Cyclosporine microemulsion formulation (sigmasporin microral) effect as first-line immunosuppressant on renal functions at 3 years.

BACKGROUND: Cyclosporine (CsA) remains a mainstay of immunosuppressive maintenance regimens in developing countries, but its effects on long-term kidney allograft survival are still unclear. Our aim was to assess a generic microemulsion CsA (Sigmasporin) for long-term impact on graft function and patient survival among stable renal transplant patients. METHODS: Over a 36-month period, patients with transplantations from >6 months earlier were maintained on CsA doses of 2-8 mg/kg/d to keep C(2) within the recommended therapeutic range. We assessed 25 efficacy and tolerability parameters of scheduled intervals. RESULTS: Twenty-seven patients (9 female, 18 male) from 6 centers in 4 Middle-Eastern countries were enrolled between 2004 and 2009. Their average age was 35.1 ± 9.8 years, body mass index ranged from 15.7 to 41.2 kg/m(2), and average time from transplantation was 2.2 ± 1.6 years. Within the 36-month observation period the CsA dose was reduced by 17.3% from 2.89 ± 0.88 mg/kg/d to achieve C(2) levels of 600-1000 ng/mL. After 36 months the glomerular filtration rate declined by 8.2% from an overall baseline mean of 72.7 ± 23.5 mL/min/1.73 m(2). It improved in 11.1% of patients and remained unchanged in 44.4%. No new cases of hypertension or diabetes mellitus were reported, and there was 1 case of borderline hyperlipidemia. Graft functions were stable, apart from 2 incidences of CsA nephrotoxicity. Both graft and patient 3-year survival rates were 100%. CONCLUSIONS: On a 3-year basis, Sigmasporin Microral was effective to maintain stable renal functions in kidney transplant patients, with safety and tolerability profiles similar to those reported in the international literature.

Factors affecting hemodialysis patients' satisfaction with their dialysis therapy.

Aim. To assess the degree of satisfaction among hemodialysis patients and the factors influencing this satisfaction. Methods. Patients were recruited from 3 Saudi dialysis centers. Demographic data was collected. Using 1 to 10 Likert scale, the patients were asked to rate the overall satisfaction with, and the overall impact of, their dialysis therapy on their lives and to rate the effect of the dialysis therapy on 15 qualities of life domains. Results. 322 patients were recruited (72.6% of the total eligible patients). The mean age was 51.7 years (±15.4); 58% have been on dialysis for >3 years. The mean Charlson Comorbidity Index was 3.2 (±2), and Kt/V was 1.3 (±0.44). The mean satisfaction score was (7.41 ± 2.75) and the mean score of the impact of the dialysis on the patients' lives was 5.32 ± 2.55. Male patients reported worse effect of dialysis on family life, social life, energy, and appetite. Longer period since the commencement of dialysis was associated with adverse effect on finances and energy. Lower level of education was associated with worse dialysis effect on stress, overall health, sexual life, hobbies, and exercise ability. Conclusion. The level of satisfaction is affected by gender, duration on dialysis, educational level, and standard of care given.

Kidney health in the Middle East.

Chronic kidney disease (CKD) is a common and costly health problem in the Middle East. The incidence of CKD is still unknown, and the incidence of end-stage renal disease (ESRD) is estimated at 100 - 140 incident cases per million population in the Middle East countries. Most of the available statistics about prevalence are of treated ESRD. Published population-based studies for incidence and prevalence of CKD and ESRD are still lacking in most of the Middle East countries. This negatively affects the health planning and effectiveness of preventive and therapeutic measures in the region. The prevalence of renal replacement therapy varies among the different countries in the Middle East. The infrastructure for these services is also variable among these countries and affects the outcome, which as yet cannot be measured accurately. The low gross national income of the Middle East countries is a major factor in negating the implementation of research, planning, and improvement of the services for CKD patients. To overcome the obstacles for the renal services in the Middle East countries, the constraints on health expenditure need to be surmounted, which is not an easy task, and related appropriately to the gross national income. Awareness within the medical community and the public at large about the advances of therapeutic and preventive measures is also an important factor for progress toward better kidney health in the Middle East.

Impact of recipient and donor nonimmunologic factors on the outcome of deceased donor kidney transplantation.

OBJECTIVE: To study the influence of nonimmunologic factors on the outcome of extended criteria deceased donor (DD) kidney transplants. METHOD: This is a retrospective study of DD transplantation carried out from January 1, 2003 to December 31, 2007, to investigate the impact on graft survival and function of donor renal function at retrieval, cold ischemia time (CIT), delayed graft function (DGF), acute rejection episodes (ARE), age, and weight of donors and recipients, transplant center activities, cause of donor death, donor-recipient gender pairing and size of the donating intensive care unit (ICU). RESULTS: At retrieval, the frequency of donors with a creatinine clearance <60 mL/min, using the Cockcroft-Gault formula, and age >40 years were 31.7% and 32%, respectively. CIT > 24 hours, DGF, and ARE occurred in 27.1%, 33.4%, and 16.5% of cases, respectively. The overall 1- and 5-year graft and patient survival rates were 88% and 79.8% and 96.6% and 92.3%, respectively. The graft function was inferior with occurrences of ARE (P = .0001), DGF (P = .0001), CIT > 20 hours (P = .005), nontraumatic the donor death (P = .022), and donor ICUs bed capacity <20 (P = .03). The odds ratio (OR) for graft loss with DGF, ARE, and donors right kidneys were 7.74 (95% confidence interval [CI] 6-13.4; P = .0001), 4.47 (95% CI, 2.6-7.6; P = .0001) and 1.7 (95% CI, 1-2.8; P = .045), respectively. Graft function was not influenced by donor renal function at retrieval, donor weight, or donor- recipient gender pairings. CONCLUSION: CIT and ARE had an impact on both graft survival and function. DGF and cerebrovascular accidents as the cause of donor death negatively affected graft function during follow-up. ICU center experience had a positive impact on graft survival. Patient survival was affected by recipient age >50 years and female to male donation versus other gender pairings. Neither donor age nor acute terminal rise in the donor serum creatinine affected graft function or survival, or patient mortality.

Six-month clinical outcome of cyclosporine microemulsion formulation (Sigmasporin Microral) in stable renal transplant patients previously maintained on sandimmun neoral.

The trial objective was to investigate the feasibility and safety of conversion to a generic microemulsion cyclosporine in stable renal transplant patients premaintained on Neoral. We enrolled 75 patients from seven centers in five Middle Eastern countries monitored them for 6 months after conversion to Sigmasporin Microral. Readings at 0, 0.5, 1, 2, 3, 4.5, and 6 months included cyclosporine blood level, serum creatinine, liver enzymes, lipid profile, blood sugar, blood pressure and adverse events. Patients included 54 men and 21 women of mean age 38.9 +/- 10.7 years at 30.3 +/- 29.3 months post-transplantation maintained on Sigmasporin Microral dose of 2.8 +/- 1.0 mg/kg per day; they were observed to be stable throughout the study period as reflected by the therapeutic blood C0 level of 181.6 +/- 102.1 and C2 of 759.2 +/- 384.4. Their absorption profile as represented by C2/C0 was 4.9 +/- 2.8, and C2/cyclosporine dose of 282.3 +/- 128.8. An average serum creatinine level of 116.1 +/- 29.5 micromol/L denoted stable graft function and their liver enzymes did not change during the study. No new-onset cases of hypertension, diabetes mellitus, or hyperlipidemia were reported among the patients. Graft function was stable for all patients, except for two incidences of mild acute rejection and two of mild cyclosporine nephrotoxicity; graft and patient survival rates were both 100%. Results of this 6-month study showed that Sigmasporin Microral was effective to maintain stable renal function in kidney transplant patients converted from Neoral with similar safety and tolerability profiles as those reported in the literature.

Therapeutic equivalence and mg:mg switch ability of a generic cyclosporine microemulsion formulation (Sigmasporin Microral) in stable renal transplant patients maintained on Sandimmun Neoral.

We tested a hypothesized pharmacokinetic difference between the reference (Sandimmun Neoral) and test (Sigmasporin Microral) products to prove therapeutic equivalence in an open, multiple fixed dose, one-way crossover, multicenter, and multinational study over a period of 29 days. Forty two stable renal transplant recipients maintained on Sandimmun Neoral were enrolled. Whole blood was collected at day 14 of the study at 0, 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after reference dosing and the same schedule was repeated at day 29 after switching on an mg:mg basis to the test product at day 15 of the study. Analysis of variance was performed for the pharmacokinetic parameters (area under the curve [AUC]0-12, maximum concentration [Cmax]) of cyclosporine using log-transformed values. Tolerability was assessed by vital signs, adverse events, and laboratory investigations. The 90% confidence interval (CI) test for the Ln-transformed, pharmacokinetic parameters was all within the US Food and Drug Administration acceptable range of 80% to 125%, as Ln area under the steady-state curve (AUCss) was within the range of 92.56 to 103.55 and Ln Cmax was within the range of 85.73 to 103.58; the same also applied for AUC0-4, which may be considered the area of greatest inter- and intra-patient variability. Furthermore, in line with the newly adopted recommendations of the Expert Advisory Committee on Bioavailability and Bioequivalence of Health Canada, the 90% CI for AUCss was within the narrow range of 90% to 112%. No significant difference in tolerability was recorded between the two products. Sigmasporin Microral (Julphar) was found to be bioequivalent and clinically interchangeable on an mg:mg basis with Sandimmun Neoral (Novartis).

Cytomegalovirus disease in renal transplant recipients: a single-center experience.

OBJECTIVES: Cytomegalovirus is the most common viral infection following kidney transplant, with overall frequencies of 50% to 80% for the infection and 20% to 60% for cytomegalovirus disease. MATERIALS AND METHODS: We retrospectively analyzed the medical records of 689 kidney transplant recipients at Jeddah Kidney Center in the Kingdom of Saudi Arabia between January 2000 and December 2005 for cytomegalovirus infection and disease. We examined the source of the donated kidneys (deceased versus living donor), the cytomegalovirus serostatus of the donor and recipient, the immunosuppressive protocol, the presence of cytomegalovirus prophylaxis, the clinical presentation of acute cytomegalovirus disease, the patient's response to treatment, and the effect of cytomegalovirus disease on graft and patient survival. RESULTS: Of 689 kidney transplant recipients, 25 (3.6%) had acute cytomegalovirus disease. All 25 patients had cytomegalovirus IgG positive/IgM negative test results prior to transplant. We noticed 2 distinct groups of patients: the first group included 9 patients with cytomegalovirus syndrome, 6 of whom received cytomegalovirus prophylaxis with ganciclovir. All patients in this group had low cytomegalovirus viral loads on polymerase chain reaction, mild disease, and responded to treatment with complete recovery and no adverse effects with respect to themselves or their grafts. The second group included 16 patients with invasive cytomegalovirus disease, 3 of whom received cytomegalovirus prophylaxis. All patients in this group had very high cytomegalovirus viral loads on polymerase chain reaction. Thirteen patients in this group (81%) responded to treatment with full recovery, and normal graft function was maintained in 10 (62%). Of the original 16 patients in this group, 3 (18.8%) died from cytomegalovirus disease and its complications. CONCLUSIONS: We report a low incidence (3.6%) of cytomegalovirus disease at our center. Cytomegalovirus prophylaxis was associated with a milder form of the disease. At our center, treatment of invasive cytomegalovirus disease produced a patient survival rate of 81% and a graft survival rate of 62%.

Posttransplant erythrocytosis in renal transplant recipients at Jeddah Kidney Center, Kingdom of Saudi Arabia.

OBJECTIVES: Posttransplant erythrocytosis is a well-known complication of renal transplant. It is a persistently elevated hematocrit level equal to or greater than 51%, or a hemoglobin level equal to or greater than 16 g/L, or both, in the absence of other causes. MATERIALS AND METHODS: We retrospectively reviewed this complication in patients who had received a renal transplant at our center between January 1991 and December 2005. RESULTS: Of 1655 renal transplant recipients, 159 patients (9.6%; 154 men, 5 women; mean age, 42 +/- 9 years) developed posttransplant erythrocytosis. The mean follow-up was 96 +/- 4 months. Posttransplant erythrocytosis appeared at an average of 8.2 +/- 5 months after transplant (range, 3-40 months) and lasted an average of 10.3 +/- 3 months (range, 7-35 months). In all 159 patients, the immunosuppressive medication regimen included prednisolone; in 144, cyclosporine was used, and in 108 patients, azathioprine was used, while in another group of patients, the latter 2 were changed to mycophenolate mofetil (n=38) and tacrolimus (n=13). Twenty-four patients (15%) were treated with phlebotomies, while 29 patients (18.2%) were given angiotensin-converting enzyme inhibitors. One hundred six patients were left untreated including 92 patients (57.9%) who received prophylactic anti-platelet medications. Remission of posttransplant erythrocytosis was seen in all treated and untreated patients. No thromboembolic complications occurred. Only 9 patients (5.7%) developed chronic allograft nephropathy during follow-up. CONCLUSIONS: Our findings suggest that posttransplant erythrocytosis is a benign condition affecting males more than females, usually manifesting in the first year after transplant. Remission of posttransplant erythrocytosis can be seen in all patients; however, some patients may require treatment with phlebotomy or angiotensin-converting enzyme inhibitors. Posttransplant erythrocytosis has no adverse effects on renal graft function.

Improving transplantation programs and patient care.

Organ transplantation is the preferred mode of replacement therapy. Currently acceptable 5-year posttransplantation survival rates are 85% for renal grafts, 70% for liver, and 65% for heart. Organ donation, however, remains a significant factor in organ transplantation, as humans are the only possible donors and the numbers of patients on waiting lists remain high. Several factors affect organ transplantation in countries in the Middle East Society for Organ Transplantation (MESOT) region, including inadequate preventive medicine, differing health infrastructures, poor awareness within the medical community and lay public regarding the importance of organ donation and transplantation, a high level of ethnicity, and poor government support of organ transplantation. Moreover, there is lack of team spirit among transplant physicians, a lack of coordination between groups that manage organ procurement and the transplant centers, and a lack of effective health insurance coverage for many persons. Three models of organ donation and transplantation exist in the MESOT region-the Saudi, Iranian, and Pakistani models. Living-organ donation, the most widely practiced form of donation in countries in the MESOT region, includes kidney and partial liver. Cadaveric organ donation has significant potential in the MESOT region. However, numerous obstacles must be overcome in MESOT countries. Resolution of these obstacles will require continuous work on many fronts. Experiences from all sources must be incorporated into new and improved models that can overcome current inadequacies. Solutions will require continued focus within the medical community, steady support from the lay public and religious institutions, as well as governmental assistance.

A proposed Saudi approach to the ethical utilization of living unrelated kidney donation.

We outline a proposal for the use of living unrelated kidney donors for transplantation. This proposal, although recommended by the Saudi National Committee on Renal Transplantation, is still under discussion and has not been implemented yet. We feel that this proposal is ethical with airtight safeguards against commercialization and for the protection of the well-being of the donor with assurance that he or she has not been coerced into donation.

Increasing organ donation rates from Muslim donors: lessons from a successful model.

As the great majority of the population in Saudi Arabia is Muslim, the Islamic views about organ donation and transplantation have been the focus of interest to the transplant community in this and other Muslim countries. The first resolution of the Islamic council in Saudi Arabia (Senior Ulama Commission) about organ donation and transplantation was issued in 1982. It permitted tissue and organ transplantation from both living and cadaveric donors. This resolution marked a new era in organ transplantation in Saudi Arabia, leading to the formation of the Saudi Center of organ transplantation (SCOT), which organizes the process of organ donation and transplantation in Saudi Arabia. There were major strategies to reach the goals of the organ procurement centers adopted by SCOT: improving the awareness of the medical community to the importance of organ donation and transplantation, improving the awareness of the public at large to the importance of organ donation and transplantation, and developing an efficient coordinated system with both the donating hospitals and the transplant centers. Various organs had been transplanted in Saudi Arabia through the end of 2002: 3759 kidney transplants (1267 cadaver, 2492 living); 279 liver transplants(225 cadaver, 54 living); 92 heart transplants; 421 cornea transplants; 8 lungs; and 5 combined kidneys and pancreas. In addition, there have been many tissue donations of bone marrow, heart valves (264 hearts), skin, and bone. Despite the success of the Saudi program, there have been public and medical obstacles that have obviated the full benefit of cadaver donors. We suggest increasing the awareness of the medical community and the public at large to the importance of organ donation and transplantation.

A survey on the prevalence and management of hepatitis B after renal transplantation in Asian-Pacific countries.

The carrier rate for hepatitis B virus (HBV) varies from 1% to 2% to 10% in Asian-Pacific countries. A survey involving 12 transplant centers from 11 countries in this region showed that 1% to 25% of kidney transplant recipients were infected with HBV, and up to 60% of these subjects showed abnormal liver biochemistry. While nearly all centers tested anti-HBs in potential kidney transplant recipients, HBV vaccination of nonimmune subjects was routine in only 66.7%. One-third of the surveyed units rejected HBsAg-positive subjects as kidney donors, while the others demonstrated differing policies in choosing the respective recipients. Two units (16.7%) excluded HBsAg-positive patients from kidney transplantation, whereas the others only excluded those with severe liver disease. Heterogeneity also applies to the immunosuppressive regimens, the use of HBV DNA in serial monitoring, and the timing of antiviral therapy in HBsAg-positive kidney transplant recipients. The data showed that despite HBV infection being a significant problem in kidney transplantation, there is a lack of uniform management policy, attributable to the clinical complexity and deficiency of research data. Although improvement in clinical outcome is likely with the advent of nucleoside analogue therapy and better monitoring, the financial implications in the adoption of these recent advances remain realistic concerns.

Current status of renal transplantation in the Kingdom of Saudi Arabia.

The reported annual incidence of end-stage renal disease in Saudi Arabia is 100 to 120 patients per million population. The first dialysis unit in Saudi Arabia was established in 1971; thereafter, rapid advances have been made in the field of renal replacement therapy. At the end of 2002, there were 144 centers offering dialysis to about 7390 patients. A National Kidney Foundation was established in 1985 to implement the cadaveric organ transplant program and to coordinate the renal care facilities. This center was renamed Saudi Center for Organ Transplantation (SCOT) in 1993 to encompass transplantation of organs other than the kidney. An impetus was achieved in 1982 with the approval by Islamic scholars of the concept of brain-death and organ transplantation. From 1979, when the first renal transplant was performed, until the end of 2002, more than 3810 renal transplants have been performed in 13 transplant centers in Saudi Arabia, in addition to 260 liver, 95 heart, 280 heart valve, 510 cornea, 4 pancreas, 8 lung, and 1000 bone marrow transplants. The survival of patients and (grafts) in those who received living related renal transplants was 98.4(96.9), 96.7(96.7), and 96.7(92.2) at 1, 3, and 5 years, respectively. Moreover, the survival of patients and grafts among those who received cadaveric donor organs was 96.2(96.2), 93(92.1), and 93(87.2), at 1, 3, and 5 years, respectively. In conclusion, there has been increased renal transplantation in Saudi Arabia and there is even more room to increase the frequency of these transplants to decrease the expanding gap between supply and demand through increasing the efforts for organ donation from living and cadaveric donors.

Posttransplant complications encountered in renal transplantation in the Middle East.

This paper discusses the commonly seen complications encountered in Middle Eastern transplant recipients, including posttransplant Kaposi's sarcoma, tuberculosis, infective diarrhea, and pregnancy.

important social factors that affect organ transplantation in Islamic countries.

Social attitudes and beliefs have direct and strong impact on people's acceptance of organ donation and brain death, and therefore affect the entire practice of organ transplantation. The views differ from one society to another, and they at least partially explain regional variations in the world with respect to success of organ transplantation. Social attitudes and ethics in Islamic countries are closely intertwined with Islamic tradition, teachings and heritage. These positions are strongly adhered to in many Islamic countries, and by Moslems who live in countries that are not predominantly Islamic. We feel that transplant physicians and transplant coordinators should be aware of these factors when dealing with potential donors and recipients. Decision-making can be facilitated if these issues are considered prior to consulting with a donor's family and if an appropriate compassionate explanation of need for transplantation and basis of brain death diagnosis is provided based on a knowledge of underlying social constraints. Such steps can make the donation process smoother for both health care workers and the family.