Damian Fogarty

Glycated Hemoglobin and Risk of Death in Diabetic Patients Treated With Hemodialysis: A Meta-analysis

BACKGROUND Studies investigating the association between glycated hemoglobin (HbA1c) level and mortality risk in diabetic patients receiving hemodialysis have shown conflicting results. STUDY DESIGN We conducted a systematic review and meta-analysis using MEDLINE, EMBASE, Web of Science, and the Cochrane Library. SETTING & POPULATION Diabetic patients on maintenance hemodialysis therapy. SELECTION CRITERIA FOR STUDIES Observational studies or randomized controlled trials investigating the association between HbA1c values and mortality risk. Study authors were asked to provide anonymized individual patient data or reanalyze results according to a standard template. PREDICTOR Single measurement or mean HbA1c values. Mean HbA1c values were calculated using all individual-patient HbA1c values during the follow-up period of contributing studies. OUTCOME HR for mortality risk. RESULTS 10 studies (83,684 participants) were included: 9 observational studies and one secondary analysis of a randomized trial. After adjustment for confounders, patients with baseline HbA1c levels ≥ 8.5% (≥ 69 mmol/mol) had increased mortality (7 studies; HR, 1.14; 95% CI, 1.09-1.19) compared with patients with HbA1c levels of 6.5%-7.4% (48-57mmol/mol). Likewise, patients with a mean HbA1c value ≥ 8.5% also had a higher adjusted risk of mortality (6 studies; HR,1.29; 95% CI, 1.23-1.35). There was a small but nonsignificant increase in mortality associated with mean HbA1c levels ≤ 5.4% (≤ 36 mmol/mol; 6 studies; HR, 1.09; 95% CI, 0.89-1.34). Sensitivity analyses in incident (≤ 90 days of hemodialysis) and prevalent patients (>90 days of hemodialysis) showed a similar pattern. In incident patients, mean HbA1c levels ≤ 5.4% also were associated with increased mortality risk (4 studies; HR, 1.29; 95% CI, 1.23-1.35). LIMITATIONS Observational study data and inability to adjust for diabetes type in all studies. CONCLUSIONS Despite concerns about the utility of HbA1c measurement in hemodialysis patients, high levels (≥ 8.5%) are associated with increased mortality risk. Very low HbA1c levels (≤ 5.4%) also may be associated with increased mortality risk.

Chronic kidney disease and diabetes in the National Health Service: a cross-sectional survey of the UK National Diabetes Audit

We investigated the prevalence of chronic kidney disease and attainment of therapeutic targets for HbA1c and blood pressure in a large UK‐based diabetes population.

Homocysteine and B-group vitamins in renal transplant patients.

Increased plasma homocysteine is an independent risk factor for cardiovascular disease. We have investigated homocysteine and B-group vitamin levels in renal transplant patients. Fasting blood was collected from 55 renal transplant recipients with good renal function and 32 age/sex matched control subjects. Total homocysteine was increased in transplant recipients in comparison to controls (10.9+/-1.5 vs. 6.7+/-1.3 micromol/l, P < 0.001). There was no difference in homocysteine between patients receiving cyclosporin (n = 39, homocysteine 11.0+/-1.5 micromol/l) and patients receiving prednisolone + azathioprine (n = 16, 10.8+/-1.6 micromol/l, mean+/-S.D.), although there was a significant correlation between homocysteine and serum cyclosporin concentration in the sub-group of patients receiving that immunosuppressive regimen (r = 0.42, P < 0.05). Levels of B-group vitamins were similar in patients and controls. Plasma homocysteine is increased in renal transplant recipients even in the presence of minor degrees of renal impairment and normal levels of B-group vitamins.

Estimated Albumin Excretion Rate Versus Urine Albumin-Creatinine Ratio for the Estimation of Measured Albumin Excretion Rate: Derivation and Validation of an Estimated Albumin Excretion Rate Equation

BACKGROUND Glomerular filtration rate estimation equations use demographic variables to account for predicted differences in creatinine generation rate. In contrast, assessment of albuminuria from urine albumin-creatinine ratio (ACR) does not account for these demographic variables, potentially distorting albuminuria prevalence estimates and clinical decision making. STUDY DESIGN Polynomial regression was used to derive an age-, sex-, and race-based equation for estimation of urine creatinine excretion rate, suitable for use in automated estimated albumin excretion rate (eAER) reporting. SETTING & PARTICIPANTS The MDRD (Modification of Diet in Renal Disease) Study cohort (N=1,693) was used for equation derivation. Validation populations were the CRIC (Chronic Renal Insufficiency Cohort; N=3,645) and the DCCT (Diabetes Control and Complications Trial; N=1,179). INDEX TEST eAER, calculated by multiplying ACR by estimated creatinine excretion rate, and ACR. REFERENCE TEST Measured albumin excretion rate (mAER) from timed 24-hour urine collection. RESULTS eAER estimated mAER more accurately than ACR; the percentages of CRIC participants with eAER within 15% and 30% of mAER were 33% and 60%, respectively, versus 24% and 39% for ACR. Equivalent proportions in DCCT were 52% and 86% versus 15% and 38%. The median bias of ACR was -20.1% and -37.5% in CRIC and DCCT, respectively, whereas that of eAER was +3.8% and -9.7%. Performance of eAER also was more consistent across age and sex categories than ACR. LIMITATIONS Single timed urine specimens used for mAER, ACR, and eAER. CONCLUSIONS Automated eAER reporting potentially is a useful approach to improve the accuracy and consistency of clinical albuminuria assessment.

Association Between Glycemia and Mortality in Diabetic Individuals on Renal Replacement Therapy in the U.K.

OBJECTIVE In the U.K., one-third of patients receiving treatment with dialysis have diabetes. Guidelines from organizations representing patients with renal disease or diabetes advocate tight glycemic control in patients with end-stage renal disease, despite glucose-lowering trials having excluded these patients. RESEARCH DESIGN AND METHODS Using national UK Renal Registry data, we tested whether glycemia as measured by hemoglobin (Hb) A1c (HbA1c) level is associated with death in adults with diabetes starting hemodialysis or peritoneal dialysis between 1997 and 2006, and observed for at least 6 months. Of 7,814 patients, we excluded those who had died within 6 months; had received transplants; were lost/recovered; or lacked measures of HbA1c, ethnicity, or Hb. Categorizing HbA1c measured in the first 6 months of starting dialysis as <6.5% (<48 mmol/mol), 6.5–7.4% (48–57 mmol/mol) (reference value), 7.5–8.4% (58–68 mmol/mol), and ≥8.5% (≥69 mmol/mol), we adjusted in proportional hazards models for age, sex, ethnicity, deprivation, year, dialysis type, and Hb, and tested for interactions. RESULTS Of 3,157 patients observed for a median time of 2.7 years, 1,688 died. For patients ≥60 years of age, we found no association between HbA1c and death; among younger patients, relative to those with HbA1c values 6.5–7.4%, the hazard ratio for HbA1c level 7.5–8.4% was 1.2 (95% CI 0.9–1.5), and for HbA1c level >8.5% was 1.5 (1.2–1.9). The projected difference in median survival time between younger patients with a reference HbA1c value versus >8.5% was 1 year. CONCLUSIONS In the absence of trials, and confounding notwithstanding, these observational data support improved glycemic control in younger patients prior to and during dialysis.

UK Renal Registry 11th Annual Report (December 2008): Chapter 6 Comorbidities and current smoking status amongst patients starting Renal Replacement Therapy in England, Wales and Northern Ireland: national and centre-specific analyses

Introduction: The prevalence of 13 comorbid conditions and smoking status at the time of starting renal replacement therapy (RRT) in England, Wales and Northern Ireland are described. Methods: Adult patients starting RRT between 2002 and 2007 in centres reporting to the UK Renal Registry (UKRR) and with data on comorbidity (n = 13,293) were included. The association of comorbidity with patient demographics, treatment modality, haemoglobin, renal function at start of RRT and subsequent listing for kidney transplantation were studied. Association between comorbidities and mortality at 90 days and one year after 90 days from start of RRT was explored using Cox regression. Results: Completeness of data on comorbidity returned to the UKRR remained poor. Of patients with data, 52% had one or more comorbidities. Diabetes mellitus and ischaemic heart disease were the most common conditions seen in 28.9% and 22.5% of patients respectively. Comorbidities became more common with increasing age (up to the 65–74 age group), were more common amongst Whites and were associated with a lower likelihood of pre-emptive transplantation, a greater likelihood of starting on haemodialysis (rather than peritoneal dialysis) and a lower likelihood of being listed for kidney transplantation. In multivariable survival analysis, malignancy and ischaemic/neuropathic ulcers were the strongest predictors of poor survival at 1 year after 90 days from start of RRT. Conclusions: The majority of patients had at least one comorbid condition and comorbidity is an important predictor of early mortality on RRT.

Family-based investigation of the C677T polymorphism of the methylenetetrahydrofolate reductase gene in ischaemic heart disease

BACKGROUND Elevated homocysteine is associated with ischaemic heart disease (IHD). The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene results in reduced MTHFR enzyme activity and reduced methylation of homocysteine to methionine resulting in mild hyperhomocysteinaemia. Case-control association studies of the role of the C677T MTHFR polymorphism in IHD have produced conflicting results. We therefore used newly described family-based association tests to investigate the role of this polymorphism in IHD, in a well-defined population. METHODS A total of 352 individuals from 129 families (discordant sibships and parent-child trios) were recruited. Linkage disequilibrium between the polymorphism and IHD was tested for using the combined transmission disequilibrium test (TDT)/sib-TDT and pedigree disequilibrium test (PDT). Homocysteine levels were measured. RESULTS Both the TDT/sib-TDT and PDT analyses found a significantly reduced transmission of the T allele to affected individuals (P=0.016 and P=0.021). There was no significant difference in homocysteine levels between affected and unaffected siblings. TT homozygotes had mean homocysteine levels significantly higher than those of TC heterozygotes (P<0.001) and CC homozygotes (P<0.001). CONCLUSIONS These data suggest that in contrast to the conventional hypothesis the T allele may be protective against IHD, independent of homocysteine levels.

The body composition and excretory burden of lean, obese, and severely obese individuals has implications for the assessment of chronic kidney disease

Obesity could affect associations between creatinine generation, estimated body surface area, and excretory burden, with effects on chronic kidney disease assessment. We therefore examined the impact of obesity on the performances of estimated glomerular filtration rate (eGFR), the urine albumin:creatinine ratio (ACR), and excretory burden in 3611 participants of the Chronic Renal Insufficiency Cohort. Urine creatinine excretion significantly increased with body mass index (BMI) (34 and 31% greater at 40 kg/m(2) or more versus the normal of 18.5-25 kg/m(2)) in men and women, respectively, such that patients with a normal BMI and an ACR of 30 mg/g had the same 24-h albuminuria as severely obese patients with ACR 23 mg/g. The bias of eGFR (referenced to body surface area-indexed iothalamate (i-)GFR) had a U-shaped relationship to obesity in men but progressively increased in women. Nevertheless, obesity-associated body surface area increases were accompanied by a greater absolute (non-indexed) iGFR for a given eGFR, particularly in men. Two men with eGFRs of 45 ml/min per 1.73 m(2), height 1.76 m, and BMI 22 or 45 kg/m(2) had absolute iGFRs of 46 and 62 ml/min, respectively. The excretory burden, assessed as urine urea nitrogen and estimated dietary phosphorus, sodium, and potassium intakes, also increased in obesity. However, obese men had lower odds of anemia, hyperkalemia, and hyperphosphatemia. Thus, for a given ACR and eGFR, obese individuals have greater albuminuria, absolute GFR, and excretory burden. This has implications for chronic kidney disease management, screening, and research.

The matrix metalloproteinase-3 (MMP-3) 5A/6A promoter polymorphism is not associated with ischaemic heart disease: Analysis employing a family based approach

Matrix metalloproteinase-3 (MMP-3) has been proposed as an important mediator of the atherosclerotic process. The possible role of the functional -1612 5A/6A polymorphism of the MMP-3 gene in the susceptibility to ischaemic heart disease (IHD) was investigated in a well-defined Irish population using two recently described family based tests of association. One thousand and twelve individuals from 386 families with at least one member prematurely affected with IHD were genotyped. Using the combined transmission disequilibrium test (TDT)/sib-TDT and the pedigree disequilibrium test (PDT), no association between the MMP-3 -1612 5A/6A polymorphism and IHD was found. Our data demonstrate that, in an Irish population, the MMP-3 -1612 5A/6A polymorphism is not associated with IHD.

Are gatekeepers to renal services referring patients equitably

Objective: Patients with chronic kidney disease (CKD) benefit from specialist interventions to retard progression of renal failure and prevent cardiovascular events. Certain patient groups have poor access to specialist renal services when dialysis is required. This study used a population-based laboratory database to investigate access to and timeliness of referral to renal specialists relatively early in the course of the disease. Methods: All tests for serum creatinine and haemoglobin (Hb) A1c in Northern Ireland in a two-year period (2001 and 2002) were retrieved for 345,441 adults. Of these, 16,856 patients had at least one serum creatinine level above 150 μmol/L in 2001 not deemed to be due to acute renal failure (crude prevalence 1.42%). This cohort was followed until the end of 2002 and the differences in the time to referral to a specialist were assessed using Coxs proportional hazards regression. Results: Diabetic patients, older patients and those living in deprived areas were significantly more likely to have serum creatinine testing, compared with non-diabetic, younger and those living in more affluent areas. Delays in referral to renal specialists for patients with raised serum creatinine levels were significantly shorter among diabetic patients, women, younger individuals, those living in rural areas, those living close to renal centres and those living in deprived areas. Overall, only 19% of diabetic patients and 6% of non-diabetic patients who had CKD had seen a renal specialist within 12 months of their index creatinine test. Conclusion: Contrary to other diseases, disadvantaged patients do not seem to be under-investigated for renal disease compared with their more affluent neighbours and are generally referred earlier for specialist assessment. However, the absolute rate of timely specialist assessment is low. Recent changes in referral criteria for CKD will result in more referrals and will have serious resource implications. Opportunities for health gain among patients with declining renal function are being missed, particularly among the old and those living furthest from specialist centres.