PubMed Health⌕ Search

Biomedical subjects

Ron Shapiro

Publications and source records attributed to Ron Shapiro.

68 records · Page 4Linked to original sources
PubMed2003

Polyomavirus allograft nephropathy: sequential assessment of histologic viral load, tubulitis, and graft function following changes in immunosuppression.

Our initial cases of polyoma virus allograft nephropathy (PVAN) received pulse steroids due to anxiety about concomitant acute rejection triggered by the presence of tubulitis. However, our current policy is to reduce immunosuppression in all cases. The aim of this study was to determine whether clinical follow-up in these patient categories shows any differences in: (a) histologic viral load, (b) grade of tubulitis, and (c) graft function. Reduced viral load assessed within 8 weeks was seen in 4/20 (20.0%) biopsies treated initially by increased immunosuppression, compared to 15/19 (83.3%) biopsies treated with reduced immunosuppression (p = 0.001, Fisher's exact test). Yet, >70% reversal of the rise in serum creatinine occurred in only 3/19 (15.8%) and 1/19 (5.3%) patients, respectively, in these two groups. Improved tubulitis was seen in 11/20 (55%) of biopsies treated with steroids, despite the lack of beneficial effect on serum creatinine in 12/19 (63.1%) instances. In biopsies not treated with any change in immunosuppression, the serum creatinine remained stable in 1/5 (20%) and worsened in 4/5 (80%) biopsies. These data demonstrate that in biopsies with PVAN and tubulitis, reduced immunosuppression is more effective in lowering viral load than steroid therapy. Lack of parallelism between viral load, tubulitis grade, and serum creatinine illustrates a complex interplay of viral and alloimmune factors leading to graft injury.

Adult↗
PubMed2003

Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients.

With the advent of highly active antiretroviral therapy (HAART), HIV positivity is no longer a contraindication for liver transplantation. Some of the antiretroviral agents, particularly protease inhibitors (e.g., ritonavir, indinavir, and nelfinavir) have been described as potent inhibitors of the metabolism of certain immunosuppressive drugs. In this article we describe a profound interaction between tacrolimus and Kaletra (Abbott Laboratories, Chicago, IL) (a combination of lopinavir and ritonavir) in 3 liver transplantation patients. Patient 1, who was maintained on a 5 mg twice daily dose of tacrolimus with a trough blood concentration around 10.6 ng/mL, required only 0.5 mg of tacrolimus per week after addition of Kaletra to achieve similar tacrolimus blood concentrations, with a half-life of 10.6 days. In patient 2, the area under the blood concentration versus time curve for tacrolimus increased from 31 ng/mL/h to 301 ng/mL/h after addition of Kaletra, with a corresponding half-life of 20 days. When the patient was subsequently switched to nelfinavir, the half-life decreased to 10.3 days. Patient 3, who was maintained with 4 to 8 mg/d of tacrolimus and a corresponding blood concentration of 10 ng/mL before Kaletra, required a tacrolimus dose of 1 mg/wk and tacrolimus concentrations of 5 ng/mL with Kaletra. In conclusion, a combination of lopinavir and ritonavir led to a much more profound increase in tacrolimus blood concentrations than use of single protease inhibitor, nelfinavir. A tacrolimus dose of less than 1 mg/wk may be sufficient to maintain adequate blood tacrolimus concentrations in patients on Kaletra. Patients may not need a further dose of tacrolimus for 3 to 5 weeks depending on liver function when therapy with Kaletra is initiated. Great caution is required in the management of tacrolimus dosage when Kaletra is introduced or withdrawn in HIV-positive patients after liver transplantation, particularly in the presence of hepatic dysfunction.

Adult↗
PubMed2003

Occurrence of urinary tract infection in patients with renal allograft biopsies showing neutrophilic tubulitis.

Lymphocytic tubulitis is a well-accepted criterion for acute cellular rejection in renal allograft biopsies. Neutrophilic tubulitis has been used as a surrogate marker for urinary tract infection, but it is not clear how reliably this lesion can be used to make this diagnosis. Biopsy findings were correlated with clinical features in 26 renal allograft biopsies with interstitial polymorphonuclear infiltrates associated with neutrophilic tubulitis. The grade of neutrophilic tubulitis exceeded the grade of lymphocytic tubulitis in 7 (44%) of 16 patients with, but in only 0 patients without, a positive urine culture. Culture confirmed urinary tract infection in 16 (62%) of 26 patients. It is possible that prior antibiotic therapy led to a false-negative culture and masked the diagnosis in two additional patients. Lymphocytic tubulitis made it difficult to exclude concurrent acute cellular rejection in all biopsies studied. In 6 (23%) of 26 patients, negative cultures and response to steroid treatment confirmed that neutrophilic tubulitis can occur in biopsies without urinary tract infection. The relative contributions of infection and rejection could not be determined in patients treated with both steroids and antibiotics. Neutrophilic tubulitis in a renal allograft biopsy should alert the clinician to the possibility of urinary tract infection, even if concurrent lymphocytic tubulitis is present. Confirmation by urine culture is needed because biopsies with ischemic injury and acute cellular or antibody-mediated rejection can show overlapping histology.

Adult↗
PubMed2003

Kidney transplantation under a tolerogenic regimen of recipient pretreatment and low-dose postoperative immunosuppression with subsequent weaning.

OBJECTIVE: The purpose of this work was to perform kidney transplantation under a regimen of immunosuppression that facilitates rather than interferes with the recently defined mechanisms of alloengraftment and acquired tolerance. SUMMARY BACKGROUND DATA: In almost all centers, multiple immunosuppressive agents are given in large doses after kidney transplantation in an attempt to reduce the incidence of acute rejection to near zero. With the elucidation of the mechanisms of alloengraftment and acquired tolerance, it was realized that such heavy prophylactic immunosuppression could systematically subvert the clonal exhaustion-deletion that is the seminal mechanism of tolerance. In addition, it has been established that the rejection response can be made more readily treatable by pretransplant immunosuppression. Consequently, we conducted kidney transplantation in compliance with 2 therapeutic principles: recipient pretreatment and the least possible use of posttransplant immunosuppression. METHODS: One-hundred fifty unselected renal transplant recipients with a mean age of 51 +/- 15 years and multiple risk factors had pretreatment with approximately 5 mg/kg of rabbit antithymocyte globulin (Thymoglobulin) in the hours before transplantation, under covering bolus doses of prednisone to prevent cytokine reactions. Minimal posttransplant immunosuppression was with tacrolimus monotherapy to which steroids or other agents were added only for the treatment of rejection. At or after 4 months after transplant, spaced-dose weaning from tacrolimus monotherapy was begun in patients who had exhibited a satisfactory course. RESULTS: One-year actuarial patient and graft survival was 97% and 92%, respectively. Although the incidence of early acute rejection was 37%, only 7% required prolonged treatment with any agent other than tacrolimus. After a follow-up of 6 to 21 months, the mean serum creatinine in patients with functioning grafts is 1.8 +/- 1.0 mg/dL. Seventy-three percent of the patients met the criteria for spaced weaning. Although rejection episodes occasionally required restoration of daily treatment, 94 (63%) of the 150 patients currently receive tacrolimus in spaced doses ranging from every other day to once a week. CONCLUSIONS: With this approach to immunosuppression, it has been possible to avoid early posttransplant overimmunosuppression and thereby to promote the evolution of a degree of partial tolerance sufficient to undertake substantial dose reduction. The strategy, which is applicable for all organ grafts, constitutes a paradigm shift in transplant management at our center.

Adult↗
PubMed2002

Pathogenesis and management of polyomavirus infection in transplant recipients.

Polyomaviruses (JC virus [JCV], BK virus [BKV], and simian virus 40 [SV40]) establish subclinical and persistent infections and share the capacity for reactivation from latency in their host under immunosuppression. JCV establishes latency mainly in the kidney, and its reactivation results in the development of progressive multifocal leukoencephalopathy. BKV causes infection in the kidney and the urinary tract, and its activation causes a number of disorders, including nephropathy and hemorrhagic cystitis. Recent studies have reported SV40 in the allografts of children who received renal transplants and in the urine, blood, and kidneys of adults with focal segmental glomerulosclerosis, which is a cause of end-stage renal disease and an indication for kidney transplantation. Clinical syndromes related to polyomavirus infection are summarized in the present review, and strategies for the management of patients who receive transplants are discussed.

Cystitis↗
PubMed2002

Quantitation of viral DNA in renal allograft tissue from patients with BK virus nephropathy.

BACKGROUND: BK virus (BKV) allograft nephropathy (BKVAN) is a complication in renal transplantation recipients. Histopathology is the gold standard for diagnosis. Quantitative polymerase chain reaction (PCR) assay for renal biopsy has not been evaluated as a diagnostic test. Determination of renal BKV load may identify patients at risk for disease before histologic nephropathy. METHODS: Quantitative PCR assay for BKV DNA was performed in 28 biopsies of patients with BKVAN; 50 biopsies were performed before a diagnosis of BKVAN, and 126 control biopsies were from patients without a history of BKVAN. RESULTS: BKV DNA was present in 19 of 50 (38%) biopsies performed 1 to 164 weeks before diagnosis of BKVAN. The viral load (mean 216 copies/cell) was lower than in biopsies of patients with BKVAN (mean 6063 viral copies/cell, <0.05). In 10 of 127 (7.8%) control biopsies, a low level of BKV DNA (mean 3.8 copies/cell) was found in three biopsies from chronic allograft nephropathy patients; two biopsies with acute rejection; four biopsies with borderline change; and one biopsy with cytomegalovirus nephritis. CONCLUSION: BKV load exceeding 59 copies per cell identified all cases of BKVAN. The diagnostic sensitivity, specificity, positive predictive value, and negative predictive value of quantitative PCR were 100%, 92.1%, 73.6%, and 100%, respectively. Lower levels of BKV DNA were identified in biopsies performed before viral nephropathy development. Future research will determine if earlier recognition of at-risk patients allows application of antiviral strategies to improve graft outcome.

BK Virus↗
PubMed2002

DNA sequencing of viral capsid protein VP-1 region in patients with BK virus interstitial nephritis.

BACKGROUND: Mutations in the viral capsid protein VP-1 region are associated with increased pathogenicity of polyomavirus in experimental systems. This study sought to determine whether analogous viral genetic changes occur in human BK virus (BKV) interstitial nephritis (ISN). METHODS: PCR was used to amplify a 94-bp nucleotide sequence of the viral capsid protein VP-1 region (positions 1740-1833, Dun numbering) in 49 biopsies obtained from 24 patients with BKV-ISN. DNA sequencing was performed by the dideoxy method. RESULT: The VP-1 region was highly polymorphic and 22 "hot spots" of sequence variability were noted. Genotypes I, II, and IV were assigned to 13, 1, and 5 cases, respectively, but 5 cases could not be unambiguously classified due to sequence heterogeneity at sites used to discriminate between genotypes. Even in cases where genotypes could be assigned, only 5 biopsies showed complete sequence identity with published genotype sequences. Sequential biopsies showed temporal changes in one or more nucleotides in all patients with multiple samples. In one patient, the initial biopsy showed viral genotype 1, although subsequent biopsies showed complex genetic patterns, including a biopsy consistent with viral genotype IV. CONCLUSIONS: Many viral strains associated with BKV-ISN are difficult to classify and possibly distinct from those described in kidney transplant recipients without BKV-ISN. VP-1 sequences undergo continual modification as patients are followed in time. This genetic instability could conceivably have implications for evasion of host immunity and development of resistance to antiviral drugs.

BK Virus↗
PubMed2002

Posttransplant diabetes mellitus in kidney allograft recipients: incidence, risk factors, and management.

BACKGROUND: Posttransplant diabetes mellitus (PTDM), associated with the use of immunosuppressants, occurs at varying rates in kidney transplant recipients. METHODS: Five transplant centers conducted a retrospective review of 435 kidney recipients completing at least 6 months of follow-up to determine risk factors, incidence, and management strategies for posttransplant glucose intolerance. A distinction was made between hyperglycemia and diabetes. RESULTS: The incidence of PTDM was found to be 4.9%. Among tacrolimus-treated patients it was 5.7%, compared with 3.3% among cyclosporine-treated patients (P=0.453). Mean daily maintenance doses of prednisone and mycophenolate mofetil (MMF) were significantly lower in tacrolimus-treated patients. Significantly more tacrolimus-treated patients were prednisone-free (9.0%/0%; P<0.001). Logistic regression analysis revealed that the absence of an antiproliferative agent correlated with the development of PTDM (odds ratio=3.56; P=0.01). CONCLUSIONS: Based on this study, we propose management guidelines specifically for glucose intolerance developing after renal transplantation. Maintenance of blood glucose levels within strict limits is recommended, and the contribution of immunosuppressive agents to the development of PTDM is accounted for. Gradual tapering of prednisone and tacrolimus is proposed for patients who develop PTDM but also bear minimal risk of rejection. Tapering and eventual withdrawal of insulin should be attempted once blood glucose levels normalize. Switching to the alternative calcineurin inhibitor should only be considered as a late intervention. Tacrolimus therapy should be considered even in patients at high risk for diabetes, because the benefit of reduced acute rejection incidence and severity, as demonstrated in other studies, outweighs the risk of PTDM.

Adolescent↗
PubMed2002

Thyroid hormone in the treatment of post-transplant acute tubular necrosis (ATN).

Delayed graft function (DGF) in cadaver kidney transplants is a common problem and is often due to acute tubular necrosis (ATN). DGF in transplants may have a deleterious effect on long-term graft survival. Since thyroid hormone has been shown to hasten recovery from ATN in experimental models, we designed a trial to determine if a defined course of triiodothyronine (T3) would improve the short- or long-term outcome of patients with DGF in cadaveric transplants. A prospective, randomized, placebo controlled, double blind trial of T3 was carried out in patients with DGF in cadaveric renal transplants. End-points were percentage requiring dialysis, percentage recovering function, time to recovery and length of hospital stay. Long-term outcomes were percentage grafts functioning at 1 year and mean serum creatinine at 1 year. Forty-four patients were randomized to receive either T3 or placebo. Three patients were dropped from each group when early biopsies disclosed that DGF was due to rejection. The groups were well matched by age, cold ischemia time of the graft, and percentage reactivity to a random panel of antigens. Baseline thyroid function studies, including T3, reverse T3 (rT3), and thyroid stimulating hormone (TSH) levels, were similar between the two groups and typical of 'euthyroid-sick syndrome'. T3 had no effect on percentage requiring dialysis, time to recovery, percentage recovering function, or length of stay. At 1 year follow-up, graft function was similar in both groups and significantly lower than that seen in patients with good initial function. Thyroid hormone, given early in the course of DGF in cadaver kidney recipients, had no effect on the course of DGF. Long-term graft function is impaired in patients who experience post-transplant DGF compared to those who have good initial function.

Adult↗
PubMed2002

The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients.

Solid organ transplantations have been performed successfully in selected HIV-positive patients with highly active antiretrovirus therapy (HAART). However, some of the medications in the HAART regimen require metabolism via the cytochrome P4503A, the same enzyme complex responsible for clearance of the calcineurin inhibitors cyclosporine and tacrolimus. Several case reports have described significant interactions between the agents used in HAART and immunosuppressive drugs. The goal of this report is to examine the extent of potential drug interactions between antiretroviral agents and tacrolimus after liver and kidney transplantation. Seven liver transplant (LTx) patients (M = 6, F = 1) and four kidney transplant (KTx) patients (M = 4) infected with HIV underwent surgery between September 1997 and January 2001. Initial immunosuppression consisted of tacrolimus and steroids for LTx patients or tacrolimus, steroids, and mycophenolate mofetil for KTx recipients. Their current baseline immunosuppression and HAART regimen were examined retrospectively. Of the seven liver recipients, one (case 4) died 2 weeks after LTx and never received HAART therapy posttransplantation. The remaining six patients were placed on a regimen consisting of two nucleoside reverse transcriptase inhibitors (NRTI) and one protease inhibitor (PI) (nelfinavir in 5, indinavir in 1) based on known viral sensitivities or history of a previous clinical response. Kidney recipients received NRTI and nonnucleoside reverse transcriptase inhibitors (NNRTI). The mean dose of tacrolimus in liver recipients was 0.6 mg/d, with mean trough concentration of 9.7 mg/mL. Compared with historic controls (liver transplant patients not on HAART), the average tacrolimus dose was 16-fold lower in patients on HAART. In contrast to liver recipients, HIV-positive kidney recipients not on PI therapy required a mean tacrolimus dose of 9.5 mg/d to maintain a mean trough concentration of 9.6 ng/mL. Of the two protease inhibitors used, nelfinavir seems to have a more profound effect than indinavir. When patients on nelfinavir alone (n = 5) were compared with a control group not on antiretroviral therapy, the need for a tacrolimus dose was 38 times lower (mean dose, 0.26 mg/d). Profound drug interactions between PI and tacrolimus have been observed requiring up to 50-fold reductions in dosage. This effect seems to be most pronounced with the use of nelfinavir as opposed to indinavir, although further experience is required to confirm this observation. In contrast, HAART using NRTI and NNRTI without the use of PI, as shown in kidney recipients, produces less significant effects on tacrolimus metabolism. Great caution and frequent drug level monitoring are necessary when HAART is introduced or withdrawn in HIV-positive recipients of organ transplants.

Adult↗
PubMed2002

Evaluation of renal function in transplant patients on tacrolimus therapy.

Glomerular filtration rate (GFR), as measured by 24-hour creatinine clearance and clearance of iothalamate, and effective renal plasma flow (ERPF), as measured by the clearance of para-aminohippuric acid (PAH), were evaluated at 2 weeks, 1 month, and 3 months after transplantation in 8 renal transplant patients and at 1 month and 1 year after transplantation in 9 liver transplant patients receiving tacrolimus (Prograf) therapy. In renal transplant patients, there was a significant increase in GFR after transplantation. There was no change in GFR at 1 and 3 months as compared to 2 weeks after transplantation, while ERPF (ml/min/1.73 m2) was lower (p < 0.05) at 3 months (212+/-42) compared to 1 month (306+/-118) after transplantation. In liver transplant patients, GFR and ERPF were below normal despite normal serum creatinine concentrations, but there was no difference in GFR or ERPF at 1 month and 1 year after transplantation. Although below normal, renal function was well preserved in transplant patients while receiving chronic tacrolimus therapy over the study period. Dosage alterations ofrenally eliminated drugs may be required for drugs with a narrow therapeutic index.

Adult↗
PubMed2002

Hemorrhagic complications of enoxaparin and aspirin in patients with kidney transplants.

STUDY OBJECTIVE: To evaluate the frequency of early posttransplant hemorrhagic complications in patients with kidney and kidney-pancreas transplants who received thromboprophylaxis with enoxaparin and aspirin. DESIGN: Retrospective chart review. SETTING: University-based tertiary care center. PATIENTS: Thirteen patients who had received enoxaparin within 10 days of kidney or kidney-pancreas transplantation. INTERVENTION: Medical records were reviewed, and data from patients who had received low-dose aspirin 81 mg once/day and enoxaparin within 10 days of transplantation were collected. MEASUREMENTS AND MAIN RESULTS: Major bleeding events were defined as intracranial or retroperitoneal bleeding, or a decrease in hemoglobin of greater than 2 g/dl that was confirmed on repeat evaluation. Nine (69%) of the 13 patients had confirmed major bleeding events and required blood transfusions. Six of the nine patients had elevated serum creatinine levels. CONCLUSION: The combination of enoxaparin and low-dose aspirin early after kidney or kidney-pancreas transplantation was associated with a high frequency of hemorrhagic events. Further evaluation is needed to determine the safety of enoxaparin in combination with aspirin after transplantation.

Adult↗
PubMedDate not supplied

Labetalol-induced hyperkalemia in renal transplant recipients.

BACKGROUND: Labetalol is a commonly used agent for perioperative hypertension in renal transplant recipients. A previous report suggested that labetalol may cause life-threatening hyperkalemia after renal transplantation. METHODS: We performed a retrospective review of 103 consecutive renal transplants to determine whether labetalol was an independent predictor of hyperkalemia treatment. Thirty-eight patients (36.9%) received labetalol, and 65 patients (63.1%) had no labetalol medication. RESULTS: Of the 103 patients, 24 (23.3%) required treatment for hyperkalemia. Thirteen (34.2%) of the patients who had labetolol medication and 11 (16.9%) of the patients who did not receive labetalol were treated for hyperkalemia (p = 0.045). Factors considered for a logistic regression model included: the use of labetalol, cold ischemia time, diabetes, and dialysis method; intake of tacrolimus, beta blockers, angiotensin-converting enzyme inhibitors, or other antihypertensives prior to admission; the mannitol dose given intraoperatively, and the 24-hour urine output postoperatively. Intravenous labetalol (odds ratio OR = 4.52, confidence interval CI = 1.33-15.28; p = 0.02), 24- hour urine output (OR = 4.4, CI = 0.97-20.1: p = 0.47), increasing cold ischemia time (OR = 1.09, CI = 1.01-1.17; p = 0.02), and continuous ambulatory peritoneal dialysis (OR = 0.17, CI = 0.29-0.98; p = 0.036) were independent predictors. CONCLUSION: Labetalol appears to increase the risk of hyperkalemia in patients after renal transplantation.

Adrenergic alpha-Antagonists↗