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Biomedical subjects

M J Bia

Publications and source records attributed to M J Bia.

At least 19 recordsLinked to original sources
PubMed2004

The evolving experience using everolimus in clinical transplantation.

Everolimus is a derivative of sirolimus, a macrocyclic lactone, originally isolated from Streptomyces hygroscopicus. Both everolimus and sirolimus have a similar mechanism of action, exerting potent inhibition of growth factor-induced proliferation of lymphocytes, as well as other hematopoietic and nonhematopoietic cells of mesenchymal origin. Each agent complexes with the FK506 binding protein 12 to inhibit cyclin dependent kinase(s), collectively termed the target of rapamycin (TOR), causing G1-S phase cell cycle arrest. Safety and efficacy have been documented in large-scale, blinded, randomized, international clinical renal and cardiac transplant trials. Everolimus is more hydrophilic, exhibits a shorter elimination half-life (approximately 30 hours), and demonstrates greater relative bioavailability compared to sirolimus. However, similar to the calcineurin inhibitors and sirolimus, everolimus is biotransformed by the cytochrome P450, 3A4 isozyme. Also similar to sirolimus, clinical experiences identified biologically relevant side effects including hyperlipidemia and exacerbation of cyclosporine (CsA)-associated nephrotoxicity. However, also similar to sirolimus, accumulating evidence suggests that the hyperlipidemia can be controlled and the CsA-associated renal effects appear reduced with a low incidence of acute rejection when everolimus is administered in combination with reduced CsA doses. The experience using everolimus in cardiac transplantation has also provided potentially important insights into the consequences of antiproliferative effects on vascular smooth muscle cells and fibroblasts where reduction in intimal expansion was identified by intravascular coronary ultrasound examination among those patients receiving everolimus. Therefore, available results suggest that the introduction of everolimus as the newest TOR inhibitor should enhance therapeutic options for immunosuppression after organ transplantation.

Clinical Trials, Phase I as Topic↗
PubMed2004

Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers used for the treatment of hypertension appear to be safe in the early posttransplant period.

Angiotensin II converting enzyme inhibitors (ACE) and angiotensin II receptor blockers (ARB) are frequently avoided as treatment for hypertension in the early posttransplant period (0 to 90 days) for fear of nephrotoxicity. The following retrospective study was designed to explore the safety of these drugs in the early posttransplant period and determine appropriate clinical criteria for starting these medications. The records of all adult renal transplants performed between January 1997 and December 2000 (N = 290) were reviewed. All patients started on ACE or ARB for treatment of hypertension within 90 days of their transplant were included in the analysis (n = 17). Controls (n = 19) were patients who were treated with a calcium channel blocker (CCB) for hypertension. Cases and controls were matched for gender and type of transplant, living or cadaver. Patients were considered to be enrolled whey they met the following criteria: hypertension, serum creatinine < or =3.0 mg/dL, or falling 1 mg/dL/d and serum potassium < or =5.5 mEq/L. Exclusion criteria were coexistent pancreas transplant, anaphylaxis to ACE, and use of ACE or ARB for treatment of posttransplant erythrocytosis. There were no differences between cases and controls in hemoglobin or serum potassium concentrations or calculated glomerular filtration rate at 3, 6, and 9 months. In renal transplant patients with reasonable allograft function, administration of ACE and ARB to treat hypertension in the early posttransplant period appears to be well tolerated and not associated with excess hyperkalemia, anemia, or acute renal dysfunction.

Angiotensin II Type 2 Receptor Blockers↗
PubMed2003

Sirolimus-based immunosuppression with reduce dose cyclosporine or tacrolimus after renal transplantation.

Sirolimus (SRL), a fermentation product of Streptomyces hygroscopicus, complexes with the FKBP12 to inhibit cyclin dependent kinase(s), collectively termed the target of rapamycin (TOR), causing G(1)-S phase cell cycle arrest. Safety and efficacy have been documented in clinical renal transplantation, but concerns were raised due to important biologically relevant side effects. Hyperlipidemia was identified, beginning with early clinical experiences, and the unexpected findings that SRL may exacerbate CsA associated nephrotoxicity was observed during the pivotal phase III studies. This report details results of our experience using SRL (target trough concentration, 10-15 ng/mL) with low dose CsA (target trough concentration, 50-100 ng/mL), seeking to determine whether this approach might provide effective immunosuppression while reducing associated nephrotoxicity. Among 121 renal transplant recipients, 62 received the SRL based regimen and 59 received MMF with all patients receiving CsA and prednisone. Similar to earlier clinical experiences, hematopoeitic abnormalities and hyperlipidemia were observed among patients who received SRL, and those abnormalities were readily controlled. However, unlike observations from the phase III SRL studies, renal function was not adversely affected. These findings support the growing body of evidence indicating that SRL based immunosuppression in combination low dose calcineurin inhibitors and corticosteroids is safe, efficacious, and without associated renal toxicity.

Blood Pressure↗
PubMed2001

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.

Amino Acids↗
PubMed2001

Gitelman's syndrome revisited: an evaluation of symptoms and health-related quality of life.

BACKGROUND: Gitelman's syndrome (GS), also called Gitelman's variant of Bartter's syndrome, is an autosomal recessive renal disorder characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria. GS is caused by inactivating mutations in the thiazide-sensitive sodium chloride cotransporter gene (NCCT). It is also known as the "milder" form of Bartter's syndrome, as patients with GS are usually diagnosed in adulthood during routine investigation. Symptoms reported in the literature range from asymptomatic, to mild symptoms of cramps and fatigue, to severe manifestations such as tetany, paralysis, and rhabdomyolysis. This is the first systematic evaluation of a large group of patients with genetically defined GS. METHODS: We evaluated the symptoms and quality of life (QOL) in 50 adult GS patients with confirmed mutations in NCCT, using a standardized questionnaire. This cohort was compared with 25 age- and sex-matched controls. RESULTS: GS patients were significantly more symptomatic than controls. The most common symptoms were salt craving, with musculoskeletal symptoms such as cramps, muscle weakness, and aches and constitutional symptoms such as fatigue, generalized weakness and dizziness, and nocturia and polydipsia. Forty-five percent of GS patients consider their symptoms a moderate to big problem. Measures of health-related QOL were significantly lower in GS patients compared with controls, particularly in terms of role limitations caused by physical health, emotion, level of energy, and general health perception. CONCLUSIONS: This descriptive study indicates that GS is not an asymptomatic disease and adversely affects QOL in these patients. Further studies are needed to assess the impact of therapy on symptoms and QOL.

Adolescent↗
PubMed2000

ACE inhibitors do not induce recombinant human erythropoietin resistance in hemodialysis patients.

Angiotensin-converting enzyme (ACE) inhibitors may exacerbate anemia in patients with chronic renal failure, as well as in dialysis patients. To better answer this question, a prospective, crossover study was conducted to evaluate the effect of ACE inhibitors on recombinant human erythropoietin (rHuEPO) requirements in hemodialysis patients. Patients administered an ACE inhibitor when entering the study remained on this drug for the initial 4 months and were then switched to another antihypertensive agent for 4 more months. Patients not initially administered an ACE inhibitor were switched to lisinopril at 4 months. rHuEPO doses were adjusted using a sliding scale based on weekly laboratory hematocrit values. The inclusion criteria were met by 51 patients undergoing dialysis. Demographics were as follows: 61% were women, 64% were black, 46% had diabetes, average age was 53.2 +/- 13.3 years, and time on hemodialysis was 38.0 +/- 44.5 months. Thirty-three patients completed the study. Hematocrit averaged 32.7% +/- 1.9% while on ACE inhibitor therapy and 33.1% +/- 2.1% off ACE inhibitor therapy (P = 0.217). There was no difference in rHuEPO dose per treatment during each period (3,500 +/- 1,549 U on ACE inhibitor therapy versus 3,312 +/- 1,492 U off ACE inhibitor therapy; P = 0.300). No significant differences were found in degree of blood pressure control or various clinical and laboratory parameters that might be associated with rHuEPO resistance between the two periods. Similarly, no differences were found in hospitalization days, duration of infections, or transfusion requirements. These findings suggest that ACE inhibitors do not contribute to rHuEPO resistance in hemodialysis patients.

Anemia↗
PubMed1999

Geriatric issues in renal transplantation.

There are an increasing amount of data which are compelling us to consider the issue of age in dealing with decisions regarding both renal transplant recipients and donors. These geriatric issues in transplantation can be summarized as follows: (1) The explosion of a geriatric population of patients with ESRD, in association with data showing a survival advantage of transplantation over wait-listed dialysis patients, demands an increase in expertise in transplantating patients over 60 years old. (2) The critical shortage in cadaveric organ supply is creating a variety of solutions including expanding the donor pool with older kidneys in which long term survival may be shorter than in kidneys from younger donors. (3) The donor shortage, in association with data demonstrating improved survival of living related and unrelated donor transplants, is generating an increased number of older (> 60 years old) individuals who want to donate to a relative, spouse or friend. Future efforts should be directed toward continued research designed to evaluate the efficacy and safety of these trends. We also need to provide improved training in geriatrics for nephrologists so that we and transplant surgeons can deliver better medical care to an aging population of patients with ESRD.

Aged↗
PubMed1997

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.

Acyclovir↗
PubMed1996

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. Bartter's syndrome is an autosomal recessive disease characterized by diverse abnormalities in electrolyte homeostasis including hypokalaemic metabolic alkalosis; Gitelman's syndrome represents the predominant subset of Bartter's patients having hypomagnesemia and hypocalciuria. We now demonstrate complete linkage of Gitelman's 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 Gitelman's syndrome. We speculate that these mutant alleles lead to reduced sodium chloride reabsorption in the more common heterozygotes, potentially protecting against development of hypertension.

Amino Acid Sequence↗
PubMed1996

Must living renal donors be hospitalized overnight prior to surgery?

To determine whether preoperative intravenous hydration was an important determinant of perioperative safety for the kidney donor or of early allograft function, 21 consecutive living donor transplants were assessed retrospectively. Donors hospitalized overnight received 1008 +/- 169 mL of intravenous fluid during the 8 h prior to operation, compared to no preoperative hydration among a cohort of 15 patients. No differences between intraoperative blood pressures, fluid administration, urine output, or time in the operating room were identified between groups. Postoperative allograft function was not compromised by the lack of hydration. We conclude that living kidney donors can safely undergo elective nephrectomy without prior intravenous hydration.

Adult↗
PubMed1995

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.

Adolescent↗
PubMed1995

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)

Adult↗
PubMed1995

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.

Ethics, Medical↗
PubMed1995

Isolated renal mucormycosis: case report and review.

The 15th reported case of isolated renal mucormycosis (infection of the kidney with fungus of the order Mucorales, in the absence of infection elsewhere in the body) is presented. The patient was a 36-year-old human immunodeficiency virus-infected man, actively using iv drugs, who suffered 6 wk of flank pain and fever before diagnosis was made by percutaneous renal biopsy. He received 4 months of amphotericin B treatment, then no therapy for 6 months before dying with no evidence of mucormycosis. Isolated renal mucormycosis should be suspected in those with an underlying immunocompromising illness or history of iv drug use who have persistent flank pain and fever, but sterile urine cultures. Computed tomographic scanning with contrast should then be performed; findings of severe inflammation or bacterial infection, despite an indolent clinical course with sterile or nondiagnostic urine and blood cultures, are suggestive of isolated renal mucormycosis, and renal biopsy under computed tomographic guidance should be performed, despite the potential risk of disseminated infection. Although our patient was treated with amphotericin B alone, nephrectomy with or without amphotericin B therapy appears to be more likely to cure infection and relieve pain and constitutional symptoms.

AIDS-Related Opportunistic Infections↗