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Rodolfo Alejandro

Publications and source records attributed to Rodolfo Alejandro.

At least 19 recordsLinked to original sources
PubMed2006

International trial of the Edmonton protocol for islet transplantation.

BACKGROUND: Islet transplantation offers the potential to improve glycemic control in a subgroup of patients with type 1 diabetes mellitus who are disabled by refractory hypoglycemia. We conducted an international, multicenter trial to explore the feasibility and reproducibility of islet transplantation with the use of a single common protocol (the Edmonton protocol). METHODS: We enrolled 36 subjects with type 1 diabetes mellitus, who underwent islet transplantation at nine international sites. Islets were prepared from pancreases of deceased donors and were transplanted within 2 hours after purification, without culture. The primary end point was defined as insulin independence with adequate glycemic control 1 year after the final transplantation. RESULTS: Of the 36 subjects, 16 (44%) met the primary end point, 10 (28%) had partial function, and 10 (28%) had complete graft loss 1 year after the final transplantation. A total of 21 subjects (58%) attained insulin independence with good glycemic control at any point throughout the trial. Of these subjects, 16 (76%) required insulin again at 2 years; 5 of the 16 subjects who reached the primary end point (31%) remained insulin-independent at 2 years. CONCLUSIONS: Islet transplantation with the use of the Edmonton protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control, but insulin independence is usually not sustainable. Persistent islet function even without insulin independence provides both protection from severe hypoglycemia and improved levels of glycated hemoglobin. (ClinicalTrials.gov number, NCT00014911 [ClinicalTrials.gov].).

Adult↗
PubMed2006

Resolution of neurotoxicity and beta-cell toxicity in an islet transplant recipient following substitution of tacrolimus with MMF.

Calcineurin inhibitors such as tacrolimus have well-recognized efficacy in organ transplantation but side effects of nephrotoxicity, neurotoxicity, and beta-cell toxicity that can be particularly detrimental in islet transplantation. Neuro- and nephrotoxicity have been demonstrated in multiple islet transplant recipients despite the relatively low serum maintenance levels typically used (3-5 ng/ml). We describe a single patient in whom symptoms and signs of neurotoxicity necessitated substitution of tacrolimus with mycophenolate mofetil (MMF), which resulted in complete symptom resolution over the subsequent 9 months. Concomitantly noted were an almost immediate improvement in glycemic control and an improved response to stimulation testing, suggesting remission of tacrolimus-induced beta-cell toxicity and insulin resistance. At 18 months post-"switch," 30 months posttransplant, the patient remains insulin independent with good glycemic control. The goal to remove calcineurin inhibitors from regimens of islet transplantation is a worthy one.

Adult↗
PubMed2005

Immunosuppression and procedure-related complications in 26 patients with type 1 diabetes mellitus receiving allogeneic islet cell transplantation.

BACKGROUND: The success of sirolimus and low-dose tacrolimus in islet cell transplantation has influenced many transplant centers to utilize this novel regimen. The long-term safety and tolerability of this steroid-free immunosuppressive protocol for allogeneic islet transplantation has yet to be determined. METHODS: We transplanted 26 adult patients with long standing type 1 diabetes mellitus between April 2000 and June 2004. Immunosuppression consisted of induction with daclizumab and maintenance therapy with tacrolimus and sirolimus. Adverse events (AEs) in patients were followed and graded using the Common Terminology Criteria for Adverse Events, version 3.0 (National Cancer Institute). RESULTS: To date, the majority of patients were able to remain on the immunosuppression combination for up to 22+/-11 months. Four patients were successfully converted to Mycophenolate Mofetil due to tacrolimus-related toxicity. Withdrawal from immunosuppression was decided in four patients due to hypereosinophilic syndrome, parvovirus infection, aspiration pneumonia, and severe depression, respectively. Six patients required filgrastim therapy for neutropenia. Transient elevation of liver enzymes was observed in most patients early after islet infusion. Increased LDL in 20 patients required medical treatment. CONCLUSION: There was a varying range of AEs, most of them mild and self-limiting; however, some required urgent medical attention. The majority of patients were able to tolerate and remain on this effective regimen. To date, no deaths, cytomegalovirus disease, graft-versus-host disease, or posttransplant lymphoproliferative disease has been observed.

Adult↗
PubMed2005

Requirements for success in clinical islet transplantation.

A few groups have endured the challenges of time, anecdotal success stories, logistic and funding impediments, to bring the field of clinical islet transplantation where it stands today. The recent improvement in clinical results has paralleled a renewed interest in islet transplantation and an increasing number of centers have entered the field. Selected institutions have now clearly demonstrated that insulin independence can be a reproducible and achievable goal. Other centers struggle with mixed results, while occasional early failures of islet transplants are still observed. This center effect underlines not just a learning curve, but also the complexity of the approach, which requires multidisciplinary expertise and attention to critical variables that need to be closely monitored to assure adequate clinical outcomes. The future success and large scale applicability of islet transplantation will rely on the synergistic research progress in critical areas that contribute to the sequential and integrated approach required for success in clinical islet transplantation.

Diabetes Mellitus, Type 1↗
PubMed2005

Transaminitis after pancreatic islet transplantation.

BACKGROUND: An asymptomatic, self-limited transaminitis uniformly follows pancreatic islet transplantation (PIT) performed through portal vein (PV) infusion. The underlying cause and significance of this transaminitis is unclear. STUDY DESIGN: Records of all patients with insulin-dependent diabetes mellitus who had undergone PIT at our institution were reviewed. All PITs were performed in conjunction with a remote pancreatic islet isolation center and done through percutaneous transhepatic PV infusion. Alanine aminotransferase (ALT) levels, serum glucose concentrations, insulin requirements, and color-flow Doppler ultrasonography examinations of the right upper quadrant were assessed before and after PIT. RESULTS: Eleven patients have undergone a total of 26 PITs. An elevated ALT level occurred in all 11 patients (100%) after the first PIT, with the median post-PIT peak ALT level reaching 187 IU/L. Transaminitis was less frequent and less marked after the second PIT. A negative correlation between viability of the pancreatic islets transplanted (r = -0.44, p = 0.03) and a positive correlation between the ratio of maximum to initial PV pressure (r = 0.41, p = 0.04) were seen with the subsequent ALT peak. Color-flow Doppler ultrasonography examinations showed no occurrences of PV thrombosis or intrahepatic hematoma. Finally, the degree of transaminitis did not correlate with post-PIT insulin requirements, indicating that post-PIT transaminitis cannot be used to measure allograft rejection or function. CONCLUSIONS: Transaminitis after PIT is common and self-limited. Post-PIT transaminitis does not signal acute rejection or serious procedure-related complications such as PV thrombosis or intrahepatic hematoma.

Adult↗
PubMed2005

How good is your glucose control?

BACKGROUND: Glycemic control is fundamental to the management of diabetes and maintenance of health. Popular measures of performance in glycemic control include A1c and self-monitoring of blood glucose (SMBG). As measures of performance, A1c has perspective, but it fails to recognize hypoglycemia, while SMBG lacking overall perspective finds use mainly by patients to simply evaluate their glycemic status and current response to therapy. An additional, preferably visual, measure of performance in diabetes management in general and glycemic control in particular is needed. METHODS: To form a visual measure of performance, a graphical method of analysis from the statistician's toolbox (known as the lag plot) was adapted. It can utilize SMBG data sets from any source, including memory meters and registry databases in call centers. Data are retrieved, processed, formatted, and then plotted on a PC screen or printer. The resulting lag plots visually characterize the performance of glucose control achieved over periods (selectable by the user) from days to months. Supporting numerical statistics provide rigorous outcome measures that correlate with glycated hemoglobin. RESULTS: Clinical use of the lag plot is illustrated in seven case studies spanning the range from no diabetes, through glucose intolerance, early-onset type 2 diabetes mellitus, type 1 diabetes, intensified therapy, pump therapy, and finally islet cell transplantation. Visual comparisons before and after action/referral show impacts of interventions, incidences of hypoglycemia, and changes in the polyglycemia of unstable diabetes. Statistical significance of observed changes are quantified. CONCLUSIONS: The simple lag plot can empower patients and their providers to identify problems in glycemic control, seek proactive action, adopt beneficial strategies, evaluate outcomes, and, most importantly, rule out interventions with no benefit.

Adult↗
PubMed2005

Rescue purification maximizes the use of human islet preparations for transplantation.

The relative inefficiency of the islet purification process may hamper obtaining enough islets for transplantation even with adequate pre-purification counts. In this study, we determined the effect of an additional purification step on total islet yields and pancreas utilization at our center. Twenty-five pancreata were processed using the automated method followed by continuous gradient purification (CGP), and the less pure islet fractions were subjected to additional rescue gradient purification (RGP). CGP and RGP islets were combined and transplanted into patients with type 1 diabetes. CGP and RGP islets showed no significant differences in cell viability, insulin secretion in vitro and function when transplanted into chemically diabetic mice. Mean RGP contribution to the final preparation was 27.9 +/- 19.9%. In 12 of 25 preparations, CGP yielded <5000 IEQ/kg of recipient body weight, and inclusion of RGP islets to the final preparation allowed to obtain the minimal islet number required for transplantation. Transplanted islets resulted in sustained C-peptide production, HbA1(C) normalization and insulin-independence or reduced insulin requirements. Taken together, our data suggest that RGP islets are comparable in terms of viability and potency to CGP islets. RGP may be of assistance in maximizing the number of islet preparations successfully used in transplant protocols.

Animals↗
PubMed2005

Islet transplantation in type 1 diabetes mellitus using cultured islets and steroid-free immunosuppression: Miami experience.

Following the success obtained with transplantation of fresh human islets under steroid-free immunosuppression, this trial evaluated the transplantation of islets that had undergone a period of in vitro culture and the potential of tumor necrosis factor (TNF-alpha) blockade to improve islet engraftment. Subjects included 16 patients with type 1 diabetes mellitus (T1DM); half were randomly assigned to receive Infliximab immediately preceding initial infusion. Immunosuppression consisted of daclizumab induction and sirolimus/tacrolimus maintenance. Out of 16 subjects 14 achieved insulin independence with one or two islet infusions; adverse events precluded completion in two. Without supplemental infusions, 11/14 (79%) subjects were insulin independent at 1 year, 6/14 (43%) at 18 months; these same subjects remain insulin independent at 33+/-6 months. While on immunosuppression, all patients maintained graft function. Out of 14 patients, 8 suffered chronic partial graft loss, likely immunological in nature, 5 of these received supplemental infusions. Currently, 11 subjects remain on immunosuppression, 8 (73%) are insulin independent, two with supplemental infusions. Insulin independent subjects demonstrated normalization of HbA1c, fructosamine and Mean Amplitude of Glycemic Excursions (MAGE) values. No clinical benefit of infliximab was identified. These results demonstrate that transplantation of cultured human islet allografts results in reproducible insulin independence in all subjects under this immunosuppressive regimen, comparable to that of freshly transplanted islets (Edmonton protocol).

Adult↗
PubMed2005

Peripheral blood cytotoxic lymphocyte gene transcript levels differ in patients with long-term type 1 diabetes compared to normal controls.

The purpose of this study was to compare mRNA levels of the cytotoxic lymphocyte (CL) gene products: granzyme B (GB), perforin (P), and fas ligand (FasL) in patients with long-term type 1 diabetes and healthy controls. The objective was to utilize this information to follow patients as they undergo islet cell transplantation at our center and to determine if changes in CL gene transcript levels correlate with graft status. We have measured mRNA levels for CL genes in peripheral blood samples from 65 long-term (>5 years) type 1 diabetes patients and 29 healthy controls. Total RNA was extracted from EDTA anticoagulated peripheral blood samples and reverse transcribed into first-strand cDNA using SuperScript II reverse Transcriptase. Quantitative, real-time PCR was utilized to determine CL gene transcript levels. mRNA levels of P and FasL genes were found to be significantly lower for patients with type 1 diabetes compared to normal controls (p < 0.05). However, there was no significant difference for GB mRNA levels between patients and controls (p > 0.05). The decreased expression of P and FasL in patients with long-term type 1 diabetes might contribute to the inability to maintain normal levels of peripheral tolerance, which is essential for protection from autoimmune disease.

Diabetes Mellitus, Type 1↗
PubMed2005

Evaluation of metabolic control using a continuous subcutaneous glucose monitoring system in patients with type 1 diabetes mellitus who achieved insulin independence after islet cell transplantation.

This study evaluated the Medtronic MiniMed Continuous Glucose Monitoring System (CGMS) in patients with type 1 diabetes mellitus who underwent successful islet cell transplantation (ICT). The results are compared to standardized self-monitoring (SMBG) of hyperglycemia and mean amplitude of glycemic excursions (MAGE). We studied 19 patients (mean age 40.0 +/- 6.7 years) in three groups: six patients post-ICT, seven patients awaiting ICT, and six normal volunteers (controls). Continuous glucose monitoring post-ICT showed remarkable glucose stability compared with patients awaiting ICT. The CGMS group showed modestly higher glucoses (mean 111.5 mg/dl) compared with controls (88 mg/dl). Postprandial glucoses in ICT recipients rarely exceeded 180 mg/dl and were similar to controls. There was no difference in asymptomatic hypoglycemia between control and post-ICT groups. However, a higher incidence of hypoglycemia was observed in patients awaiting ICT. HbA1c and MAGE pre- and post-ICT were 8.3 +/- 0.9% and 6 +/- 0.3% (p < 0.001) and 109 +/- 34 and 41 +/- 11 (p < 0.001), respectively. No complications were associated with CGMS. This study suggests ICT significantly improves metabolic control and rate of hypoglycemia when compared with controls and patients awaiting ICT. Similar improvement in metabolic control was observed with SMBG, HbA1c, and MAGE. Although CGMS was not demonstrated to be a superior tool for routine assessment in ICT, it is very helpful in special clinical situations.

Adult↗
PubMed2004

Alterations of the female reproductive system in recipients of islet grafts.

BACKGROUND: Transplantation of allogeneic tissues is becoming a wider practice for the replacement of organ function lost to congenital or acquired pathologies. Chronic immunosuppression remains a necessity to prevent organ rejection, despite increased risks of infection, organ toxicity, and malignancies. Abnormalities of female gonadal function in patients of reproductive age are recognized, however, pathological alterations of the reproductive system in patients treated with new generation immunosuppressive drugs are still poorly documented. METHODS: We report herein our observations of abnormalities of the reproductive system in 13 female recipients of allogeneic islets for type 1 diabetes, under immunosuppression therapy based on daclizumab induction and tacrolimus/sirolimus maintenance. RESULTS: Menstrual cycle alterations and clinically significant ovarian cysts were frequently observed in our patients, some requiring medical or surgical intervention. All ovarian cysts appeared of benign nature. CONCLUSIONS: Our findings suggest that pre- and posttransplant evaluation of female patients should include menstrual history, baseline pelvic ultrasound, and hormonal levels to assess the presence and monitor the progression of such alterations.

Adolescent↗
PubMed2004

Procurement of the human pancreas for pancreatic islet transplantation.

BACKGROUND: The full potential of pancreatic islet transplantation (PIT) has not been realized because of the difficulties associated with islet isolation, particularly when associated with a remote islet isolation center. Herein, we describe the principles of pancreatic procurement for PIT, which have allowed us to achieve a successful pancreatic islet isolation rate 67% of the time when using a remote islet isolation center. METHODS: Between January 16, 2002 and June 30, 2003, 39 pancreata were procured and processed for PIT at a distant islet isolation center. All pancreata were procured by a single surgeon, and special attention was given to careful dissection of the pancreas, maintenance of arterial inflow and the pressure differential between arterial and venous systems during perfusion, rapid organ cooling, and rapid removal of the pancreas from the body. RESULTS: Twenty-six of 39 (67%) procured pancreata yielded more tha 5,000 islet equivalents (IEQ)/kg recipient weight and were transplanted. Median IEQs per isolation was 413,867, whereas median purity and viability were 65% and 100%, respectively. The median time for pancreatic excision was 34 minutes, whereas cold ischemia time was 6 hours and 40 minutes. DISCUSSION: The principles we have adopted for pancreatic procurement for PIT have resulted in a 67% islet isolation success rate despite the maintenance of more than 5,000 IEQ/kg and the use of a remote islet isolation center.

Adolescent↗
PubMed2004

Development of a human pancreatic islet-transplant program through a collaborative relationship with a remote islet-isolation center.

BACKGROUND: With the development of the Edmonton Protocol, pancreatic islet transplantation (PIT) now offers insulin-dependent diabetic patients metabolic stability. The PIT Food and Drug Administration (FDA) regulations, pancreatic islet isolation (PII) techniques, and clinical PIT protocols are challenging and make PIT program development daunting. PURPOSE: Review of the establishment of a PIT program through a collaborative relationship with a remote PIT/PII center. METHODS: Four key elements are required: (1) development of a collaborative relationship with an established PIT/PII center, (2) achievement of institutional review board and FDA approval at both centers, (3) generation of standard operating procedures, and (4) development of a multidisciplinary PIT team. RESULTS: Securing a collaborative relationship with an experienced PIT/PII center permitted our program to develop in less than 18 months. Twenty-two PITs were completed in the first clinical year. CONCLUSIONS: Collaboration with an experienced PIT/PII center allows developing programs to focus on patient safety and care, prudent use of pancreata, and consolidates PII expertise and experience.

Adult↗
PubMed2004

Cytomegalovirus prevalence and transmission after islet allograft transplant in patients with type 1 diabetes mellitus.

Cytomegalovirus (CMV) serological status of transplant donors and recipients has important implications on antiviral prophylaxis, morbidity/mortality, donor selection and hospital stay. We evaluated CMV prevalence in our islet transplant candidates (ITC) in comparison with organ donors. We correlated the CMV serological status of our ITC with serology for Epstein-Barr virus and Parvovirus B19, auto-antibodies, patient's age, age at DM onset, duration of DM, gender, race, ABO group, HLA haplotype and C-peptide levels. Cytomegalovirus transmission after islet transplant using the Edmonton regimen was also evaluated. Cytomegalovirus seropositivity varied according to patient group, age, gender and race. Type 1 DM patients had reduced odds of CMV seropositivity when compared with organ donors. In all groups studied, older patients, females, and non-Caucasians were more likely to be CMV seropositive. In addition, no CMV reactivation, infection or disease was observed among our transplanted patients using this steroid-free regimen even after donor/recipient CMV mismatch.

Adolescent↗
PubMed2004

Assessment of cytotoxic lymphocyte gene expression in the peripheral blood of human islet allograft recipients: elevation precedes clinical evidence of rejection.

Studies in nonhuman primates have demonstrated that elevation of the cytotoxic lymphocyte (CL) genes granzyme B, perforin, and Fas ligand in peripheral blood precedes islet allograft rejection. The purpose of this study was to determine whether this approach has utility for prediction of human islet allograft loss. We studied 13 patients who had long-term type 1 diabetes and were treated with steroid-free immunosuppression and given sequential islet cell infusions. All recipients became insulin independent, and eight of them experienced deterioration in glycemic control, followed by reinitiation of insulin therapy. Frequent peripheral blood samples were collected to monitor CL gene mRNA levels with real-time PCR. For the eight back-to-insulin patients, there was a clear elevation of CL gene mRNA levels 25-203 days before the onset of frequent hyperglycemia. Granzyme B was the most reliable indicator of ongoing graft loss. Additional correlations with infection were noted; however, evidence of sensitization in antidonor mixed lymphocyte reaction was observed in seven of eight patients who experienced partial graft loss, whereas this was not seen when upregulated CL gene expression was associated with infection. The results suggest that, when taken into consideration with other clinical parameters, elevated CL gene levels may enable prediction of islet allograft loss.

Biomarkers↗
PubMed2004

Use of D-STAT to prevent bleeding following percutaneous transhepatic intraportal islet transplantation.

An infrequent but nevertheless concerning complication associated with percutaneous transhepatic islet transplantation is bleeding. Historically in 61 procedures at this institution, we experienced four bleeding complications in three patients (6.6%), two requiring blood transfusion (3.3%) and two asymptomatic intraperitoneal bleeds detected sonographically at 24 h postprocedure (3.3%). It is suggested that the source of the majority of these bleeds is the liver parenchymal tract following removal of the infusion catheter combined with a significant dose of heparin administered to prevent portal vein thrombosis. Various techniques have been used to reduce the risk of tract bleeding, including gelfoam, intravascular coils, and cautery. In our experience gelfoam alone has been used to plug the catheter tract (n = 47); however, in the aforementioned three patients, this technique failed, either due to dislodgement of, or bleeding peripheral to, the plug. This article describes the use of D-Stat, a collagen/thrombin paste that is injected into the peripheral tract. In five consecutive cases performed using D-Stat, there has been no bleeding or thromboses detected. D-Stat combined with a single gelfoam plug offers a quick, easy, efficacious way of sealing the entire catheter tract without leaving any permanent hardware in the liver. This new method may simplify tract closure and reduce bleeding complications in islet transplantation.

Animals↗
PubMed2004

Lack of cytomegalovirus transmission after pancreatic islet transplantation.

In spite of antiviral prophylaxis, the transmission rate of cytomegalovirus (CMV) after solid organ transplantation remains high. In contrast, CMV transmission has never been reported following pancreatic islet transplantation (PIT). Eleven (seven CMV seronegative, four CMV seropositive) recipients underwent a total of 26 PITs. Following PIT recipients were monitored clinically and tested monthly for CMV antigenemia. Valganciclovir was given to all patients for 100 days after each PIT. Follow-up ranged from 6 to 24 months (median 14.5 months). Pancreatic islet grafts were procured from 18 CMV seropositive and 8 seronegative donors (69% and 31% of donors, respectively). In total there were 6 R+D+, 3 R+D-, 12 R-D+, and 5 R-D-PITs. No patient developed CMV antigenemia or symptoms consistent with CMV infection at any time following PIT. Routine posttransplant testing of PIT recipients demonstrated that neither CMV transmission nor CMV infection occurred after PIT.

Adult↗