First outbreak of colonization by linezolid- and glycopeptide-resistant Enterococcus faecium harbouring the cfr gene in a UK nephrology unit.

AIM: To describe an outbreak of colonization by linezolid- and glycopeptide-resistant Enterococcus faecium harbouring the cfr gene in a UK nephrology unit. METHODS: Isolates of linezolid-resistant E. faecium were typed by pulsed-field gel electrophoresis (PFGE), and examined by polymerase chain reaction (PCR) and sequencing for the transmissible cfr gene that confers resistance to linezolid. Enhanced environmental cleaning, initial and weekly screening of all patients, and monitoring of adherence to standard infection control precautions were implemented. FINDINGS: Five patients with pre-existing renal disease were found to have rectal colonization with linezolid-resistant E. faecium over a two-week period. The index case was a 57-year-old male from India who had travelled to the UK. One patient also had a linezolid-resistant E. faecium of a different PFGE profile isolated from a heel wound. All isolates were confirmed to harbour the cfr gene by PCR and Sanger sequencing, and all were resistant to glycopeptides (VanA phenotype). CONCLUSIONS: This article describes the first UK outbreak with a single strain of linezolid- and glycopeptide-resistant E. faecium harbouring the cfr gene, affecting five patients in a nephrology unit. Following the implementation of aggressive infection control measures, no further cases were detected beyond a two-week period.

The Digital Heart Manual: A pilot study of an innovative cardiac rehabilitation programme developed for and with users.

OBJECTIVE: Patients are seeking greater choice and flexibility in how they engage with self-management programmes. While digital innovations offer opportunities to deliver supportive interventions to patients undergoing cardiac rehabilitation little is known about how accessible, useful and acceptable they are for this group. This project developed a digital version of a leading evidenced cardiac rehabilitation programme, the Heart Manual (HM). The prototype was developed and evaluated iteratively in collaboration with end users. METHODS: Using a mixed methods design 28 participants provided feedback using semi-structured questionnaires and telephone interviews. RESULTS: Rich data revealed the perceived user-friendliness of the HM digital format and its effectiveness at communicating the programme's key messages. It flagged areas requiring development, such as more flexible and intuitive navigation pathways. These suggestions informed the refinement of the resource. CONCLUSION: This evaluation offers support for the new Digital Heart Manual and confirms the value of employing a user-centred approach when developing and improving online interventions. The system is now in use and recommendations from the evaluation are being translated into quality improvements. PRACTICE IMPLICATIONS: The Digital Heart Manual is user friendly and accessible to patients and health professionals, regardless of age, presenting a suitable alternative to the paper version.

Investigation of outbreaks of Pneumocystis jirovecii pneumonia in two Scottish renal units.

Pneumocystis jirovecii is recognized as an opportunistic pathogen. In recent years, human-to-human transmission of P. jirovecii has been demonstrated. However, outbreaks of P. jirovecii infections are not well defined because the epidemiological setting that facilitates transmission is not fully understood. This article describes two outbreaks of P. jirovecii pneumonia (PCP) in renal transplant patients in the West of Scotland. In total, 25 patients in two geographically contiguous locations were affected. Allele B was identified as the dominant type, along with allele A3. It was not possible to determine the exact reason for clustering of cases, although the outpatient clinic setting featured in one of the outbreaks. The outbreaks ceased with the use of trimethoprim-sulphamethoxazole prophylaxis; the target populations that received prophylaxis were different in the two outbreaks. Infection control teams should be alert to the possibility of outbreaks of PCP.

CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth.

Metastasis of solid tumors is associated with poor prognosis and bleak survival rates. Tumor-infiltrating myeloid cells (TIMs) are known to promote metastasis, but the mechanisms underlying their collaboration with tumor cells remain unknown. Here, we report an oncogenic role for microRNA (miR) in driving M2 reprogramming in TIMs, characterized by the acquisition of pro-tumor and pro-angiogenic properties. The expression of miR-21, miR-29a, miR-142-3p and miR-223 increased in myeloid cells during tumor progression in mouse models of breast cancer and melanoma metastasis. Further, we show that these miRs are regulated by the CSF1-ETS2 pathway in macrophages. A loss-of-function approach utilizing selective depletion of the miR-processing enzyme Dicer in mature myeloid cells blocks angiogenesis and metastatic tumor growth. Ectopic expression of miR-21 and miR-29a promotes angiogenesis and tumor cell proliferation through the downregulation of anti-angiogenic genes such as Col4a2, Spry1 and Timp3, whereas knockdown of the miRs impedes these processes. miR-21 and miR-29a are expressed in Csf1r+ myeloid cells associated with human metastatic breast cancer, and levels of these miRs in CD115+ non-classical monocytes correlates with metastatic tumor burden in patients. Taken together, our results suggest that miR-21 and miR-29a are essential for the pro-tumor functions of myeloid cells and the CSF1-ETS2 pathway upstream of the miRs serves as an attractive therapeutic target for the inhibition of M2 remodeling of macrophages during malignancy. In addition, miR-21 and miR-29a in circulating myeloid cells may potentially serve as biomarkers to measure therapeutic efficacy of targeted therapies for CSF1 signaling.

Taurolidine-citrate-heparin catheter lock solution reduces staphylococcal bacteraemia rates in haemodialysis patients.

BACKGROUND: Infection is second only to cardiovascular disease as a cause of death in the haemodialysis (HD) population. AIM: : To assess the effect of introducing catheter lock solution taurolidine-citrate-heparin to all tunnelled central venous catheters (TCVCs) on staphylococcal bloodstream infection rates in patients on chronic HD. DESIGN: Observational, prospective analysis of the incidence rates of staphylococcal bacteraemic events in National Health Service (NHS) Greater Glasgow & Clyde and NHS Forth Valley between April 2011 and June 2013, with taurolidine-citrate-heparin catheter lock solution introduced July 2012. METHODS: Data were collected each calendar quarter through a structured query language interrogation of the renal unit electronic patient record, with staphylococcal bacteraemic events expressed per 1000 vascular access exposed days. Comparison between pre- and post-intervention periods was made by student's t-testing. RESULTS: Two hundred and thirty-nine staphylococcal bacteraemic events occurred over a total of 424,835 HD days in 565 patients; 81 events in 289,389 arterio-venous fistula or graft (AVF/AVG) HD days and 158 events in 135 446 TCVC HD days. Following the introduction of taurolidine-citrate-heparin, bacteraemic events in patients dialysing via a TCVC fell from 1.59/1000 HD days to 0.69/1000 HD days, P = 0.004. The staphylococcal bacteraemia rate in AVF/AVGs remained unchanged; 0.30 vs. 0.26/1000 HD days, P = 0.52. CONCLUSIONS: Replacing heparin 5000 IU with Taurolidine-citrate-heparin as catheter lock solution was associated with a statistically significant 56% reduction in staphylococcal bloodstream infection rates in our TCVC HD population.

Stratifying risk in chronic kidney disease: an observational study of UK guidelines for measuring total proteinuria and albuminuria.

BACKGROUND: Proteinuria predicts poor renal and cardiovascular outcomes. Some guidelines recommend measuring proteinuria using albumin:creatinine ratio (ACR), while others recommend total protein:creatinine ratio (TPCR). AIM: To compare renal outcomes and mortality in the populations identified by these different recommendations. DESIGN: Retrospective longitudinal cohort study. METHODS: Baseline ACR and TPCR measurements were obtained from 5586 patients with chronic kidney disease (CKD) attending a Scottish hospital nephrology clinic. The cohort was divided into three groups with concordant results by ACR and TPCR (no proteinuria; low proteinuria; significant proteinuria) and one group with discordant results (significant proteinuria with TPCR, but not ACR). Outcomes were assessed using Kaplan-Meier plots and Cox proportional hazards models. RESULTS: Median follow-up was 3.5 years [interquartile range (IQR) 2.1-6.0]; 844 (15%) died at 3.0 years (IQR 1.8-4.7) and 468 (8%) started renal replacement therapy (RRT) at 1.7 years (IQR 0.6-3.4). Proteinuria was associated with a substantially increased risk of RRT and death. Patients with significant proteinuria by TPCR, but not ACR (n = 231) had high renal risk, and the highest all-cause mortality (log-rank P < 0.001). With multivariate analysis the risk fell below those with significant proteinuria with concordant results by ACR and TPCR but remained considerably higher than those without significant proteinuria. CONCLUSION: Proteinuria screening with TPCR identifies an additional 16% of patients with significant proteinuria, not identified using ACR. This subgroup has high renal risk, and high risk of all-cause mortality and therefore warrant identification. Guideline recommendations on proteinuria screening in CKD should be reconsidered.

Severe statin-induced rhabdomyolysis mimicking Guillain-Barré syndrome in four patients with diabetes mellitus treated with fusidic acid.

BACKGROUND: An interaction between fusidic acid and HMG coenzyme A reductase inhibitors (statins), resulting in rhabdomyolysis, has been described. Pain and mild weakness are common presenting symptoms. CASE REPORT: We report four patients with Type 2 diabetes prescribed long-term statin treatment who, following treatment with fusidic acid, presented atypically with painless, severe flaccid paralysis suggestive of Guillain-Barré syndrome. This, together with nerve conduction studies consistent with Guillain-Barré syndrome, resulted in the delayed recognition of rhabdomyolysis in these cases. CONCLUSIONS: The addition of fusidic acid can precipitate rhabdomyolysis in patients with diabetes already taking a statin. This can present with rapidly progressive weakness resembling Guillain-Barré syndrome. We recommend that creatine kinase is checked in patients with diabetes on statin therapy who present with profound weakness and routinely in those commenced on prolonged courses of fusidic acid.

The link between circulating markers of endothelial function and proteinuria in patients with primary glomerulonephritis.

INTRODUCTION: It is well established that there is an increase in the incidence of cardiovascular mortality in patients with proteinuric renal disease. The magnitude of the increase in risk is unlikely to be explained by traditional risk factors for cardiovascular disease alone. Proteinuria itself may constitute an additional risk factor, and proteinuric patients are known to have a degree of endothelial dysfunction. The nature of this relationship between proteinuria and endothelial function is the subject of intense investigation. AIM: The aim of this study was to examine the relationship between proteinuria and endothelial dysfunction, as reflected by serum von Willebrand factor (vWF), and the soluble cell adhesion molecules VCAM and ICAM, in patients with primary glomerulonephritis (GN). A secondary aim was to discern whether any relationship could be explained by renal function, lipid profile, inflammation or blood pressure. METHODS: A cross-sectional study was undertaken in consecutive patients attending a general nephrology clinic with biopsy-proven primary GN. Patients with end-stage renal disease (ESRD), those on immunosuppressive drugs, or with intercurrent infective illnesses were excluded. Blood pressure and body mass index were recorded. Routine lab assays were undertaken for serum creatinine, lipid profile, and 24-hour urinary protein (U(Prot)). Additional serum samples were stored at -80 degrees C for subsequent measurement of vWF, VCAM, ICAM and sensitive C reactive protein (sCRP). RESULTS: Data were collected from 129 (86 male) patients. Mean (standard deviation) estimated creatinine clearance was 64 (32) ml/min, and median (interquartile range) 24-hour proteinuria was 1.1 (0.22-2.9) g. Mean vWF was 173 (68) IU/dl, median VCAM, ICAM and sCRP were 594 (410-708) ng/ml, 235 (208-286) ng/ml, and 2.33 (0.83-5.68) mg/l, respectively. There was a significant positive correlation between vWF and U(Prot) (Spearman rank correlation, r = 0.41, p < 0.001). When split into tertiles, according to U(Prot) (0-500 mg, 500-2000 mg, and > 2000 mg), there was a significant, stepwise increase in mean vWF (p < 0.001), log VCAM (p < 0.001), and log ICAM (p = 0.002). On multivariate analysis with vWF as the continuous dependent variable, U(Prot), age, total cholesterol and sCRP were the only significantly independent correlates (model-adjusted R2 = 33%). CONCLUSION: In patients with primary GN, there is a significant association between endothelial activation as reflected by vWF, VCAM, or ICAM and increasing proteinuria. Elevations in vWF, as well as being related to classical risk factors, are associated with increases in total proteinuria and low-grade inflammation. Thus, future prospective studies should examine the extent to which vWF and other circulating markers of endothelial activation predict coronary heart disease risk in patients with proteinuric renal disease.

Intensified treatment of patients with type 2 diabetes mellitus and overt nephropathy.

BACKGROUND: Diabetic nephropathy is the single most common cause of chronic renal failure requiring dialysis. Effective treatment exists, but no clinical audit or large trial has reduced the rate of loss of renal function as effectively as in small groups of intensively managed patients. AIM: To determine the effect of intensive vs. standard medical management on the rate of progression of renal failure in patients with diabetic nephropathy. DESIGN: Prospective randomized controlled study. METHODS: Patients with type 2 diabetes and nephropathy were randomly allocated to an intensive group (n = 47) or control group (n = 43). Treatment targets were the same for both groups, but the intensive group were seen as often as required to meet the targets; controls were seen at their normal clinics. The primary end-point was the rate of progression of renal disease in the second year. RESULTS: The groups were well matched at baseline. During follow-up, the intensive group had lower mean SBP, DBP and cholesterol. Median rate of progression of renal failure in the intensive group fell from 0.44 ml/min/month in the first year to 0.14 ml/min/month in the second year, compared to 0.49 ml/min/month and 0.53 ml/min/month in the control group (p = 0.04 for second year). Patients in the intensive group spent significantly less time in hospital. DISCUSSION: Intensive treatment slowed progression of renal disease within 2 years in patients with established diabetic nephropathy. Mean creatinine clearance at the start of the trial was 55 ml/min, so assuming that the rates of progression achieved at the end of the second year persisted, onset of dialysis would be delayed by 20 years in the intensive group compared with the control group.

Urinary transferrin, high molecular weight proteinuria and the progression of renal disease.

AIMS: Proteinuria predicts rate of progression in a variety of nephropathies. There is considerable evidence that iron-transferrin is toxic to proximal tubular cells in vitro, and recent clinical work suggests that selectivity of proteinuria influences the outcome of renal disease. The aim of this study was to examine the relationship between the nature of proteinuria and progression of renal disease. METHODS: This was a prospective, cross-sectional study in 66 patients with primary glomerulonephritis, diabetic nephropathy and a variety of other renal diseases. Urinary transferrin was measured by sandwich ELISA and correlated with rate of change in estimated creatinine clearance (ECC). Urinary SDS-PAGE was undertaken to divide proteinuria into tertiles according to molecular weight and to quantify the protein in each tertile. The magnitude of each tertile was then correlated with rate of change in ECC over a median period of 20 months. RESULTS: Rate of change of renal function correlated with total proteinuria (r2 = 18%, p < 0.001) and albuminuria (r2 = 17%, p < 0.001), but not urinary transferrin (r2 = 0%, p = 0.235). On univariate analysis high molecular weight proteinuria (r2 = 21%, p < 0.001), intermediate molecular weight proteinuria (r2 = 15%, p = 0.001) and low molecular weight proteinuria (r2 = 10%, p = 0.005) correlated with rate of change in ECC as did total fasting cholesterol (r2 = 7%, p = 0.003). On multivariate analysis, however, the only independent predictors of rate of change in ECC were high molecular weight proteinuria (r2 = 19%, p < 0.001), and total fasting cholesterol (r2 = 5%, p = 0.035). CONCLUSIONS: We found no evidence to support the hypothesis that iron-transferrin is important in the development of human renal injury. High molecular weight proteinuria correlates more strongly with rate of progression of renal disease than intermediate molecular weight, low molecular weight or even total proteinuria. This suggests either, that one or more high molecular weightproteins are implicated in causing progressive renal impairment, or that loss of size selectivity at the glomerular basement membrane is associated with accelerated tubulointerstitial damage.

Diabetic nephropathy: how effective is treatment in clinical practice?

BACKGROUND: Diabetic nephropathy is the most common cause of end-stage renal failure in patients starting dialysis in the developed world. In clinical trials, interventions, particularly blood pressure control, have achieved major reductions in the rate of decline in renal function. AIM: To investigate whether results from clinical trials can be achieved in routine clinical practice. DESIGN: Observational study of 170 consecutive patients referred to a combined diabetic-renal clinic over a 10 year period. METHODS: We collected demographic and laboratory data from the electronic patient record. RESULTS: Median serum creatinine at referral was 170 micromol/l and was >350 micromol/l in 26% of patients. Mean blood pressure (BP) was 159/85. The publication of guidelines by the Scottish Intercollegiate Guidelines Network in 1997, recommending more active intervention and earlier referral, had no impact on referral BP and creatinine. In the 125 patients with at least 1 year follow-up, significant improvements in BP, albuminuria, HbA(1c) and serum cholesterol were seen. In the 63 patients followed up for 3 years (median creatinine 120 micromol/l), the median rate of decline in renal function slowed from 0.52 ml/min/month (first year) to 0.27 ml/min/month (third year) (p=0.003), nearly doubling the time to end-stage renal failure. DISCUSSION: Patients referred early to a combined diabetic-renal clinic benefited by slowing in the rate of decline of renal function. A challenging but achievable standard for audit would be to reduce the rate of progression to <0.25 ml/min/month in 70% of patients with diabetic nephropathy presenting with a serum creatinine <150 micromol/l.

The atherogenic lipoprotein phenotype: small dense LDL and lipoprotein remnants in nephrotic range proteinuria.

The dyslipidaemia in nephrotic-range proteinuria is believed to contribute to the increased atherogenesis associated with the condition. Excess small dense low density lipoprotein (LDLIII) contributes to this risk. Lipoprotein remnants (RLP) may also be implicated but have not been studied in this population. We measured the plasma concentration of low density lipoprotein (LDL) subfractions (by density gradient ultracentrifugation), RLP (by immunoaffinity gel), very low density lipoprotein (VLDL) subfractions, post heparin lipases and cholesteryl ester transfer protein (CETP) activity in 27 patients with glomerular disease and albuminuria >2.0g. These were compared with 27 age and sex matched controls. Proteinuric patients had increased LDLIII concentration (patients 182 (84:267) vs. controls 31 (27:62); P<0.0001) with reduced lighter LDLI (36 (24:43) vs 69 (46:101); P<0.0005) and LDLII (124 (79:220) vs 178 (129:236); P<0.04, all mg/dl, median+interquartile range). RLP-cholesterol (RLP-C) and triglyceride (RLP-TG) were increased in proteinuric patients (RLP-C 18.9 (11.0:26.9) vs 7.7 (6.0:8.8); P<0.0001, RLP-TG 35.8 (11.8:54.7) vs. 7.2 (4.3:10.0); P<0.0001, all mg/dl). Increased LDLIII and RLP were independent of renal function. VLDL(1) and VLDL(2) concentrations were increased by 258 and 260% (both P<0.0001). CETP activity was increased by 46% (P<0.005). Lipoprotein and hepatic lipase activities did not differ from control values. LDLIII concentration (r(2)=45.7%, P<0.001), RLP-C (r(2)=85.2%, P<0.001) and RLP-TG (r(2)=87.5%, P<0.001) all correlated positively with plasma triglyceride. Moreover, increased LDLIII was associated with both RLP-C (r(2)=31.3%, P<0.002) and RLP-TG (r(2)=33.6%, P<0.002). Excess LDLIII and RLP are present in nephrotic-range proteinuria and add to the spectrum of cardiovascular risk factors present in proteinuric patients. Increases in LDLIII and RLP are closely related to plasma triglyceride. The association between excess RLP and LDLIII suggests that RLP contribute to the increased atherogenicity attributed to the atherogenic lipoprotein phenotype.

Hypotension, autonomic failure, and cardiac hypertrophy in transgenic mice overexpressing the alpha 1B-adrenergic receptor.

alpha(1)-Adrenergic receptors (alpha(1A), alpha(1B), and alpha(1D)) are regulators of systemic arterial blood pressure and blood flow. Whereas vasoconstrictory action of the alpha(1A) and alpha(1D) subtypes is thought to be mainly responsible for this activity, the role of the alpha(1B)-adrenergic receptor (alpha(1B)AR) in this process is controversial. We have generated transgenic mice that overexpress either wild type or constitutively active alpha(1B)ARs. Transgenic expression was under the control of the isogenic promoter, thus assuring appropriate developmental and tissue-specific expression. Cardiovascular phenotypes displayed by transgenic mice included myocardial hypertrophy and hypotension. Indicative of cardiac hypertrophy, transgenic mice displayed an increased heart to body weight ratio, which was confirmed by the echocardiographic finding of an increased thickness of the interventricular septum and posterior wall. Functional deficits included an increased isovolumetric relaxation time, a decreased heart rate, and cardiac output. Transgenic mice were hypotensive and exhibited a decreased pressor response. Vasoconstrictory regulation by alpha(1B)AR was absent as shown by the lack of phenylephrine-induced contractile differences between ex vivo mesenteric artery preparations. Plasma epinephrine, norepinephrine, and cortisol levels were also reduced in transgenic mice, suggesting a loss of sympathetic nerve activity. Reduced catecholamine levels together with basal hypotension, bradycardia, reproductive problems, and weight loss suggest autonomic failure, a phenotype that is consistent with the multiple system atrophy-like neurodegeneration that has been reported previously in these mice. These results also suggest that this receptor subtype is not involved in the classic vasoconstrictory action of alpha(1)ARs that is important in systemic regulation of blood pressure.

Patients with nephrotic-range proteinuria have apolipoprotein C and E deficient VLDL1.

BACKGROUND: Impaired very low-density lipoprotein (VLDL) clearance contributes to dyslipidemia in nephrotic-range proteinuria. VLDL can be subdivided into large light VLDL1 (Sf 60 to 400) and smaller, denser VLDL2 (Sf 20 to 60). In nephrotic-range proteinuria, the clearance of VLDL1 is delayed. VLDL1 lipolysis is influenced by apolipoprotein CII (apoCII) and apoCIII, whereas apoE regulates receptor-mediated clearance. METHODS: To ascertain whether impaired VLDL1 clearance was related to a deficiency in apolipoproteins on VLDL1, we measured VLDL subfraction concentrations and VLDL1 apolipoprotein and lipid compositions in 27 patients with glomerular disease and urinary albumin> 2 g/24 h along with 27 age- and sex-matched controls. RESULTS: Proteinuric patients had increased plasma VLDL1, VLDL2, apoCII, apoCIII (all P < 0.001), and apoE concentration (P < 0.002). Patients appeared to have smaller VLDL1 particles, as assessed by triglyceride per particle (median + interquartile range, moles per VLDL1 particle): patients, 4.9 (3.0 to 7.9) x103; controls, 7.0 (4.6 to 15.7) x103, P < 0.05, with reduced apoCII, 4.2 (3.1 to 8.2) versus 9.9 (7.4 to 23.2), P < 0.0004; apoCIII, 16.6 (9.1 to 27.2) versus 29.3 (18.5 to 69.4), P < 0.02; and apoE content, 0.17 (0.08 to 0.44) versus 0.48 (0.31 to 1. 31), P < 0.006. The VLDL1 surface free cholesterol to phospholipid results were increased in proteinuric patients (0.55 +/- 0.17 vs. 0. 40 +/- 0.18, P < 0.002, all mean +/- SD). For all patients, VLDL1 apoCII, apoCIII, and apoE contents per particle were related to particle size (apoCII, r2 = 61.5%, P < 0.001; apoCIII, r2 = 75.8%, P < 0.001; apoE, r2 = 58.2%, P < 0.001) and inversely to the free cholesterol to phospholipid ratio (apoCII, r2 = 41.6%, P < 0.001; apoCIII, r2 = 38.8%, P < 0.001; apoE, r2 = 11.7%, P < 0.05). Multivariate analysis suggested that the relative lack of apoCII and apoCIII on patients VLDL1 was related to smaller particle size and increased free cholesterol:phospholipid (FC:PL) ratio. Particle size but not free cholesterol determined the apoE content of VLDL1. CONCLUSIONS: We postulate that impaired VLDL1 clearance in nephrotic-range proteinuria results from the appearance of particles deficient in apoCII, apoCIII, and apoE. VLDL1 apoC deficiency is associated with the formation of smaller particles with a high FC:PL ratio, and is likely to cause inefficient lipolysis. VLDL1 apoE deficiency is associated with smaller VLDL1 particles but not altered VLDL1 surface lipid content, and may reduce receptor-mediated clearance of this lipoprotein.

Atherogenic lipoprotein phenotype in end-stage renal failure: origin and extent of small dense low-density lipoprotein formation.

End-stage renal failure (ESRF) is associated with dyslipidemia and accelerated atherosclerosis. Triglyceride-rich lipoproteins accumulate and qualitative changes take place in low-density lipoprotein (LDL), with a predominance of the small dense LDL phenotype. Increased small dense LDL (LDLIII) is a known risk factor for cardiovascular disease. To assess the extent of LDLIII formation in ESRF and identify factors contributing to LDLIII production, we analyzed LDL subfractions by density-gradient ultracentrifugation, very low-density lipoprotein subfractions, and lipase activity in 75 patients with ESRF (25 hemodialysis [HD], 25 peritoneal dialysis [PD], and 25 predialysis patients) and 40 age- and sex-matched controls. The percentage of LDLIII was increased in all three patient groups compared with controls (PD, 33% +/- 29% [mean +/- SD]; P < 0.005; HD, 30% +/- 22%; P < 0.01; predialysis, 26% +/- 26%; P < 0.01; all versus controls, 14% +/- 10%). Plasma LDLIII concentration was increased only in PD patients (median, 84 mg/dL; interquartile range [IQR], 29 to 160 mg/dL versus controls; median, 31 mg/dL; IQR, 26 to 54 mg/dL). In other patient groups, total LDL level was less, with heterogeneity in LDLIII concentrations. Forty percent of PD patients and 28% of HD and predialysis patients had LDLIII concentrations greater than 100 mg/dL compared with 2.5% of controls (P = 0.002). Plasma triglyceride levels (r(2) = 38.4%; P < 0.001) and hepatic lipase activity (r(2) = 6.7%; P < 0.03) were independent predictors of LDLIII concentration. The strong association between LDLIII concentration and triglyceride level was present in all three patient groups (HD, r(2) = 47.9%; PD, r(2) = 45. 2%; predialysis, r(2) = 25.8%); plasma triglyceride levels greater than 177 mg/dL (2.0 mmol/L) had an 86% specificity and 79% sensitivity for predicting an LDLIII concentration greater than 100 mg/dL. We conclude that the atherogenic lipoprotein phenotype predominates in ESRF, with excess LDLIII particularly prominent in PD patients. Atherogenic levels of LDLIII are found in patients with triglyceride levels greater than 177 mg/dL. This is likely to represent a further cardiovascular risk factor in this population.

Rhabdomyolysis and acute renal failure resulting from alcohol and drug abuse.

Rhabdomyolysis is a common cause of acute renal failure (ARF) associated with drug misuse. Abuse of the gel formulation of temazepam has been a particular problem in the West of Scotland. We performed a retrospective review of dialysis-dependent ARF from rhabdomyolysis and drug misuse in the West of Scotland, 1986-1997. We identified 76 patients, of whom 87% were male. Seventeen cases occurred in the first 6 years, compared with 59 in the subsequent 6 years. Median age was 32. Thirty cases followed intravenous drug misuse, 46 followed oral drug misuse. The substances most frequently misused were alcohol (54%), heroin (24%) and parenteral temazepam (17%). The temazepam cases all followed the introduction of the gel formulation. Three out of 4 patients requiring limb amputation had injected temazepam. Of intravenous drug misusers tested, 72% were hepatitis-C-positive. Some 43% of patients had deprivation scores in the worst category. ARF due to rhabdomyolysis from substance misuse is increasing in our area. Alcohol is frequently responsible. The introduction of the gel formulation of temazepam has contributed to the increase. Those at risk in this study were young, male, had a high incidence of hepatitis C and lived in the most deprived areas.

Increased atherogenicity of low-density lipoprotein in heavy proteinuria.

BACKGROUND: Heavy proteinuria is associated with marked abnormalities of lipoprotein metabolism and increased risk of atherogenesis. It is possible that qualitative as well as quantitative changes occur in lipoproteins to contribute to increased cardiovascular risk; for example, it is known that LDL exhibits heterogeneity, with small, dense LDL III particles being more atherogenic. METHODS: We investigated LDL subfractions (measured by density gradient ultracentrifugation), VLDL subfractions, and post-heparin lipases in 12 patients with primary glomerular disease and 24-h albuminuria >2.5 g. These were compared to 23 age- and sex-matched controls. RESULTS: Total LDL concentrations were similar in proteinuric patients and controls; however, there was a shift in subfraction distribution. The larger LDL I and LDL II particles were lower in the proteinuric group (29 +/- 24 vs 62 +/- 26 mg/dl P=0.011 and 121 +/- 80 vs 197 +/- 74 mg/dl P=0.028), whereas the concentration of atherogenic LDL III (small dense) was higher (135 +/- 64 vs 75 +/- 71 mg/dl P=0.0016). The concentration of total VLDL and both its subfractions were increased in the patients with proteinuria. Post-heparin hepatic and lipoprotein lipase levels were similar to normal. CONCLUSIONS: These findings suggest that the atherogenicity of LDL is increased in patients with heavy proteinuria because of the redistribution towards smaller denser particles. Since small, dense LDL has a lower affinity for the LDL receptor, the altered nature of the lipoprotein in proteinuria may decrease its clearance by the receptor-mediated pathway and contribute to the reduced clearance of LDL observed in this population. This may contribute to progression of renal failure or the accelerated vascular disease found in patients with heavy proteinuria.