Functional impairment of cytomegalovirus specific CD8 T cells predicts high-level replication after renal transplantation.

Human cytomegalovirus (HCMV) remains an important cause of morbidity after allotransplantation, causing a range of direct effects including hepatitis, pneumonitis, enteritis and retinitis. A dominant risk factor for HCMV disease is high level viral replication in blood but it remains unexplained why only a subset of patients develop such diseases. In this detailed study of 25 renal transplant recipients, we show that functional impairment of HCMV specific CD8 T cells in the production of interferon gamma was associated with a 14-fold increased risk of progression to high level replication. The CD8 T-cell impairment persisted during the period of high level replication and was more prominent in patients above 40 years of age (odds ratio = 1.37, p = 0.01) and was also evident in dialysis patients. Threshold levels of functional impairment were associated with an increased risk of future HCMV replication and there was a direct relationship between the functional capacity of HCMV ppUL83 CD8 T cells and HCMV load (R(2)= 0.83). These results help to explain why a subset of seropositive individuals develop HCMV replication and are at risk of end-organ disease and may facilitate the early identification of individuals who would benefit from targeted anti-HCMV therapy after renal transplantation.

Interpreting regulatory authority guidance on immunosuppressive therapy for renal transplantation: a response to the UK's National Institute for Clinical Excellence (NICE).

AIMS: A group of UK consultant transplant physicians and surgeons (the Consensus Group) met to consider the implications and interpretation of the National Institute for Clinical Excellence's (NICE) Technology Appraisal No. 85 on the use of immunosuppressive therapy for renal transplantation in adults. METHODS: This group considered what the implications of these guidelines might be for clinical practice and consensus was developed on those areas which were potentially open to different interpretations. A wider survey of nephrologists and transplant surgeons throughout the UK was also performed to gauge the impact of the NICE recommendations. RESULTS AND CONCLUSIONS: The outcome of the discussions of the Consensus Group are presented with particular reference to the recommendations of how to respond to calcineurin inhibitor (CNI) intolerance. The survey suggested that the publication of this NICE guidance has resulted in relatively few changes in prescribing practice: UK transplant centers continue to use a wide range of locally developed protocols for immunosuppressive therapy. These include the use of agents such as mycophenolate mofetil (MMF) and sirolimus, despite the fact that both drugs appeared to receive only conditional acceptance in the NICE Guidelines.

Donor-derived human herpes virus 8-related Kaposi's sarcoma in renal allograft ureter.

We present a case of human herpes virus 8 (HHV8)-associated Kaposi sarcoma (KS) occurring in a renal allograft ureter from a male donor. The female patient presented with a rising creatinine due to ureteric obstruction, and subsequent histological examination of the excised tumor revealed a KS. The tumor tested positive for HHV8 antigen and, using in situ hybridization to identify X and Y chromosomes, we were able to demonstrate that the tumor was of male origin. In the absence of any other KS lesions, this suggested that the tumor arose due to reactivation of latent HHV8 in the donor tissue, permitted by the recipient's immunosuppression. The patient was managed by a gradual reduction in immunosuppression and there has been no subsequent recurrence of the tumor. KS in renal transplantation is discussed in detail including the possible utility of pre-transplant HHV8 screening.

Successful therapeutic use of rituximab in refractory Wegener's granulomatosis after renal transplantation.

Wegener's granulomatosis is a significant cause of end-stage renal disease requiring renal replacement therapy. Treatment of relapses is often difficult as immunosuppressive therapy can be limited by various factors including graft survival in renal transplantation. Rituximab is a novel therapeutic approach in those conditions. We present the case of a 42 year-old Caucasian woman who had been diagnosed with Wegener's granulomatosis 15 years ago. Predominantly affected organs were kidneys and pituitary gland. Five years later she reached end-stage renal failure and received a renal transplant soon after. She suffered from continuous relapses involving pulmonary hemorrhage and treatment became increasingly difficult. Symptoms resolved soon after single administration of low dose rituximab.

Review article: renal function assessment in cirrhosis - difficulties and alternative measurements.

BACKGROUND: Renal function in patients with cirrhosis is important prognostically, both before and following liver transplantation. Its prognostic impact is reflected by the inclusion of serum creatinine in the model for end-stage liver disease score, which is now used for recipient prioritization on liver transplantation waiting lists in the USA. AIM: To review the accuracy of the surrogate markers for the assessment of renal function, i.e. glomerular filtration rate, particularly in patients with cirrhosis. METHOD: We reviewed the available literature in PubMed regarding the markers for GFR evaluation and the factors which affect their accuracy in cirrhosis. RESULTS: Although creatinine is widely available, it is an unreliable marker of glomerular filtration rate, particularly in patients with cirrhosis. Clearance of exogenous markers is considered the 'gold standard', but this methodology has many drawbacks, particularly poor applicability. Several mathematical formulae for estimated glomerular filtration rate are used to overcome some of these limitations: Cockcroft-Gault and Modification of Diet in Renal Disease formulae are the most frequently applied, but they are based on serum creatinine. CONCLUSIONS: Due to the inaccuracy of serum creatinine and its derived formulae in estimating glomerular filtration rate, alternative serum markers, such as cystatin C, and new formulae are desirable. These need formal evaluation in patients with cirrhosis so as to have a reliable surrogate of glomerular filtration rate, and to obviate many problems that are associated with using creatinine and estimated glomerular filtration rate.

Kinetics of cytomegalovirus load decrease in solid-organ transplant recipients after preemptive therapy with valganciclovir.

The availability of valganciclovir (VGCV) has significantly simplified the treatment of human cytomegalovirus (HCMV) infection after solid-organ transplantation. We show that there was no difference in the kinetics of the decrease in HCMV load after preemptive therapy with VGCV in 22 solid-organ transplant recipients (T1/2=2.16 days), compared with that in 23 patients treated with intravenous ganciclovir (GCV) (T(1/2) = 1.73 days; P=.63). Preemptive therapy with VGCV provides control of HCMV replication that is comparable to that achieved with preemptive intravenous therapy with GCV.

Calycoureterostomy: a novel technique for post-renal transplant stricture.

Stenosis and necrosis of the ureter are amongst the severe complications after renal transplantation. Several surgical techniques like simple nephrostomy or native pyeloureterostomy using the native ureter have been applied for repair. We report a case of modification to the conventional pyeloureterostomy where the native ureter was anastomosed to the transplant calyx to restore continuity of the urine collecting system. This technique is recommended as a feasible alternative when secondary reconstruction by native pyeloureterostomy is not possible.

Renovascular disease is associated with low producer genotypes of the anti-inflammatory cytokine interleukin-10.

Cytokines are important mediators of inflammatory and proliferative responses in disease states including atherosclerosis. Genetic variations in cytokine production could potentially influence the outcome of these responses. The aim of this study was to determine whether cytokine gene polymorphism might influence the development of atherosclerotic renal artery stenosis. Sixty-six patients with atherosclerotic renal artery stenosis and 100 normal healthy individuals were genotyped for interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-2 promoter region polymorphism. TNF-a, TNF-d, and IL-10 microsatellite polymorphisms were also analyzed. The frequency of the anti-inflammatory cytokine IL-10 promoter (-1082 A positive) GA and AA genotypes which are associated with low production were higher in the patient group when compared to the control group. The AA-TT-AA homozygous genotype combination of three single-nucleotide polymorphisms at -1082, -819, and -592 in the IL-10 gene was also observed at a higher frequency in the patient group compared to the controls. The frequency of TNF-alpha, IL-6, and IL-2 polymorphisms did not show any significant difference between the patient and control groups. To correlate IL-10 genotypes with differences in IL-10 protein expression, in vitro mRNA and protein levels were analyzed in lipopolysaccharide-stimulated peripheral blood mononuclear cells from 22 patients with renal artery stenosis and 33 controls. Individuals genotyped as A positive at position -1082 produced lower levels of IL-10 protein and had lower copy numbers of mRNA when compared to individuals genotyped as A negative in both patient and control groups. The increased frequency of the low producer IL-10 promoter, -1082 A-positive genotype in patients with renal artery stenosis, suggests that IL-10 may protect against the development of atherosclerotic renovascular disease.

Pregnancy in renal transplant recipients: the Royal Free Hospital experience.

BACKGROUND: For women with end-stage renal failure of child-bearing age, renal transplantation offers a chance to start a family. Pregnancies in renal transplant recipients involve risks for graft and fetus, and need to be carefully managed. AIM: To identify graft, fetal and maternal outcomes in our patients, and compare our results with those of the large national transplant registries. DESIGN: Retrospective case-note review. METHODS: We assessed the outcomes of 48 pregnancies in 24 renal transplant recipients. Obstetric data and renal parameters were examined in 27-30 pregnancies that progressed to delivery. RESULTS: Mean time from transplantation to pregnancy was 6.5 years, with an unfavourable outcome in patients who conceived within 1 year. There was a 41% incidence of fetal growth restriction (FGR), and 33% of infants were small for gestational age. FGR was associated with maternal hypertension, a pre-pregnancy serum creatinine (SCr) >/= 133 micro mol/l (1.5 mg/dl), calcineurin inhibitors and the use of cardioselective beta blockers. Two patients with pre-pregnancy SCr > 200 micro mol/l lost their grafts within 3 years of delivery. A permanent significant decline in graft function occurred in 20%, by 6 months post delivery. DISCUSSION: FGR with SGA infants occurs frequently. Atenolol should be avoided in pregnancy and Metoprolol should not be combined with calcineurin inhibitors. Pregnancy appeared to have a deleterious effect on graft function in patients with SCr > 155 micro mol (1.75 mg/dl). Patients with pre-pregnancy SCr 200 micro mol/l are at greatest risk.

Effect of fluvastatin on acute renal allograft rejection: a randomized multicenter trial.

BACKGROUND: Statin therapy has been reported to reduce the acute rejection rate following renal transplantation in a pilot study. The present study is the first randomized, double-blind and adequately powered study to examine the effect of statins on acute rejection of renal allografts. METHODS: A total of 364 patients were randomly assigned to receive either fluvastatin 40 mg or placebo in combination with conventional cyclosporine-based immunosuppressive therapy. The primary end point was treated first acute rejection. Secondary end points included biopsy-proven rejection, histological severity of rejection, occurrence of steroid-resistant rejection, and serum creatinine at three months following transplantation. RESULTS: Fluvastatin was well tolerated; no patients developed myositis or rhabdomyolysis. There was no difference in the acute rejection rate [86 (47.3%) fluvastatin vs. 87 (47.8%) placebo] and no significant difference in the severity of rejection, steroid resistant rejection or mean serum creatinine at three months (160 micromol/L vs. 160 micromol/L). Total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol and triglyceride levels increased following renal transplantation. With the exception of the increase in HDL-C, which was augmented, the increases in lipid parameters were significantly reduced by fluvastatin (total cholesterol +17.5% vs. 35.7%; LDL-C +6.3% vs. 46.7%; HDL-C +43.3% vs. 38.1%; triglyceride +52.2% vs 77.6%). CONCLUSIONS: Contrary to the reported effects of statins, fluvastatin had no effect on the incidence or severity of acute rejection following renal transplantation. There were no increases in adverse events. A significant and potentially beneficial alteration in the lipid profile was observed in the early post transplant period. We conclude that fluvastatin may be used safely to correct dyslipidemia in patients with end-stage renal failure through the peri-transplant period.

The safety and efficacy of MMF in lupus nephritis: a pilot study.

Inducing and maintaining remission in patients with lupus nephritis may be difficult. Current treatments have significant toxicity. Mycophenolate mofetil (MMF) limits damage in murine models of lupus nephritis. We have assessed the efficacy and tolerability of MMF in the treatment of patients with long-standing or resistant lupus nephritis. We have treated 13 patients with biopsy proven lupus nephritis (two membranous nephropathy, four membranous nephropathy with superimposed proliferative changes, seven with proliferative glomerulonephritis). All patients had relapsed on conventional treatment or there were pressing indications to minimise steroid dosage or avoid alkylating agents. Nine out of 13 were treated with MMF and prednisolone, 3/10 with MMF alone and 1/10 with MMF, prednisolone and cyclosporine. Thirteen patients were treated with MMF for up to 37 months (median 25 months). Three patients were withdrawn from MMF during the first 8 months of treatment. The remainder tolerated MMF (median dose 1 g/day). Serological improvements were observed in 9/13 and steroid dosage was reduced in 8/10 patients. Infections occurred in 3/13. One patient relapsed. MMF significantly reduced the rate of decline of renal function. MMF should be considered in the treatment of long-standing or resistant lupus nephritis. Controlled clinical trials are required to confirm these findings.

Atrial thrombus and central venous dialysis catheters.

A native arteriovenous fistula is the first choice for hemodialysis access. Despite improved catheter designs and the use of internal jugular veins, thrombotic complications still occur when tunneled central venous catheters are used as an alternative. Although right atrial thrombus (RAT) is a well-characterized complication of long-term central venous cannulation, particularly when used for parenteral nutrition and chemotherapy in pediatric practice, only 9 reported cases previously have been associated with the long-term use of central venous catheters for hemodialysis. We report five cases of RAT seen at our unit between 1994 and 1998 in patients who had been dialyzed using tunneled catheters. In four of five cases, the diagnosis was made during the investigation of hemoptysis or dyspnea. In the fifth case, a screening transthoracic echocardiogram revealed the thrombus. Three of five of the patients suffered pulmonary emboli, and a fourth patient had an unexplained electromechanical dissociation cardiac arrest without definite evidence of pulmonary embolus. Our experience suggests that anticoagulated patients with RAT remain at risk of pulmonary embolism. One of our patients successfully underwent atrial thrombectomy. In four of five of our cases and four of nine cases in the literature, the central venous catheter tip was within the right atrium. Positioning of the central venous catheter tip low down in the superior vena cava or in the right atrium has been advocated to improve dialysis adequacy and to reduce the incidence of catheter thrombosis. However, placement of the catheter tip within the right atrium may be associated with an increased risk of RAT.

Effects of lactate-buffered and lactate-free dialysate in CAVHD patients with and without liver dysfunction.

BACKGROUND: Continuous modalities of renal replacement deplete patients of bicarbonate, which is traditionally replaced indirectly by lactate in dialysate or replacement fluids. We have compared a new lactate-free dialysate (unbuffered dialysate with separate bicarbonate replacement of dialytic bicarbonate loss) with standard lactate-buffered dialysate in terms of acid-base control, lactate accumulation, and hemodynamic stability in patients undergoing continuous renal replacement therapy in an intensive care unit. METHODS: A nonrandomized crossover cohort study involving 54 patients with multi-organ failure (of whom 19 had significant hepatic dysfunction) was performed. All patients completed 24-hour continuous hemodiafiltration against both lactate-buffered and lactate-free dialysate. Arterial pH, blood gases, bicarbonate, and lactate, venous sodium, blood pressure, and inotrope requirements were measured before and at six hourly intervals during the first 24 hours of dialysis against each dialysate. RESULTS: Lactate-free dialysate provided more rapid control of acidosis than lactate buffered with less total administration of buffer than that given during the lactate-buffered period (total mmol bicarbonate vs. total mmol lactate + bicarbonate). Lactate accumulation was slight in both periods, but was higher during lactate-buffered continuous venovenous hemodiafiltration (CVVHD). The mean arterial pressure rose during lactate-free dialysis with decreased inotrope doses and fell during lactate-buffered dialysis with increased inotrope requirement. Results in patients with liver dysfunction were not significantly different from those without it. CONCLUSIONS: Over the time scale of 24 hours, lactate derived from continuous dialysis circuits is efficiently cleared from the blood of most patients with multi-organ failure, but with less effect on systemic acidosis than is produced by equivalent amounts of bicarbonate.

Prospective study of human betaherpesviruses after renal transplantation: association of human herpesvirus 7 and cytomegalovirus co-infection with cytomegalovirus disease and increased rejection.

BACKGROUND: Human herpesvirus 6 (HHV-6) and HHV-7 are two lymphotropic herpesviruses, which, like cytomegalovirus (CMV), have the potential to be pathogenic in immunocompromised individuals. We have conducted a prospective investigation to compare the natural history of HHV-6 and HHV-7 infection with that of CMV after renal transplantation. METHODS: Polymerase chain reaction was used to identify infections and quantify the viral load of CMV, HHV-6, and HHV-7 in peripheral blood samples from 52 renal transplant recipients. Betaherpesvirus infections were related to defined clinical criteria obtained by detailed examination of the clinical records of each patient for the immediate 120-day posttransplant period. RESULTS: CMV was the most commonly detected virus after transplant (58% of patients), followed by HHV-7 (46%) and HHV-6 (23%). Examining the time to first polymerase chain reaction positivity, HHV-7 infection was detected earlier than CMV (P=0.05). The median maximum CMV viral load was significantly higher than those for HHV-6 (P=0.01) and HHV-7 (P<0.0001) and a trend for HHV-7 viral load to be greater than HHV-6 (P=0.08). Clinicopathological analyses revealed that, in those patients with rejection, HHV-7 was associated with more episodes of rejection (P=0.02). In addition, there was a significant increase in CMV disease occurring in patients with CMV and HHV-7 co-infection compared to those with CMV infection only (P=0.04). CONCLUSIONS: HHV-7 should be further investigated as a possible co-factor in the development of CMV disease in renal transplant patients and may potentially exacerbate graft rejection. No clear pathological role was observed for HHV-6.

Calcineurin inhibitors enhance low-density lipoprotein oxidation in transplant patients.

BACKGROUND: Our objective was to assess the pro-oxidant status of neoral and tacrolimus in renal transplant patients and monitor the protection provided by vitamin C and vitamin E in normalizing low density lipoprotein (LDL) oxidation lag time of tacrolimus-treated patients. METHODS: Plasma LDL was isolated by density gradient ultracentrifugation from renal transplant patients receiving neoral, tacrolimus and tacrolimus with vitamin C and vitamin E. Oxidation was initiated by the addition of CuCl2 at 37 degrees C and monitored at 234 nm over 480 minutes and oxidation lag time was computed. Total antioxidant capacity of serum was measured using the enhanced chemiluminescent method. RESULTS: LDL from tacrolimus-treated patients had significantly lower oxidation lag time and serum antioxidant activity in comparison with neoral-treated patients, and this was particularly significant during the first four months after transplantation. Vitamin C and E supplementation in tacrolimus treated patients provided protection against oxidation and normalized their oxidation lag time. CONCLUSION: Calcineurin-inhibiting drugs, CsA and tacrolimus, have pro-oxidant activity and they increase the susceptibility of LDL to oxidation. Neoral formulation is fortified with DL-alpha tocopherol and therefore provides protection against oxidation. The present study clearly demonstrates the benefit of giving vitamin C and E supplements to patients taking tacrolimus and this seems to be particularly important during the early period after transplantation.

Quantity of human cytomegalovirus (CMV) DNAemia as a risk factor for CMV disease in renal allograft recipients: relationship with donor/recipient CMV serostatus, receipt of augmented methylprednisolone and antithymocyte globulin (ATG).

A prospective longitudinal study of 87 renal allograft recipients identified 31 patients with cytomegalovirus (CMV) viraemia. Previous studies have identified CMV viraemia, donor positivity, and CMV load in urine as independent risk factors for disease following renal transpl antation. We used quantitative-competitive polymerase chain reaction (QC-PCR) to quantify the CMV DNA load in blood from these patients, and report that it is a significant and independent risk factor for CMV disease. Patients with symptomatic CMV infection had significantly higher maximum CMV loads than those with no disease (P = .0003). We also found that peak loads were significantly higher in individuals experiencing primary CMV infection (P < .01), and CMV re-infection (P < .05) compared with recipients reactivating endogenous CMV. Univariate analysis revealed that CMV DNA load in blood, donor seropositivity, and receipt of antithymocyte globulin (ATG) were all significantly associated with disease (P = .005, .04, and .05, respectively). However, the association of donor/recipient serostatus, and receipt of ATG became nonsignificant in multivariate analyses whereas the significance of the quantity of CMV DNAemia was maintained, illustrating that CMV load plays a central role in the pathogenesis of CMV disease.