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Background Kidney transplantation is associated with an increased risk of bone fracture and rapid loss of bone mineral density after kidney transplantation. Study Design Randomized controlled trial. Setting & Participants Patients were randomly assigned to treatment (n = 46) or control (no treatment; n=47) groups. Patients were stratified according to parathyroid hormone level and sex. Those with parathyroid hormone level less than 150 pg/mL were excluded. Intervention The treatment and control groups received pamidronate, 1 mg/kg, perioperatively and then at 1, 4, 8, and 12 months or no treatment, respectively. All received calcium (500 mg) and vitamin D (400 units) daily. Immunosuppression was cyclosporine and prednisolone, with no difference in dosing between the 2 groups. Outcomes & Measurements Bone mineral density was evaluated by means of dual-energy x-ray absorptiometry of the lumbar spine and hip at baseline and 3, 6, 12, and 24 months, with the primary end point at 1 year of percentage of change in bone mineral density from baseline. Clinical fractures were recorded and also evaluated by means of spinal radiographs at baseline and 1 and 2 years. Results Pamidronate protected bone mineral density at the lumbar spine; bone mineral density increased by 2.1% in the treatment group and decreased by 5.7% in the control group at 12 months ( P = 0.001). Protection was also seen in Ward's area of the hip ( P = 0.002) and the total hip ( P = 0.004). There was no difference in femoral neck bone mineral density loss between the 2 groups. Fracture rates in the treatment and control groups were 3.3% and 6.4% per annum, respectively. Limitations This study was not powered to detect differences in fracture rates. Conclusion Pamidronate protects against posttransplantation bone loss at the lumbar spine and Ward's area of the hip.

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.

Human cytomegalovirus can cause a diverse range of diseases in different immunocompromised hosts. The pathogenic mechanisms underlying these diseases have not been fully elucidated, though the maximal viral load during infection is strongly correlated with the disease. However, concentrating on single viral load measures during infection ignores valuable information contained during the entire replication history up to the onset of disease. We use a statistical model that allows all viral load data sampled during infection to be analysed, and have applied it to four immunocompromised groups exhibiting five distinct cytomegalovirus-related diseases. The results show that for all diseases, peaks in viral load contribute less to disease progression than phases of low virus load with equal amount of viral turnover. The model accurately predicted the time of disease onset for fever, gastrointestinal disease and pneumonitis but not for hepatitis and retinitis, implying that other factors may be involved in the pathology of these diseases.

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.

Many renal transplant centres now try to avoid blood transfusion prior to renal transplantation, to avoid alloimmunization due to antibody production against donor antigens usually present on contaminating white cells. Post- or peri-operative transfusions are usually not considered to present problems, since the patient is heavily immunosuppressed. We present a patient who suffered a rare transfusion reaction, that we believe may have initiated a severe vascular rejection of a kidney transplant, probably mediated by Kidd blood group antigens.

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.

Forty-eight patients who provided 2 consecutive blood samples that tested positive for cytomegalovirus DNA by polymerase chain reaction (PCR) were randomized to receive either full-dose ganciclovir ( 5 mg/kg intravenously [iv] twice daily) or half-dose ganciclovir (5 mg/kg iv once daily) plus half-dose foscarnet (90 mg/kg iv once daily) for 14 days. In the ganciclovir arm, 17 (71%) of 24 patients reached the primary end point of being CMV negative by PCR within 14 days of initiation of therapy, compared with 12 (50%) of 24 patients in the ganciclovir-plus-foscarnet arm (P = .12). Toxicity was greater in the combination-therapy arm. In patients who failed to reach the primary end point, baseline virus load was 0.77 log(10) higher, the replication rate before therapy was faster (1.5 vs. 2.7 days), and the viral decay rate was slower (2.9 vs. 1.1 days) after therapy. Bivariable logistic regression models identified baseline virus load, bone-marrow transplantation, and doubling time and half-life of decay as the major factors affecting response to therapy within 14 days. This study did not support a synergistic effect of ganciclovir plus foscarnet in vivo.

Background: Most previous studies demonstrating the feasibility of transjugular kidney biopsy have used a modified Colapinto aspiration biopsy needle. We present 25 high-risk patients, with contraindications to percutaneous renal biopsy, who underwent transjugular kidney biopsy using a transvenous side-cut needle. This technique is easier to learn and can be performed by an interventional radiologist with transjugular liver biopsy experience and equipment. The needle is designed for optimal cortical sampling but has a high incidence of capsular perforation. Elective coil embolization was used in selected patients to reduce the risk of bleeding. Methods: We retrospectively reviewed the indications for obtaining renal histology, based on clinical presentation, and the specific indications for transjugular biopsy. Transjugular kidney biopsy was assessed for sampling effectiveness and adequacy, the impact of histology on patient management, and technique complication rates. Results: Renal tissue was obtained in 23 cases, with diagnostic biopsies in 21 of 23 (91.3%). A mean of 3.5 cores were obtained with 9.9 glomeruli per procedure for light microscopy (range, 0 to 32), 2.2 (range, 1 to 7) for electron microscopy, and adequate tissue for immunoflorescence available in 11 of 23 biopsies. Histology influenced patient management in all 23 cases. Capsular perforation was recorded in 73.9% (17 of 23) of cases with 6 undergoing elective coil embolization. Two major complications occurred, both in patients with multiple risk factors for bleeding. One required coil embolization of an arterio-calyseal system fistula. A further patient developed renal vein thrombosis 6 days after a failed transjugular kidney biopsy. Conclusion: Transjugular kidney biopsy provides a histological diagnosis in high-risk patients, making an important contribution to patient management.

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 40mg 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 μmol/L vs. 160 μmol/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.

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.

however, his liver extended 4 cm below the right costalmargin and the spleen was just palpable. Urine outputWe report two cases of renal, hepatic and respiratory was 20 ml/h with only red cells detected in his urine,failure occurring with the haemophagocytic syndrome of which

Minimal change nephropathy (MCN) is the dominant cause of idiopathic nephrotic syndrome in childhood and accounts for 25% of cases of adult nephrotic syndrome [1]. Each new episode of nephrotic syndrome adversely affects quality of life and is associated with complications including infection, thromboembolism and urinary loss of binding transport proteins. Proteinuria usually remits with high dose corticosteroid treatment; however, a significant minority responds incompletely or relapses frequently, providing a difficult therapeutic challenge. Furthermore, the management of frequent relapses with multiple courses of corticosteroids is associated with appreciable morbidity, including muscle atrophy, skin fragility and growth retardation. We report the use of sirolimus (rapamycin) in combination with tacrolimus (FK-506) to induce and maintain remission successfully in a case of chronic resistant MCN. To our knowledge, this is the first report of sirolimus/tacrolimus combination therapy in the treatment of MCN.

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.

A high affinity chimeric CD25 mAb (chRFT5: SDZ CHI 621) blocking interleukin-2 binding to the interleukin-2 receptor alpha-chain was evaluated in a phase I/II study in human renal cadaveric transplantation. The chRFT5 was well tolerated with no immediate adverse effects during 6 spaced infusions (from before transplantation to day 24) in 24 patients escalating from 2.5- to 25-mg dosages. The chRFT5 had a long terminal half-life with a mean of 13.1 days. There was good correlation between the detection of chRFT5 in the serum by radioimmunoassay, the coating and suppression of CD25 on T cells, and antibody activity in patient serum samples. The chRFT5 activity persisted in vivo for up to 120 days. No antibody response to the chRFT5 was detected in any of the patients, even though two patients who required treatment with antithymocyte globulin or OKT3 developed xenogeneic antiglobulin responses while chRFT5 was still present in vivo. There was a 33% incidence of rejection and the first rejection episode always occurred during chRFT5 therapy. Patients who did not reject during therapy did not reject during the first year following transplantation. Equal numbers of patients received dual and triple immunosuppressive therapy together with chRFT5. Posttransplant lymphoproliferative disorder developed in 2 patients, both on triple therapy, at 9 months after transplantation. The disorder did not develop in any patient receiving dual therapy, and no further cases have been observed to a minimum of 2 years' follow-up. No other viral, fungal, or bacterial infectious complications were prevalent in patients treated with chRFT5.

SummaryBackgroundCytomegalovirus end-organ disease can be prevented by giving ganciclovir when viraemia is detected in allograft recipients. Values of viral load correlate with development of end-organ disease and are moderated by pre-existing natural immunity. Our aim was to determine whether vaccine-induced immunity could do likewise.MethodsWe undertook a phase-2 randomised placebo controlled trial in adults awaiting kidney or liver transplantation at the Royal Free Hospital, London, UK. Exclusion criteria were pregnancy, receipt of blood products (except albumin) in the previous 3 months, and simultaneous multiorgan transplantation. 70 patients seronegative and 70 seropositive for cytomegalovirus were randomly assigned from a scratch-off randomisation code in a 1:1 ratio to receive either cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant or placebo, each given at baseline, 1 month and 6 months later. If a patient was transplanted, no further vaccinations were given and serial blood samples were tested for cytomegalovirus DNA by real-time quantitative PCR (rtqPCR). Any patient with one blood sample containing more than 3000 cytomegalovirus genomes per mL received ganciclovir until two consecutive undetectable cytomegalovirus DNA measurements. Safety and immunogenicity were coprimary endpoints and were assessed by intention to treat in patients who received at least one dose of vaccine or placebo. This trial is registered with ClinicalTrials.gov, NCT00299260.Findings67 patients received vaccine and 73 placebo, all of whom were evaluable. Glycoprotein-B antibody titres were significantly increased in both seronegative (geometric mean titre 12 537 (95% CI 6593–23 840) versus 86 (63–118) in recipients of placebo recipients; p

Summary During a 6 year period 60 patients with atherosclerotic renovascular disease were followed by a single renal unit. Angiotensin converting enzyme inhibitors were being taken by 22% of patients at the time of diagnosis of the atherosclerotic renovascular disease. Intervention to revascularize renal tissue by surgery or angioplasty was performed in 32 patients. Revascularization was not undertaken because of unilateral disease, patient preference, poor operative risk or renal size. The mean age for the nonintervention group was 66.9 years and 63.4 years for the intervention group. Peripheral vascular, disease was common in both groups (96% nonintervention group versus 86% intervention group). There was a statistically significant difference in improvement in renal function in the intervention group (34.4% versus 10.7%) in spite of more patients being dialysis dependent in the intervention group (28.1% versus 14.3%). There was no statistically significant difference in survival between the two groups although the trend was for better survival in the group with intervention. Patients presenting with impaired renal function and atherosclerotic renovascular disease can have useful improvement in renal function with revascularization without any detriment to survival.

We report a patient with phenytoin-induced pseudolymphoma mimicking cutaneous T-cell lymphoma (CTCL). Despite withdrawal of phenytoin, there was persistence of the cutaneous eruption and lymphadenopathy. Southern blot analysis of immunoglobulin and T-cell receptor genes was therefore used to assess whether there was a clonal lymphoid expansion. However, no rearrangement of the beta T-cell receptor gene or immunoglobulin heavy-chain gene was detected in tissue DNA from skin and lymph nodes. One year later the patient became asymptomatic, although he is still at risk of developing a true malignant lymphoma in the future, a condition known as pseudo-pseudolymphoma. It is suggested that genotypic studies may help in the initial diagnosis and the subsequent management of such patients.

We have conducted a double-blind, placebo-controlled trial of human lymphoblastoid interferon prophylaxis of cytomegalovirus (CMV) infection in 74 renal transplant recipients. Interferon (3 x 10(6) units was given thrice weekly for the first 6 weeks, then twice weekly for a further 8 weeks. During the period of interferon therapy, the incidence of CMV excretion was lower in the interferon group (28% versus 50%, P = 0.065), mainly due to a significant reduction of CMV reactivation (9% versus 56%, P = 0.02). However, for the whole study period (including the follow-up period after interferon therapy), there was no difference in the incidence of CMV excretion (44% versus 53%). The onset of CMV excretion was delayed (8.2 +/- 0.8 to 20.9 +/- 5.5 weeks, P = 0.04). The duration of CMV excretion was also reduced (11.1 +/- 3.1 to 29.4 +/- 5.7 weeks, P = 0.008). The number of positive CMV isolates from urine and saliva was significantly less in the interferon group. There was no difference in the site of CMV excretion. Of the patients in the treatment group who excreted CMV, 43% developed disease as compared to 63% in the control group (difference not significant). There was also no significant difference in the severity of the CMV infection between the two groups. Benefit appears to be restricted to seropositive recipients of seronegative kidneys. The interferon regime used in this study was well tolerated, with mild fever being the only reported side-effect. No patient had to stop therapy because of toxicity. The incidence of rejection and graft loss was not different between the two groups.

Human cytomegalovirus (HCMV) infection is associated with a series of direct and indirect effects following renal transplantation. However, the presence of HCMV in the kidney and its relationship with acute rejection and long-term graft function remain to be fully elucidated. Sixty-two biopsies derived from 30 renal transplant recipients with signs of clinical rejection were analyzed for HCMV using a sensitive in situ DNA hybridization method. Biopsies were also subjected to staining with anti-C4d antibodies and an anti-caspase 3 antibody to detect humoral rejection and apoptosis, respectively. In 21 patients, serial serum creatinine levels over 5 years of follow-up were analyzed. HCMV DNA was detected in biopsies from 21/30 (70%) of the patients and 32/62 (52%) of the individual biopsies. HCMV DNA was detected early after transplant and was localized to renal tubule epithelial cells but not associated with apoptosis. HCMV DNAemia developed within 2 weeks of detecting HCMV DNA in the biopsy in 53% of patients. Ninety percent of patients experiencing HCMV disease had HCMV DNA in their biopsy. HCMV DNA was equally distributed between patients with or without histological evidence of acute rejection and was detected more frequently in patients with peritubular C4d deposits. Creatinine levels at 12 months post-transplant were significantly higher in patients with HCMV DNA and remained elevated over the 5 years of follow-up. HCMV DNA is frequently detected in renal tubular epithelial cells early after renal transplantation, precedes DNAemia and is associated with poor long-term graft function.

Background. Epstein-Barr virus (EBV) is associated with posttransplant lymphoproliferative disease. We monitored the incidence of EBV viraemia in adult renal transplant recipients and investigated the association with clinical parameters. Methods. Whole blood from 115 renal transplant patients was tested regularly by quantitative polymerase chain reaction (PCR) assay for EBV DNA during the first 90 days posttransplantation. Results. Sixty four of 115 (56%) patients had detectable EBV DNA in blood (>100 copies/mL) on at least one occasion. The median time to first DNA detection was 15 days post-transplant and median viral load was 598 copies/mL (range 119–53,649 copies/mL). Multivariate Cox-regression analyses showed that patients receiving mycophenolate mofetil (MMF) on the day of transplant had a significantly lower risk of EBV viraemia compared to those who received no MMF (Hazard ratio=0.518, 95% CI 0.307–0.875, p=0.014). Conclusions. EBV viraemia is common during the early posttransplant period in adult renal transplant recipients. Our results suggest a role of MMF in preventing EBV viraemia, however further work is required to identify the mechanism(s) involved.

Background. BK nephropathy (BKN) is an important cause of renal transplant dysfunction, believed to be associated with higher levels of immunosuppression. We assessed the experience of BKN in renal transplant patients in the London region. Methods. All six London transplant centers participated and case notes of patients with BKN in 2004 to 2005 were reviewed. Results. There were 17 cases of BKN, giving an incidence of 2.1%. Median time to diagnosis was 9 months. Median baseline creatinine rose from 150 to 196 μmol/L. At diagnosis, 16 patients were on tacrolimus, 15 on mycophenolate mofetil, and 10 on triple therapy with tacrolimus, mycophenolate mofetil, and prednisolone. Management of BKN involved reducing immunosuppression; cidofovir was used in two patients and methylprednisolone in five for acute rejection. Median follow-up time was 29.2 months. Creatinine returned to baseline in four patients, remained elevated in 12 and one patient lost his graft. The new median baseline creatinine was 216 μmol/L. Eight patients underwent repeat biopsies of which four became negative for BKV and three subsequently cleared the virus on blood and urine polymerase chain reaction and urine decoy cells. Overall, eight patients cleared the virus. None of age, sex, viral load, or biopsy characteristics (Banff ct score, Drachenberg grade, and number of BKV positive cells) were associated with poorer outcome when patients with increase in creatinine of less than 30% (n=7) or more than 30% (n=10) from baseline were compared. Conclusion. The incidence of BKN in this study is comparable with previous studies, with more favorable outcomes. It supports the association of BKN with potent immunosuppression.

Seventy-seven stable, nondiabetic, cadaveric renal transplants were randomized at 1 year to convert from cyclosporin A to azathioprine or to continue on cyclosporin A. Prednisolone was increased twofold during the period of conversion, and there was a 3-week overlap period during which azathioprine and cyclosporin A were given. No grafts were lost due to rejection related to conversion, but 9 of the 33 patients who were randomized to convert experienced rejection episodes and 6 were returned to cyclosporin A. Conversion to azathioprine resulted in a drop in creatinine and improvement in blood pressure control. In the group randomized to stay on cyclosporin A, 6 patients had to be subsequently converted to azathioprine because of cyclosporin A toxicity in spite of well-controlled plasma levels. The creatinine levels after successful conversion remained stable whereas those of the patients continuing on cyclosporin A showed a progressive decline. We conclude that conversion from cyclosporin A to azathioprine can be achieved safely. Progressive deterioration in graft function with continuing cyclosporin A therapy does occur and should be taken as an indication for conversion.

Background The significance of late urinary tract infections (UTIs) after renal transplantation and their association with scarring and graft dysfunction remains controversial. We sought to define the prevalence of renal scarring in allograft recipients with a history of late recurrent UTIs, to determine whether the presence of vesicoureteric reflux (VUR) confers an increased risk of scarring and to establish whether scarring correlates with graft dysfunction. Methods Among 307 renal allograft recipients, we identified 56 (18%) with late recurrent UTIs (> or =3/year). A total of 32 patients had undergone further investigation by both 2,3 dimercapto-succinic acid single-photon emission computed tomography (99mTc-DMSA SPECT) scan and micturating cystourethrogram (MCUG). Results Of the 32 patients, 24 (75%) had scars on 99mTc-DMSA SPECT and 15 (47%) had reflux on MCUG. Thirteen of these 15 patients with reflux (87%) had scars, although there was no significant correlation between number of scars and degree of reflux. Eleven of 17 patients (65%) with UTIs but without VUR had scars, as did 12 of 14 (86%) with previous graft pyelonephritis. The pattern of scarring (typically multiple focal cortical defects) suggested infection as the cause. This pattern was not seen in a contemporary cohort with vascular occlusions and was rarely seen in patients with chronic allograft nephropathy. Scarring was not associated with inferior graft survival (median follow-up, 15 years). Conclusions In patients with late UTIs, renal scarring is a frequent finding. Scarring may occur even in asymptomatic patients without VUR. The lack of an effect on graft survival may reflect successful intervention with prophylactic antibiotics and surveillance urine cultures. Late recurrent UTIs may be damaging to renal allografts, even in the absence of reflux.

OBJECTIVE(S): Apart from proper hydration, only oral N-acetylcysteine (NAC) has shown efficacy in reducing radiographic contrast media (RCM)-induced acute renal failure, though its benefit has been challenged. We investigated the effect of intravenous (i.v.) NAC on renal function in patients with vascular disease receiving RCM for angiography. METHODS: Single-center, randomized, double-blind, placebo-controlled trial. Based on a previous study, a trial with 44 patients each in placebo and treatment arms would give at least 80% power to show a statistically significant difference at the 5% level. Vascular patients undergoing angiography were consented and segregated into those whose serum creatinine (SC) level was normal or raised (men >1.32 mg/dl; women >1.07 mg/dL). All patients received 500 mL i.v. normal saline 6 to 12 hours prior to and then after angiography. Groups with normal SC and raised SC were randomly assigned to either 1 g of NAC with normal saline before and after angiography or nothing (placebo). Main outcome measures were change in SC and creatinine clearance (CrCl) as measured 1, 2, and 7 days postangiography (with comparison between active and placebo groups using unpaired t test) and incidence of acute renal decline (>25% or 0.5 mg/dL rise in SC) at 48 hours (with comparison between active and placebo using the Fisher exact test). RESULTS: Forty-six patients received NAC (29 normal SC, 17 raised SC), and 48 received placebo (27 normal SC, 21 raised SC). There was no significant difference in postangiography SC or CrCl at any of the time points measured between NAC and placebo in patients with either normal or raised SC. In the raised SC group, 3 patients from both the NAC and placebo groups suffered acute renal declines. Importantly, at 48 hours, the impaired SC group had a significant reduction in CrCl (-14% +/- 41% vs +18% +/- 58%: P = .0142) and a significant rise in SC (+7.0 +/- 25% vs -1.6% +/- 10%; P = .0246) when compared with the normal SC group. CONCLUSIONS: NAC (i.v. at 1 g) precontrast and postcontrast does not confer any benefit in preventing RCM-induced nephropathy in vascular patients. Patients with pre-existing raised SC have an increased risk of renal impairment as defined by a fall in CrCl and a rise in SC post-RCM when compared with patients with normal SC who appear to benefit from hydration.

Background. Treatment of adults with idiopathic membranoproliferative glomerulonephritis (IMPGN) is often unrewarding with similar to60% of patients progressing to end-stage renal failure within 10 years. Although children with IMPGN may respond to Steroid therapy, there is no significant benefit to treating adult IMPGN patients with immunosuppression.Methods. Outcome measures in five patients with IMPGN who were treated with oral prednisolone and mycophenolate mofetil (MMF) (treatment group) were compared with six patients with IMPGN who did not receive immunosuppression (control group).Results. There was no significant difference between either group in baseline clinical characteristics or systolic and diastolic blood pressure during observation. In the treatment group, there was a significant reduction in proteinuria from a baseline of 5.09 to 1.97 g/24 h (P = 0.003) at 6 months, 1.96 g/24 h (P = 0.003) at 12 months and 2.59 g/24 h (P = 0.015) at 18 months. There was no significant change in proteinuria over 18 months in the control group. Serum creatinine concentration and creatinine clearance did not change significantly over 18 months in the treatment group. In the control group, there were significant changes in serum creatinine and creatinine clearance over 18 months [baseline 103 to 159 mumol/l (P = 0.004) and baseline 108 to 67 ml/min (P > 0.001), respectively] when compared to baseline, although the differences were not significant when the two groups were compared directly.Conclusions. This preliminary study suggests that in the short term, the combination of MMF and prednisolone can significantly reduce proteinuria and may preserve renal function in patients with IMPGN.

A 47-year-old female received a well-matched cadaveric renal transplant for treatment of end-stage renal failure secondary to type 1 diabetes. The kidney had three arteries on a patch with a single vein and was anastamosed end to side onto the corresponding right external iliac vessels. The iliac vessels were normal at the time of surgery. The post-operative period was complicated by bleeding around the transplant and formation of a peri-transplant collection which required repeated surgical drainage. During the first 4 weeks, she had delayed graft function and was dialysed via an internal jugular line. She did not have any femoral venous access inserted. A transplant biopsy on day 23 showed acute tubular necrosis and mild tubulitis, suggestive of rejection, and she was treated with methylprednisolone. By day 36 post-transplant, she was noted to have a swollen right leg. A leg venogam excluded thrombosis but revealed a tight right iliac vein stenosis (Figure 1a) for which she underwent a successful venoplasty with good radiological resolution (Figure 1b). Her urine output started to improve, and by day 41 she was dialysis independent with a falling creatinine. Her creatinine stabilized at 140–150 mmol/l but 72 days posttransplant, her creatinine started to rise in association with swelling of her leg. On day 81 post-transplant (creatinine 194 mmol/l), she underwent a further successful venoplasty. One year post-transplant, the patient remains well with a creatinine of 128 mmol/l and no swelling of her leg. Discussion

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 μmol/l (1.5 mg/dl), calcineurin inhibitors and the use of cardioselective β blockers. Two patients with pre-pregnancy SCr > 200 μmol/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 μmol (1.75 mg/dl). Patients with pre-pregnancy SCr 200 μmol/l are at greatest risk.

Nearly 30% of patients with autoimmune thyroid disease have proteinuria w1x. Membranous glomerulonephritis is the most common finding when thyroid disease is associated with nephrotic range proteinuria. There are only three previous reports of autoimmune thyroid disease and minimal change glomerular disease (MCD). We report the case of a patient in whom Graves’ disease and MCD were diagnosed simultaneously and in whom relapse of the Graves’ disease was invariably accompanied by relapse of MCD.

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.

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 CuCl 2 at 37°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-α 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.

Three cases of cerebral venous sinus thrombosis (CVST) occurring in patients with minimal change nephrotic syndrome (MCNS) are described. Personality change in two of these patients was wrongly attributed to steroid therapy prior to the discovery of the CVST. In addition, von Willebrand factor (vWF) levels were grossly elevated in one patient, during a previous relapse of MCNS, prior to developing CVST, and may be a useful prognostic tool in predicting thrombotic events in nephrotic patients.

Renal transplant recipients are at risk of severe morbidity and mortality from CMV disease. We have undertaken routine surveillance for CMV shedding on 133 transplant recipients, using a rapid culture technique, in order to assess the incidence of CMV infection and disease in these patients and to assess the prognostic significance of detection in whole blood, throat swab specimens, or urine. Donor CMV seropositivity was associated with posttransplant CMV infection (P < 0.05) and disease (P = 0.06). CMV infection and disease were associated with the receipt of anti-T-cell antibodies (P < 0.0001 and P = 0.08, respectively). First shedding of virus from any site occurred earlier posttransplant in those recipients who developed disease (median 39 days) than in those who did not (median 55 days)(P < 0.05). Detection of virus in blood occurred at a median time of 16 days before onset of symptoms, compared with 9 days before symptoms in urine, and 3 days after onset of symptoms from throat swab. A positive blood culture represented a relative risk of 7.1 for the subsequent development of disease, compared with 2.1 and 1.8 for positive urine and saliva cultures, respectively. The addition of urine cultures to blood cultures increased the sensitivity for identification of those at risk--however, the relative risk was reduced to 5.8. We conclude that routine surveillance for CMV shedding, especially in blood and urine, can identify recipients at high risk of CMV disease, and propose a trial in which those with asymptomatic viremia are allocated to receive ganciclovir or placebo, in order to assess the efficacy of "preemptive" therapy in this group of patients.

Total cholesterol (TC) levels were lower than expected in some patients with advanced renal disease and nephrotic-range proteinuria. Studies of 35 clinically stable nonuremic patients and of 12 nephrotic patients with advancing renal failure were therefore performed. Analysis of pooled biochemical data from 35 patients who were hypercholesterolemic on entry to the clinic revealed a positive correlation between TC and reciprocal creatinine (l/Cr) while serum albumin (ALB) was negatively correlated with l/Cr and TC. In the 12 nephrotic patients with negative reciprocal creatinine slopes there was a strong correlation between the slopes of l/Cr and TC. These data suggest that plasma cholesterol falls in the nephrotic hypercholesterolemic patients in whom renal disease progresses, and that the slopes of plasma cholesterol and reciprocal creatinine are closely related.

Changes in renal function caused by angiotensin-converting-enzyme (ACE) inhibitors can be detected on 99mTc-DTPA renography so that DTPA scanning before and after a single dose of captopril can be used to screen for renovascular disease. We have performed captopril-DTPA scans with renal arteriography on 104 patients, of whom 27 had renal artery stenosis, all due to atheroma. Using a 5% fall in divided function or a delay of greater than 15 min in time to peak activity on one side after captopril, or the finding of greater than 90% divided function on one side before captopril as criteria for a positive scan, a sensitivity of 93% and specificity of 70% was achieved. The negative predictive value of the test in our population was 93%. Bilateral improvement in renographic function after captopril was seen in patients with accelerated phase hypertension. The presence of bilateral renal artery disease did not reduce the sensitivity of the test, but sensitivity was reduced (75%) in patients with renal impairment. Clinical characteristics in our patients most strongly associated with renal artery stenosis were abdominal bruit, recurrent left ventricular failure, and peripheral vascular disease. In view of the well-publicized risks of ACE inhibitor therapy, care should be exercised in the use of these agents in such patients.

Four patients presented with nephrotic syndrome associated with hypothyroidism; none had thyroid antibodies. Hypothyroidism resolved on remission of nephrotic syndrome in two patients; thyroxine (T4) replacement was ineffective during periods of gross proteinuria in another, and the fourth had had normal thyroid function a year before presentation. Urinary T4 excretion was measured in ten further patients with proteinuria. It was detectable in the urine in five, who had significantly lower serum free T4 (8.5 [95% confidence interval 5.8-11.2] vs 13.9 [11.1-16.7] pmol/l; p less than 0.01) and free triiodothyronine (3.1 [2.2-4.0] vs 4.9 [3.8-6.0] pmol/l; p less than 0.01) concentrations than the five patients without detectable urinary T4.

Renal transplant patients (n = 116) attending an outpatients clinic were screened for hypomagnesaemia. No azathioprine-treated patients (n = 46) but 24% (17 of 70) of the cyclosporin treated patients were hypomagnesaemic. The hypomagnesaemia in all cases was associated with a renal magnesium leak. This leak did not correlate with plasma bicarbonate, urate, calcium, cyclosporin or creatinine concentrations, nor did it correlate with the use of loop diuretics or duration of the transplant. A renal magnesium leak is common in renal transplant patients treated with cyclosporin and it is independent of other markers of nephrotoxicity.

The beneficial effect of elective transfusion on renal allograft survival must be weighed against the risks of sensitisation. We report a randomised controlled trial in which patients in end-stage renal failure who were non-parous and not previously transplanted or transfused, were entered in a transfusion protocol during which one group received no drugs (controls), one received azathioprine, and one received cyclosporin. Each group was given three identical transfusions of leucocyte-enriched fresh blood at 2-3 week intervals. The transfused blood was of known HLA type and donor/recipient pairs were completely mismatched. Sensitisation rates were assessed by T and B cell cross-matches between donor and recipients and by the screening of all sera against lymphocytes from 40 random donors. Fifty-one patients have completed the protocol, 20 in the control group, 12 in the azathioprine group, and 19 in the cyclosporin group. The sensitisation rate in the control group was 30%, occasionally of high titre, and persistent. In the azathioprine group, 25% developed anti-HLA antibodies and reactivity was of high titre and was broadly specific. Sensitisation in the cyclosporin group was 10%, was narrowly specific, reacting with only 10% of a panel, and was transient. There was no difference in graft survival between the groups. We conclude that cyclosporin therapy concurrent with third-party transfusion reduces the incidence, titre, and duration of sensitisation.

Biopsies of normal kidneys taken at time of transplantation were studied using a variety of immunofluorescent and cytochemical techniques. A heterogeneous population of HLA-DR+ cells was found, mainly confined to the intertubular interstitium. The majority of these cells (80%) were positive when stained with a rabbit anti-factor VIII antiserum suggesting that they were endothelial cells. A minority however (20%) were factor VIII- but were positively stained with FMC17, a monoclonal antibody (McAb) directed against human monocyte/macrophage antigens. Positive staining of this subpopulation was also noted with RFD1, a McAb which reacts with an antigen on human interdigitating cells (ID cells). Cytochemical reactions revealed that these cells contain adenosine triphosphatase (ATPase) and acid phosphatase (ACP) and thus do not conform to the phenotype of tissue histiocytes. The phenotype of this latter population is identical with that of the ID cells found in tonsil, thymus and spleen and it is suggested that they play a major role in initiating the process of renal allograft rejection.

The relative importance of increased lipoprotein synthesis and decreased lipoprotein catabolism is examined in 13 patients with untreated nephrotic syndrome by the use of intravenous fat tolerance tests analysed in relation to other parameters of lipid metabolism. Increased lipoprotein synthesis in nephrotic patients was indicated by the fact that at a given fractional clearance rate of Intralipid (K2), nephrotic patients had higher serum TG concentrations than did control subjects. A defect in lipoprotein catabolism was also suggested by the frequent finding of intermediate density lipoproteins on electrophoresis and the marginally low (p = 0.05) mean K2 in nephrotic patients. A highly significant (p less than 0.001) positive correlation between HDL-cholesterol concentrations and postheparin fractional clearance rates (K'2) of Intralipid led to the speculation that in the severe nephrotic state (albumin less than 20 g/l) the loss of high density lipoproteins may contribute to the hyperlipidaemia.

The urinary excretion of two proteins, B-2-microglobulin (beta 2M) and N-acetyl-B-D-glucosaminidase (NAG) was measured in 25 patients with rheumatoid arthritis (RA) on nonsteroidal anti-inflammatory drugs (NSAID). Although beta 2M excretion was normal NAG excretion was raised. As NAG excretion by a group of osteoarthritis patients receiving similar doses of NSAIDs was normal, it is concluded that rheumatoid disease per se may be associated with mild renal tubular dysfunction. Twelve of the above 25 patients were then given oral triethylphosphine-gold (auranofin) 6 mg daily and urinary beta 2M and NAG were measured after 6 months' treatment. Urinary excretion of beta 2M and NAG was also measured in 13 patients with RA established on intramuscular sodium aurothiomalate (MGST) and NSAIDs. Neither auranofin nor myocrisin were found to further significantly increase beta 2M and NAG excretion. These results suggest that gold compounds are not toxic to renal tubular epithelium.

The value of captopril-enhanced 99mTc DTPA scintigraphy as a screening test for renovascular disease was prospectively studied in 44 hypertensive patients suspected to have renal-artery stenosis. Renal impairment (plasma creatinine greater than 130 mumol/l) was present in 29 patients. At angiography 13 patients had unilateral stenosis, two bilateral stenosis, and 29 patients had no renovascular disease. Captopril induced a fall in split renal function in the kidney ipsilateral to the stenosis in all patients with unilateral disease (mean 52 +/- 23% to 44 +/- 21% of total renal function; P less than 0.001). A positive captopril scintigram (defined as a fall of 5% or more in split renal function) had a sensitivity of 85% and a specificity of 72% in the detection of unilateral renal-artery stenosis. Captopril-enhanced 99mTc DTPA scintigraphy is a promising non-invasive screening test for the detection of renal-artery stenosis.

We assessed the nephrotoxicity of ionic and non-ionic radiocontrast material (CM) in two groups of patients in a prospective study. One group of 25 potential live kidney donors was studied following conventional renal angiography, carried out as part of the routine pre-operative assessment. The other group of 49 renal transplant patients with varying degrees of renal impairment was studied following digital vascular imaging carried out for investigation of hypertension. Plasma creatine, urinary N-acetyl-D-glucosaminidase (NAG), urinary microglobulin (B2M) and urinary protein excretion were measured before and after the imaging procedure. There were no significant changes in these parameters following digital vascular imaging, but there were increases in plasma creatinine (p less than 0.005) and urinary NAG creatinine ratio (p less than 0.002) in the conventional angiography group following the procedure. Substantial proteinuria developed in 35% of patients following conventional angiography. The differences in nephrotoxicity of radiocontrast agents during the two procedures could not be accounted for by the dose of material used, but probably reflect the effect of differences in the route of administration on the maximal concentration of the material reaching the kidney. Non-ionic radiocontrast material proved less toxic than ionic and may be preferable in conventional angiography.

Patients on continuous ambulatory peritoneal dialysis (CAPD) were studied for three years. 29 of them who had been on CAPD for six months or more were compared with patients on intermittent peritoneal dialysis (IPD) and on haemodialysis (HD). CAPD patients had significantly higher levels of HDL-cholesterol than HD patients. Urea, potassium, phosphate, and urate levels were significantly lower, and haemoglobin levels significantly higher, than in the IPD and HD groups. 43 CAPD patients studied had a peritonitis rate of 2.22 episodes per patient-year. CAPD offers an alternative form of dialysis to those unsuitable for HD, but until peritonitis rates can be reduced CAPD cannot rival HD as a long-term treatment.

Cyclosporine A enhances platelet aggregation. In view of the reported increase in thromboembolic episodes following cyclosporine A (CyA) therapy, the effect of this drug on platelet aggregation and thromboxane A 2 release was investigated. The addition of CyA, at therapeutic concentrations to platelet rich plasma from normal subjects in vitro was found to increase aggregation in response to adrenaline, collagen and ADP. Ingestion of CyA by healthy volunteers was also associated with enhanced platelet aggregation. The CyA-mediated enhancement of aggregation was further enhanced by the addition in vitro of therapeutic concentrations of heparin. Platelets from renal allograft recipients treated with CyA also showed hyperaggregability and increased thromboxane A 2 release, which were most marked at "peak" plasma CyA concentration and less so at "trough" concentrations. Platelet hyperaggregability in renal allograft patients on long–term CyA therapy tended to revert towards normal following the replacement of CyA with azathioprine. Hypertensive patients with renal allografts on nifedipine therapy had normal platelet function and thromboxane release in spite of CyA therapy. These observations suggest that CyA-mediated platelet activation may contribute to the pathogenesis of the thromboembolic phenomena associated with the use of this drug. The increased release of thromboxane A 2 (a vasoconstrictor) may also play a role in mediating CyA-related nephrotoxicity.