocrine abnormalities in chronic renal failure.

Much needs to be achieved in improving survival and quality of life for chronic renal failure patients. Progress in attaining this goal may accrue from attention to underlying pathophysiologic processes early and throughout a persons life. The endocrine perturbations described in this article--alterations in the homeostasis of phosphorus, calcium, vitamin D and parathyroid hormone; erythropoietin deficiency; and sexual dysfunction in uremia--provide good examples for the need to identify early and manage prospectively over time manifestations of chronic renal failure. The complexity of the skeletal and extraskeletal sequelae of dysregulated mineral metabolism and the complications of chronic anemia have been discussed, while stressing possible implications of these endocrine abnormalities for both morbidity and mortality. There is a great need for more randomized clinical trials to evaluate new and old treatment approaches, with the goal of developing better evidence-based practice guidelines.

Severe Rhabdomyolysis as a Consequence of the Interaction of Fusidic Acid and Atorvastatin

Rhabdomyolysis is a known complication of statin therapy and may be triggered by a pharmacokinetic interaction between a statin and a second medication. Fatal statin-induced rhabdomyolysis has an incidence of 0.15 deaths/million prescriptions. We describe 4 cases of severe rhabdomyolysis with the common feature of atorvastatin use and coadministration of fusidic acid. All cases involved long-term therapy with atorvastatin; fusidic acid was introduced for treatment of osteomyelitis or septic arthritis. Three cases occurred in the setting of diabetes mellitus, with 2 in patients with end-stage renal disease, suggesting increased susceptibility to atorvastatin-fusidic acid-induced rhabdomyolysis in these patient populations. Of the 4 patients in this series, 3 died. Fusidic acid is a unique bacteriostatic antimicrobial agent with principal antistaphylococcal activity. There have been isolated reports of rhabdomyolysis attributed to the interaction of statins and fusidic acid, the cause of which is unclear. Fusidic acid does not inhibit the cytochrome P450 3A4 isoenzyme responsible for atorvastatin metabolism; increased atorvastatin levels due to inhibition of the glucuronidation pathway may be responsible. Considering the low frequency of fusidic acid use, the appearance of 4 such cases within a short time and in a small population suggests the probability that development of this potentially fatal complication may be relatively high.

Predicting the outcome of renal replacement therapy in severe acute renal failure

Continuous renal replacement therapy (CRRT), such as continuous venovenous hemofiltration, has theoretical advantages over intermittent hemodialysis (IHD) that are related to cardiorespiratory stability, metabolic control, and fluid balance allowing nutritional supplementation. However, retrospective and controlled studies fail to show these advantages because of comorbidity associated with triage to CRRT. To compare outcomes using IHD versus CRRT, we applied published risk stratification models (Cleveland Clinic Foundation, Lohr index, and APACHE II) to the 349 patients with acute renal failure requiring renal replacement therapy at University of Michigan over the 2 year period including 1995 and 1996. The Cleveland Clinic Foundation model best predicted overall mortality, but our CRRT patients had excess, unpredicted mortality that was particularly prominent in the lower risk categories. The Lohr clinical score predicted mortality less accurately but also was associated with higher, unpredicted mortality at lower risk scores among the CRRT patients. APACHE II scores did not predict mortality very well among IHD, CRRT, or the combined group of patients. We conclude that the need for CRRT itself predicts mortality over and above that included in published risk models. Either CRRT is associated with some unidentified morbidity (e.g., treatment associated infection) or, more likely, triage to CRRT is associated with as yet unspecified comorbidity not detected in existing risk stratification schemes. It will be important to address these issues in any future studies evaluating outcome or comparing renal replacement therapy modalities among patients with severe acute renal failure.

Early readmission and length of hospitalization practices in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

Background:  Rising hospital care costs have created pressure to shorten hospital stays and emphasize outpatient care. This study tests the hypothesis that shorter median length of stay (LOS) as a dialysis facility practice is associated with higher rates of early readmission.

Posttransplant bone disease: a case illustrating dramatic improvements in bone density with vitamin D replacement therapy.

Although bisphosponates are proposed as first-line treatment for posttransplant bone disease they are not optimal in all situations. A kidney transplant recipient developed hypercalcemia from mobilization of extraskeletal calcium. He had low serum parathyroid hormone and vitamin D; high calcium excretion; and normal calcium intake. Bone biopsy revealed severe osteomalacia. Bisphosphonates, used in the early treatment of acute hypercalcemia, were not indicated to treat osteomalacia. However, over several months serum calcium declined sufficiently to allow treatment of the bone disease with oral calcitriol. Dual-energy radiographic absorptiometry over the next 2 years documented dramatic improvements in bone density (percent of young-normal controls) : from 63 to 85%, at the lumbar spine; from 38 to 67%, at the femoral neck. This response to treatment could not have been achieved with an antiresorptive strategy. Optimal management of posttransplant bone disease requires a diagnostic approach, which considers all plausible contributing factors.

Expression of Grb7 growth factor receptor signaling protein in kidney development and in adult kidney

Grb7, a signaling protein whose physiological function is unknown, binds receptor tyrosine kinases important for normal kidney development. By investigating and correlating Grb7 gene expression with that reported for Grb7-binding receptors, we provide clues to Grb7 function(s). RT-PCR and immunoblot were used to demonstrate Grb7 gene and protein expression in the mature kidney. Additional RT-PCR studies detected gene expression in all microdissected adult nephron segments examined, except glomeruli, and in the mouse metanephric kidney from embryonic day 11 (E11) through to day 17 (E17). In situ hybridization at E14 demonstrated the following cellular pattern of localization: Grb7 mRNA in metanephric epithelia of mesenchymal and ureteric bud origin; no expression in the undifferentiated mesenchyme; and little expression in podocyte-destined cells or primitive glomeruli. Grb7 mRNA was also present in the epithelia of the lung and gut at E14. Thus Grb7 may have a basic function in growth factor signaling in terminally differentiated epithelia along the nephron and in developing epithelia in the kidney, lung, and gut. It is localized in a pattern permissive for a role in Her2 and Ret receptor signaling.Grb7, a signaling protein whose physiological function is unknown, binds receptor tyrosine kinases important for normal kidney development. By investigating and correlating Grb7 gene expression with that reported for Grb7-binding receptors, we provide clues to Grb7 function(s). RT-PCR and immunoblot were used to demonstrate Grb7 gene and protein expression in the mature kidney. Additional RT-PCR studies detected gene expression in all microdissected adult nephron segments examined, except glomeruli, and in the mouse metanephric kidney from embryonic day 11( E11) through to day 17( E17). In situ hybridization at E14 demonstrated the following cellular pattern of localization: Grb7 mRNA in metanephric epithelia of mesenchymal and ureteric bud origin; no expression in the undifferentiated mesenchyme; and little expression in podocyte-destined cells or primitive glomeruli. Grb7 mRNA was also present in the epithelia of the lung and gut at E14. Thus Grb7 may have a basic function in growth factor signaling in terminally differentiated epithelia along the nephron and in developing epithelia in the kidney, lung, and gut. It is localized in a pattern permissive for a role in Her2 and Ret receptor signaling.