Immunosuppressed Renal Transplant Research Articles

Co-infusion of donor adipose tissue-derived mesenchymal and hematopoietic stem cells helps safe minimization of immunosuppression in renal transplantation – single center experience

Background: Stem cell therapy (SCT) is used for immunosuppression minimization in renal transplantation (RT). We carried out a prospective study to evaluate the benefits of co-infusion of donor adipose-derived mesenchymal stem cells (AD-MSC) + hematopoietic stem cells (HSC) in living donor RT (LDRT) under non-myeloablative conditioning. Methods: In a demographically balanced three-armed LDRT trial with 95 patients in each arm, group-1 received portal co-infusion of AD-MSC + HSC, group-2 received HSC and group-3 received no SCT. Lymphoid irradiation and anti-thyroglobulin were used for conditioning. Results: SCT was safe. At 1 and 5 years post-transplant, patient survival was 100% and 94.7% in group-1, 100% and 95.7% in group-2, and 94.7% and 84% in group-3, death-censored graft survival was 100% and 94.6% in group-1, 100% and 91.3% in group-2, and 98.9% and 94.4% in group-3 with mean serum creatinine (mg/dL) of 1.38 and 1.39 in group-1, 1.48 and 1.51 in group-2, and 1.29 and 1.42 and in group-3. Rejection episodes and immunosuppression requirement were lesser in SCT groups versus controls with best results noted in group-1. Conclusion: Coinfusion of donor AD-MSC +HSC in portal circulation pre-transplant under non-myeloablative conditioning is safe and effective for immunosuppression minimization in LDRT.

Aneurysmal Degeneration of the Inflow Artery after Arteriovenous Access for Hemodialysis

After arteriovenous fistula creation, the arterial flow increase can lead to aneurysmal degeneration, even increased after fistula ligation or renal transplant immunosuppression. The aim of this study is to describe the therapeutic options and outcomes of true aneurysms of the inflow artery after arteriovenous fistula for hemodialysis. Prospectively collected data of patients with true aneurysmal degeneration of the inflow artery after fistula creation (excluding pseudoaneuryms, anastomotic or infected aneurysms, or surgical complications), surgically repaired between January 2010 and February 2014 (cohort study) have been included. Patient demographics and access characteristics, symptoms, treatment, and follow-up have been reviewed. 12 patients (75% men, median age 63 years) were treated for aneurysmal degeneration of the axillary (1), brachial (6), or radial (5) artery. They had had a previous distal arteriovenous fistula (7 radiocephalic, 3 brachiocephalic, 2 brachiobasilic) created 15.6 years before (range 9.9-28.5) and the majority of them were currently ligated or thrombosed. Most patients were symptomatic (pain [6], distal embolization [1]). They were treated by means of a bypass (using the cephalic [3], basilic [4], or saphenous vein [2]), direct ligature (2), or excision with end-to-end reconstruction (1). No major complications or ischemic symptoms occurred before discharge. After a median follow-up of 8.6 months (3.1-36.5), one patient needed re-operation for new proximal brachial aneurysmal degeneration, and another presented with an asymptomatic post-traumatic thrombosis of the proximal axillary artery and brachial bypass. No other complications, bypass dilatation or ischemic symptoms occurred during follow-up. Inflow artery aneurysmal degeneration can occur after long-term arteriovenous access. Surgical treatment by autogenous bypass exclusion in most cases (or ligation or end-to-end reconstructions in selected cases) is a safe and effective option.

Mixed Chimerism: Good News or Bad News?

Mixed Chimerism: Good News or Bad News?

Alemtuzumab Induction in Renal Transplantation Permits Safe Steroid Avoidance with Tacrolimus Monotherapy

The use of alemtuzumab as induction immunosuppression for renal transplantation introduces the possibility of long-term tacrolimus monotherapy, avoiding maintenance with both corticosteroids and mycophenolate mofetil (MMF). We conducted a single-center, prospective, open-label, randomized controlled trial comparing two steroid avoidance regimens between December 2006 and November 2010. One hundred and sixteen adult patients were randomized to either basiliximab induction followed by tacrolimus and MMF maintenance or to alemtuzumab induction followed by tacrolimus monotherapy. The primary endpoint was noninferiority of isotopic glomerular filtration rate at 1 year; secondary endpoints included patient and graft survival, incidence of delayed graft function, and incidence and severity of biopsy-proven acute rejection. The two groups were well matched for all baseline demographics. Isotopic glomerular filtration rate was comparable between the groups at 1 year (57±26 mL/min for alemtuzumab group and 53±21 mL/min for basiliximab group; P=0.42). Secondary endpoints were also similar between the groups. The rate of biopsy-proven acute rejection by 12 months was lower in the alemtuzumab group (n=6 vs. n=14 in basiliximab arm) just reaching statistical significance (P=0.049); however, a single extra case in the alemtuzumab arm included when considering clinically treated rejection removes this significance (P=0.082). Similar rates of cardiovascular, infective, and neoplastic complications were observed in both groups. Forty-seven (81.0%) of the patients in the alemtuzumab group remained on tacrolimus monotherapy at 12 months. Renal transplantation with alemtuzumab induction followed by tacrolimus monotherapy leads to good graft and patient outcomes, with no major differences detected compared with basiliximab induction and tacrolimus/MMF maintenance at 1 year.

Effect of Cyclosporine on the Relevant Biochemical Parameters in Renal Transplantation Patients in Mosul/Iraq

Cyclosporine (sandimmune) is the backbone of immunosuppression in renal transplantation. However, it leads to multiple side effects, most of which are dose-dependent. In this respect, the quality of renal functions is undoubtedly linked to cyclosporine drug levels. Blood sample from 44 kidney-transplant recipients and 28 healthy control were collected, then serum Urea, Creatinine, Sodium (Na+), Potassium(K+), Cholesterol, Triglyceride, HDL-c, LDL-c, VLDL-c, Glutathione GSH and Malondialdehyde MDA were estimated. The current study showed that serum Cholesterol, TG, HDL-c, LDL-c and VLDL-c were significantly increased in renal transplantation patients comparing with the control group, The result also has been revealed that GSH concentration was decreased in renal recipient patients while MDA was increased renal recipient patients as comparing with the control group. On other hand Cholesterol, Triglyceride, HDL-c, LDL-c, VLDL-c, and MDA exhibited a weak correlation with dose of cyclosporine while GSH exhibibted reciprocal correlation with CsA dose.

Long‐term experience of steroid‐free pediatric renal transplantation: Effects on graft function, body mass index, and longitudinal growth

Increased focus on the potential negative side effects of steroid usage in pediatric transplantation has led to steroid minimization or steroid-free transplantation. In this study, we report results after complete steroid avoidance in renal transplantation in the period 1994-2009. We evaluate the effects of complete steroid avoidance on allograft function, BMI, and linear growth. The majority of transplanted children were induced with antithymocyte globulin and immunosuppressed with a calcineurin inhibitor and mycophenolate mofetil. Steroids were given only when rejection occurred or due to comorbidities. Anthropometric data were collected from 65 transplantations in 60 children. Patient survival was 93%; graft survival was 81% after five yr (N = 42) and 63% after 10 yr (N = 16). Acute rejection within the first year of transplantation was 9%. The distribution of the children's BMI before transplantation was normal; the mean BMI-SDS was 0.21 before transplantation, and this value remained stable during the next five yr. Post-transplantation the children demonstrated significant improved growth as the mean height-SDS increased significantly from -1.7 to -1.1. Catch-up growth was most pronounced in the youngest (< six yr). Steroid-free immunosuppression in pediatric renal transplantation is safe and protects against steroid-induced obesity and short stature.

Immunosuppression in Renal Transplantation and Dyslipidemia, Which Factors Should Be Considered?

Dear Editor, Secondary dyslipidemia is the most common form of lipid metabolism derangement, due to the fact that primitive dyslipidemia represent only 0.5-2% of cases (1). Transplantation is a common cause of dyslipidemia, it has been shown that it defines metabolic syndrome, a common finding in renal transplant recipients (RTR) (2), and statins are within the top 15 drugs used by these patients (3). Moreover the increasing prescription of statins in this population is related to the frequent screening for dyslipidemia in transplanted patients (3). Immunosuppression could cause hypercholesterolemia and Cyclosporine (CsA) is widely used as immunosuppressive drug even if in the recent years physicians prescribe more frequently Tacrolimus than CsA (3). Moreover renal function in RTR is reduced and in many causes they are long-term treated with steroids. An additional risk factor for dyslipidemia should be taken into account in RTR such as chronic kidney disease, a condition in which triglycerides are increased and HDL-cholesterol is reduced. The main causes of these alterations are increased plasma levels of VLDL, IDL, LDL, Lp(a) and reduced activity of hepatic triglyceride lipase and peripheral lipoprotein lipase (4). Hypercholesterolemia secondary to steroids is due to hyperinsulinemia and peripheral insulin resistance increases hepatic synthesis of VLDL, moreover steroids reduce the release of ACTH with up-regulation of LDL-cholesterol hepatic receptors (5). On the contrary, the mechanism responsible for hypercholesterolemia during CsA treatment is still a matter of debate. CsA is a lipophilic drug and is carried by HDL and LDL cholesterol; it has been suggested that the drug impairs hepatic clearance of LDL (6). Moreover hepatic sterol regulatory element binding protein-2 is activated leading to increased VLDL synthesis, and secretion of bile and bile salts is impaired causing reduced cholesterol elimination (7). Hosseini et al. (8) study evaluated the relationship between CsA and dyslipidemia in RTR; they showed that plasma levels of cholesterol and triglycerides started increasing 4-12 months after beginning of immunosuppressive therapy, while subsequently HDL-cholesterol decreased and LDL-cholesterol increased. Logistic regression analysis showed that female gender and serum creatinine were the major risk factors for hypercholesterolemia and hypertriglyceridemia; on the contrary, CsA was not related to them. Similar results were shown by Laufer et al. (9) in heart transplant recipients. In their study the main risk factors were the history of cardiac disease leading to transplantation and steroids therapy. Hricik et al. (10) evaluated RTR and showed that reduction of steroid’s dose caused decreasing total plasma cholesterol levels. Cardiovascular disease is a major problem in RTR due to its relationship with morbidity and mortality and graft loss. Statins seem to have a protective effect in RTR, especially on risk of major cardiac events and they need to be considered during patients follow-up (4).

Association of Donor and Recipient Calcineurin Inhibitor Pharmacogenomic Variation with Long-Term Allograft Survival

Introduction: Calcineurin inhibitors (CNI) remain a cornerstone of renal transplantation immunosuppression. Whilst monitoring of blood CNI levels have been the traditional tool for adjusting CNI administration, it is clear that this is an imperfect strategy. Although data is conflicting, there is evidence that single nucleotide polymorphisms (SNPs) within genes involved in ciclosporin metabolism and transport are associated with ciclosporin pharmacokinetics. Less data is available in regard to polymorphisms of the donor, although small studies suggest an association between genetic variation in the ABCB1 gene and “acute ciclosporin nephrotoxicity” and allograft failure. Both focussed on the C3435T polymorphism within ABCB1, an exonic SNP for which the TT genotype is associated with reduced P-gp expression. The purpose of this study was to further assess the relationship of both donor and recipient genotype with the hard outcomes of allograft survival and mortality. Methods: Positive findings from an initial study cohort were examined in two further independent populations, in a study incorporating a total of 6169 transplant recipients and their respective donors followed for a period of up to 20 years. The initial cohort consisted of 811 Caucasian transplant donors and their respective recipients transplanted at he Queen Elizabeth Hospital Birmingham between 1996 and 2006, for which genomic DNA was available. All patients received ciclosporin and corticosteroids as primary immunosuppression, with 23% receiving mycophenolate (77% azathioprine). A comprehensive survey of sequence variation in the target genes was assessed using a “gene tagging” approach based on data from the Hapmap Project, as well as specifically investigating previously identified relevant polymorphisms. Genes studied were: CyP3A4, CyP3A5, ABCB1 (MDR1), PXR, Cyclophilin. Results: Kaplan-Meier analysis revealed that the donor ABCB1 genotype at C3435T was associated with death-censored allograft failure. Inferior outcomes were seen for kidneys from donors expressing the CC genotype. This difference persisted in a Cox proportional hazards model (donor CC versus non-CC genotype: Hazard Ratio [HR]: 1.69; 95%CI: 1.20, 2.40; p=0.003), adjusted for the following: donor age, gender, source (living versus deceased), serum creatinine, hypertension history; recipient age, race, duration of dialysis, cause of renal failure, transplant number, panel reactive anti-HLA antibodies; donor-recipient HLA mismatch. This association between donor ABCB1 genotype at C3435T was next examined in the 2 replication cohorts, the first consisting of 697 patients transplanted in Belfast, and the second consisting of 4656 recipients reported to the Collaborative Transplant Study. In neither of these cohorts was there evidence of an association between donor genotype and death-censored graft failure. No association between any other gene variants (donor or recipient) and either death-censored graft survival or mortality were seen in the Birmingham cohort, and so no attempt was made to replicate these analyses in the other cohorts. Conclusion: This study does not support the concept that either donor or recipient variation at genes relevant for CNI metabolism and transport influences the hard outcomes of kidney transplantation, and reaffirms the importance of replication cohorts prior to assigning relevance to such genetic biomarkers.

Conversion From Tacrolimus/Mycophenolic Acid to Tacrolimus/Leflunomide to Treat Cutaneous Warts in a Series of Four Pediatric Renal Allograft Recipients

The challenge of immunosuppression in pediatric renal transplantation is to balance preventing rejection while avoiding infectious complications. A dermatological complication of immunosuppression is viral warts, which cause significant disfigurement and increase the risk of skin malignancy. We present three pediatric and adolescent renal allograft recipients with multiple, recalcitrant verrucae vulgares lesions and one patient with molluscum contagiosum who were switched from mycophenolate mofetil to leflunomide. Teriflunomide metabolite levels were carefully maintained between 50,000 and 100,000 ng/mL to balance its immunosuppressive and antiviral properties. No adverse events requiring discontinuation of leflunomide were encountered. Switching from mycophenolate mofetil to leflunomide successfully cleared verrucae vulgares and molluscum lesions in all four renal transplant patients. The ability to minimize and even resolve warts can improve quality of life by reducing risk of skin malignancies and emotional distress in solid organ transplant patients. Leflunomide is a potential therapeutic option for posttransplantation patients with skin warts because it serves both as an adjunct to the immunosuppressive regimen and an antiviral agent.

Case of mucosal lentiginous melanoma in situ on the upper lip with a long radial growth phase

Dear Editor, Melanoma of the oral mucosa is a rare condition and lip melanoma is even rarer. Lip melanoma has been reported to behave aggressively and to be usually encountered at an advanced stage at diagnosis. However, in-depth understanding of lip melanoma is limited due to extreme rarity. Therefore, the disease is commonly misdiagnosed and patients with an initial misdiagnosis are more likely to die. Herein, we report a case of mucosal lentiginous melanoma of the upper lip over the long term. A 72-year-old Korean male presented with a pigmented patch on the upper lip in July 2009. He recalled that the 1-cm pigmented macule had been on his upper lip for 10 years and had gradually increased in size. He received renal transplantation and subsequent immunosuppression in 2006 and the lesion had abruptly grown in size. Physical examination revealed a 5.2 cm · 4.7 cm asymmetrical pigmented patch with an irregular border and color variegation located on the inner labial mucosa, the cutaneous side of the upper lip, and perioral skin (Fig. 1). The gingiva and maxilla were spared. No lymph node enlargement was detected. He was taking medica-

Infections: The Achilles Heel of Immunosuppression for Renal Transplantation and Immunological Renal Disease Management in the Top End of Northern Australia: Case Reports

Improved immunosuppression regimens have led to better survival for patients with renal transplant grafts and patients with immunological renal diseases worldwide. However, this is not the case in the Northern Territory of Australia. Available limited published data from the Northern Territory of Australia have shown poor outcomes for renal transplantation with survival for both patients and grafts around 50% at 5 years suggesting death with a functioning graft as the commonest cause of graft loss. These studies have shown that the leading cause of death is infections. Achieving the right level of immunosuppression to prevent rejection in renal transplantation and achieve remission in immunological renal diseases can be a major challenge in areas with high prevalence of infections such as the Northern Territory. We present 2 cases of the challenges from infections of immunosuppression in renal transplantation and immunological renal diseases in the Northern Territory of Australia. A 57 year old Aboriginal woman received a deceased donor renal transplant in 2006. She has been plagued by recurrence of several life threatening infections including urinary tract, cytomegalovirus, and severe cryptococcocus infections. This resulted in immunosuppression reduction and failure of the transplant 5 years post transplantation. A 20 year old Aboriginal woman presented with a combination of severe lupus nephritis and severe sepsis. She fully recovered after treatment with antibiotics and careful immunosuppression. However, she has had recurrent hospital admissions with life threatening infections resulting in stopping the immunosuppression. She then had severe lupus nephritis flare leading to dialysis dependence and will need a renal transplant. The cases illustrate the need for tailored and robust immunosuppression and transplant work up protocols. To that effect, prospective studies to analyse outcomes in immunosuppressed individuals, pharmacokinetic studies assessing whether the conventionally recommended drug levels are appropriate for this population and culturally appropriate educational programmes need to be performed.

Potent Immunosuppression for ABO-Incompatible Renal Transplantation May Not Be a Risk Factor for Malignancy

ABO-incompatible (ABOi) renal transplantation has been increasing, but malignant tumor is a troubling complication of kidney transplantation due to potent immunosuppression. Few previous studies, however, have demonstrated that potent immunosuppression for ABOi living-donor renal transplantation (LDRT) is a risk factor for malignancy. In the present research, data on 252 LDRT patients ftom 2003 to 2008 were retrospectively analyzed to clarify whether ABOi LDRT was associated with malignancy. A potent immunosuppressive regimen for ABOiLDRT consisted of splenectomy, cyclophosphamide, and double-filtration plasmapheresis to minimize the risk of antibody-mediated rejection, in addition to conventional immunosuppresssants including calcineurin inhibitor, prednisolone, and anti-CD25 monoclonal antibody. A total of 11 incidences of malignancy were observed during a median follow-up of 48 months. The incidence rates in ABO-compatible (ABOc; n = 189) and ABOi (n = 63) LDRT groups were 4.2 % (8/189) and 4.8 % (3/63), respectively. Kaplan-Meier survival analysis showed no statistical difference in event-free survival for malignancy between ABOc and ABOiLDRT groups (log-rank P = .73). Multivariable Cox regression analyses identified no associations of malignancy with ABOi LDRT or any immunosuppressant use. In conclusion, our investigation suggested that potent immunosuppression with splenectomy and cyclophosphamide for ABOi LDRT may not be a risk fietor for malignancy.

Current state of renal transplant immunosuppression: Present and future.

For kidney transplant recipients, immunosuppression commonly consists of combination treatment with a calcineurin inhibitor, an antiproliferative agent and a corticosteroid. Many medical centers use a sequential immunosuppression regimen where an induction agent, either an anti-thymocyte globulin or interleukin-2 receptor antibody, is given at the time of transplantation to prevent early acute rejection which is then followed by a triple immunosuppressive maintenance regimen. Very low rejection rates have been achieved at many transplant centers using combinations of these agents in a variety of protocols. Yet, a large number of recipients suffer chronic allograft injury and adverse events associated with drug therapy. Regimens designed to limit or eliminate calcineurin inhibitors and/or corticosteroid use are actively being pursued. An ideal immunosuppressive regimen limits toxicity and prolongs the functional life of the graft. This article contains a critical analysis of clinical data on currently available immunosuppressive strategies and an overview of therapeutic moieties in development.

Belatacept: from rational design to clinical application

Gradually improved immunosuppression has contributed significantly to the progress achieved in transplantation medicine so far. Nevertheless, current drug regimens are associated with late graft loss--in particular as a result of immunologic damage or drug toxicity--and substantial morbidity. Recently, the costimulation blocker belatacept (marketed under the name Nulojix®) has been approved for immunosuppression in renal transplantation. Belatacept (a mutated version of CTLA4Ig) is a fusion protein rationally designed to block CD28, a critical activating receptor on T cells, by binding and saturating its ligands B7-1 and B7-2. In phase II and III trials, belatacept was compared with cyclosporine (in combination with basiliximab, MMF, and steroids). Advantages observed with belatacept include superior graft function, preservation of renal structure and improved cardiovascular risk profile. Concerns associated with belatacept are a higher frequency of cellular rejection episodes and more post-transplant lymphoproliferative disorder (PTLD) cases especially in EBV seronegative patients, who should be excluded from belatacept-based regimens. Thus, after almost three decades of calcineurin inhibitors as mainstay of immunosuppression, belatacept offers a potential alternative. In this article, we will provide an overview of belatacept's preclinical development and will discuss the available evidence from clinical trials.

Clinical application of mTORi based immunosuppression for renal transplantation in India

Long-term renal graft survival is hampered by allograft dysfunction and cardiovascular disease resulting from calcineurin inhibitors (CNIs). This has led to the development of immunosuppressive regimens involving mammalian target of rapamaycin (mTOR) inhibitors, sirolimus and everolimus. They seem to provide long-term benefits for kidney function in transplant patients because of their anti-proliferation and anti-tumor properties and absence of nephrotoxicity. Their use has been evaluated in therapeutic regimens aimed at reducing the nephrotoxicity associated with CNIs. Both proactive and reactive strategies have been used. Whether existing strategies of using mTORi in renal transplantation is applicable for Indian patient's remains to be seen. Data on side effect profile, economic viability and the impact of these drugs on infections, particularly in India, are worth documenting. After briefly reviewing available data from India, this article explores the indications, patient populations; timing and practical aspects as well as the safety and efficacy of mTORi-based regimens for renal transplantation and suggests a framework which could allow transplant physicians to tailor its use to their own practice with particular reference to the Indian subcontinent.

Single shot of alemtuzumab as induction therapy after kidney transplantation is sufficient

In an earlier study, we were able to show that Tac monotherapy following 2 × 20 mg alemtuzumab induction is at least as effective as Tac-based triple-drug immunosuppression in cadaveric renal transplantation. We were interested to learn whether 1 × 30 mg of alemtuzumab is as effective as 2 × 20 mg. Patients of the initial study group (group A) received 20 mg alemtuzumab on days 0 and 2, and tac monotherapy from day 2 on. This group acted as control group for the new arm (group C), where patients were given only 1 × 30 mg alemtuzumab on day 0 followed by Tac monotherapy from day 2 on with the same target levels as in the control group. Frequency of rejection at 6 months was 15% in the control group compared to 6% in the study group and 20% at 12 months in group A versus 6% in group C (P = 0.034). Time to rejection was 4.9 months in group A and 0.8 in group C. One-year patient survival was 98.5% in both groups, graft survival 96.9% in group A, and 98.5% in group C. Safety profile was similar in both groups apart from more viral and bacterial infections in group C. Single shot alemtuzumab induction of 30 mg is as effective as 2 × 20 mg in cadaveric renal transplantation.

Induction of tolerance to parental parathyroid grafts using allogeneic thymus tissue in patients with DiGeorge anomaly

DiGeorge anomaly can affect both thymic and parathyroid function. Although athymia is corrected by allogeneic thymus transplantation, treatment options for hypoparathyroidism have been unsatisfactory. Parathyroid transplantation offers the potential for definitive cure but remains challenging because of graft rejection. Some allogeneic parathyroid grafts have functioned in adult recipients in the context of immunosuppression for renal transplantation. Other efforts have attempted to reduce the allogenicity of the parathyroid grafts through manipulation of the parathyroid tissues before transplantation (by using encapsulation or special culture techniques). Recently, we demonstrated the efficacy of parental parathyroid transplantation when combined with allogeneic thymus transplantation in an infant with complete DiGeorge anomaly. The recipient developed tolerance toward the parathyroid donor. The parathyroid graft has functioned for 5 years after transplantation without the need for continued immunosuppression or calcium supplementation. We observed that matching of the allogeneic thymus graft to the parathyroid donor HLA class II alleles that are unshared with the recipient appears to be associated with the induction of tolerance toward the parathyroid graft. Further work is needed to determine the optimal means for using combined allogeneic thymus and parental parathyroid transplantation to correct hypoparathyroidism in patients with both complete and partial DiGeorge anomaly.

Management of HCV infection in chronic kidney disease.

The prevalence of chronic infection with the hepatitis C virus (HCV) in patients with chronic kidney disease is higher than in the general population. The estimated prevalence is 13% in haemodialysis, with wide variations geographically and between units in the same country. A liver biopsy is a useful tool for deciding whether to start antiviral therapy and to exclude concomitant causes of liver dysfunction. Examples of this include non-alcoholic fatty liver disease, whose incidence is on the rise, and haemosiderosis, which may affect the progression of the disease and determine the response to antiviral therapy. In addition, the transjugular approach can be used to measure the hepatic venous pressure gradient and confirm the existence of portal hypertension. Chronic hepatitis due to HCV has been shown to reduce survival in haemodialysis, renal transplantation and graft survival. It is the fourth leading cause of death and the leading cause of post-renal transplantation liver dysfunction. HCV behaves as an independent risk factor for the occurrence of proteinuria; it increases the risk of developing diabetes mellitus, de novo glomerulonephritis and chronic allograft nephropathy; it leads to a deterioration in liver disease and causes a greater number of infections. An increased frequency of fibrosing cholestatic hepatitis has also been described which, together with the rapid evolution to cirrhosis, can significantly increase morbidity and mortality and lead to the need for liver transplantation. In addition, immunosuppression in renal transplantation predisposes a reactivation of HCV. However, as the pharmacokinetics of interferon and ribavirin is impaired in kidney failure and their use has adverse effects on function and graft survival, a combination therapy must be limited to non-transplanted individuals with an estimated glomerular filtration rate greater than 50ml/min, and with the interferon being used as monotherapy in dialysis. The fact that a quarter of HCV-positive patients evaluated for a renal transplant have bridging fibrosis or cirrhosis in the liver biopsy may renew renal pre-transplant treatment planning.

Comparison of Basiliximab and Daclizumab With Triple Immunosuppression in Renal Transplantation

Purpose Graft rejection is a serious problem despite immunosuppressive agents. Immunosuppression has been achieved with monoclonal antibodies (mAb) that bind specifically to the α subunit of the interleukin (IL)-2 receptor present on activated T lymphocytes. We explored the effects of two of the mAbs–daclizumab and basiliximab–on graft function. Materials and methods Our 1543 renal transplant recipients received baseline therapy with cyclosporine or tacrolimus plus corticosteroids and mycophenolate mofetil. In addition standard dosages intravenously of daclizumab ( n = 156) or basiliximab ( n = 45) in were administered intravenously to 201 renal transplant patients who included 122 men and 79 women of overall mean age of 30 ± 13.7 years. Results Patient and donor characteristics including age, sex, causes of renal failure, presence of comorbidities, panel-reactive antibodies, and numbers of human leukocyte antigen–mismatched were similar between the groups. During a mean follow-up of 27 ± 20 months, biopsy-proven acute rejection was observed in three patients in the basiliximab group and 23 in the daclizumab group. Cytomegalovirus infection occurred in 13 patients. There was no case of posttransplant lymphoproliferative disorder. Three polyoma BK nephropathies were detected in the daclizumab group. No hypersensitivity reaction occurred in either group. One-year patient survival was 100% in the basiliximab group and 99% in the daclizumab group, with graft survivals of 95% versus 94%, respectively. The mean creatinine levels at discharge were 2 mg/dL versus 2.3 mg/dL and at 12 months, 1.3 mg/dL versus 1.2 mg/dL, respectively. Conclusions Acute rejection episodes remain a significant risk factor for the development of graft dysfunction and poor long-term graft survival. IL-2R antagonists were effective antibody therapies. There was no apparent difference between basiliximab and daclizumab treatment.

Five‐year experience using sirolimus‐based, calcineurin inhibitor‐free immunosuppression in pediatric renal transplantation

From December 2003 to December 2008, we employed a protocol for withdrawing TAC and converting to SRL in a cohort of low-risk renal pediatric transplant recipients. We report our experience in these children with respect to graft survival, AR episodes, renal function, and adverse events. All patients received basiliximab induction and TAC, MMF, and prednisone. Criteria for conversion to SRL included first transplants without histologic evidence for AR on three-month surveillance biopsies. Patient exclusion criteria included AR prior to or before surveillance biopsies, polyoma (BK) virus nephropathy, a history of nephrotic syndrome, or multiple organ transplants. Fifty-one of 137 patients who received transplants from December 2003 to December 2008 met criteria for withdrawal of TAC and were converted to SRL. SRL was discontinued in 11 children because of adverse events within 12 months after conversion. Among the remaining 40 patients, actuarial graft survival was 91% at five yr. AR occurred in 13% of patients within one yr after conversion. Complications from SRL included aphthous ulcers (30%); viremia with BK virus (20%), EBV (13%), and CMV (3%); proteinuria (7%); elevated cholesterol (7%); diabetes mellitus (2%); thrombocytopenia (2%); erectile dysfunction (2%); and lymph edema (2%). SRL was discontinued in 20%, predominantly for aphthous ulcers. Our experience with SRL-based immunosuppression demonstrates that a CNI-free regimen can be successful in lower-risk patients meeting our selection criteria. Aphthous ulcers and BK virus viremia were the most prevalent adverse events.