Long-Term Outcomes of Kidney Transplant Recipients with Bladder Dysfunction: A Single-Center Study.

BACKGROUND: Long-term outcomes of kidney transplantation recipients with bladder dysfunction or prior bladder surgery are not well characterized. MATERIAL AND METHODS: Electronic records of 1753 recipients of kidney-alone transplant between January 2000 and December 2008 were reviewed. We found that 1652 recipients had normal bladder function, 80 had bladder dysfunction, and 21 had bladder substitute or urinary diversion. Kaplan-Meier survival curves and multivariable regression modeling were performed to determine survival outcomes. RESULTS: Kaplan-Meier graft survival (p=.11) and patient survival (p=.18) were lower in recipients with bladder surgery but not statistically significant. Multivariate analysis demonstrated inferior graft survival (HR 3.57, 95% CI 1.06-12.1, p =0.04) and a trend towards inferior patient survival (HR 3.19, 95% CI .71-14.5, p=0.13) in reci-pients with bladder surgery. The major cause of graft failure was chronic rejection for normal function (17.1%) and bladder dysfunction (28.5%), and infection for bladder surgery (28.5%). Post-operative urinary infectious and surgical complications were higher in recipients with bladder dysfunction (35%) and substitutes (52.3%) compared with normal function (12.8%). CONCLUSIONS: Kidney transplant recipients with prior bladder surgery have an increased risk of graft failure and an increased risk of infectious urinary complications. These risks should be considered in recipient selection and post-transplant management.

Forced TR2/TR4 expression in sickle cell disease mice confers enhanced fetal hemoglobin synthesis and alleviated disease phenotypes.

Sickle cell disease (SCD) is a hematologic disorder caused by a missense mutation in the adult ß-globin gene. Higher fetal hemoglobin (HbF) levels in red blood cells of SCD patients have been shown to improve morbidity and mortality. We previously found that nuclear receptors TR2 and TR4 repress expression of the human embryonic ε-globin and fetal γ-globin genes in definitive erythroid cells. Because forced expression of TR2/TR4 in murine adult erythroid cells paradoxically enhanced fetal γ-globin gene expression in transgenic mice, we wished to determine if forced TR2/TR4 expression in a SCD model mouse would result in elevated HbF synthesis and thereby alleviate the disease phenotype. In a "humanized" sickle cell model mouse, forced TR2/TR4 expression increased HbF abundance from 7.6% of total hemoglobin to 18.6%, accompanied by increased hematocrit from 23% to 34% and reticulocyte reduction from 61% to 18%, indicating a significant reduction in hemolysis. Moreover, forced TR2/TR4 expression reduced hepatosplenomegaly and liver parenchymal necrosis and inflammation in SCD mice, indicating alleviation of usual pathophysiological characteristics. This article shows that genetic manipulation of nonglobin proteins, or transcription factors regulating globin gene expression, can ameliorate the disease phenotype in a SCD model animal. This proof-of-concept study demonstrates that modulating TR2/TR4 activity in SCD patients may be a promising therapeutic approach to induce persistent HbF accumulation and for treatment of the disease.