Further lessons from knockout man.
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Humans↗
Biomedical subjects
G H Neild
Publications and source records attributed to G H Neild.
European randomised trial of dual versus triple tacrolimus-based regimens for control of acute rejection in renal allograft recipients.
Two large multicentre studies have shown superiority of tacrolimus-based immunosuppressive regimens compared with standard cyclosporine-based therapy in renal transplantation. In these studies, tacrolimus was used in a triple drug regimen of tacrolimus, corticosteroids, and azathioprine. The present study aimed to determine whether a tacrolimus-based dual regimen achieves a similar efficacy and safety profile compared with conventional triple therapy. In this prospective, open, multicentre trial, 249 patients were randomised to receive either dual therapy (n = 125) of oral tacrolimus (initial daily dose of 0.2 mg/kg) and oral prednisone or additionally, as a triple therapy (n = 124), oral azathioprine. The primary endpoint was the incidence of acute rejection at month 3. In addition, all patients were included into a follow-up evaluation at 1 year after transplantation. Both treatment groups had similar baseline characteristics. At month 3, patient survival was 97.6 % (dual) and 96.7 % (triple); graft survival was 92.7 % (dual) and 91.7 % (triple). The incidence of treated acute rejection confirmed by biopsy was 27.4 % (dual) and 24.8 % (triple); difference 2.6 %, 95 % CI [-9.4 %-12.9 %], P = 0.755. The incidence of corticosteroid-resistant rejection (biopsy-confirmed) was 9.7 % (dual) and 10.7 % (triple). The overall adverse events profile was similar; leukopenia (1.6 % vs 11.6 %, P = 0.002) was more frequent with triple therapy. Between months 4 and 12, six (dual) and eight (triple) patients had a rejection. At month 12, patient survival was 95.6 % (dual) and 93.6 % (triple); graft survival was 91.8 % (dual) and 90.7 % (triple). Tacrolimus proved to be efficacious and safe with both dual and triple low-dose regimens. The addition of azathioprine to a tacrolimus/corticosteroid-based therapy did not result in an increased efficacy.
Acute Disease↗
Multi-organ renal failure in the elderly.
Periodically the question is posed "Why the persistently high mortality in acute renal failure?". By 1986, little progress seemed to have been made in improving outcome and it was stated that once oliguria was resistant to volume replacement and cardiac support, the patient had at best only a 50% chance of surviving. During the period 1960-1985, it can be shown that although outcome was not improving, older and sicker patients were being treated. Reviewing the literature of the past decade, the age and case mix of patients appears stable, but there is no suggestion of improvement in outcome. ARF with sepsis continues to have a mortality of 65 to 80%, and the outcome remains poor in elderly patients with failure of two or more organs. Progress has been slow in Intensive Care Units, and the past 20 years has seen little more than a move away from parenteral towards enteral feeding. Recent advances, however, in ventilatory techniques and the use of supra-physiological doses of glucocorticoids may lead to some improvement in outcome.
Acute Kidney Injury↗
Uremic concentrations of guanidino compounds inhibit neutrophil superoxide production.
BACKGROUND: In uremia, diminished reactive oxygen intermediate (ROI) production is an important consequence of impaired neutrophil function. We have studied the effect of guanidino compounds, known uremic toxins, on neutrophil ROI production in vitro. METHODS: Neutrophils from healthy volunteers were exposed for three hours to individual or mixed guanidino compounds (GCmix) at concentrations encountered in uremic plasma. After removal of guanidino compounds, neutrophils were activated by adhesion, N-formyl-methionyl-leucyl-phenyalanine (fMLP), phorbol 12-myristate 13-acetate (PMA), or opsonized zymosan, and superoxide production was measured by lucigenin chemiluminescence (CL). The direct effect of guanidino compounds on superoxide production in activated neutrophils was also measured. The energy status (ATP and creatine phosphate), antioxidant status (total glutathione), and glycolytic flux (lactate production) were measured. RESULTS: The GCmix pretreatment decreased the superoxide production in activated neutrophils (fMLP or zymosan) by 50% (P < 0.01) and the ATP concentration by 60% (P < 0.05), and it inhibited glycolytic flux (lactate production) by 45% (P < 0.01), but did not alter glutathione concentration. Simultaneous exposure to GCmix and activation did not inhibit nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in cell lysates, but inhibited superoxide formation in zymosan-activated intact neutrophils, and this inhibition was reversed following removal of the guanidino compounds. CONCLUSION: Guanidino-succinate, -propionate, and -butyrate were individually as potent as the GCmix. Inhibition of neutrophil superoxide generation by guanidino compounds results from a depressed energy status. Uremic concentrations of guanidino compounds significantly inhibit neutrophil metabolism, and this has serious implications for their function in host defense.
Adenosine Triphosphate↗
Outcome in patients with end-stage renal disease following heart or heart--lung transplantation receiving peritoneal dialysis.
BACKGROUND: End-stage renal disease (ESRD) complicates 5--10% of heart and heart--lung transplant patients. We report our experience of peritoneal dialysis (PD) in 17 such patients. METHODS: Between March 1995 and February 1999, 13 heart transplant and four heart--lung transplant patients (11 male, 6 female) joined our PD programme (10 continuous ambulatory PD, seven automated PD). Median time from heart or heart--lung transplantation to ESRD was 9 years (range 1--13 years), and median age at introduction of renal replacement therapy was 51 years (range 23--66 years). The frequency of exit-site infections, peritonitis, and PD survival (including technique failure and death) in the transplant group (TxP) was calculated retrospectively. These were compared with two contemporary control groups: PD patients immunosuppressed for other indications (ISP, n=19) and, all other patients recruited onto the PD programme (NISP, n=132). RESULTS: Median follow-up was 10 months (range 2--27 months) for TxP, 7 months (range 2--29 months) for ISP, and 14 months (range 1--48 months) for NISP groups. The frequency of exit-site infections was similar in each group: 1 in 26 months for TxP; 1 in 30 months for ISP, and 1 in 27 months for NISP (P=NS). The frequency of peritonitis was greater in the TxP group at 1 in 15 months, compared with 1 in 20 months for ISP and 1 in 29 months for NISP (TxP vs NISP, P<0.05). PD failure following infection was 23.5% for TxP, 10.5% for ISP, and 12.9% for NISP. Actuarial PD survival at 24 months was only 25.2% in the TxP group compared with 79% in the NISP group. There were no deaths related to immediate complications of PD. CONCLUSIONS: Increased risk of PD peritonitis and reduced PD survival is reported in this cohort of 17 heart and heart--lung recipients with ESRD. Nevertheless, for patients with severely impaired cardiac function, PD may still offer therapeutic advantage.
Adolescent↗
A 161-year-old case of renal transplantation.
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Aged↗
Oncologist's nephropathy.
A 46-year-old, previously fit man underwent standard primary chemotherapy and then further standard chemotherapy, followed by high-dose chemotherapy (without total body irradiation) and an autologous marrow transplant for relapsed non-Hodgkin's lymphoma. He also received antibiotics, antifungals and antivirals during this time. He developed episodic renal impairment with remissions, but his renal function never returned to baseline. Renal biopsy demonstrated the lesion to be due to thrombotic microangiopathy; he was treated by an angiotension II receptor antagonist, low-dose aspirin and warfarin. Seven years later the renal function remains mildly impaired but stable. This unusual iatrogenic nephropathy is discussed.
Antineoplastic Combined Chemotherapy Protocols↗
The renal pathology of primary antiphospholipid syndrome: a distinctive form of endothelial injury.
Some features of the vascular and glomerular pathology of primary antiphospholipid syndrome (APS) are well recognized, but we describe novel glomerular ultrastructural changes that we consider to be pathognomonic of APS. Renal biopsies from eight patients with APS were examined by light and electron microscopy. All had anti-cardiolipin antibodies, and the clinical presentation ranged from fulminant multi-system disease to isolated proteinuria. By light microscopy, the hexamine silver stain showed a combination of glomerular basement membrane wrinkling and reduplication. By electron microscopy, redundant, wrinkled segments of basement membrane were accompanied by a 'new' straighter thin basement membrane adjacent to the endothelium. In two cases the presence of these antibodies was not suspected clinically, and there was no clinical history or evidence of a thrombotic microangiopathy. We describe a distinctive glomerular lesion that represents an unexplained form of endothelial injury in this syndrome.
Adult↗
Tropheryma whippelii DNA in saliva of healthy people.
In a random sample of 40 healthy people, 35% showed evidence of Tropheryma whippelii DNA in their saliva. Consistent detection of T. whippelii DNA on repeated sampling suggests that this organism can be an oral commensal.
Actinobacteria↗
Advertising of "Sandimmun Neoral".
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Advertising↗
S-nitrosothiols are stored by platelets and released during platelet-neutrophil interactions.
Interaction between platelets and neutrophils is important in vascular injury. We have investigated the storage and release of nitric oxide (NO) by platelets interacting with neutrophils. Shear-activated platelets were added to neutrophils in suspension and both superoxide and peroxynitrite formations monitored by lucigenin- and luminol-enhanced chemiluminescence. In addition, intraplatelet S-nitrosothiols were measured by dichlorofluorescein fluorescence following displacement of NO by mercuric chloride. Addition of activated platelets to neutrophils caused free radical production and platelet-neutrophil rosette formation. Pretreatment of platelets with 20 microM S-nitrosoglutathione changed the balance between luminol and lucigenin chemiluminescence in favor of luminol, whereas S-nitrosoglutathione in platelet-free plasma did not produce these changes. This pattern was also observed both following inhibition of neutrophil NO synthase and in a neutrophil-free superoxide-generating system. Inhibition of platelet NO synthase decreased luminol and increased lucigenin chemiluminescence. These effects were reversed by L-arginine. Platelet activation increased intraplatelet S-nitrosothiols from 1.93+/-0.19 (mean +/- SD) to 4.9+/-1.10 x 10(-18) mol/platelet (P < 0.01); this increase halved following NO synthase inhibition, but was enhanced by approximately 220% following incubation with S-nitrosoglutathione. These results show that during shear stress platelets store S-nitrosothiols, which can be derived either endogenously from NO synthesis or exogenously by sequestration of S-nitrosoglutathione. Release of stored NO during platelet-neutrophil interaction alters the interaction of NO with superoxide and could modulate vascular inflammation.
Arginase↗
Adolescent nephrourology: preventing progressive renal failure.
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Acute Kidney Injury↗
Community nephrology: audit of screening for renal insufficiency in a high risk population.
BACKGROUND: The rate of acceptance onto dialysis programmes has doubled in the past 10 years and is steadily increasing. Early detection and treatment of renal failure slows the rate of progression. Is it feasible to screen for patients who are at increased risk of developing renal failure? We have audited primary care records of patients aged 50-75 years who have either hypertension or diabetes, and are therefore considered to be at high risk of developing renal insufficiency. Our aim was to see whether patients had had their blood pressure measured and urine tested for protein within 12 months, and plasma creatinine measured within 24 months. METHODS: This was a retrospective study of case notes and computer records in 12 general practices from inner and greater London. A total of 16,855 patients were aged 50-75 years. From this age group, 2693 (15.5%) patients were identified as being either hypertensive or diabetic, or both. RESULTS: Of the 2561 records audited, 1359 (53.1%) contained a plasma creatinine measured within 24 months, and 11% of these (150) had a value > 125 micromol/l. This equates to a prevalence of renal insufficiency of > 110,000 patients per million in this group. Forty two patients (28%) had been referred to a nephrologist. Of records audited, 73% contained a blood pressure measurement and 29% contained a test for proteinuria within 12 months. CONCLUSIONS: There is a high prevalence of chronic renal insufficiency in hypertensive and diabetic patients. It is feasible to detect renal insufficiency at a primary care level, but an effective system will require computerized databases that code for age, ethnicity, measurement of blood pressure and renal function, as well as diagnoses.
Aged↗
Fatal microcystin intoxication in haemodialysis unit in Caruaru, Brazil.
BACKGROUND: After a drought in February, 1996, all 126 patients in a haemodialysis unit in Caruaru, north-east Brazil, developed signs and symptoms of acute neurotoxicity and subacute hepatotoxicity following the use of water from a lake with massive growth of cyanobacteria (blue-green algae). 60 patients died. METHODS: Besides recording clinical details and outcome at follow-up, we arranged laboratory, radiological, and histological investigations on the patients and toxicological studies of serum and haemodialysis water filters. FINDINGS: The acute presentation was with malaise, myalgia and weakness, nausea and vomiting, and tender hepatomegaly, with a range of neurological symptoms from tinnitus, vertigo, headaches, and deafness to blindness and convulsions. Liver injury ranged from abnormal liver-function test results to rapidly progressive and fatal hepatic failure. Biochemical investigations revealed gross hyperbilirubinaemia, abnormal liver enzyme activities, and hypertriglyceridaemia, but there was no evidence of haemolysis or microangiopathy. Histology revealed a novel acute toxic hepatitis with diffuse panlobular hepatocyte necrosis, neutrophil infiltration, canalicular cholestasis, and regenerative multinucleate hepatocytes. Samples of serum, dialysis filters, and water-treatment columns contained microcystins, the highly toxic low-molecular-weight hepatotoxins produced by cyanobacteria. INTERPRETATION: Cyanobacteria present water-borne hazards to health via drinking water and recreational water. Haemodialysis presents an additional high-risk exposure route: when they enter directly into the circulation, microcystins can lead to fatal clinical syndromes ranging from acute neurotoxic illness to subacute liver failure.
Bacterial Toxins↗
Renal nuclear medicine: can it survive the millennium?
Much of the progress in renal nuclear medicine has been driven by technological development, but without rigorous assessment the value of some of these studies has been overestimated. The only tests to achieve gold standard status are the isotopic GFR, the DMSA renogram to detect cortical abnormalities and the captopril renogram when used to define those hypertensive patients who will not benefit from renovascular intervention. Consensus guidelines must be followed and routine protocols for combination tests must be developed, but even so isotopic renography is likely to be overtaken by competing technologies which can provide one test to give simultaneous information about both structure and function.
Animals↗
Renal transplantation following renal failure due to urological disorders.
BACKGROUND: Renal allograft outcome, during an 8 year period (1985-1992), has been assessed in 56 renal transplants performed in 55 patients who had end-stage renal failure as a consequence of urological abnormalities. The abnormalities were: primary vesicoureteric reflux (VUR) or renal dysplasia (26 patients); posterior urethral valves (PUV) (15); neuropathic bladders (6); vesico-ureteric tuberculosis (5); bladder exstrophy (3); and prune belly syndrome (1). Six patients had augmented bladders, and eight transplants were performed in seven patients with urinary diversions. RESULTS: Overall, 1 and 5 year actuarial graft survival was 89 and 66%, with mean creatinine of 154 micromol/l +/- 11 (SE) and 145 +/- 9 respectively. Patients with abnormal bladders or conduits (n = 28) had worse graft function than those with normal bladders (n = 28) although graft survival was not significantly different in the two groups at 1 and 5 years: 93 and 75% with normal bladders vs 86 and 57% with abnormal systems. Symptomatic urinary tract infections were common in the first 3 months after transplantation (63%); fever and systemic symptoms occurred in 39% with normal bladders and 59% with abnormal bladders. Urinary tract infection directly contributed to graft loss in six patients with abnormal bladders, but had no consequences in those with normal bladders. CONCLUSIONS: Abnormal bladders must be assessed urodynamically before transplantation, and after transplantation adequacy of urinary drainage must be re-assessed frequently. Prophylactic antibiotics are now given for the first 6 months and urinary tract infections must be treated promptly. With these measures, good results, similar to those of patients without urological problems, can be obtained.
Adolescent↗
Nature and biological significance of free radicals generated during bicarbonate hemodialysis.
This study investigates evidence of oxidative stress during bicarbonate hemodialysis by measuring total glutathione and lipid peroxidation products in plasma, and characterizes the free radicals produced by neutrophils from healthy volunteers when incubated in vitro with increasing concentrations of bicarbonate. Blood samples were taken from nine hemodialysis patients before and after two hemodialysis sessions. Plasma hydroperoxides and total glutathione were measured. A significant increase was found in total glutathione (1.04 +/- 0.4 versus 2.11 +/- 0.9 microM, P < 0.001) and hydroperoxides by ferrous oxidation in xylenol orange version 2 method (4.6 +/- 0.53 versus 6.4 +/- 0.63 microM, P < 0.001) after hemodialysis, which indicated increased oxidative injury during hemodialysis. Normal neutrophils, activated by contact adhesion, produced a dose-dependent increase in free radical production (measured by luminol-enhanced chemiluminescence) when incubated with increasing concentrations of bicarbonate (up to 35 mM). Bicarbonate had the same effect on the chemiluminescence of a cell-free hypoxanthine/acetaldehyde system generating superoxide, but not on a glucose oxidase/myeloperoxidase system generating hydrogen peroxide and hypochlorous acid. These findings are consistent with (1) the hypothesis that superoxide generated during hemodialysis reacts with bicarbonate to form the toxic carbonate and formate radicals and (2) our previous observation that some patients undergoing bicarbonate (but not lactate) dialysis have increased plasma concentrations of formate after hemodialysis. It is suggested that the increased plasma total glutathione and hydroperoxide concentrations are a result of lipid peroxidation by these species. These reactive radicals can initiate lipid peroxidation and contribute to the cardiovascular complications of hemodialysis patients.
Aged↗