Cardiovascular and renal outcomes following percutaneous coronary intervention in a population with renal disease: a case-control study.

BACKGROUND: Patients with renal disease are less likely to undergo percutaneous coronary intervention (PCI) due to concerns about poor outcomes. AIM: We describe outcomes following PCI in individuals with chronic kidney disease (CKD), as compared with matched controls with comparable CKD who did not undergo PCI. We also identified factors predictive of poor outcomes following PCI amongst patients with CKD. DESIGN: Retrospective observational case-control study. METHODS: Cases were individuals with CKD (stages 1-5) undergoing PCI between 2008 and 2014. Controls were age, gender and creatinine-matched individuals not requiring PCI. We compared mortality between groups using Kaplan-Meier curves and Cox regression modelling. We assessed changes in serum creatinine using Wilcoxon Rank testing. We explored the relationship between biochemical and haematological measures (baseline creatinine, calcium, phosphate, calcium-phosphate product, parathyroid hormone, white cell count, haemoglobin, platelet count, c-reactive protein and total cholesterol) and post-PCI mortality, using logistic regression. RESULTS: We identified 144 cases and 144 controls. Mortality was significantly lower amongst cases compared with controls [hazard ratio 0.46 (95% confidence intervals 0.31, 0.69)]. PCI did not result in a significant change in renal function (P=0.52). Amongst cases, serum creatinine and calcium-phosphate product were predictors of mortality following PCI. CONCLUSION: Cases undergoing PCI had lower mortality, and PCI was not associated with accelerated CKD progression. On this data, PCI should not be deferred as a treatment option in patients with CKD. Serum creatinine and calcium-phosphate product predict mortality following PCI in this cohort, and may be useful in risk-stratifying patients with CKD being considered for PCI.

Renal quality outcomes framework and eGFR: impact on secondary care.

BACKGROUND: The prognostic significance of impaired renal function has driven the need for its early recognition and the widespread introduction of the estimated glomerular filtration rate (eGFR) reporting, and the incorporation of Chronic Kidney Disease (CKD) in the revised Quality Outcomes Framework (QOF) of the General Medical Services (GMS) contract in the UK. AIM: To characterize the effect of these changes on referral numbers and appropriateness to a nephrology service, and the impact of a newly introduced Map of Medicine(R)-based patient care pathway coupled to the systematic screening of all new referrals. METHODS: The study was carried out within a single NHS Trust covering five primary health care Local Health Boards and a population of 560,000. RESULTS: Introduction of eGFR reporting and CKD QOF domains was associated with a rapid 61% increase in new patient referral, and an increase in the mean age of the patients at referral from 63.0 +/- 18.1 to 69.1 +/- 18.5. The referrals did not correlate with the QOF reported prevalence of CKD. Systematic screening of new referrals demonstrated 36% to be either inappropriate or inadequate in terms of clinical information supplied. Introduction of the renal patient care pathway was associated with a fall in both the number of inadequate and total new referrals received. Overall 62% of all primary care practices registered with the Map of Medicine(R) and these sent a higher proportion of appropriate referrals and were less likely to generate referrals with inadequate information. The initiative also enabled managed discharges from secondary to primary care settings, freeing up outpatient capacity. CONCLUSION: The study describes the impact of the introduction eGFR reporting and revision of the GMS contract with Renal QOF, on patient referrals to a nephrology service. In addition, we provide evidence that a new management pathway has helped to regulate and proactively manage the increased demand within the current resources.

Equity of access to dialysis facilities in Wales.

BACKGROUND: Demand for dialysis, particularly, in-centre haemodialysis (HD), is growing, and more units will be needed. Travel time to treatment is consistently a major area of concern for patients. AIM: To analyse access to current dialysis facilities in Wales, and use the data to help plan for new dialysis units. METHODS: We analysed a combination of UK Renal Registry, Welsh population census data, the Welsh Index of Multiple Deprivation 2005 (WIMD), travel time and geographical information systems. RESULTS: Prevalence of HD fell significantly with increasing travel time from units. This was not influenced by the WIMD. Prior to the opening of a new HD unit in Aberystwyth, prevalence in the surrounding area was significantly lower than for Wales as whole, but within 2 years, prevalence had risen to approximate national levels. In Haverfordwest, an area >30 min drive from any current facility, prevalence is consistently and significantly lower than for Wales as a whole, and has not shown the growth seen elsewhere in the country. DISCUSSION: The ability to combine data has enabled modelling of the likely immediate impact of opening a new unit in Haverfordwest, and also provided an estimate of its required capacity. This multidisciplinary approach to demand analysis should help to highlight areas of under-provision, and facilitate the planning of the sites and sizes of new dialysis units in Wales.

The snuffbox arteriovenous fistula for vascular access.

OBJECTIVES: to determine the applicability, patency rates and factors influencing patency of snuffbox arteriovenous fistulae for haemodialysis access. DESIGN: retrospective non-randomised study. MATERIALS AND METHODS: patency was determined by reference to an ongoing database and dialysis records of 645 vascular access procedures between 1985 and 1997, including 210 snuffbox fistulae in 201 patients. RESULTS: snuffbox fistulae comprised 189/376 (50%) primary procedures. Records of 208 snuffbox fistulae were available for patency analysis by the life-table method. Twenty-two (11%) thrombosed within 24 hours of operation. After six weeks 80% were used for dialysis. Cumulative patency was 65% at 1 year and 45% at 5 years. After thrombosis of snuffbox fistulae, ipsilateral wrist fistulae could be constructed in 45%. Fistula patency was significantly better in men than women (p<0.001) and for left- than right-sided fistulae (p<0.001). Diabetes, age >70 years, and the prior commencement of haemodialysis did not significantly affect fistula survival. CONCLUSIONS: the snuffbox AV fistula gives a long segment of arterialised vein for needling and preserves proximal vessels. It is feasible in 50% of patients requiring primary access and has good long-term patency, especially in men. A more proximal fistula may be preferable in women with smaller vessels.

The association between retinal ischaemia and end-stage renal damage in thrombotic microangiopathy.

Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are conditions in which thrombocytopenia and microangiopathic haemolytic anaemia are associated with organ damage due to thrombotic microangiopathy (TMA). The prognosis for adults with HUS is variable, with some patients presenting with an acute illness from which a full recovery is made, whilst others develop irreversible renal failure. Evidence of retinal ischaemia was noted on presentation in a normotensive patient with irreversible renal failure due to HUS. This study examined prospectively the optic fundi of all patients who subsequently presented to a single adult renal unit (catchment population approximately 700,000) with HUS. Eleven patients presented with HUS over 12 years (1985-1997). Six patients with irreversible renal failure had retinal abnormalities either at the time or within a few days of initial presentation. The other five patients whose renal function recovered did not develop retinal changes during the course of their illness. Retinal ischaemia associated with TMA is a poor prognostic sign in adults with HUS.

Hepatic uptake of amino acids immediately after liver transplantation is well preserved despite altered plasma profiles.

BACKGROUND: The liver is one of the principal organs responsible for the uptake and release of amino acids in the body. The ability of the transplanted liver to clear plasma amino acids is associated with a functioning allograft. However, clinical assessment is limited by the inability to access the portal vein postoperatively. Therefore, using a porcine liver transplant model, we examined (1) the plasma levels of amino acids presented to the new hepatic allograft and (2) the capacity of the new allograft to clear these amino acids from the circulation. MATERIALS AND METHODS: Two groups of commercially bred pigs were studied: a control group (n = 8) underwent laparotomy and a transplanted group (n = 6) underwent orthotopic liver transplantation (LT) using veno-venous bypass. All pigs had catheters placed in the carotid artery and portal and hepatic veins and ultrasonic transit time flow probes placed around the hepatic artery and portal vein. Plasma profiles of 23 amino acids were analyzed by high-pressure liquid chromatography. Hepatic balances of amino acids, using arteriovenous difference techniques coupled with hepatic blood flows, were also analyzed on postoperative day 1. RESULTS: Neither portal vein blood flow (703 +/- 74 ml/min vs 666 +/- 82 ml/min) nor hepatic artery blood flow (322 +/- 43 ml/min vs 209 +/- 59 ml/min) was significantly different between the control and the transplanted groups, respectively. The transplanted group had significantly increased plasma levels of alanine (135 +/- 13 mumol/l vs 382 +/- 72 mumol/l), hydroxyproline (30 +/- 5 mumol/l vs 60 +/- 9 mumol/l), methionine (25 +/- 2 mumol/l vs 55 +/- 10 mumol/l), ornithine (36 +/- 5 mumol/l vs 141 +/- 33 mumol/l), phenylalanine (84 +/- 5 mumol/l vs 120 +/- 12 mumol/l), threonine (75 +/- 9 mumol/l vs 159 +/- 27 mumol/l), and tryptophan (17 +/- 2 mumol/l vs 31 +/- 4 mumol/l). The transplanted group also had significantly decreased plasma levels of isoleucine (122 +/- 12 mumol/l vs 85 +/- 8 mumol/l) and taurine (71 +/- 7 mumol/l vs 35 +/- 7 mumol/l). These individual amino acid changes were not accompanied by impairment in the net hepatic amino acid balance or the hepatic fractional extraction of amino acids between the two groups. CONCLUSION: These results suggest that the circumstances associated with liver transplantation alter the fasting amino acid profile immediately postoperatively. However, liver transplantation does not impair the normal hepatic allograft uptake of most plasma amino acids. Thus, the changes observed in the circulating levels of amino acids may represent alterations in nonhepatic production and/or utilization. Furthermore, altered plasma amino acid profiles following liver transplantation are not necessarily indicative of impaired hepatic allograft amino acid metabolism.

Mechanisms of hyperinsulinemia and hyperglucagonemia after liver transplantation.

These studies were undertaken to evaluate the mechanisms for changes in plasma insulin and glucagon levels observed post-liver transplantation. Two groups of pigs were studied: a control group (n = 8) underwent laparotomy and catheter placement in the carotid artery and portal and hepatic veins. Hepatic blood flow was measured by ultrasonic flow probes placed around the hepatic artery and portal vein. An experimental group (n = 8) underwent orthotopic liver transplantation and similar instrumentation. On Day 1 after surgery, an estimate of insulin and glucagon secretion and hepatic extraction was determined using arteriovenous difference techniques. Serum assays were performed for markers of hepatic and renal function. Plasma insulin levels of the transplanted pigs were higher in the carotid artery (4 +/- 1 microU/ml vs 7 +/- 1 microU/ml), but not in the hepatic vein (5 +/- 1 microU/ml vs 7 +/- 1 microU/ml) and in the portal vein (10 +/- 2 microU/ml vs 12 +/- 2 microU/ml). Arterial plasma C-peptide was significantly greater in the transplanted group (0.23 +/- 0.02 ng/ml vs 0.42 +/- 0.03 ng/ml); however, the molar ratio of C-peptide and insulin was not different between the two groups (3.6 +/- 0.9 vs 3.4 +/- 0.4). Plasma glucagon levels of the transplanted pigs were significantly elevated in the carotid artery (111 +/- 11 pg/ml vs 323 +/- 65 pg/ml), portal vein (221 +/- 27 pg/ml vs 495 +/- 69 pg/ml), and hepatic vein (142 +/- 15 pg/ml vs 395 +/- 58 pg/ml). The estimate of pancreatic secretion of insulin (115 +/- 28 microU/kg.min) vs 71 +/- 21 microU/kg.min) and glucagon (2.0 +/- 0.4 ng/kg.min vs 2.7 +/- 0.7 ng/kg.min) and the fractional hepatic extraction rate of insulin (35 +/- 8% vs 32 +/- 5%) were not different between the two groups. However, the hepatic fractional extraction rate of glucagon was significantly decreased in the transplanted group (25 +/- 5% vs 11 +/- 3%). Therefore, the hyperglucagonemia observed 24 hr following liver transplantation is partly due to reduced hepatic fractional extraction of glucagon while the hyperinsulinemia is mainly due to the nonhepatic clearance of insulin. We speculate that decreased renal function may contribute to the hyperinsulinemia, elevated C-peptide concentrations, and hyperglucagonemia.

Decreased patient analgesic requirements after liver transplantation and associated neuropeptide levels.

BACKGROUND: Decreased morphine requirements have been reported after liver transplantation when compared with other types of major abdominal surgery. The aim of this study was to examine plasma concentrations of three neuropeptides involved in pain modulation-metenkephalin (ME), beta-endorphin (BE), and substance P (SP)-in patients undergoing orthotopic liver transplantation (OLT) and in control patients undergoing other liver operations. We then compared the postoperative analgesic requirements in these two groups of patients. METHODS: Plasma levels of ME, BE, and SP were measured by radioimmunoassay at preincision, preemergence, and for 3 days after operation in 13 patients undergoing OLT and in 10 control patients. Patient-controlled analgesia morphine delivery was recorded for all patients postoperatively, and plasma morphine, its metabolites, and patient pain and sedation scores were also measured. RESULTS: ME levels were elevated in all OLT patient samples when compared with control patient samples. BE levels were not significantly different at any time. SP levels were significantly decreased only in preincision and preemergence OLT patient samples. Total patient-controlled analgesia morphine delivered during the first 3 postoperative days was significantly less in OLT patients (70+/-8 mg) than in control patients (101+/-12 mg). Plasma morphine, morphine-3-glucuronide, and morphine-6-glucuronide levels were decreased in OLT patients, however, statistical significance was seen only in the morphine-6-glucuronide results. CONCLUSIONS: We have shown that postoperative analgesic requirements are decreased in OLT patients, and we suggest that associated increased peripheral ME levels may be contributing to this decreased requirement. Based on our results, circulating BE and SP are less significant factors affecting postoperative analgesic requirements.

Liver transplantation is associated with increased met-enkephalin levels in the pig.

BACKGROUND: It has been reported that less postoperative morphine is required following liver transplantation than is required following open cholecystectomy. This may be attributable to endogenous factors rather than to altered morphine pharmacokinetics. We measured the plasma concentrations of two endogenous neuropeptides associated with pain modulation, substance P (SP) and met-enkephalin (ME), in pigs undergoing liver transplantation and in control pigs undergoing laparotomy. METHODS: With the approval of the institutional Animal Care Committee, pigs were anesthetized with ketamine (30 mg/ kg,i.m.), atropine (0.05 mg/kg, i.m.) and acetylpromazine (0.1 mg/kg, i.m.). Anesthesia was maintained with isoflurane in oxygen. Pigs in the transplantation group (n = 10) underwent liver transplantation and control pigs (n = 10) underwent laparotomy. Blood samples for SP and ME measurement were collected pre-incision (Pre-In), pre-emergence (Pre-Em) from anesthesia, 6-12 hours, 18 hours, and 24 hours after surgery. SP and ME levels were determined by radioimmunoassay. Results are expressed as mean +/- SEM (in pg/ml of plasma for both peptides) and were compared by the non-parametric Mann-Whitney U test. Statistical significance was inferred if P < 0.05. RESULTS: Plasma ME levels were significantly increased in the transplanted pigs at Pre-Em, 6-12 hours and 18 hours after surgery. No statistically significant difference was observed for plasma SP level between the control and transplant pigs. CONCLUSIONS: Liver transplantation in the pig model is associated with increased concentrations of endogenous ME (but not SP) in plasma for at least 18 hours after surgery as compared to animals undergoing laparotomy.

Outcomes analysis for 50 liver transplant recipients: the Vanderbilt experience.

Healthcare reform has mandated scrutiny of the fiscal aspects of patient care as well as medical outcomes. Therefore, we reviewed our experience with 50 liver transplant recipients from a multidisciplinary collaborative transplant team. From February 1991 to July 1994, of 175 patients referred, 75 were formally evaluated for transplantation; 56 (76%) of these patients were accepted for transplantation; 50 patients underwent 53 transplants. Operative mortality of 6 per cent, retransplantation rate of 6 per cent, 6-month actuarial survival of 88 per cent, 1-year survival of 86 per cent, and the 2 and 3-year survival of 83 per cent were unchanged over time. Quality of life evaluated by the Karnofsky Performance Status was a mean of 55 pretransplant, 72 at 3 months, 79 at 6 months, 84 at 1 year, 88 at 2 years, and 95 at 3 years, demonstrating improved general health and functional rehabilitation after transplantation. Psychosocial Adjustment to Illness Scale scores demonstrated significant improvement following transplantation, improving most dramatically in the vocation environment, domestic environment, and sexual relationship domains. Postoperative length of stay has declined with an average of 28 days in 1991, 22 days in 1992, 19 days in 1993, and 14 days in 1994. Average total hospital, organ procurement, and physician charges for the transplantation hospitalization was $165,000. Average 91-92 hospital charges were $154,000 and were reduced in 93-95 to $103,000 (P < .05). We found that charges and length of stay decreased over time, while the outcome and quality of patient care was maintained. We believe the collaborative practice, case management, and revised patient care protocols are responsible.

Tumor necrosis factor-alpha augments the pro-inflammatory interaction between PMN and GBM via a CD18 dependent mechanism.

Acute glomerulonephritis is frequently associated with intraglomerular neutrophil (PMN) accumulation and the intensity of the inflammatory reaction is correlated with elevated concentrations of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF alpha). PMN are thought to damage glomeruli due to a combination of reactive oxygen species and proteolytic enzymes. Using an in vitro model of anti-GBM nephritis the effects of TNF alpha on GBM damage by PMN were evaluated. The interaction of GBM and PMN resulted in a low grade respiratory burst that was significantly augmented by the addition of TNF alpha. Luminol dependent chemiluminescence (LCL) was increased from 2.4 x 10(6) to 48.1 x 10(6) (P < 0.05). The GBM induced LCL could be > 85% inhibited by blocking with monoclonal antibodies (mAbs) to the common beta chain of the PMN beta 2 integrin family (CD18), but was unaffected by mAbs to CD11a or CD11b subunits. Degradation of GBM, however, was not influenced by either TNF alpha priming of PMN or anti-beta 2 integrin mAbs. When PMN were incubated with GBM-anti-GBM IgG complex they underwent an increase in LCL from 2.4 x 10(6) to 31.1 x 10(6). They also degraded more GBM than controls (10.1% vs. 1.8%). These aspects of PMN activation were Fc receptor mediated, dependent upon anti-GBM IgG being bound to GBM and inhibited by mAb to the PMN Fc receptor. These studies show that TNF alpha can modulate the inflammatory response of PMN in contact with GBM in a CD18 dependent manner. In contrast, Fc receptor mediated events are uninfluenced by TNF alpha.

Relative roles of elastase and reactive oxygen species in the degradation of human glomerular basement membrane by intact human neutrophils.

Glomerular basement membrane (GBM) damage and proteinuria occurring during the early phase of acute glomerulonephritis are often neutrophil (PMN) dependent. The present study sought to identify the potential roles of PMN derived elastase and reactive oxygen species (ROS) in the pathogenesis of glomerular basement damage in an homologous in vitro model of anti-GBM nephritis using intact PMN. Human PMN (5 x 10(6)), incubated with human GBM (0.5 mg) pretreated with human anti-GBM IgG, degraded 10.3 +/- 1.1% of the GBM type IV collagen in six hours (8 micrograms/hr), and underwent a two-hour respiratory burst. The same number of sonically disrupted PMN solubulized 22.4 +/- 5.1% of GBM under the same incubation conditions. The inclusion of the elastase inhibitors alpha 1 proteinase inhibitor (alpha 1Pi), and a smaller highly-specific synthetic compound (L658,758), reduced degradation by PMN homogenates by 84.8% and 85.7%, respectively, whereas they were only able to inhibit intact PMN mediated degradation by a maximum of 49.2% and 50.9%, respectively. The inclusion of EDTA (10 mM), an inhibitor of metalloproteinases, reduced GBM degradation by APMA activated and disrupted PMN by only 7.5%. Incubation of PMN with diphenylene iodonium (DPI) abolished PMN reactive oxygen species generation by > 95% but preserved elastase release. This compound did not directly affect GBM degradation. It did, however, abolish the inhibitory effect of ROS on alpha 1Pi activity and thus indirectly reduced GBM damage by up to 20%.

Intra-peritoneal free elastase in CAPD peritonitis.

Neutrophil (PMN) recruitment into the peritoneum during acute bacterial peritonitis is an important part of the host defense barrier in CAPD patients. However, the subsequent phagocytosis of bacteria may also lead to PMN degranulation and the release of lysosomal enzymes. We determined the concentration of neutrophil elastase, both in complex with its natural inhibitor alpha 1Pi (E alpha 1Pi), and in uncomplexed, free form, in infected and normal CAPD peritoneal fluid by ELISA. In addition elastase activity was estimated in a casein degradation assay. Infected fluid contained a median (range) of 1.4 nM (0 to 9.2) free elastase by ELISA and 1.2 nM (0 to 11.9) activity. There were strong correlations between the peritoneal leukocyte count and both immunoreactive elastase and activity (r = 0.816, P < 0.001, 0.687, P < 0.01, respectively). In contrast, normal fluid contained 0.0 nM (0 to 0.32) immunoreactive elastase (P < 0.01) and 0.0 nM (0 to 0.6) elastase activity (P < 0.001). E alpha 1Pi complexes were raised significantly during peritonitis at 6.2 nM (0 to 34.3) and were barely detectable in normal fluid 0.0 nM (0 to 0.17; P < 0.005). The study shows that small but significant quantities of uninhibited elastase can be detected in the peritoneal fluid of CAPD patients with acute bacterial peritonitis. This observation may have important implications for the pathogenesis of peritoneal membrane damage and the phlogistic response to infection.

An audit of appropriate tests in renal biopsy coagulation screens.

Hematological, biochemical, and clinical data was collected over a 15-month period on all adult (greater than 16 years) patients assessed for percutaneous biopsy of native kidneys in a major renal unit. The frequency, causes, interrelationships, and treatment of the abnormalities, along with factors resulting in delay or cancellation of renal biopsies were subsequently subjected to audit. Overall, 30 of 147 coagulation screens were abnormal. The most common coagulopathy was a prolonged bleeding time (BT), which accounted for 58.6% of these. A prolonged BT was not clearly related to other hematological or biochemical indices, and proved to be treatable with arginine vasopressin (DDAVP). The majority of abnormalities occurred in isolation (23/30), and eight of 30 were related directly to current anticoagulant or antiplatelet medication. All but two patients with abnormalities proceeded to renal biopsy after successful corrective measures, but 21 of 30 were delayed by between 1 hour and 14 days. None of the remaining 117 biopsies were delayed, although seven were cancelled for a variety of reasons. The prothrombin consumption index provided no additional useful management information. Our clotting screen, modified by this audit, should safely and efficiently detect clotting abnormalities before renal biopsy.

Effect of dialyser composition and reuse on neutrophil count and elastase alpha-1 proteinase inhibitor complex formation.

To assess the inter-relationship of leucopenia and PMN elastase release we undertook a prospective crossover study of 6 patients dialysed with new and reused cuprophane, cellulose acetate and polysulfone membranes. Serial blood samples were analysed for PMN count, and elastase-alpha 1-proteinase inhibitor complex (E alpha 1PI) concentrations. After 15 min dialysis with new membranes median PMN counts fell by 72.2%, 25.3% and 22.1% with cuprophane, cellulose and polysulfone, respectively. With reuse the decreases were reduced to 6.4%, 8% and 13.6%. All membranes produced a gradual increase of E alpha 1PI. Median E alpha 1PI accumulation rates (ng ml-1 min-1) with new membranes were 175, 169 and 187 for cuprophane, cellulose acetate and polysulfone, respectively. With reuse of cuphrophane and cellulose acetate these rates fell to 99 and 109 (p less than 0.05 and p less than 0.05, respectively), however, with polysulfone it remained unchanged at 180 ng ml-1 min-1. This study highlights differences between two aspects of the neutrophil response to haemodialysis, and demonstrates that extrapolation from individual parameters to conclusions concerning biocompatibility may be inappropriate.