Guy H. Neild

Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study.

BACKGROUND Renal involvement is frequently present in antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitis and is an important cause of end-stage renal failure (ESRF). METHODS This retrospective, multicenter, sequential cohort study reports presenting features and outcome of 246 new patients diagnosed in London, UK, between 1995 and 2000. RESULTS Diagnostic subgroups were microscopic polyangiitis, 120 patients (49%); Wegeners granulomatosis (WG), 82 patients (33%); renal-limited vasculitis, 33 patients (13.5%); and Churg-Strauss angiitis, 11 patients (4.5%). Median age was 66 years, 57% were men, and median creatinine level at presentation was 3.87 mg/dL (342 micromol/L). ANCA was present in 92%. Cumulative patient survival at 1 and 5 years was 82% and 76%, respectively. Mortality was associated with age older than 60 years (P < 0.001), development of ESRF (P < 0.001), initial creatinine level greater than 2.26 mg/dL (200 micromol/L; P = 0.01), and sepsis (P < 0.048). ESRF occurred in 68 patients (28%), of whom 47% died. Fifty-six patients who presented with a creatinine level greater than 5.65 mg/dL (500 micromol/L) survived, and 31 patients (55%) achieved dialysis independence. Relapse occurred in 34% after a median of 13 months and was more common in patients with WG (P = 0.048) and proteinase 3-ANCA (P = 0.034). Leukopenia occurred in 41% and was associated with sepsis (P < 0.001). CONCLUSION Mortality and morbidity of ANCA-associated systemic vasculitis are improving compared with previous series, but remain high. Renal vasculitis often affects older patients, who have a particularly poor outcome. Early diagnosis improves outcome. Leukopenia, caused by immunosuppressive therapy, should be avoided because of the close association with sepsis and death.

Inhibition of Nitric Oxide Synthesis Reduces Infarct Size by an Adenosine-Dependent Mechanism

BACKGROUND Nitric oxide (NO) is both a potent endogenous vasodilator with potential to attenuate ischemia-reperfusion injury and a mediator of tissue injury. The aim of the present study was to investigate the mechanism by which prior inhibition of NO synthesis can lessen ischemia-reperfusion injury in the isolated rabbit heart. METHODS AND RESULTS We examined the effects of inhibition of NO synthesis on infarct size using a model of coronary artery ligation in isolated rabbit hearts perfused at a constant flow rate of 35 mL/min. Infarct size averaged 65% of the zone at risk after 45 minutes of ischemia and 180 minutes of reperfusion. The addition of 30 mumol/L NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis, to the perfusate reduced the infarct-to-risk (I/R) ratio to an average of 41% (P < .05 versus control). This effect was abolished by pretreatment with 75.5 mumol/L 8-p-sulfophenyl theophylline (SPT), an adenosine receptor antagonist (I/R ratio, 63%). Ischemic preconditioning (5 minutes of ischemia and 10 minutes of reperfusion) before 45 minutes of ischemia and 3 hours of reperfusion reduced the I/R ratio to an average of 21%, and this was not augmented by pretreatment with L-NAME (I/R ratio, 20%). However, all protection due to preconditioning and L-NAME was lost in hearts pretreated with SPT (I/R ratio, 59%). In a separate set of experiments, adenosine concentration in the coronary perfusate and myocardial lactate concentrations were measured. Treatment with L-NAME increased the average adenosine concentration in the perfusate from 5.7 mumol/L per 100 g of heart (control) to a peak of 24.0 mumol/L per 100 g of heart; however, there was no effect on average myocardial lactate concentration (control, 4.6 mumol/g dry wt; L-NAME, 5.5 mumol/g dry wt). In contrast, after 5 minutes of global ischemia, the average adenosine concentration peaked at 139.0 mumol/L per 100 g of heart, and the average myocardial lactate concentration increased to 27.1 mumol/g dry wt. CONCLUSIONS Infarct size limitation after inhibition of NO synthesis shares a common mechanism with that of ischemic preconditioning and is dependent on the release of adenosine. However, in this model, adenosine release after inhibition of NO synthesis is not secondary to myocardial ischemia. The protection of the heart against ischemic injury by adenosine appears to be concentration dependent.

Copper chelation-induced reduction of the biological activity of S-nitrosothiols.

1 The effect of copper on the activity of the S‐nitrosothiol compounds S‐nitrosocysteine (cysNO) and S‐nitrosoglutathione (GSNO) was investigated, using the specific copper chelator bathocuproine sul‐phonate (BCS), and human washed platelets as target cells. 2 Chelation of trace copper with BCS (10 μm) in washed platelet suspensions reduced the inhibition of thrombin‐induced platelet aggregation by GSNO; however, BCS had no significant effect on the anti‐aggregatory action of cysNO. BCS inhibited cyclic GMP generation in response to both cysNO and GSNO. 3 The effect of BCS was rapid (within 30 s), and could be abolished by increasing the platelet concentration to 500 times 109 1−1. 4 In BCS‐treated platelet suspensions, the addition of Cu2+ ions (0.37–2.37 μm) led to a restoration of both guanylate cyclase activation and platelet aggregation inhibition by GSNO. 5 The anti‐aggregatory activity of GSNO was reduced in a concentration‐dependent manner by the copper (I)‐specific chelators BCS and neocuproine, and to a smaller extent by desferal. No effect was observed with the copper (II) specific chelator, cuprizone, the iron‐specific chelator, bathophenanthroline sulphonate, or the broader‐specificity copper chelator, d‐penicillamine. 6 In both BCS‐treated and ‐untreated platelet suspensions, cys NO was more potent than GSNO as a stimulator of guanylate cyclase. In BCS‐treated platelet suspensions there was no significant difference between the anti‐aggregatory potency of cysNO and GSNO; however, in untreated suspensions, GSNO was significantly more potent than cysNO. Thus, when copper was available, GSNO produced a greater inhibition of aggregation than cysNO, despite being a less potent activator of guanylate cyclase. 7 The breakdown of cysNO and GSNO was measured spectrophotometrically by decrease in absor‐bance at 334 nm. In Tyrode buffer, cysNO (10 μm) broke down at a rate of 3.3 μm min−1. BCS (10 μm) reduced this to 0.5 μm min−1. GSNO, however, was stable, showing no fall in absorbance over a period of 7 min even in the absence of BCS. 8 We conclude that copper is required for the activity of both cysNO and GSNO, although its influence on anti‐aggregatory activity is only evident with GSNO. The stimulatory effect of copper is unlikely to be explained solely by catalysis of S‐nitrosothiol breakdown. The enhancement by copper of th anti‐aggregatory activity of GSNO, relative to cysNO, suggests that copper may be required for biological activity of GSNO which is independent of guanylate cyclase stimulation.

Role of a copper (I)-dependent enzyme in the anti-platelet action of S-nitrosoglutathione.

1 S‐nitrosoglutathione (GSNO) is a potent and selective anti‐platelet agent, despite the fact that its spontaneous rate of release of nitric oxide (NO) is very slow. Our aim was to investigate the mechanism of the anti‐aggregatory action of GSNO. 2 The biological action of GSNO could be mediated by NO released from S‐nitrosocystylglycine, following enzymatic cleavage of GSNO by γ‐glutamyl transpeptidase. The anti‐aggregatory potency of GSNO was not, however, altered by treatment of target platelets with the γ‐glutamyl transpeptidase inhibitor acivicin (1 mM). γ‐Glutamyl transpeptidase is not, therefore, involved in mediating the action of GSNO. 3 The rate of breakdown of S‐nitrosoalbumin was increased from 0.19 ± 0.086 nmol min−1 to 1.52 ± 0.24 nmol min−1 (mean±s.e.mean) in the presence of cysteine (P < 0.05, n = 4). Inhibition of platelet aggregation by S‐nitrosoalbumin was also significantly increased by cysteine (P < 0.05, n = 4), suggesting that the biological activity of S‐nitrosoalbumin is mediated by exchange of NO from the protein carrier to form the unstable compound cysNO. Breakdown of GSNO showed a non‐significant acceleration in the presence of cysteine, from 0.56 ± 0.22 to 1.77 ± 0.27 nmol min−1 (mean±s.e.mean) (P = 0.064, n = 4), and its ability to inhibit platelet aggregation was not enhanced by cysteine. This indicates that the anti‐platelet action of GSNO is not dependent upon transnitrosation to form cysNO. 4 Platelets pretreated with the copper (I)‐specific chelator bathocuproine disulphonic acid (BCS), then resuspended in BCS‐free buffer, showed resistance to the inhibitory effect of GSNO. These findings suggest that BCS impedes the action of GSNO by binding to structures on the platelet, rather than by chelating free copper in solution. 5 Release of NO from GSNO was catalysed enzymatically by ultrasonicated platelet suspensions. This enzyme had an apparent Km for GSNO of 12.4 ± 2.64 μm and a Vmax of 0.21 ± 0.03 nmol min−1 per 108 platelets (mean±s.e.mean, n = 5). It was inhibited by BCS, but not by the iron chelator bathophenathroline disulphonic acid, nor by acivicin. 6 We conclude that the stable S‐nitrosothiol compound GSNO may exert its anti‐platelet action via enzymatic, rather than spontaneous release of NO. This is mediated by a copper‐dependent mechanism. The potency and platelet‐selectivity of GSNO may result from targeted NO release at the platelet surface.

Adult care of children from pediatric urology.

PURPOSE In this article we highlight the difference, from established adult urology, in required approach to the care of adolescents and young adults presenting with the long-term consequences of the major congenital anomalies of the genitourinary tract. We review some abnormalities of the kidneys, progressive renal failure and disorders of bladder function from which general conclusions can be drawn. MATERIALS AND METHODS The published literature was reviewed and augmented with material from our institutional databases. For renal function the CAKUT (congenital abnormalities of the kidney and urinary tract) database at University College London Hospitals was used, which includes 101 young adult patients with CAKUT in whom the urinary tract has not been diverted or augmented. For bladder function some data are from patient records at Boston Childrens Hospital. RESULTS Adolescents who grow up with the burden of a major congenital anomaly have an overwhelming desire to be normal. Many achieve high levels of education and occupy a wide range of employment scenarios. Babies born with damaged kidneys will usually experience improvement in renal function in the first 3 years of life. Approximately 50% of these cases will remain stable until puberty, after which half of them will experience deterioration. Any urologist who treats such patients needs to test for proteinuria as this is a significant indicator of such deterioration. In its absence, the urologist must have a reasonable strategy for seeking a urological cause. The most effective management for nephrological renal deterioration is with angiotensin converting enzyme inhibitors, which slow but do not prevent end stage renal failure. Renal deterioration is generally slower in these patients than in those with other forms of progressive renal disease. The bladder is damaged by obstruction or by functional abnormalities such as myelomeningocele. Every effort should be made to stabilize or reconstruct the bladder in childhood. A dysfunctional bladder is associated with or causes renal damage in utero, but continued dysfunction will cause further renal damage. Bladder function often changes in puberty, especially in boys with posterior urethral valves who may experience high pressure chronic retention. Dysfunction is managed with antimuscarinic drugs, clean intermittent self-catheterization and intestinal augmentation. Adult urologists must be able to manage the long-term problems associated with these treatments. CONCLUSIONS Pediatric conditions requiring management in adolescence are rare but have major, lifelong implications. Their management requires a broad knowledge of pediatric and adult urology, and could well be a specialty in its own right. Therefore, adult urologists must remain aware of the conditions, the problems that they may encounter and the special management required for these patients to live normal lives.

A novel therapy with testosterone and sildenafil for erectile dysfunction in patients on renal dialysis or after renal transplantation

Background We undertook a prospective pilot study in a small cohort of patients with renal replacement therapy to determine the cause of erectile dysfunction (ED) and evaluate the role of testosterone replacement therapy and sildenafil. Methods We investigated 12 patients (eight post-transplant and four on haemodialysis) who presented with ED for hypogonadism and cavernosal insufficiency. We assessed sexual performance before and after treatment by a questionnaire method based on the modified International Index of Erectile Function (IIEF) and National Institutes of Health (NIH) rating. Patients received 250 mg intramuscular monthly injections of testosterone cypionate and 50-100 mg sildenafil orally once or twice weekly for 12 months. Therapeutic response was considered good if the patient could maintain an erection adequate for successful sexual intercourse (NIH criteria) and had a marked improvement in the overall sexual performance (IIEF scoring). Results Before treatment all patients had severe ED with a poor IIEF score while 11 also had diminished libido. Eleven patients had diminished testicular volume and six had elevated follicle-stimulating hormone levels suggestive of germ cell damage. All patients had a good response to the therapeutic trial of testosterone and sildenafil. Conclusions Therapy with testosterone and sildenafil may be indicated for those with both cavernosal arterial insufficiency and reproductive hormone abnormalities. Further longer-term data are needed to determine the safety and efficacy of this novel regimen.

Renal outcome in adults with renal insufficiency and irregular asymmetric kidneys

BackgroundThe commonest cause of end-stage renal failure (ESRF) in children and young adults is congenital malformation of the kidney and urinary tract. In this retrospective review, we examine whether progression to ESRF can be predicted and whether treatment with angiotensin converting enzyme inhibitors (ACEI) can delay or prevent this.MethodsWe reviewed 78 patients with asymmetric irregular kidneys as a consequence of either primary vesico-ureteric reflux or renal dysplasia (Group 1, n = 44), or abnormal bladder function (Group 2, n = 34). Patients (median age 24 years) had an estimated GFR (eGFR) < 60 ml/min/1.73 m2 with at least 5 years of follow up (median 143 months). 48 patients received ACEI. We explored potential prognostic factors that affect the time to ESRF using Cox-regression analyses.ResultsAt start, mean (SE) creatinine was 189 (8) μmol/l, mean eGFR 41 (1) ml/min 1.73 m2, mean proteinuria 144 (14) mg/mmol creatinine (1.7 g/24 hrs). Of 78 patients, 36 (46%) developed ESRF, but none of 19 with proteinuria less than 50 mg/mmol and only two of 18 patients with eGFR above 50 ml/min did so. Renal outcome between Groups 1 and 2 appeared similar with no evidence for a difference. A benefit in favour of treatment with ACEI was observed above an eGFR of 40 ml/min (p = 0.024).ConclusionThe similar outcome of the two groups supports the nephrological nature of progressive renal failure in young men born with abnormal bladders. There is a watershed GFR of 40–50 ml/min at which ACEI treatment can be successful at improving renal outcome.

Progressive neurological disease induced by tacrolimus in a renal transplant recipient: Case presentation

BackgroundTacrolimus and cyclosporine, both calcineurin inhibitors, can cause neurological side effects. While mild symptoms such as tremor are well recognised, severe complications including seizures and encephalopathy are poorly documented following renal transplantation.Case presentationWe report a 42 year old man who received a cadaver renal transplant. He received tacrolimus and prednisolone. The course was uneventful for 6 weeks when he became intermittently confused, with unsteady gait and slurred speech. Following a grand mal convulsion he was admitted. He had no focal neurological signs, cerebrospinal fluid was normal; electroencephalogram was consistent with temporal lobe partial epilepsy. The magnetic resonance imaging of brain showed widespread changes with multiple areas of low signal intensity in brain stem and cerebral hemispheres. He was readmitted 3 weeks later after further fits, despite anti-convulsant therapy. He was psychotic with visual hallucinations, and rapidly became obtunded. Although his tacrolimus blood concentration had been kept in the normal range, his symptoms improved dramatically when the tacrolimus was stopped.ConclusionSevere central nervous system toxicity from calcineurin inhibitors has been rarely reported in renal transplantation and we found only one report of tacrolimus-induced toxicity in an adult. We believe the condition is frequently undiagnosed. It is a very important diagnosis not to miss as the remedy is simple and failure may result in unnecessary brain biopsy, as well as irreversible injury.

The true clinical significance of renography in nephro-urology

Isotopic renography is a non-invasive technique used routinely by the clinician to provide information about kidney structure and function. Whilst there is no doubt of its value in the accurate measurement of glomerular filtration rate and in the detection of parenchymal abnormalities, its role in the diagnosis of renovascular disease (especially in patients with renal insufficiency), the exclusion of obstruction and the evaluation of the patient with either acute renal failure or renal transplant dysfunction remains unproven. In part, this reflects a failure to standardise protocols and rigorously evaluate diagnostic techniques. Recent developments in ultrasound, computerised X-ray tomography and nuclear magnetic resonance now present the clinician with rival techniques and emphasise the need for the clinical development of isotopic renography.

Endothelin-1 in the rabbit: interactions with cyclo-oxygenase and NO-synthase products

1 Endothelin‐1 infusion (5–40 pmol kg−1 min−1) in the normal anaesthetized rabbit, produced a dose‐dependent increase in mean arterial blood pressure (MAP) and reduced renal blood flow (RBF) and glomerular filtration rate (GFR), when compared with an equivalent infusion of physiological saline. 2 Endothelin, 20 pmol kg−1 min−1, was also assessed in animals pretreated with either indomethacin (2 mg kg−1), methylene blue (1.6 mg kg−1 h−1) or NG‐monomethyl l‐arginine (l‐NMMA, 10 mg kg−1 h−1). 3 The effect of endothelin on MAP and RBF was enhanced (P = 0.05 and <0.01 respectively) by the cyclo‐oxygenase inhibitor, indomethacin, without any significant change in the effect on GFR. 4 Methylene blue and l‐NMMA, inhibitors of endothelium‐derived relaxant factor (EDRF), enhanced the effect of endothelin on each of the parameters measured (P < 0.01). 5 Our results are consistent with endothelin having a predominant effect on pre‐glomerular vascular resistance to reduce GFR. Endothelin appears to stimulate the release of vasodilator prostanoids and EDRF which oppose its effects. Thus endothelin may have an important role in the complex control of GFR in the rabbit.