Induction Therapy for Kidney Transplant Recipients: Do We Still Need Anti-IL2 Receptor Monoclonal Antibodies?

Induction therapy with antilymphocyte biological agents is widely used after kidney transplantation, most commonly T lymphocyte-depleting rabbit-derived antithymocyte globulin (rATG) or an IL-2 receptor antagonist (IL2RA). Early randomized trials showed that rATG or IL2RA induction reduces early acute rejection, prompting recommendations by Kidney Disease Improving Global Outcomes that IL2RA induction be used routinely in first-line therapy after kidney transplantation, with lymphocyte-depleting induction reserved for high-risk cases. These studies, however, mainly used outdated maintenance regimens. No large randomized trial has examined the effect of IL2RA or rATG induction versus no induction in patients receiving tacrolimus, mycophenolic acid and steroids. With this triple maintenance therapy, the addition of induction may achieve an absolute risk reduction for acute rejection of only 1-4% in standard-risk patients without improving graft or patient survival. In contrast, rATG induction lowers the relative risk of acute rejection by almost 50% versus IL2RA in patients with high immunological risk. These recent data raise questions about the need for IL2RA in kidney transplantation, as it may no longer be beneficial in standard-risk transplantation and may be inferior to rATG in high-risk situations. Updated evidence-based guidelines are necessary to support clinicians deciding whether and what induction therapy is required for their transplant patients today.

Single-Center Case Series of Donor-Related Malignancies: Rare Cases With Tremendous Impact.

BACKGROUND: Donor-related malignancy is a rare complication of organ transplantation. METHODS: In this case series, we discuss three cases of donor-related cancers in kidney transplant recipients who were registered in our center between 1979 and 2015. They account for an incidence of 0.29% of donor-related malignancies of a total of 1015 transplanted kidney grafts (deceased and living donors). The three cases that we describe presented in different ways and with different severity, although the response to the initiated treatment was comparable. RESULTS: All three patients not only survived their cancer episode but also had a complete oncological remission and underwent successful second kidney transplantation, accounting for a 100% survival rate in our small cohort. CONCLUSIONS: Despite the very low incidence of this complication, transplant clinicians must be aware of the occurrence of donor-related malignancies when selecting a donor and should be able to diagnose and treat a case of donor-related cancer.

Cell-Free DNA: An Upcoming Biomarker in Transplantation.

After organ transplantation, donor-derived cell-free DNA (ddcfDNA) can be detected in the recipient's blood and urine. Different ddcfDNA quantification techniques have been investigated but a major breakthrough was made with the introduction of digital droplet PCR and massive parallel sequencing creating the opportunity to increase the understanding of ddcfDNA kinetics after transplantation. The observations of increased levels of ddcfDNA during acute rejection and even weeks to months before histologic features of graft rejection point to a possible role of ddcfDNA as an early, noninvasive rejection marker. In this review, we summarize published research on ddcfDNA in the transplantation field thereby elaborating on its clinical utility.

Cost analysis in favor of a combined approach for cytomegalovirus after kidney transplantation: a single-center experience.

BACKGROUND: In kidney transplant recipients, cytomegalovirus (CMV) can cause significant morbidity, mortality, and costs, which can be prevented by universal antiviral prophylaxis or preemptive therapy. METHODS: With the aim to improve our understanding of the advantages and disadvantages of these interventions, we documented resource use for 101 consecutive kidney transplant recipients in our center receiving preemptive therapy and estimated resource use for 2 alternative scenarios. RESULTS: At 100 days after transplantation, the mean total costs of our preemptive strategy including monitoring and treatment with intravenous ganciclovir was €2545 per patient. At €4853 per patient, these costs were highest for the CMV-positive donor/CMV-negative recipient (D+/R-) patient subgroup (n = 28), who frequently require recurrent treatment. A treatment scenario with valganciclovir prophylaxis for D+/R- and R+ patients, in which we ignored late-onset disease after discontinuation of prophylaxis, resulted in an estimated cost of €1892 per patient. A combined approach using valganciclovir prophylaxis in the D+/R- group and a preemptive strategy in the R+ groups would result in the lowest mean and median costs per patient (€1701). CONCLUSION: Our study suggests that a combined approach, using valganciclovir prophylaxis in D+/R- patients and preemptive treatment in R+ patients, may result in the lowest cost. This approach seems reasonable as it restricts expensive prophylactic drug therapy to those who would benefit the most, whereas it limits the risk for drug toxicity and late-onset disease in those at lower risk for CMV.

Organ procurement after euthanasia: Belgian experience.

Euthanasia was legalized in Belgium in 2002 for adults under strict conditions. The patient must be in a medically futile condition and of constant and unbearable physical or mental suffering that cannot be alleviated, resulting from a serious and incurable disorder caused by illness or accident. Between 2005 and 2007, 4 patients (3 in Antwerp and 1 in Liège) expressed their will for organ donation after their request for euthanasia was granted. Patients were aged 43 to 50 years and had a debilitating neurologic disease, either after severe cerebrovascular accident or primary progressive multiple sclerosis. Ethical boards requested complete written scenario with informed consent of donor and relatives, clear separation between euthanasia and organ procurement procedure, and all procedures to be performed by senior staff members and nursing staff on a voluntary basis. The euthanasia procedure was performed by three independent physicians in the operating room. After clinical diagnosis of cardiac death, organ procurement was performed by femoral vessel cannulation or quick laparotomy. In 2 patients, the liver, both kidneys, and pancreatic islets (one case) were procured and transplanted; in the other 2 patients, there was additional lung procurement and transplantation. Transplant centers were informed of the nature of the case and the elements of organ procurement. There was primary function of all organs. The involved physicians and transplant teams had the well-discussed opinion that this strong request for organ donation after euthanasia could not be waived. A clear separation between the euthanasia request, the euthanasia procedure, and the organ procurement procedure is necessary.

Simultaneous kidney-parathyroid allotransplantation from a single donor after 20 years of tetany: a case report.

Persistent hypocalcemia after total parathyroidectomy and autotransplantation is rare and occasionally has been treated using allotransplantation of parathyroid tissue. We present the case of a 32-year-old woman with terminal renal failure who at age 5 years underwent a first renal transplantation from a brain-dead donor. The graft was lost as a result of acute rejection. Tertiary hypoparathyroidism developed, which was treated with total parathyroidectomy and implantation in the forearm of a standardized amount of parathyroid tissue. The graft failed, and hypoparathyroidism developed. Despite a second implantation of cryopreserved autologous tissue, severe hypocalcemia persisted with a tendency for tetany. Although the patient was highly dependent on high-dose vitamin D(3) (tacalcitol) and calcium supplements, regular paresthesias and tetany developed. At age 9 years, the patient underwent a second renal transplant from a living related donor (her mother). After 18 years, the graft was lost as a result of chronic cyclosporine toxicity and angiosclerosis. Four years later, the patient underwent combined kidney and parathyroid transplantation from a local brain-dead donor. Preservation of the parathyroid glands was in University of Wisconsin solution, with cold ischemia time of 14 hours. Directly after the renal transplantation, parathyroid transplantation was performed, with implantation in the forearm of the total amount of donor parathyroid tissue. Postoperatively, there was recovery of parathyroid function, and the patient was able to discontinue vitamin D and calcium supplements after more than 20 years.

Malignancy after kidney transplantation: still a challenge.

Long-term complications of continuous immunosuppression still remain a serious threat and are currently drawing the attention of transplant physicians. Wimmer et al. show that malignancy occurs approximately fourfold more frequently in renal-transplant recipients than in a normal control population. Besides immunosuppression, viruses probably play an important oncogenic role in transplant recipients. The retrospective analysis by Wimmer et al. suggests that mTOR inhibitors and interleukin-2 receptor antibodies are promising immunosuppressive drugs to reduce the risk of cancer after transplantation. These preliminary results must be confirmed in large, prospective, randomized, controlled trials, with long follow-up, designed to evaluate the incidence of de novo malignancy in transplant recipients.

Reduced-exposure cyclosporine is safe and efficacious in de novo renal transplant recipients treated with enteric-coated mycophenolic acid and basiliximab.

BACKGROUND: The lower limit of exposure to calcineurin inhibitors has not yet been established in de novo renal transplant patients receiving mycophenolic acid therapy with basiliximab. METHODS: A 12-month, multicenter, randomized, open-label trial was carried out in which de novo renal transplant patients received enteric-coated mycophenolate sodium, cyclosporine microemulsion, steroids and basiliximab. Patients were randomized to receive standard-exposure (n = 45) or reduced-exposure (n = 44) cyclosporine, based on differing C2 target ranges, after the first month post-transplant. RESULTS: Cyclosporine exposure gradually increased over the first month and was lower than previously recommended. Mean calculated creatinine clearance (primary end-point) was similar in the standard-exposure and reduced-exposure groups at month 6 (55.3+/-3.2 ml/min and 61.5+/-3.7 ml/min respectively, n.s.). There were 4 deaths but no death-censored graft losses, resulting in 95.5% patient and graft survival at one year in both groups. At 6 and 12 months, the incidence of biopsy-proven acute rejection was 17.8% and 17.8% in the standard-exposure group, and 13.6% and 15.9% in the reduced-exposure group. Adverse events were similar between treatment groups. Exploratory analyses could not identify a lower limit for the optimal CsA exposure range, but results suggested that high exposure at one year was associated with deteriorating renal function. CONCLUSIONS: These results indicate that enteric-coated mycophenolate sodium with reduced-exposure cyclosporine, steroids and basiliximab induction has an excellent therapeutic effect and is safe in de novo kidney transplant recipients. Lower C2 targets than previously recommended, particularly early post-transplant, do not appear to be associated with compromised efficacy.

Haemodialysis-associated anaphylactic and anaphylactoid reactions.

Anaphylactic and anaphylactoid reactions related to haemodialysis have been increasingly described for almost 3 decades. The majority of these cases used to occur with ethylene oxide sterilized, and complement-activating cellulose membranes. However, a considerable number of publications have focused on polyacrylonitrile AN69 high flux membranes, angiotensin converting enzyme inhibitors and iron as other important causes of potentially severe haemodialysis-related anaphylactoid reactions. Clinical manifestations vary considerably and generally do not allow differentiation between IgE-mediated anaphylaxis and anaphylactoid reactions (e.g. from nonspecific mediator release). Successful management of these patients requires multidisciplinary approach and involves prompt recognition and treatment by the attending physician, and identification of the offending agent(s) with subsequent avoidance of the incriminated compound(s). This review focuses on some major causes of anaphylactoid and anaphylactic reactions during haemodialysis. Special consideration is given to the therapeutic and diagnostic approach.

Blood cyclosporine level soon after kidney transplantation is a major determinant of rejection: insights from the Mycophenolate Steroid-Sparing Trial.

Target organs express antigens directly recognized by antigen-specific T cells, thereby precipitating rejection. When early T-cell activation is inhibited, there is a low risk of rejection. We sought to determine the predictive values of serial posttransplant blood cyclosporine trough (C(0)) concentrations to minimize the risk for a first rejection episode compared with 2-hour postdose (C(2)) drug concentrations. The final aim of the study was to identify a concentration range for the best predictive pharmacokinetic parameter that should be targeted to reduce the risk of rejection. This possibility was explored in 334 de novo kidney transplant recipients who participated in the prospective, multicenter Mycophenolate Steroid-Sparing Trial. Among measurements performed during the first 6 months postsurgery, cyclosporine C(0) levels measured early after transplantation were the strongest predictor of acute graft rejection. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while patients with levels lower than 300 ng/mL showed a more than double risk. Cyclosporine trough values predicted allograft rejection with an accuracy of 74%, while C(2) levels had no predictive value. These findings underline the need to target cyclosporine therapy early posttransplant to modulate T-cell activation.

Renovascular hypertension: diagnostic and therapeutic challenges.

Atherosclerotic renal artery stenosis (ARAS) is associated with two common clinical syndromes: renovascular hypertension and ischemic nephropathy, which often coexist. The ensuing renovascular disease constitutes the fastest-growing etiology of end-stage renal disease. Diagnostic work-up for hemodynamical significant renal artery stenosis should be restricted to patients suspected to be at moderate or high risk for renovascular disease. Patients at moderate risk should first undergo a screening test, like Doppler ultrasonography or captopril-enhanced scintigraphy. In case of a positive screening test, renal artery imaging with either spiral computed tomography angiography or magnetic resonance angiography with Gadolinium is indicated. Patients at high risk for renovascular disease may be directly referred for intra-arterial renal artery angiography, the golden standard diagnostic procedure. A renal artery stenosis with narrowing of > 50-60% of the lumen, is considered hemodynamically significant, and may be suitable for treatment with angioplasty or angioplasty plus stent placement (in case of osteal renal artery stenosis). The therapeutic approach of the hypertensive patient with a hemodynamically significant renal artery stenosis is currently a matter of great debate. In any case optimal medical therapy with antihypertensive, lipid-lowering, and platelet-inhibiting drugs should be instituted, since such approach may not only prevent the progression to end-stage renal disease, but may also prevent the progression of extra-renal vascular disease, which affects the majority of these patients. Current evidence suggests that angioplasty (with additional stent placement in case of osteal renal artery stenosis) may benefit a subset of patients with significant RAS, i.e. patients with a resistance index < 80% at the level of the segmental renal arteries, and patients with bilateral RAS or patients with unilateral RAS with a unique functioning kidney. Prospective, randomized and controlled studies with clearly defined clinical endpoints are needed to better define the absolute and relative indications of angioplasty (plus stenting) in the setting of renal artery stenosis.

Four cases of red blood cell aplasia in association with the use of mycophenolate mofetil in renal transplant patients.

Mycophenolate mofetil (MMF) is one of the new immunosuppressive drugs used in renal transplantation. MMF inhibits the de novo purine synthesis. Since this purine synthesis in lymphocytes entirely depends on the de novo pathway, MMF is considered to cause a selective inhibition of T- and B lymphocytes. Recently, 4 transplant patients out of 30 developed a severe anemia in the early post-transplantation period. Their immediate post-transplantation immunosuppression consisted of corticosteroids, cyclosporine and MMF. They all received anti-T-lymphocyte globulin (ATG) as induction treatment or because of rejection. In all 4 patients, iron supplementation and a treatment with erythropoietin were started. Blood loss, deficiencies, hemolysis, drug interactions or viral infections were excluded as causes of the anemia. Bone marrow biopsies were carried out, showing pure red cell aplasia that was ascribed to the use of MMF. Cessation or reduction of MMF was followed by a hematological improvement after 5-9 days. We hypothesized that MMF has a broader antiproliferative effect than its proposed lymphocyte-specific effect.

Oxidative modification of low-density lipoproteins and the outcome of renal allografts at 1 1/2 years.

BACKGROUND: Previous studies reported a significant association between hyperlipidemia of the recipient and chronic allograft nephropathy (CAN). However, the nature and the pathogenic mechanism of circulating lipid abnormalities in CAN remain unclear. METHODS: In a prospective study of 50 consecutive adult recipients of a cadaveric renal allograft, we investigated the impact of lipid abnormalities on the outcome of the graft at 1 1/2 years. Besides morphometric analysis of implantation and protocol biopsies, clinical and biochemical variables were studied at three-month intervals. Plasma concentrations of oxidized low-density lipoprotein (OxLDL) were determined by means of enzyme-linked immunosorbent assay. Immunohistochemical staining for OxLDL and macrophages was performed on paired renal biopsies. Study end points were the fractional interstitial volume and the 24-hour creatinine clearance at 11/2 years. RESULTS: High-density lipoprotein (HDL) cholesterol of the recipient < or =47 mg/dL was a risk factor for the functional (RR = 1.56; 95% CI, 0.978 to 2.497) and the morphological (RR = 2.75; 95% CI, 1.075 to 7.037) outcome of the graft, mainly in patients without acute rejection (RR = 2.03; 95% CI, 1.13 to 3.65, and RR = 4.67; 95% CI, 1.172 to 18.582, respectively). Interstitial accumulation of OxLDL was inversely associated with HDL cholesterol (R = -0.476, P = 0.019), and was associated with a higher density of tubulointerstitial macrophages (R = 0.656, P = 0.001) and a higher fractional interstitial volume at 11/2 years (P = 0.049). CONCLUSION: Decreased HDL cholesterol levels of the recipient adversely affect the outcome of renal allografts through the accumulation of OxLDL in the renal interstitium of the graft. Interstitial accumulation of OxLDL was associated with the presence of macrophages and the development of interstitial fibrosis.

Morphometric analysis of renal vessels. Advantage of the multisector area approach to cross-sections.

OBJECTIVE: To determine the most accurate morphometric approach to overcoming the obstacles of limited number, angle of section and irregular contours of vascular structures in analyzing vascular sections of renal biopsies. STUDY DESIGN: The luminal area of 451 cortical arterioles in 65 Masson-trichrome-stained renal sections was assessed with a computer-assisted imaging system connected to a Leica DMR microscope (Mikroskopie und Systeme GmbH, Wetzlar, Germany). The luminal area measured by the imaging system was used as the gold standard, against which three mathematical sector approaches and one classical approach were evaluated. The accuracy of these approaches was evaluated by means of the relative deviation from the measured value and of the degree of overestimation or underestimation. Intraobserver and interobserver variability were determined for the most accurate mathematical approach. RESULTS: As compared to measured luminal area, the sector elliptical approach yielded the lowest relative deviation (13.4 +/- 12.5%), without significant overestimation or underestimation (-0.6 +/- 18.3%). The intraobserver and interobserver correlation coefficients for this method were 82.3% and 86.5%, respectively. CONCLUSION: The sector elliptical approach is the most accurate mathematical approach to vascular sections in renal biopsies.

Fibrous intimal thickening at implantation as a risk factor for the outcome of cadaveric renal allografts.

BACKGROUND: During the past decade, the donor age of cadaveric renal allografts steadily increased. Because cerebrovascular injury is the main cause of death in this donor population, an increased prevalence of atherosclerotic lesions in the retrieved grafts could be anticipated. In a prospective study, we investigated the predictive value of morphologic lesions at implantation for the functional and morphologic outcome of cadaveric renal allografts at 1 1/2 years. METHODS: In 50 consecutive adult recipients of a cadaveric renal allograft, under cyclosporine-based regimen, implantation biopsies and subsequent protocol biopsies at 18 months were performed, and morphometrically analyzed for the extent of glomerulosclerosis, interstitial fibrosis, and atherosclerosis. Risk factors were assessed at implantation and during the subsequent observation period of 18 months. Endpoints for this study were: the 24-hr creatinine clearance (normalized for body surface area) and the fractional interstitial volume at 1 1/2 years. RESULTS: In multivariate analysis, fibrous intimal thickening at implantation (FIT) was the main determinant of the functional and morphologic outcome at 1 1/2 years. FIT represented a relative risk of 4.55 for interstitial fibrosis (95% CI=1.855-11.138), and 1.89 for impaired renal function (95% CI=1.185-3.007) at 1 1/2 years. FIT adversely affected fractional interstitial volume at 1 1/2 years (34.3 vs. 27.7%, P=0.004), as well as renal function (54 vs. 68 ml/min/1.73 m2, P=0.028). CONCLUSIONS: Fibrous intimal thickening at implantation is a determinant risk factor for the functional and morphologic outcome of cadaveric renal allografts at 1 1/2 years.