Abdul Hammad

CMV mismatch does not affect patient and graft survival in UK renal transplant recipients.

Background. Cytomegalovirus (CMV) is one of the major infections encountered posttransplantation. UK Guidelines (2003) recommend CMV prophylaxis or screening with preemptive treatment for all high risk recipients. Studies predating the widespread use of CMV prophylaxis have shown that CMV seronegative recipients (R−) receiving a renal allograft from a CMV seropositive donor (D+) have worse outcomes than those avoiding primary CMV infection. Therefore, it has been suggested that CMV matching should be a part of the UK national deceased donor kidney allocation scheme. Methods. We examined patient and allograft survival according to donor and recipient CMV serostatus in 10,190 UK adult and pediatric deceased donor renal transplant recipients transplanted between 2000 and 2007. We also ascertained CMV prophylaxis strategies in all UK renal transplant units. Results. Twenty-one of the 22 UK renal transplant centers used prophylactic oral valganciclovir for 3 months posttransplant in the D+R− transplants, having done so for a median of 4 years. Unadjusted data showed that D+R+ rather than D+R− transplants had the lowest patient and allograft survivals at 3 years posttransplant. However, after adjustment for donor age, there was no significant effect of donor and recipient CMV serostatus on allograft or patient survival. Conclusions. These findings suggest that in an era where CMV prophylaxis is used routinely in D+R− transplants, the previously noted adverse effects of primary CMV infection on allograft and patient survival can be avoided (perhaps through a reduction in the incidence and/or severity of primary CMV infection), without using a CMV-matching allocation scheme.

Campath, calcineurin inhibitor reduction and chronic allograft nephropathy (3C) study: background, rationale, and study protocol

BackgroundKidney transplantation is the best treatment for patients with end-stage renal failure, but uncertainty remains about the best immunosuppression strategy. Long-term graft survival has not improved substantially, and one possible explanation is calcineurin inhibitor (CNI) nephrotoxicity. CNI exposure could be minimized by using more potent induction therapy or alternative maintenance therapy to remove CNIs completely. However, the safety and efficacy of such strategies are unknown.Methods/DesignThe Campath, Calcineurin inhibitor reduction and Chronic allograft nephropathy (3C) Study is a multicentre, open-label, randomized controlled trial with 852 participants which is addressing two important questions in kidney transplantation. The first question is whether a Campath (alemtuzumab)-based induction therapy strategy is superior to basiliximab-based therapy, and the second is whether, from 6 months after transplantation, a sirolimus-based maintenance therapy strategy is superior to tacrolimus-based therapy. Recruitment is complete, and follow-up will continue for around 5 years post-transplant. The primary endpoint for the induction therapy comparison is biopsy-proven acute rejection by 6 months, and the primary endpoint for the maintenance therapy comparison is change in estimated glomerular filtration rate from baseline to 2 years after transplantation. The study is sponsored by the University of Oxford and endorsed by the British Transplantation Society, and 18 centers for adult kidney transplant are participating.DiscussionLate graft failure is a major issue for kidney-transplant recipients. If our hypothesis that minimizing CNI exposure with Campath-based induction therapy and/or an elective conversion to sirolimus-based maintenance therapy can improve long-term graft function and survival is correct, then patients should experience better graft function for longer. A positive outcome could change clinical practice in kidney transplantation.Trial registrationClinicalTrials.gov, NCT01120028 and ISRCTN88894088

Cytomegalovirus-specific CD8+ T cells do not develop in all renal transplant patients at risk of virus infection

Cytomegalovirus (CMV) is an important pathogen in immunosuppressed renal transplant patients. At greatest risk are CMV IgG seronegative recipients (R-) of kidneys from CMV IgG seropositive donors (D+), although not all develop CMV disease. The aims of the study were to determine whether D+/R- patients who do or do not go on to develop CMV disease differ in their CD8+ T cell responses to CMV. Responses to the immunodominant NLVPMVATV peptide from the CMV structural protein pp65 in HLA-A2+ renal transplant patients were quantified using HLA tetramers/pentamers. Most D+/R+ patients had detectable tetramer+ cells while most D-/R- patients did not. Around 50% of D+/R- patients had some CD8+ tetramer+ cells and there was a strong correlation between % tetramer+ cells and the occurrence of a CMV infection post-transplantation (P<0.005). 18/41 (44%) of CMV negative patients receiving a kidney from a CMV+ donor failed to develop a detectable CMV infection, or significant numbers of tetramer+ cells. There was no relationship between CMV infection and acute cellular rejection. There was a tendency for patients who were given pre-emptive antiviral therapy to have lower levels of tetramer+ cells but this was not statistically significant. Hence the results show that CMV- patients receiving a kidney from a CMV+ donor do not inevitably acquire CMV infection. Those without CMV disease did not show any T cell response while most patients with detectable CMV developed specific CD8+ T cells.

RENAL TUBULAR PEPTIDE CATABOLISM IN CHRONIC VASCULAR REJECTION

Chronic vascular rejection (CR) is the commonest cause of renal transplant loss, with few clues to etiology, but proteinuria is a common feature. In diseased native kidneys, proteinuria and progression to failure are linked. We proposed a pathogenic role for this excess protein at a tubular level in kidney diseases of dissimilar origin. We demonstrated in both nephrotic patients with normal function and in those with failing kidneys increased renal tubular catabolisman and turnover rates of a peptide marker, Aprotinin (Apr), linked to increased ammonia excretion and tubular injury. These potentially injurious processes were suppressed by reducing proteinuria with Lisinopril. Do similar mechanisms of renal injury and such a linkage also occur in proteinuric transplanted patients with CR, and if so, is Lisinopril then of beneficial value? We now examine these aspects in 11 patients with moderate/severe renal impairment (51CrEDTA clearance 26.2 ± 3.3 mL/min/1.73m2), proteinuria (6.1 ± 1.5 g/24 h) and biopsy proven CR. Lisinopril (10–40 mg) was given daily for 2 months in 7 patients. Four others were given oral sodium bicarbonate (Na HCO3) for 2 months before adding Lisinopril. Renal tubular catabolism of intravenous 99mTc-Apr (Apr* 0.5 mg, 80 MBq), was measured before and after Lisinopril by γ-ray renal imaging and urinary radioactivity of the free radiolabel over 26 h. Fractional degradation was calculated from these data. Total 24 h urinary N-acetyl-β-glucoaminidase (NAG) and ammonia excretion in fresh timed urine collections were also measured every two weeks from two months before treatment. After Lisinopril proteinuria fell significantly (from 7.8 ± 2.2 to 3.4 ± 1.9 g/24 h, p < 0.05). This was associated with a reduction in metabolism of Apr* over 26 h (from 0.5 ± 0.05 to 0.3 ± 0.005% dose/h, p < 0.02), and in fractional degradation (from 0.04 ± 0.009 to 0.02 ± 0.005/h, p <0.01). Urinary ammonia fell, but surprisingly not significantly and this was explained by the increased clinical acidosis after Lisinopril, (plasma bicarbonate fell from 19.1 ± 0.7 to 17.4 ± 0.8 mmol/L, p <0.01), an original observation. Total urinary NAG did fall significantly from a median of 2108 (range 1044–3816) to 1008 (76–2147) μmol/L, p < 0.05. There was no significant change in blood pressure or in measurements of glomerular hemodynamics. In the 4 patients who were given Na HCO3 before adding Lisinopril, both acidosis (and hyperkalemia) were reversed and neither recurred after adding Lisinopril. These observations in proteinuric transplanted patients after Lisinopril treatment have not been previously described.

Induction of IL-8(CXCL8) and MCP-1(CCL2) with oxidative stress and its inhibition with N-acetyl cysteine (NAC) in cell culture model using HK-2 cell

Renal transplantation can often be complicated due to delayed graft function, which is a direct sequel of ischaemia reperfusion injury. The adverse outcome of delayed graft function is not only short term but the long-term function of the graft is also affected. Therefore, it is important to understand the mechanisms of ischaemia reperfusion injury. Reactive oxygen species are the key mediators in ischaemia reperfusion injury causing direct cell damage which also initiate inflammation by inducing chemokines. The presence of inflammation is a marker of severe delayed graft function. However, the effect of oxidative stress on the expression of key chemokines has not been fully established yet. Therefore, the aim of this study was to measure the oxidative stress response and the secretion of chemokines in a cell culture model that mimics the effects of ischaemia reperfusion injury in immortalised human renal proximal tubular epithelial cells, HK-2. Cells were treated with varying concentrations of hydrogen peroxide and markers of oxidative stress response and chemokine release were measured. Exposure to hydrogen peroxide induced a significant increase in the activity of the antioxidant enzyme glutathione peroxidase and the levels of the chemokines Interleukin-8 (IL-8; CXCL8) and MCP-1 (CCL2). A dose related increase of chemokine secretion was also observed. The cytokine Interleukin-1β (IL-1β) at 1 ng/ml significantly potentiated the expression of both IL-8 (CXCL8) and MCP-1 (CCL2) which showed synergistic response in the presence of hydrogen peroxide. Pre-incubation of the cells with the anti-oxidant N-acetyl cysteine (NAC) strongly suppressed the induction of both IL-8 and MCP-1 when stimulated with hydrogen peroxide and IL-1β. This study demonstrates the potential of anti-oxidants like N-acetyl cysteine in ameliorating the effects of ischaemia reperfusion injury thus suggesting a new therapeutic approach in renal transplantation. These findings can have potential implications for clinical use to prevent ischaemia reperfusion injury in renal transplantation.

Forgotten ureteric stents in renal transplant recipients: Three case reports

Ureteric stents are widely used in renal transplantation to minimize the early urological complications. Ureteric stents are removed between two and 12 weeks following trans-plantation, once the vesico-ureteric anastomosis is healed. Ureteric stents are associated with considerable morbidity due to complications such as infection, hematuria, encrustations and migration. Despite the patient having a regular follow-up in the renal transplant clinic, ureteric stents may be overlooked and forgotten. The retained or forgotten ureteric stents may adversely affect renal allograft function and could be potentially life-threatening in immunocompromised transplant recipients with a single transplant kidney. Retrieving these retained ureteric stents could be challenging and may necessitate multimodal urological treatments. We report three cases of forgotten stents in renal transplant recipients for more than four years. These cases emphasize the importance of patient education about the indwelling ureteric stent and possibly providing with a stent card to the patient. Maintaining a stent register, with a possible computer tracking system, is highly recommended to prevent such complications.

Impact of sensitivity of human leucocyte antigen antibody detection by Luminex technology on graft loss at 1 year

Background The clinical relevance of the detection of human leucocyte antigen (HLA) antibodies in sera of renal transplant recipients by highly sensitive methods such as Luminex alone is uncertain and a matter of debate. The choice of output thresholds affects antibody detection and thus organ allocation, yet there are no internationally agreed threshold levels. This study aims at evaluating our current practice of using an MFI threshold of 1000 in antibody detection. Methods We carried out a case–control study by looking at 761 renal transplant recipients at one unit between 2000 and 2010. Of these, there were 93 cases of graft loss within 1 year and stored serum samples of 40 cases were available for testing. Controls were selected (graft function >2 years) and individually matched according to age, sex, number of transplants and date of transplant. All 40 cases and 40 controls had negative crossmatch by complement-dependent cytotoxicity (CDC) at the time of transplant, and pre-transplant sera were re-analysed for the presence of detectable HLA and donor-specific antibodies (DSAs) using Luminex screen and single-antigen beads and MFI threshold values of 1000, 2000 and 4000. Results In nearly 48% of cases with graft loss within a year, HLA antibodies were detectable by Luminex when using a 1000 MFI threshold. This was 25% greater than in controls (P = 0.017). There was also a 15% increase in detected DSAs; however, statistical significance depends on the inclusion or exclusion of one specific case. Using MFI thresholds of 2000 and 4000, no DSAs were found in any long-term surviving grafts. Conclusions Selection of appropriate MFI cut-off values influences the detection of DSAs and, thus, organ allocation. Using a threshold of 1000 led to the detection of DSAs in 5% of long-term graft survivors in our population and should be considered too sensitive. Using a detection threshold of 2000 is sufficiently sensitive and leads to clinically relevant detection of DSA.

Long‐ and short‐term outcomes in renal allografts with deceased donors: A large recipient and donor genome‐wide association study

Improvements in immunosuppression have modified short‐term survival of deceased‐donor allografts, but not their rate of long‐term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short‐ and long‐term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large‐scale genome‐wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant‐pairs with replication in 5866 complete pairs. We studied deceased‐donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long‐ or short‐term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.

CD56+ T cells are increased in kidney transplant patients following cytomegalovirus infection

CD56+ T cells previously have been identified as potentially cytotoxic lymphocytes, and relative numbers are increased in some infectious diseases.

Kidney Procurement From Donors After Circulatory Death; Is There Scope for Improvement?

WereadwithinterestthepaperbyAusaniaetal.(1),whichreviewed data from the UK national transplant database.It was a thorough examination of important recovery crite-ria contributing to increased rates of kidney damage fromdonors after circulatory death (DCD). The authors reporta reduced rate of kidney procurement damage (11% vs.19%) since the previous study by Wigmore et al. in 1999(2). However, this timely and relevant study might be fur-ther improved if the authors could be invited to clarify sev-eral points.The audit spanned a period of significant change in organretrieval practices in the United Kingdom. The inceptionoftheNationalOrganRetrievalService(NORS)inApril2010 aimed to enable organ procurement to be performedby dedicated, consultant led teams. These were to pro-vide a high quality retrieval service, close supervision andtraining to junior NORS team members (3). Although thepaper does refer to these changes, it does not analyze thedata with respect to them. It would be interesting to com-pare rates of organ damage, and the grade/experience ofthe retrieving surgeon, before and after the introduction ofNORS to demonstrate the impact of changing national re-trieval arrangements. It would be of great concern to findthat retrieval injuries continued unabated despite a movetoward a consultant delivered service.With respect to the data collected, it relied on the report-ing of damage by the retrieving surgeon. This introducesa reporting bias reliant upon honesty and recognition ofinjuries at the time of procurement. Although alluded to inthepaper,identificationofmissedretrievalinjuries,andpo-tential further damage at the time of bench preparation ofthe graft, are more readily assessed by the implanting sur-geon. It is this assessment, along with factors such as theadequacy of perfusion, that dictate if a DCD kidney is usedor discarded. It would be of use to have an analysis of theconcordance between the injuries and adequacy of perfu-sion reported by both retrieving and implanting surgeons.Weagreewiththeauthors’assertionsthatthisdatashouldbe collected in future.Finally, the authors rightly point out the expansion in useof DCD donor kidneys by the majority of UK centers. EvenwiththeadventofNORS,suchorganshavegenerallybeentransplanted in “local” centers to limit transport cold is-chemia times. In the future, DCD donor kidneys might beoffered into the national matching scheme. Consequently,it is imperative that there is early recognition of retrieval in-juryandgoodcommunicationbetweensurgeonstoensurethat only transplantable grafts are offered and transportednationally. This paper clearly demonstrates that there is aneed to continue efforts to improve the quality of procure-ment surgery in this challenging group of donors.