Zak K. Shihabi

Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy

Introduction: Medullary cystic kidney disease 2 (MCKD2) and familial juvenile hyperuricaemic nephropathy (FJHN) are both autosomal dominant renal diseases characterised by juvenile onset of hyperuricaemia, gout, and progressive renal failure. Clinical features of both conditions vary in presence and severity. Often definitive diagnosis is possible only after significant pathology has occurred. Genetic linkage studies have localised genes for both conditions to overlapping regions of chromosome 16p11-p13. These clinical and genetic findings suggest that these conditions may be allelic. Aim: To identify the gene and associated mutation(s) responsible for FJHN and MCKD2. Methods: Two large, multigenerational families segregating FJHN were studied by genetic linkage and haplotype analyses to sublocalise the chromosome 16p FJHN gene locus. To permit refinement of the candidate interval and localisation of candidate genes, an integrated physical and genetic map of the candidate region was developed. DNA sequencing of candidate genes was performed to detect mutations in subjects affected with FJHN (three unrelated families) and MCKD2 (one family). Results: We identified four novel uromodulin (UMOD) gene mutations that segregate with the disease phenotype in three families with FJHN and in one family with MCKD2. Conclusion: These data provide the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders. UMOD is a GPI anchored glycoprotein and the most abundant protein in normal urine. We postulate that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible for the clinical changes of interstitial renal disease, polyuria, and hyperuricaemia found in MCKD2 and FJHN.

Comparison of glycated albumin and hemoglobin A1c levels in diabetic subjects on hemodialysis

Glycated albumin is thought to more accurately reflect glycemic control in diabetic hemodialysis patients than hemoglobin A(1c) because of shortened red cell survival. To test this, glycated hemoglobin and albumin levels were measured in blood samples collected from 307 diabetic subjects of whom 258 were on hemodialysis and 49 were without overt renal disease. In diabetic subjects with renal disease, relative to those without, the mean serum glucose and glycated albumin concentrations were significantly higher while hemoglobin A(1c) tended to be lower. The glycated albumin to hemoglobin A(1c) ratio was significantly increased in dialysis patients compared with the controls. Hemoglobin A(1c) was positively associated with hemoglobin and negatively associated with the erythropoietin dose in hemodialysis patients, whereas these factors and serum albumin did not significantly impact glycated albumin levels. Using best-fit multivariate models, dialysis status significantly impacted hemoglobin A(1c) levels without a significant effect on glycated albumin. Our results show that in diabetic hemodialysis patients, hemoglobin A(1c) levels significantly underestimate glycemic control while those of glycated albumin more accurately reflect this control.

Glycated Albumin and Risk of Death and Hospitalizations in Diabetic Dialysis Patients

BACKGROUND AND OBJECTIVES Relative to hemoglobin (Hb) A(₁c), glycated albumin (GA) more accurately reflects glycemic control in patients with diabetes mellitus and ESRD. We determined the association between GA, HbA(₁c), and glucose levels with survival and hospitalizations in diabetic dialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Quarterly GA levels were measured for up to 2.33 years in 444 prevalent patients with diabetes and ESRD. Proportional hazard time-dependent covariate models were computed with adjustment for demographic characteristics, comorbidities, and laboratory variables. Similar analyses were performed for available HbA(₁c) and monthly random serum glucose determinations. RESULTS The participants were 53% male, 54% African American, 43% Caucasian, 90% on hemodialysis, with a mean (SD) age of 62 (12) years and median follow-up duration of 2.25 years. GA and HbA(₁c) mean ± SD 21.5% ± 6.0%, median 20.4% and mean ± SD 6.9% ± 6.6%, median 1.6%, respectively. There were 156 deaths during the observation period. In best-fit models, predictors of death included increasing GA, increasing age, presence of peripheral vascular disease, decreasing serum albumin, and decreasing hemoglobin concentrations. HbA(1c) and random serum glucose concentrations were not predictive of survival. Increasing GA levels were associated with hospitalization in the 17 days after measurement, whereas HbA(₁c) was not. CONCLUSIONS In contrast to the HbA(₁c) and random serum glucose values, GA accurately predicts the risk of death and hospitalizations in patients with diabetes mellitus and ESRD. The GA assay should be considered by clinicians who care for patients with diabetes on dialysis.

COMPARISON OF GLYCATED ALBUMIN AND HEMOGLOBIN A1c CONCENTRATIONS IN DIABETIC SUBJECTS ON PERITONEAL AND HEMODIALYSIS

♦ Background: Relative to hemoglobin A1c (HbA1c), percentage of glycated albumin (GA%) more accurately reflects recent glycemic control in diabetic hemodialysis (HD) patients. ♦ Methods: To determine the accuracy of glycemic assays in a larger sample including patients on peritoneal dialysis (PD), HbA1c and GA% were measured in 519 diabetic subjects: 55 on PD, 415 on HD, and 49 non-nephropathy controls. ♦ Results: Mean ± SD serum glucose levels were higher in HD and PD patients relative to non-nephropathy controls (HD 169.7 ± 62 mg/dL, PD 168.6 ± 66 mg/dL, controls 146.1 ± 66 mg/dL; p = 0.03 HD vs controls, p = 0.13 PD vs controls). GA% was also higher in HD and PD patients (HD 20.6% ± 8.0%, PD 19.0% ± 5.7%, controls 15.7% ± 7.7%; p < 0.02 HD vs controls and PD vs controls). HbA1c was paradoxically lower in dialysis patients (HD 6.78% ± 1.6%, PD 6.87% ± 1.4%, controls 7.3% ± 1.4%; p = 0.03 HD vs controls, p = 0.12 PD vs controls). The serum glucose/HbA1c ratio differed significantly between dialysis patients and controls (p < 0.0001 HD vs controls, p = 0.002 PD vs controls), while serum glucose/GA% ratio was similar across groups (p = 0.96 HD vs controls, p = 0.64 PD vs controls). In best-fit multivariate models with HbA1c or GA% as outcome variable, dialysis status was a significant predictor of HbA1c but not GA%. ♦ Conclusions: The relationship between HbA1c and GA% differs in diabetic patients with end-stage renal disease who perform either PD or HD compared to those without nephropathy. HbA1c significantly underestimates glycemic control in peritoneal and hemodialysis patients relative to GA%.

Relationship between Assays of Glycemia in Diabetic Subjects with Advanced Chronic Kidney Disease

Background: Relative to hemoglobin A1c (HbA1c), glycated albumin (GA) more accurately reflects recent glycemic control in diabetic patients on hemodialysis and peritoneal dialysis. These assays have yet to be compared in patients with advanced chronic kidney disease (CKD). Methods: HbA1c and GA were simultaneously measured in 303 diabetic subjects: 70 with CKD prior to dialysis (CKD-stage 4), 184 with CKD after transplantation (TXP-stage 3) and 49 non-nephropathy controls. Results: Mean estimated GFR was 76, 46 and 26 ml/min in controls, TXP-3 and CKD-4 cases, respectively. Mean (SD) HbA1c (%) and GA (%) concentrations were 7.30 (1.40) and 16.8 (4.9) in controls, 7.28 (1.66) and 21.5 (6.4) in CKD-4 cases, and 7.21 (1.62) and 21.2 (5.5) in TXP-3 cases, respectively. The GA:HbA1c ratio differed significantly between non-nephropathy controls and both groups of CKD patients (both p < 0.001), but not between CKD-4 and TXP-3 cases (p = 0.92). The glucose:HbA1c ratio was inversely associated with GFR in all 254 nephropathy cases (r = –0.13; p = 0.04), while glucose:GA did not vary significantly based upon GFR (r = –0.08; p = 0.24). Conclusions: The relationship between glycated albumin and HbA1c is influenced by the presence of reduced GFR in diabetic patients with CKD. The accuracy of the HbA1c assay in diabetic subjects with severe nephropathy requires further investigation, although HbA1c performs relatively well with milder CKD.

Determination of gabapentin in serum by capillary electrophoresis

A rapid capillary electrophoresis method for the quantification of gabapentin, a new anticonvulsant drug, in serum was developed. The assay involves derivatization of gabapentin with fluorescamine to provide a chromophore for UV-fluorescence detection. The migration time is about 11 min. The assay was linear between 0 and 20 mg/l. No other therapeutic drugs or amino acids interfered with the gabapentin peak. The relative standard deviation is 2.4% at a mean of 11 mg/l (n = 17). The mean serum level for 52 patients on this drug was 5.2 mg/l with a range of 0-12 mg/l.

Supplemental taurine in diabetic rats: effects on plasma glucose and triglycerides.

The present study has indicated that significant shifts in plasma, urinary, and tissue taurine and in non-taurine dialyzable amines occur in the STZ-induced diabetic rat, especially in the kidney. Taurine administration at relatively low dosage ameliorated only kidney taurine concentration. Anticipated alterations in plasma glucose and creatinine were observed but neither of these changes was affected by taurine administration. Similarly, urinary output of creatinine, glucose, and NAG increased significantly among diabetic rats, but none of these were detectably influenced by taurine. Increases in plasma triglycerides observed in STZ-induced diabetes appear to be attenuated by taurine administration, and although cholesterol concentrations were lower in taurine-treated rats, the differences were not statistically significant. These findings should encourage further studies of these effects in rats as a useful model for several complications of human diabetes including atherosclerosis, retinopathy, and nephropathy.

Predicting the Glomerular Filtration Rate in Bariatric Surgery Patients

Background/Aims: Identifying the best method to estimate the glomerular filtration rate (GFR) in bariatric surgery patients has important implications for the clinical care of obese patients and research into the impact of obesity and weight reduction on kidney health. We therefore performed such an analysis in patients before and after surgical weight loss. Methods: Fasting measured GFR (mGFR) by plasma iohexol clearance before and after bariatric surgery was obtained in 36 severely obese individuals. Estimated GFR was calculated using the Modification of Diet in Renal Disease equation, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation using serum creatinine only, the CKD-EPI equation using serum cystatin C only and a recently derived equation that uses both serum creatinine and cystatin C (CKD-EPIcreat-cystC) and then compared to mGFR. Results: Participants were primarily middle-aged white females with a mean baseline body mass index of 46 ± 9, serum creatinine of 0.81 ± 0.24 mg/dl and mGFR of 117 ± 40 ml/min. mGFR had a stronger linear relationship with inverse cystatin C before (r = 0.28, p = 0.09) and after (r = 0.38, p = 0.02) surgery compared to the inverse of creatinine (before: r = 0.26, p = 0.13; after: r = 0.11, p = 0.51). mGFR fell by 17 ± 35 ml/min (p = 0.007) following surgery. The CKD-EPIcreat-cystC was unquestionably the best overall performing estimating equation before and after surgery, revealing very little bias and a capacity to estimate mGFR within 30% of its true value over 80% of the time. This was true whether or not mGFR was indexed for body surface area. Conclusions: In severely obese bariatric surgery patients with normal kidney function, cystatin C is more strongly associated with mGFR than is serum creatinine. The CKD-EPIcreat-cystC equation best predicted mGFR both before and after surgery.

Ethnic variation in the correlation between random serum glucose concentration and glycated haemoglobin.

Aims  To determine if the relationship between serum glucose concentration and glycated haemoglobin is different between African‐Americans and whites.

Measuring the glomerular filtration rate in obese individuals without overt kidney disease.

Background: Identifying methods to accurately measure the glomerular filtration rate (GFR) in obese individuals without kidney overt kidney disease is necessary to understanding the pathophysiology and natural history of obesity-related kidney disease. Methods: Using a cross-sectional design, iohexol clearance and disposition was measured, an optimal sampling schedule was identified, and the reliability of GFR-estimating methods was described in 29 obese individuals with normal serum creatinine levels. Iohexol disposition was measured using population pharmacokinetics. The agreement with GFR-estimating equations was assessed by intraclass coefficients. Results: Mean age was 44 ± 10 years, body mass index 45 ± 10, creatinine 0.7 ± 0.2 mg/dl (62 ± 18 µmol/l) , and cystatin C 0.83 ± 0.18 mg/dl (8.3 ± 1.8 mg/l). Iohexol disposition fit a two-compartment model and 5 sampling windows were identified over a 4-hour period to optimize model accuracy and minimize blood draws. Precision was not compromised with this sampling design. Neither creatinine nor cystatin C were linearly correlated with the measured GFR though cystatin C was independent of body composition. Agreement was fair to poor between the measured GFR and GFR-estimating equations. Conclusion: This study offers a rigorous method to study obesity-related kidney disease and improve upon suboptimal GFR-estimating methods.