Margaret J. Bia

Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.

Maintenance of fluid and electrolyte homeostasis is critical for normal neuromuscular function. Bartters syndrome is an autosomal recessive disease characterized by diverse abnormalities in electrolyte homeostasis including hypokalaemic metabolic alkalosis; Gitelmans syndrome represents the predominant subset of Bartters patients having hypomagnesemia and hypocalciuria. We now demonstrate complete linkage of Gitelmans syndrome to the locus encoding the renal thiazide-sensitive Na–Cl cotransporter, and identify a wide variety of non-conservative mutations, consistent with loss of function alleles, in affected subjects. These findings demonstrate the molecular basis of Gitelmans syndrome. We speculate that these mutant alleles lead to reduced sodium chloride reabsorption in the more common heterozygotes, potentially protecting against development of hypertension.

Evaluation of living renal donors: The current practice of US transplant centers

To examine practice patterns regarding how living donors are evaluated and selected in the U.S., a survey was sent to all 231 United Network of Organ Sharing (UNOS)-approved transplant centers. Respondents from 75% of centers completed the questionnaire, all of whom utilize living donors for renal transplantation. Although the use of living-unrelated donors is also widely accepted (in 92% of centers), only 31% of responding centers performed such transplants in 1992, indicating a discrepancy between acceptance and actual practice. Morbidity (0.23%) and mortality (0.03%) of kidney donation continue to be low. The long-term risk of renal insufficiency in kidney donors appears to be similar to, or lower than, that in the general population. There is substantial variability in how potential donors are evaluated and what they are told regarding the risk involved in renal donation. There is also variability in exclusion criteria such as the acceptance of older donors (>55 years old); those with borderline-to-mild hypertension, and those with borderline low glomerular filtration rate. Larger centers tended to be less rigid in their exclusion criteria compared with smaller centers. While our results indicate widespread acceptance and use of living donors, they also highlight the need for future studies to examine the efficacy of tests used in the evaluation process and to determine the long-term risks of renal donation.

Reduced incidence of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder using preemptive antiviral therapy.

BACKGROUND Posttransplant lymphoproliferative disorder (PTLD) has been observed with increasing frequency consequent to the availability of more effective and potent immunosuppression. Prior work suggested that a peripheral blood monitoring strategy detecting peripheral B lymphoproliferation was effective in the early diagnosis of PTLD among 7 of 179 (3.9%) consecutive transplant recipients. Each of those seven patients received at least one course of antithymocyte globulin, Minnesota antilymphocyte globulin, or OKT3 before developing PTLD. METHODS To determine whether antiviral prophylaxis might reduce the incidence of PTLD, a subsequent group of 198 consecutive recipients received either ganciclovir or acyclovir during antilymphocyte antibody administration. When the donor or recipient were cytomegalovirus-seropositive, ganciclovir was given; acyclovir was used when both were cytomegalovirus-seronegative. Baseline and protocol posttransplant cell surface profiles were obtained using immunofluorescence and flow cytometry to detect T cells, lymphocyte activation markers, and the CD19 B cell antigen. RESULTS Demographic factors, including the incidence of recipients more than 50 years of age, non-Caucasians, previous transplantation, and diabetes mellitus, were similar in both groups. Additionally, the number of patients receiving antilymphocyte preparations was similar. However, only one patient (0.5%) from the latter group who received preemptive antiviral therapy developed PTLD. Although elevations in CD19+ B cells preceded clinical PTLD among each of the seven earlier patients, evidence of peripheral B cell proliferation was not demonstrated for the sole patient from the latter group, which suggests a possible effect of antiviral therapy. CONCLUSIONS Prophylactic antiviral therapy may reduce the sensitivity of peripheral monitoring for B lymphoproliferation, but the dramatic reduction in PTLD incidence strongly supports its use among transplant recipients at risk.

POSTTRANSPLANT BONE DISEASE: EVIDENCE FOR A HIGH BONE RESORPTION STATE

Loss of bone is a significant problem after renal transplant. Although bone loss in the first post transplant year has been well documented, conflicting data exist concerning bone loss after this time.It is equally unclear whether bone loss in long-term renal transplant recipients correlates with bone turnover as it does in postmenapausal osteoporosis. To examine these issues, we conducted a cross-sectional study to define the prevalence of osteoporosis in long-term (>1 year) renal transplant recipients with preserved renal function (mean creatinine clearance 73±23 ml/min). Bone mineral density (BMD) was measured at the hip, spine and wrist by DEXA in 69 patients. Markers for bone formation (serum osteocalcin) and bone resorption [urinary levels of pyridinoline (PYD) and deoxypyridinoline (DPD)] were also measured as well as parameters of calcium metabolism. Correlations were made between these parameters and BMD at the various sites. The mean age of the patients was 45±11 years. Eighty eight percent of patients were on cyclosporine (12% on tacrolimus) and all but 2 were on prednisone [mean dose 9±2 mg/day)]. Osteoporosis (BMD more than 2.5 SD below peak adult BMD) at the spine or hip was diagnosed in 44% of patients and osteopenia was present in an additional 44%. Elevated levels of intact parathyroid hormone (i PTH) were observed in 81% of patients. Elevated urinary levels of PYD or DPD were present in 73% of patients and 38% had elevated serum levels of osteocalcin. Levels of calcium, and of 25(OH) and 1,25(OH)2 vitamin D were normal. In a stepwise multiple regression model that included osteocalcin, PYD, DPD, intact PTH, age, years posttransplant, duration of dialysis, cumulative prednisone dose, smoking, and diabetes: urinary PYD was the strongest predictor of bone mass. These results demonstrate that osteoporosis is common in long-term renal transplant recipients. The data also suggest that elevated rates of bone resorption contribute importantly to this process.

Microalbuminuria and hypertension in long-term renal donors

In order to determine whether th protenuria observed in some renal donors was glomerular or tubular in orgin, and to determine whether creatinine clearanee was an accurate index of glomerular filteration rate (GFR) in subjects with reduced nephron mass, 29 donors were evaluated 9–18 years after uninephrectomy. Results were compared with those in 31 age-, sex-, and race-matched controls evaluated at the same time. Mean creatinine clearacne (Ccreat) in donor was 78% that of controls, which was similar to the 85% ratio of inulin clearance (Cin) in donors compared with that of controls. Furthermore, the ratio of Ccreat/Cin was similar in both donors adn controls. One third of the renal donors had an elevated albumin excreation compared with controls (microalbuminuraia [12–220 mg/24 hr] in seven patients; 301 and 1084 mg/24 hr in two patients). There was no correlation between albuminuria an blood pressure, nor was there a demonstrable clinical cause for the albuminuria in most patients. In contrast to these recults, excreation of beta-2 microgluobulin, an index of tubular proteinuria, was normal in all but one patient. The prevalence of hypertension was higher in donors compared with the expected prevalence adjusted for age, sex, and race.These reuslts verify that creatinine clearance is a reliable measure of GFR in long-term renal donors. They also demonstrate an increased frequency of glomerular proteinuria and hypertension in renal donors. Despite these mild abnormalties, GFR is well preserved for up to 18 years postuninephrectomy.In order to determine whether the proteinuria observed in some renal donors was glomerular or tubular in origin, and to determine whether creatinine clearance was an accurate index of glomerular filtration rate (GFR) in subjects with reduced nephron mass, 29 donors were evaluated 9-18 years after uninephrectomy. Results were compared with those in 31 age-, sex-, and race-matched controls evaluated at the same time. Mean creatinine clearance (Ccreat) in donor was 78% that of controls, which was similar to the 85% ratio of inulin clearance (Cin) in donors compared with that of controls. Furthermore, the ratio of Ccreat/Cin was similar in both donors and controls. One third of the renal donors had an elevated albumin excretion compared with controls (microalbuminuria [12-220 mg/24 hr] in seven patients; 301 and 1084 mg/24 hr in two patients). There was no correlation between albuminuria and blood pressure, nor was there a demonstrable clinical cause for the albuminuria in most patients. In contrast to these results, excretion of beta-2 microglobulin, an index of tubular proteinuria, was normal in all but one patient. The prevalence of hypertension was higher in donors compared with the expected prevalence adjusted for age, sex, and race. These results verify that creatinine clearance is a reliable measure of GFR in long-term renal donors. They also demonstrate an increased frequency of glomerular proteinuria and hypertension in renal donors. Despite these mild abnormalities, GFR is well preserved for up to 18 years postuninephrectomy.

Management of Cardiovascular Disease in Renal Transplant Recipients

Cardiovascular disease is a major cause of graft loss and the leading cause of death in renal transplant recipients. Although there are robust data on the frequency of risk factors and their contributions to cardiovascular disease in this population, few trials have demonstrated the benefit of modifying these risk factors to reduce cardiovascular events. Nevertheless, it is widely accepted that the clinical acumen filtered through the best available studies in the general population be used to treat individual renal transplant recipients given their high cardiovascular mortality. Transplant task forces and the Kidney Disease Outcomes Quality Initiative have created guidelines for this purpose. This review examines the data available for prevention and treatment of major risk factors contributing to cardiovascular disease in renal transplant recipients. The contribution of immunosuppressive agents to each risk factor and the evidence to support lifestyle modification as well as drug therapy are examined. Reducing cardiovascular risk factors requires an integrative approach that is best accomplished by a team of health care professionals. It creates a significant challenge but one that must be met if allograft survival is to improve.

The evaluation and selection of living kidney donors

As the number of living kidney donations in the United States increases, it is important to continue to assess the manner in which potential living donors are evaluated and selected. Ethical issues can be framed using principles that are understandable to patients and physicians. Existing evidence suggests that, for most suitable donors, the short- and long-term risks of kidney donation are small enough to be outweighed by the potential benefits to the donor and recipient. A thorough but efficient evaluation of potential living donors, as outlined in this review, can effectively minimize the risks. However, mechanisms to provide long-term follow-up of all living donors are still needed. Appropriate surveillance mechanisms not only will minimize any long-term risks to individuals who have already donated a kidney but will also provide the data needed to accurately assess the risk, however small, for future donors. With or without these data, living donations will likely continue to play an increasingly important role in renal transplantation.

Enalapril treatment of posttransplant erythrocytosis: efficacy independent of circulating erythropoietin levels

To determine the mechanism of action by which angiotensin-converting enzyme (ACE) inhibitors lower hematocrit in patients with posttransplant erythrocytosis, indices of red blood cell production and red blood cell destruction were obtained serially for 6 months from 10 renal transplant patients receiving treatment with enalapril for this problem. Before treatment, five patients had an elevated red blood cell mass, four had plasma volume contraction, and one had both. The mean hemoglobin concentration decreased by 2 g/dL (range, 0.5 to 3.3 g/dL), from 17 +/- 1 g/dL to 15 +/- 1 g/dL (P = 0.001) following 6 months of enalapril therapy. Similarly, the mean hematocrit decreased by 8% (range, 3% to 12%), from 52% +/- 2% to 44% +/- 3% (P = 0.001) during the same period. The mean reticulocyte count tended to decrease, although the change was not significant. The red blood cell mass decreased dramatically by 15% to 50%, from 32 +/- 9 mL/kl to 23 +/- 4 mL/kg (P = 0.008). Although serial erythropoietin levels declined steadily in two patients, there was no consistent change in the other patients. Mean levels decreased modestly, from 20 +/- 11 mU/mL at baseline to 12 +/- 5 mU/mL at 6 months, a change that was not statistically significant. Mean levels at each time point were not statistically different from the mean pretreatment value. Furthermore, during enalapril therapy, there was no correlation between mean circulating erythropoietin level and mean hematocrit (r = 0.43, P = 0.20) or hemoglobin concentration (r = 0.36, P = 0.30) or between changes in these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Etiology of hypercalcemia in hemodialysis patients on calcium carbonate therapy.

Fourteen of 39 dialysis patients (36%) became hypercalcemic after switching to calcium carbonate as their principal phosphate binder. In order to identify risk factors associated with the development of hypercalcemia, indirect parameters of intestinal calcium reabsorption and bone turnover rate in these 14 patients were compared with results in 14 eucalcemic patients matched for age, sex, length of time on dialysis, and etiology of renal disease. In addition to experiencing hypercalcemic episodes with peak calcium values of 2.7 to 3.8 mmol/L (10.7 to 15.0 mg/dL), patients in the hypercalcemic group exhibited a significant increase in the mean calcium concentration obtained during 6 months before the switch, compared with the mean value obtained during the 7 months of observation after the switch (2.4 +/- 0.03 to 2.5 +/- 0.03 mmol/L [9.7 +/- 0.2 to 10.2 +/- 0.1 mg/dL], P = 0.006). In contrast, eucalcemic patients exhibited no change in mean calcium values over the same time period (2.3 +/- 0.05 to 2.3 +/- 0.05 mmol/L [9.2 +/- 0.2 to 9.2 +/- 0.2 mg/dL]). CaCO3 dosage, calculated dietary calcium intake, and circulating levels of vitamin D metabolites were similar in both groups. Physical activity index and predialysis serum bicarbonate levels also were similar in both groups. However, there was a significant difference in parameters reflecting bone turnover rates between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Parameters of high bone-turnover predict bone loss in renal transplant patients: a longitudinal study.

BACKGROUND Osteoporosis is a serious complication of kidney transplantation. Various factors have been postulated to contribute to posttransplant bone loss, among them treatment with corticosteroids, the use of cyclosporine and cyclosporine-like agents, and persistent hyperparathyroidism. In a previous cross-sectional study of long-term renal transplant recipients, we observed that osteoporosis or osteopenia was present in 88% of patients. Because biochemical markers of bone formation (serum osteocalcin) and bone resorption (urine pyridinoline, PYD, and deoxypyridinoline, DPD) were elevated in the majority of study subjects, we hypothesized that elevated rates of bone-turnover contribute to posttransplant bone loss in long-term renal transplant patients. This study was performed to examine this hypothesis. METHODS The study population was composed of 62 patients who were more than 1-year postrenal transplantation and who had preserved renal function. They were followed prospectively for 1 year. Biochemical markers of bone-turnover were measured at study entry, and patients were classified as having high bone-turnover based on elevated urinary levels of at least one marker of bone resorption (i.e., PYD or DPD) and/or serum osteocalcin (group 1). If none of these were present, they were classified as having normal bone-turnover (group 2). Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry (DEXA) at time of entry into the study and again after 1 year of follow-up. The changes in BMD at the lumbar spine, hip, and wrist over the period of the study were compared between the high and normal bone-turnover groups. RESULTS Forty-three patients (69%) were classified as having high bone-turnover (Group 1), and 19 patients (31%) were classified as having normal bone-turnover (Group 2). There was a statistically significant difference in change in BMD between the two groups at the lumbar spine (-1.11+/-0.42%, high bone-turnover, vs. 0.64+/-0.54%, normal bone-turnover; P=0.02) and the hip (-0.69+/-0.38%, high bone-turnover, vs. 1.36+/-0.66%, normal bone-turnover; P=0.006). Whereas group 2 had stable bone mass, group 1 exhibited bone loss at these skeletal sites. CONCLUSIONS Our results indicate that bone loss is greater in renal transplant recipients with elevated biochemical markers of bone-turnover, suggesting that these markers may be useful in identifying patients at risk for continued bone loss. These data support the hypothesis that continued bone loss in long-term renal transplant recipients is associated with high bone-turnover. If accelerated bone resorption does play a role in posttransplant bone loss, this would provide a strong rationale for use of antiresorptive therapy for the prevention and treatment of this complication.