Ayman F. Refaie

Long-term outcome of live donor kidney transplantation for renal amyloidosis

BACKGROUND The short-term outcome of kidney transplantation in patients with amyloidosis has been reported. The aim of this study is to investigate long-term results in patients with renal amyloidosis. METHODS We studied results of renal transplantation in 23 amyloidotic transplant recipients compared with those in a control group of 47 nonamyloidotic patients. Amyloidosis was secondary to familial Mediterranean fever (FMF) in 16 patients, whereas it was primary (idiopathic) in 7 transplant recipients. The 2 groups were homogeneous regarding age, sex, HLA matching, immunosuppression, and duration of transplantation. RESULTS Five- and 10-year actuarial graft survival rates were similar in both groups (79.35% versus 84.04% and 65.92% versus 56.61%, respectively ). Five- and 10-year actuarial patient survival rates also were similar (80% versus 94% and 68% versus 87%, respectively). Moreover, 72.4% of controls experienced at least 1 rejection episode, whereas only 43.5% of amyloidotic transplant recipients experienced 1 or more such events (P = 0.02). Nonetheless, mean serum creatinine concentrations did not differ between the 2 groups during the observation period. Maintenance colchicine therapy prevented the recurrence of both FMF symptoms and amyloidosis. Recurrence was documented in only 1 amyloidotic transplant recipient (4.3%) 10 years posttransplantation. Significant gastrointestinal (GI) problems were more frequent in amyloidotic patients (65% versus 38%; P = 0.03). Amyloidotic patients with GI problems, except for 2 patients, were administered cyclosporine. Eleven of these patients had FMF, which appeared to reflect the effects of both cyclosporine and colchicine. Infections were similar in the groups; whereas amyloidotic patients had significantly lower blood pressures. CONCLUSION In our experience, long-term (5 to 10 years) outcome of live related donor kidney transplantation in patients with amyloidosis is similar to that in the general transplant population.

Insulin-producing cells from adult human bone marrow mesenchymal stem cells control streptozotocin-induced diabetes in nude mice.

Harvesting, expansion, and directed differentiation of human bone marrow-derived mesenchymal stem cells (BM-MSCs) could provide an autologous source of surrogate β-cells that would alleviate the limitations of availability and/or allogenic rejection following pancreatic or islet transplantation. Bone marrow cells were obtained from three adult type 2 diabetic volunteers and three nondiabetic donors. After 3 days in culture, adherent MSCs were expanded for two passages. At passage 3, differentiation was carried out in a three-staged procedure. Cells were cultured in a glucose-rich medium containing several activation and growth factors. Cells were evaluated in vitro by flow cytometry, immunolabeling, RT-PCR, and human insulin and c-peptide release in responses to increasing glucose concentrations. One thousand cell clusters were inserted under the renal capsule of diabetic nude mice followed by monitoring of their diabetic status. At the end of differentiation, ~5–10% of cells were immunofluorescent for insulin, c-peptide or glucagon; insulin, and c-peptide were coexpressed. Nanogold immunolabeling for electron microscopy demonstrated the presence of c-peptide in the rough endoplasmic reticulum. Insulin-producing cells (IPCs) expressed transcription factors and genes of pancreatic hormones similar to those expressed by pancreatic islets. There was a stepwise increase in human insulin and c-peptide release by IPCs in response to increasing glucose concentrations. Transplantation of IPCs into nude diabetic mice resulted in control of their diabetic status for 3 months. The sera of IPC-transplanted mice contained human insulin and c-peptide but negligible levels of mouse insulin. When the IPC-bearing kidneys were removed, rapid return of diabetic state was noted. BM-MSCs from diabetic and nondiabetic human subjects could be differentiated without genetic manipulation to form IPCs that, when transplanted, could maintain euglycemia in diabetic mice for 3 months. Optimization of the culture conditions are required to improve the yield of IPCs and their functional performance.

Critical evaluation of the factors influencing erectile function after renal transplantation

A total of 400 male renal transplant recipients (RTR) were investigated. Data on medical, sexual history, clinical examination and laboratory variables were collected. The severity of erectile dysfunction (ED) was assessed using the International Index of Erectile Function questionnaire. Univariate and multivariate logistic regression analyses were used to determine prognostic variables, which have independent impact on erectile function. ED was detected in 35.8% of the whole group. Current erectile function as compared to pretransplant status was improved, deteriorated or remained static in 44, 12.5 and 43.5% of the evaluated transplant recipients, respectively. After logistic regression analysis, age, hemoglobin level and presence of DM and/or peripheral neuropathy had significant and independent negative impact on erectile function. We concluded that renal transplantation has varying effects on erectile function. ED is highly prevalent among RTR and its pathogenesis is multifactorial.

Effect of Erythropoietin on Sexual Potency In Chronic Haemodialysis Patients: A Preliminary Study

Six male dialysis patients were submitted to a Doppler study of the deep penile arteries and intracavernosal injection of 30 mg papaverine under basal conditions before and after erythropoietin therapy. Penile tumescence was recorded after 15 min by measuring the length and the circumference of the penis as well as the erectile angle between the penis and the legs with the patient in standing position. Haematocrit was raised by erythropoietin therapy from 19.3 +/- 4.5 to 31.2 +/- 5.5 within 3 months. Five patients completed the study. We encountered a significant improvement in the frequency of sexual intercourse per month from 1.3 +/- 0.5 to 2.3 +/- 0.8 (p = 0.014). Furthermore, an increase was observed in the penile brachial index (from 0.87 +/- 0.1 to 0.91 +/- 0.1) and in the papaverin induced increase in penile length (4.6 +/- 1.4 cm versus 5.2 +/- 1.1 cm), penile circumference (2.7 +/- 0.14 cm versus 2.7 +/- 0.27 cm) as well as in the erectile angle (61.7 +/- 37.1 versus 80 +/- 23.5 degrees). These changes were not statistically significant. There was a significant correlation between the increase in the erectile angle and the increase in frequency of intercourse (p = 0.04). In conclusion, erythropoietin treatment could improve the sexual potency in uraemic patients under chronic haemodialysis therapy.

Generation of Insulin-Producing Cells from Human Bone Marrow-Derived Mesenchymal Stem Cells: Comparison of Three Differentiation Protocols

Introduction. Many protocols were utilized for directed differentiation of mesenchymal stem cells (MSCs) to form insulin-producing cells (IPCs). We compared the relative efficiency of three differentiation protocols. Methods. Human bone marrow-derived MSCs (HBM-MSCs) were obtained from three insulin-dependent type 2 diabetic patients. Differentiation into IPCs was carried out by three protocols: conophylline-based (one-step protocol), trichostatin-A-based (two-step protocol), and β-mercaptoethanol-based (three-step protocol). At the end of differentiation, cells were evaluated by immunolabeling for insulin production, expression of pancreatic endocrine genes, and release of insulin and c-peptide in response to increasing glucose concentrations. Results. By immunolabeling, the proportion of generated IPCs was modest (≃3%) in all the three protocols. All relevant pancreatic endocrine genes, insulin, glucagon, and somatostatin, were expressed. There was a stepwise increase in insulin and c-peptide release in response to glucose challenge, but the released amounts were low when compared with those of pancreatic islets. Conclusion. The yield of functional IPCs following directed differentiation of HBM-MSCs was modest and was comparable among the three tested protocols. Protocols for directed differentiation of MSCs need further optimization in order to be clinically meaningful. To this end, addition of an extracellular matrix and/or a suitable template should be attempted.

Effect of Treatment of Anaemia with Erythropoietin on Neuromuscular Function in Patients on Long Term Haemodialysis

To study the effect of treatment of anaemia with recombinant human erythropoietin (r-HUEPO) on neuromuscular function in patients undergoing haemodialysis for chronic renal failure, six patients were given r-HUEPO in an initial dose of 50 u/kg three times a week and their haemoglobin concentration was measured. The dose was increased by 25 u/kg every four weeks if the response was not satisfactory. In five patients anaemia had been corrected within 12 weeks of initiation of treatment. Neuromuscular function was evaluated before treatment, half way through, and after correction of anaemia by clinical examination and neurophysiological studies including motor nerve conduction velocity, distal latency, electromyography and test for neuromuscular fatigue. After correction of anaemia there was a significant increase in motor nerve conduction velocity, a decrease in the duration of motor unit action potential, and a lessening of neuromuscular fatigue. We conclude that treatment of anaemia with r-HUEPO in patients with chronic renal failure undergoing haemodialysis may improve neuromuscular function.

Kimura disease: a case report and review of the literature with a new management protocol.

Kimura disease (KD) is a chronic inflammatory disorder with angiolymphatic proliferation, usually affecting young men of Asian race but is rare in other races. The etiology of KD is still unknown. It is often accompanied by nephrotic syndrome. Herein, we present an atypical manifestation of Kimura disease occurring in a Caucasian man with steroid-responsive early membranous glomerulonephritis. Kimura disease can present atypically in a middle-aged Caucasian man with secondary steroid-responsive nephrotic syndrome. Steroid, endoxan, and MMF can be used safely and successfully in such situation. The diagnosis of KD can be difficult and misleading, and patients with this disease are often evaluated using avoidable procedures by just not being aware of KD.

Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells into Insulin-Producing Cells: Evidence for Further Maturation In Vivo

The aim of this study was to provide evidence for further in vivo maturation of insulin-producing cells (IPCs) derived from human bone marrow-derived mesenchymal stem cells (HBM-MSCs). HBM-MSCs were obtained from three insulin-dependent type 2 diabetic volunteers. Following expansion, cells were differentiated according to a trichostatin-A/GLP protocol. One million cells were transplanted under the renal capsule of 29 diabetic nude mice. Blood glucose, serum human insulin and c-peptide levels, and glucose tolerance curves were determined. Mice were euthanized 1, 2, 4, or 12 weeks after transplantation. IPC-bearing kidneys were immunolabeled, number of IPCs was counted, and expression of relevant genes was determined. At the end of in vitro differentiation, all pancreatic endocrine genes were expressed, albeit at very low values. The percentage of IPCs among transplanted cells was small (≤3%). Diabetic animals became euglycemic 8 ± 3 days after transplantation. Thereafter, the percentage of IPCs reached a mean of ~18% at 4 weeks. Relative gene expression of insulin, glucagon, and somatostatin showed a parallel increase. The ability of the transplanted cells to induce euglycemia was due to their further maturation in the favorable in vivo microenvironment. Elucidation of the exact mechanism(s) involved requires further investigation.

Is matching for human leukocyte antigen-DR beneficial in pediatric kidney transplantation?

This Practice Point commentary discusses the findings and limitations of a report by Gritsch et al., in which the authors concluded that human leukocyte antigen (HLA)-DR-mismatched kidneys from deceased donors aged 35 years or less are suitable for use in pediatric patients. We highlight the issues to be considered before adopting such an allocation policy. Gritsch et al. reported that the 5-year survival rates of grafts with zero HLA-DR mismatches were identical to those of grafts that were completely mismatched for HLA-DR; however, the report did not provide information about the immunosuppressive regimens used or the frequency of rejection episodes and their treatment. Children who receive HLA-DR-mismatched kidneys will ultimately be exposed to more-intensive immunosuppression in order to overcome the potentially increased risks of acute rejection, graft failure and sensitization. In spite of recent improvements in immunosuppressive therapy, we believe that HLA matching remains crucial for the survival of kidney transplants.

Sirolimus for visceral and cutaneous Kaposi's sarcoma in a renal-transplant recipient

The incidence of Kaposis sarcoma among recipients of solid organs is about 500 times the rate in the general population, suggesting a role for immunosuppression in its development. On the basis of these findings, we investigated the impact of sirolimus on cutaneous and disseminated visceral Kaposis sarcoma in a renal-transplant recipient. The introduction of sirolimus in this patient allowed complete regression of Kaposis sarcoma (cutaneous and visceral) with preservation of excellent renal function. Meanwhile, in view of the available observational reports, we think that sirolimus should be included in the standard treatment for Kaposis sarcoma after transplantation, to permit remission of the sarcoma (both cutaneous and visceral) while preserving the renal function.