Epstein-Barr virus infection in adult renal transplant recipients.

Epstein-Barr virus (EBV) DNAemia in the first year posttransplantation has been studied extensively. There is a paucity of information on prevalence and sequelae of EBV infection in adult renal transplantation beyond the first year. This single-center study examines the relationship between EBV DNAemia and demographic, immunosuppressive, hematologic and infection-related parameters in 499 renal transplant recipients between 1 month and 33 years posttransplant. Participants were tested repeatedly for EBV DNAemia detection over 12 months and clinical progress followed for 3 years. Prevalence of DNAemia at recruitment increased significantly with time from transplant. In multivariate adjusted analyses, variables associated with DNAemia included EBV seronegative status at transplant (p = 0.045), non-White ethnicity (p = 0.014) and previous posttransplant lymphoproliferative disease (PTLD) diagnosis (p = 0.006), while low DNAemia rates were associated with mycophenolate mofetil use (p < 0.0001) and EBV viral capsid antigen positive Epstein-Barr nuclear antigen-1 positive serostatus at transplant (p = 0.044). Patient and graft survival, rate of kidney function decline and patient reported symptoms were not significantly different between EBV DNAemia positive and negative groups. EBV DNAemia is common posttransplant and increases with time from transplantation, but EBV DNAemia detection in low-risk (seropositive) patients has poor specificity as a biomarker for future PTLD risk.

Reducing cardiovascular morbidity and mortality from hypertension in end-stage renal disease.

Hypertension typically worsens with declining renal function, and is an almost universal feature of end-stage renal disease. Treating hypertension clearly reduces the likelihood of cardiovascular disease in nonrenal populations, with greater absolute benefit in those who have greater severity of underlying cardiovascular disease. Patients with chronic renal diseases are at enormous cardiovascular risk. Although our approach to hypertension in patients with early renal insufficiency has become more aggressive, the rationale has switched over the past decade from cardiovascular risk reduction to slowing the loss of renal function. Reliance on observational studies, especially using mortality as the outcome, has not allowed a consistent, rational approach to the treatment of hypertension in dialysis patients.

Down-regulation of human osteoblast PTH/PTHrP receptor mRNA in end-stage renal failure.

BACKGROUND: Resistance to the action of parathyroid hormone (PTH) has been demonstrated in end-stage renal failure and is considered to be important in the pathogenesis of secondary hyperparathyroidism. The mechanism of resistance is unknown. However, altered regulation of cellular PTH/PTH-related protein (PTH/PTHrP) receptor (PTH1R) has been assumed to be important. METHODS: We have used in situ hybridization to examine PTH1R mRNA expression by osteoblasts in human bone and have compared the expression in high- and low-turnover renal bone disease, high-turnover nonrenal bone disease (healing fracture callus and Pagetic bone), and normal bone. Bone biopsies were formalin fixed, ethylenediaminetetraacetic acid decalcified, and paraffin wax embedded. A 1.8 kb PTH1R cDNA probe, labeled with 35S, was used, and the hybridization signal was revealed by autoradiography. The density of signal over osteoblasts was quantitated using a semiautomated Leica image analysis software package. RESULTS: The mean density of PTH1R mRNA signal over osteoblasts in renal high-turnover bone was only 36% of that found in nonrenal high-turnover bone (P < 0.05) and 51% of that found in normal bone (P < 0.05). Osteoblast PTH1R mRNA signal in adynamic bone from individuals with diabetes mellitus was 28% of normal bone (P < 0.05) and 54% of that found in renal high-turnover bone (P < 0.05). CONCLUSIONS: These results demonstrate a down-regulation of osteoblast PTH1R mRNA in end-stage renal failure in comparison to normal and high-turnover bone from otherwise healthy individuals, and provide an insight into the mechanisms of "skeletal resistance" to the actions of PTH.

Cellular mechanisms of renal osteodystrophy.

Renal osteodystrophy affects all patients with end-stage renal failure, resulting in significant skeletal and extra-skeletal morbidity. The patterns of disease seen in bone are the result of changes in calcium, phosphate, parathyroid hormone (PTH), and vitamin D metabolism, as well as the effects of uremia. Standard histological techniques, however, give little insight into the altered biological activity or mechanisms of disease at the cellular level. In order to examine the cellular abnormalities in renal bone disease we have performed a series of in situ hybridization studies to examine renal bone cell expression of genes for PTH receptor (PTHR1), transforming growth factor beta (TGF-beta) and insulin growth factor 1 (IGF-I). PTHR1 mRNA was expressed predominantly by osteoblasts, but also by resorbing osteoclasts, suggesting that these cells may be stimulated directly by PTH. Semi-quantitative analysis of gene expression showed down-regulation of PTHR1 mRNA by osteoblasts in renal bone compared with normal, fracture and Pagetic bone. This may be important in the pathogenesis of skeletal resistance seen in end-stage renal failure, altering the "threshold" at which PTH has its effects on bone cells. TGF-beta and IGF-I mRNA expression was also decreased, suggesting that synthesis of these factors, postulated to be mediators of PTH, is also downregulated.