Quantification and classification of potassium and calcium disorders with the electrocardiogram: What do clinical studies, modeling, and reconstruction tell us?

Diseases caused by alterations of ionic concentrations are frequently observed challenges and play an important role in clinical practice. The clinically established method for the diagnosis of electrolyte concentration imbalance is blood tests. A rapid and non-invasive point-of-care method is yet needed. The electrocardiogram (ECG) could meet this need and becomes an established diagnostic tool allowing home monitoring of the electrolyte concentration also by wearable devices. In this review, we present the current state of potassium and calcium concentration monitoring using the ECG and summarize results from previous work. Selected clinical studies are presented, supporting or questioning the use of the ECG for the monitoring of electrolyte concentration imbalances. Differences in the findings from automatic monitoring studies are discussed, and current studies utilizing machine learning are presented demonstrating the potential of the deep learning approach. Furthermore, we demonstrate the potential of computational modeling approaches to gain insight into the mechanisms of relevant clinical findings and as a tool to obtain synthetic data for methodical improvements in monitoring approaches.

Optimal EPO dosing in hemodialysis patients using a non-linear model predictive control approach.

Anemia management with erythropoiesis stimulating agents is a challenging task in hemodialysis patients since their response to treatment varies highly. In general, it is difficult to achieve and maintain the predefined hemoglobin (Hgb) target levels in clinical practice. The aim of this study is to develop a fully personalizable controller scheme to stabilize Hgb levels within a narrow target window while keeping drug doses low to mitigate side effects. First in-silico results of this framework are presented in this paper. Based on a model of erythropoiesis we formulate a non-linear model predictive control (NMPC) algorithm for the individualized optimization of epoetin alfa (EPO) doses. Previous to this work, model parameters were estimated for individual patients using clinical data. The optimal control problem is formulated for a continuous drug administration. This is currently a hypothetical form of drug administration for EPO as it would require a programmable EPO pump similar to insulin pumps used to treat patients with diabetes mellitus. In each step of the NMPC method the open-loop problem is solved with a projected quasi-Newton method. The controller is successfully tested in-silico on several patient parameter sets. An appropriate control is feasible in the tested patients under the assumption that the controlled quantity is measured regularly and that continuous EPO administration is adjusted on a daily, weekly or monthly basis. Further, the controller satisfactorily handles the following challenging problems in simulations: bleedings, missed administrations and dosing errors.

Unraveling the relationship between mortality, hyponatremia, inflammation and malnutrition in hemodialysis patients: results from the international MONDO initiative.

BACKGROUND/OBJECTIVES: Hyponatremia is a risk factor for mortality in hemodialysis (HD) patients. It is not well known to which extent the comorbidities, malnutrition, fluid status imbalance and inflammation are related to hyponatremia and affect outcomes. SUBJECTS/METHODS: We studied 8883 patients from the European subset of the international MONitoring Dialysis Outcomes initiative. Nutritional and fluid statuses were assessed by bioimpedance spectroscopy. Fluid depletion was defined as overhydration⩽-1.1 l and fluid overload as overhydration>+1.1 l, respectively. Malnutrition was defined as a lean tissue index below the 10th percentile of age- and gender-matched healthy controls. Hyponatremia and inflammation were defined as serum sodium levels <135 mEq/l and C-reactive protein levels>6.0 mg/l, respectively. We used logistic regression to test for predictors of hyponatremia and Cox proportional hazards analysis to assess the association with all-cause mortality. RESULTS: Hyponatremia was predicted by the presence of malnutrition (odds ratio (OR)=1.49 (95% confidence interval (CI)=1.30-1.70), inflammation (OR=1.44 (95% CI=1.26-1.64)) and fluid overload ((>+1.1 l to +2.5 l) OR=0.73 (95% CI=0.62-0.85)) but not by fluid depletion (OR=1.34 (95% CI=0.92-1.96)). Malnutrition, inflammation, fluid overload, fluid depletion and hyponatremia (hazard ratio=1.70 (95% CI=1.46-1.99)) were independent predictors for all-cause mortality. CONCLUSIONS: In HD patients, hyponatremia is associated with malnutrition, inflammation and fluid overload. Hyponatremia maintained predictive for all-cause mortality after adjustment for malnutrition, inflammation and fluid status abnormalities. The presence of hyponatremia may assist in identifying HD patients at increased risk of death.

Association between pre hemodialysis serum sodium concentration and blood pressure: results from a retrospective analysis from the international monitoring dialysis outcomes (MONDO) initiative.

A recent study from the United Kingdom indicates an association between pre hemodialysis (HD) serum sodium (SNa(+)) and systolic and diastolic blood pressure (SBP and DBP) in chronic HD patients. We extend this analysis to an international cohort of incident HD patients. The Monitoring Dialysis Outcomes initiative encompasses patients from 41 countries. Over 2 years monthly pre-HD SNa(+) levels were used as predictors of pre-HD SBP and DBP in a linear mixed model (LMM) adjusted for age, gender, interdialytic weight gain, diabetes, serum albumin and calcium. Similar models were constructed with DBP as outcome. Analyses were carried out stratified by continent (North and South America; Europe and Asia). LMMs were also constructed for the entire observation period of 2 years, and separately the first and the second year after HD initiation. We studied 17 050 incident patients and found SNa(+) to have a significant slope estimate in the LMM predicting pre-HD SBP and DBP (ranging from 0.22 to 0.29 and 0.10 to 0.21 mm Hg per mEq l(-1), respectively, between the continents). The findings were similar in subsets of SBP and SNa(+) tertiles, and separately analyzed for the first and second year. Our analysis shows an independent association between SNa, SBP and DBP in a large intercontinental database, indicating that this relation is a profound biological phenomenon in incident and prevalent HD patients, generalizable to an international level and independent of SBP and DBP magnitude.

Saliva urea dipstick test: application in chronic kidney disease.

BACKGROUND: A noninvasive test for determining elevated levels of blood urea nitrogen (BUN) may be useful under circumstances in which there is limited access to laboratories. Because saliva urea nitrogen (SUN) parallels BUN, we investigated the diagnostic performance of a semiquantitative SUN dipstick to test for elevated BUN levels in patients with chronic kidney disease (CKD). MATERIALS AND METHODS: Patients with CKD Stages 1 to 5D were studied. 50 µl of saliva were transferred onto the SUN test strip (Integrated Biomedical Technology, Elkhart, Indiana, IN, USA). SUN was determined after 1 minute by visual comparison of the color of the moistened test pad with 6 calibrated color blocks. Interobserver reproducibility was evaluated by independent observers, masked to urea concentrations of 6 calibrated urea solutions. Correlation between SUN and BUN was quantified by Spearman's rank correlation coefficient (RS), Kappa Statistic was employed to evaluate within-sample reproducibility of duplicates. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic performance of SUN. RESULTS: 68 patients (31 females, 60 ± 14 years; 34 hemodialysis patients, 34 patients CKD Stages 1 - 4) were studied. Interobserver coefficient of variation was 4.9% at SUN levels > 50 mg/dl; within-sample reproducibility was 90%. SUN and BUN were correlated significantly (RS = 0.63; p < 0.01). Elevated BUN was diagnosed with high accuracy by SUN determination (area under the ROC curve: 0.90 (95% CI 0.85 - 0.95)). CONCLUSION: Semiquantitative dipstick measurements of SUN can reliably identify CKD patients with elevated BUN levels.

Significance of self-reported sleep quality (SQ) in chronic kidney disease (CKD): the Renal Research Institute (RRI)-CKD study.

BACKGROUND: There has been limited research on sleep quality (SQ) in CKD. METHODS: This prospective cohort study of adults with CKD Stages 3 - 5 at four US centers collected self-reported SQ information from the Kidney Disease Quality of Life (KDQOL) instrument, including an estimated SQ score (0 - 100), and 3 SQ-related questions. "Poor" SQ was defined as SQ score < or = 60. Logistic and multiple linear regression assessed associations between SQ and its potential predictors. Times to death and end stage renal disease (ESRD) were examined using Cox regression. A comparison with SQ in ESRD patients from the Dialysis Outcomes and Practice Patterns Study (DOPPS), was additionally performed. RESULTS: Mean SQ score was 59.4 +/- 23.6 (n = 689), and "poor" SQ was reported by 57%. Mean estimated glomerular filtration rate (eGFR) was 24.9 +/- 10.6 ml/min/1.73 m2. Higher SQ significantly correlated with KDQOL mental and physical component summary scales. Significant predictors of lower SQ score included--younger age, presence of dyspnea, self-reported depression, pain, and itchness. There were no significant pairwise differences in SQ from CKD Stage 3 through ESRD. Self-reported daytime sleepiness was significantly associated with higher risk of mortality prior to ESRD (HR = 1.85, p = 0.02). CONCLUSION: Self-reported "poor" SQ was common in a CKD cohort (Stages 3 - 5) and was not only associated with lower quality of life scores and several modifiable symptoms, but also with higher risk of pre-ESRD mortality. Greater attention to this clinical problem is highly recommended in this high-risk population.

Assessment of body composition in dialysis patients by arm bioimpedance compared to MRI and 40K measurements.

This study used multi-frequency bioimpedance spectroscopy (BIS) of the arm and whole body to estimate muscle mass (MM) and subcutaneous adipose tissue (SAT) in 31 hemodialysis (HD) patients comparing these results with magnetic resonance imaging (MRI) and body potassium ((40)K) as gold standards. Total body and arm MM (MM(MRI)) and SAT (SAT(MRI)) were measured by MRI. All measurements were made before dialysis treatment. Regression models with the arm (aBIS) and whole body (wBIS) resistances were established. Correlations between gold standards and the BIS model were high for the arm SAT (r(2) = 0.93, standard error of estimate (SEE) = 3.6 kg), and whole body SAT (r(2) = 0.92, SEE = 3.5 kg), and for arm MM (r(2) = 0.84, SEE = 2.28 kg) and whole body MM (r(2) = 0.86, SEE = 2.28 kg). Total body MM and SAT can be accurately predicted by arm BIS models with advantages of convenience and portability, and it should be useful to assess nutritional status in HD patients.

A method for the estimation of hydration state during hemodialysis using a calf bioimpedance technique.

Although many methods have been utilized to measure degrees of body hydration, and in particular to estimate normal hydration states (dry weight, DW) in hemodialysis (HD) patients, no accurate methods are currently available for clinical use. Biochemcial measurements are not sufficiently precise and vena cava diameter estimation is impractical. Several bioimpedance methods have been suggested to provide information to estimate clinical hydration and nutritional status, such as phase angle measurement and ratio of body fluid compartment volumes to body weight. In this study, we present a calf bioimpedance spectroscopy (cBIS) technique to monitor calf resistance and resistivity continuously during HD. Attainment of DW is defined by two criteria: (1) the primary criterion is flattening of the change in the resistance curve during dialysis so that at DW little further change is observed and (2) normalized resistivity is in the range of observation of healthy subjects. Twenty maintenance HD patients (12 M/8 F) were studied on 220 occasions. After three baseline (BL) measurements, with patients at their DW prescribed on clinical grounds (DW(Clin)), the target post-dialysis weight was gradually decreased in the course of several treatments until the two dry weight criteria outlined above were met (DW(cBIS)). Post-dialysis weight was reduced from 78.3 +/- 28 to 77.1 +/- 27 kg (p < 0.01), normalized resistivity increased from 17.9 +/- 3 to 19.1 +/- 2.3 x 10(-2) Omega m(3) kg(-1) (p < 0.01). The average coefficient of variation (CV) in three repeat measurements of DW(cBIS) was 0.3 +/- 0.2%. The results indicate that cBIS utilizing a dynamic technique continuously during dialysis is an accurate and precise approach to specific end points for the estimation of body hydration status. Since no current techniques have been developed to detect DW as precisely, it is suggested as a standard to be evaluated clinically.

Consequences of overhydration and the need for dry weight assessment.

Despite significant progress in the fields of dialysis technology and medical therapy, mortality of hemodialysis (HD) patients remains high. Chronic overhydration is a major contributor to the high cardiovascular morbidity and mortality observed in HD patients. The difficulty of measuring excess fluid accurately and the determination of 'dry weight' are reflected in the abundant literature on overhydration. Data indicate that a significant proportion of HD patients are not at 'dry weight'. Considering its impact on cardiovascular diseases, the relation between excess fluid, sodium, interdialytic weight gain, hypertension and cardiac diseases needs more attention. Clearly the reduction of sodium intake is of prime importance. This can be achieved by a reduction of dietary sodium intake, individualized dialysate sodium concentration, avoidance of sodium profiling and use of hypertonic saline during dialysis. These measures are expected to result in less thirst and consecutive water intake, thereby facilitating achieving dry weight (DW). In concert, the application of new tools for DW assessment such as continuous intradialytic bioimpedance spectroscopy measurement, means to prevent intradialytic symptoms (e.g. glucose bolus instead of hypertonic saline; improved hemodynamic stability by reduced dialysate temperature) may be operative in reducing morbidity and mortality in HD patients.

The impact of visceral mass on survival in chronic hemodialysis patients.

In chronic hemodialysis, patient survival is positively correlated with body weight and body mass index (BMI). This relationship extends even to obese patients with a BMI >30 kg/m2. We have put forward the hypothesis that this survival benefit may be due to a lower average synthesis rate of uremic toxins (expressed as amount per time per unit of body weight) in larger patients, because the relative contribution of the high metabolic rate organs (HMRO) to body weight in these patients is lower and HMRO are most likely to be the prime source of uremic toxins. In addition, the average uremic toxin concentration in larger patients may be lower because of the larger distribution volume. Based on these assumptions, a better survival in patients with a lower HMRO to body weight fraction (HMRO%BW) can be predicted. To test this hypothesis we estimated gender- and race-specific HMRO mass by means of recently published regression models in 2,004 incident hemodialysis patients. Cox proportional hazards models were used to assess the association between age, serum albumin concentration, eKt/V, and HMRO% BW and mortality. High HMRO%BW was significantly associated with increased mortality (hazard ratio 1.323 [95% CI: 1.186 to 1.477]). Mean survival time was longest in the low HMRO%BW tertile (1,031 days [95%CI: 974 to 1,087]), 935 days [95%CI: 886 to 984] in the middle, and 876 days [95%CI: 825 to 926] in the high HMRO%BW tertile (p<0.0001; log rank test). These results support the hypothesis predicting that a low HMRO mass per unit of weight confers a beneficial effect on survival.

A mathematical model comparing solute kinetics in low- and high-BMI hemodialysis patients.

BACKGROUND: Patients with low Body Mass Index (BMI) on maintenance hemodialysis have a higher mortality risk than patients with elevated BMI. We investigated the use of kinetic modeling to test different hypotheses which have been advanced to explain this relationship. METHODS: Equations from a three-pool urea-kinetic mathematical model (hepatic mass, extracellular fluid, muscle mass and adipose tissue) were solved to yield predictive profiles of solute and putative toxin concentrations versus time for patients of different body weights. RESULTS: For the interdialytic interval, our mathematic model suggests that extracellular solute/toxin concentration increases more rapidly in small patients. Additionally, time average concentration (TAC) is higher for this cohort. A lower value of the muscle mass and adipose tissue mass-transfer coefficient (K(MMAT)), which determines the rate of solute release into the extracellular fluid, exacerbates this difference. CONCLUSION: These results suggest that higher mortality for smaller dialysis patients may be mediated by higher time average toxin concentration, especially for solutes with a low mass-transfer coefficient value.

Evaluation of treatment adherence in type 1 diabetes: a novel approach.

BACKGROUND: Intensified insulin therapy requires outstanding compliance but no measure of therapy adherence has been agreed upon. The aim of the current study was to test the hypothesis that treatment adherence, as described by a novel multiple regression model, relates to glycosylated haemoglobin and hypoglycaemia frequency in type 1 diabetes. Furthermore, we sought to analyse the complex diurnal patterns of therapy adherence. MATERIALS AND METHODS: Thirty type 1 diabetes patients (20 females and 10 males), treated with intensified insulin therapy, were studied in a retrospective manner. Patients were trained to follow treatment algorithms for adjusting regular insulin dosage which took into account the actual blood glucose, food intake and the time of the day. By means of multiple linear regression analysis, with regular insulin dosage as the dependent variable, blood glucose and food intake as the independent variables, the insulin treatment algorithms actually used by the individual patient were retrieved. The correlation between prescribed and implemented insulin therapy served as a measure of adherence. Metabolic control was assessed by glycosylated haemoglobin and hypoglycaemia frequency. RESULTS: Median glycosylated haemoglobin was 7.7% (range: 6.3-10.8); median monthly hypoglycaemia frequency was 3.8 (range: 0-9.8). Patients with good metabolic control (glycosylated haemoglobin < 7.7 and/or hypoglycaemia frequency < 3.8 per month) adhered to prescribed insulin dosing algorithms more frequently than those with poor metabolic control. CONCLUSIONS: In patients with type 1 diabetes on intensified therapy a positive relationship between adherence to the therapy prescribed and metabolic control exists.

A kinetic model of calcium mass balance during dialysis therapy.

A kinetic model of Ca mass balance during dialysis has been developed. It is a single-compartment, variable-volume model to compute Ca mass balance during dialysis in its volume of distribution, the extracellular fluid. The model was used to analyze literature data which were suitable for the assessment of Ca mass balance over the course of dialysis. The modeled analyses predicted the serial plasma Ca concentrations very well. The mass balance analyses revealed a pool of rapidly diffusible Ca beyond the extracellular fluid distribution volume where Ca could be mobilized (M+(Ca)) or sequestered (M-(Ca)) very rapidly at rate equal but opposite in sign to dialyzer flux and thus effectively maintain near constant plasma Ca in the face of dialyzer Ca concentration gradients. This pool is likely the large pool of diffusible (miscible) Ca in connective tissue and on bone surfaces. Analysis of net Ca flux during dialysis with Cdi(Ca) = 2.50 mEq/l suggests that 80% of patients are in positive Ca balance during dialysis. Further studies are required to verify the model and to develop a model of interdialytic Ca mass balance.

Metabolic consequences of body size and body composition in hemodialysis patients.

Small body mass index is associated with increased mortality in chronic hemodialysis patients. The reasons for this observation are unclear but may be related to body composition. This study aimed to investigate the body composition in chronic hemodialysis patients. The difference between body mass and the sum of muscle, bone, subcutaneous, and visceral adipose tissue masses, measured by whole body magnetic resonance imaging, was defined as the high metabolic rate compartment representing the visceral mass. Protein catabolic rate was calculated from urea kinetics. Forty chronic hemodialysis patients (mean age 54.7 years; 87.5% African Americans; 45% females) were studied. High metabolic rate compartment expressed in percent of body weight was inversely related to body weight (r=-0.475; P=0.002) and body mass index (r=-0.530; P<0.001). In a multiple linear regression model, protein catabolic rate was significantly correlated only with high metabolic rate compartment (r=0.616; P<0.001). Assuming that protein catabolic rate in addition to protein intake reflects urea and uremic toxin generation, it follows that high metabolic rate compartment is the major compartment involved in their generation. Consequently, uremic toxin production rate may be relatively higher in patients with low body weight and low body mass index as compared to their heavier counterparts. The poorer survival observed in smaller dialysis patients may be related to these relative differences.

Application of bioimpedance techniques to peritoneal dialysis.

Peritoneal dialysis (PD) has been used as a home dialysis therapy for renal replacement for more than 30 years. In a recent assessment of treatment quality, the mortality of patients on PD was referenced as being higher than of those on hemodialysis. Several reports suggest that a high proportion of PD patients are overhydrated. Clinical assessment of dry weight in PD patients is difficult and further complicated by the paucity of signs and symptoms indicative of dehydration (such as intradialytic hypotension or muscle cramps). Monitoring tools used for fluid status estimation during hemodialysis, e.g. online blood volume and blood pressure measurement, are not readily available in PD patients. Bioimpedance analysis technique has been considered as a potential tool to measure body fluid non-invasively, inexpensively and simply. Although Bioimpedance analysis has been used in clinical studies for more than 20 years, the knowledge of the electrical properties of body tissues is still evolving. In this review we aim to clarify the principles of different bioimpedance techniques and to introduce their applications in PD patients.

The role of nuclear factor-kappa B in bacterial translocation in cholestatic rats.

Xanthinoxidase (XO) derived radical species are involved in bacterial translocation (BT) in cholestatic rats. The mechanism by which XO influences remains unclear. It has been shown recently that nuclear factor-kappa B (NF-kappaB), a ubiquitous transcription factor, can be activated by oxidative stress and thereby promote the process of BT. We investigated the effects of NF-kappaB inactivation on the incidence of BT in cholestatic rats. Sprague-Dawley rats were randomly assigned to one of eight groups: groups 1-4 were sham laparotomized rats either untreated (S1) or treated for 5 days with thalidomide (S2), curcumin (S3), or Inchin-ko (ICK; S4); groups 5-8 underwent common bile duct ligation (CBDL) for 5 days and were either untreated (C1) or treated with thalidomide (C2), curcumin (C3), or ICK (C4). After 5 days bacteriological cultures were performed from portal blood and V. cava, from the central mesenteric lymph node complex (MLN), spleen, and liver. The intensity of the activated NF-kappaB-subunit p65/p50 in the ileum mucosa was estimated by light microscopy and a scoring system from 1 to 20. Malondialdehyde (MDA) and myeloperoxidase activity (MPO) in the ileum were evaluated and expressed as U/g dry weight. Thalidomide and ICK reduced in CBDL-rats significantly the BT rate (63% vs. 18%, 63% vs. 30%, P<0.01). Enzyme estimations (MDA, MPO, and GSH) in sham operated animals showed no significant changes in the untreated groups compared with the treated groups. CBDL-rats pre-treatment with all three compounds caused a significant increase of MDA levels if groups were compared with the untreated C1-group (C1 31.6+/-7.7, C2 54.5+/-12.2, C3 53.3+/-11.2, and C4 47.2+/-9.4). GSH was reduced after the pre-treatment by all compounds but only significantly after curcumin pre-treatment (C1 vs. C3: 13.9+/-1.8 vs. 7.1+/-1.8; P<0.05). MPO estimations were significantly higher in the untreated C1-group if compared with groups C2, C3, and C4 (C1 1036.4+/-340.9, C2 709.9+/-125.9, C3 545.2+/-136.6, and C4 556.7+/-247.4; P<0.05). Thalidomide inhibited significantly the activation of NF-kappaB (C2 vs. C1: 6.0+/-4.5 vs. 12.7+/-5.3; P<0.01). Likewise, Curcumin and ICK suppressed NF-kappaB activation, but this did not reach significance in this experiment. NF-kappaB is involved in the process of BT in cholestatic rats and may be activated by XO derived ROS. We assume that the activated NF-kappaB initiates transcription of target genes inducing cytokine production, which in turn disrupts the tight junctions leading to BT from the intestinal lumen to the MLNs and circulation.

Gender, age and seasonal effects on IgA deficiency: a study of 7293 Caucasians.

BACKGROUND: The frequency of serum IgA deficiency (SIgAD) differs between populations. We examined the prevalence of SIgAD in healthy Caucasians. MATERIALS AND METHODS: Serum immunoglobulin A (SIgA) was measured in 7293 volunteers (2264 women, 5029 men) aged 30 +/- 14.2 years (mean +/- SD; range: 12-66). Serum immunoglobulin A and subnormal SIgA levels were defined by a SIgA level < 0.07 g L(-1), and between 0.07 and 0.7 g L(-1), respectively. Means were compared by analysis of variance (anova) and analysis of covariance (ancova); frequencies by the chi(2) test. RESULTS: Fifteen subjects (0.21%; one woman, 14 men) had SIgAD. Subnormal SIgA levels were found in 155 persons (2.13%): 21 females (0.93% of the females) and 134 males (2.66% of the males; difference: 1.74%; 95% CI: 1.12-2.33%; P < 0.001). Males were more likely to have subnormal SIgA levels or SIgAD (odds ratio 3.09, 95% CI: 1.97-4.85). The prevalence of SIgAD and subnormal SIgA was lowest in winter (chi(2) = 14.8; P = 0.002; 3 d.f.; and chi(2) = 43.2; P < 0.001; 3 d.f., respectively). Serum immunoglobulin A concentrations were significantly higher during winter. Serum immunoglobulin A levels increased with age on average by 0.2 +/- 0.06 g L(-1) per decade of life (P < 0.001). Taking into account the influence of age, SIgA concentration was lower in females as compared with males. CONCLUSION: The prevalence of SIgAD and subnormal SIgA levels is increased in males. There exists a significant influence of gender, age and seasons on SIgA levels.

UROMODULIN mutations cause familial juvenile hyperuricemic nephropathy.

Gout, which is commonly associated with hyperuricemia, affects 0.2% of the population. Hyperuricemia has a heterogeneous etiology that may be due to either over production and/or reduced renal clearance, of urate. In order to identify the mechanisms underlying reduced excretion of urate, we undertook positional cloning studies of familial juvenile hyperuricaemic nephropathy (FJHN), which is an autosomal dominant disorder characterized by hyperuricaemia, a low fractional renal excretion of urate, and chronic renal failure that is associated with interstitial fibrosis. The FJHN locus has been previously localized to a 22 centiMorgan interval flanked centromerically by D16S401 and telomerically by D16S3069, on chromosome 16p11-p13. This interval contains over 120 genes and we selected 13 renal expressed sequences to search for mutations in 5 unrelated FJHN families that contained 21 affected and 24 unaffected members. This revealed 5 heterozygous missense mutations (Cys77Tyr, Cys126Arg, Asn128Ser, Cys255Tyr and Cys300Gly) that altered evolutionary conserved residues in the gene encoding UROMODULIN. UROMODULIN, which is an 85 Kda glycoprotein, has roles in renal stone formation, the modulation of immune responses, and urothelial cytoprotection. The results of our studies, which have identified the gene causing FJHN, now indicate a further, novel role for UROMODULIN in urate metabolism.

Coronary anatomy predicts presence or absence of renal artery stenosis. A prospective study in patients undergoing cardiac catheterization for suspected coronary artery disease.

AIMS: This study aimed to determine the prevalence of renal artery stenosis (RAS) and associated risk factors in patients undergoing cardiac catheterization for suspected coronary artery disease (CAD). METHODS: One hundred and seventy-seven consecutive patients (62 females) with a serum creatinine concentration <2.0mg.dl(-1) were studied. Abdominal aortography followed cardiac catheterization to screen for RAS. RESULTS: In 110 patients (62%) CAD and in 19 patients (11%) significant RAS (luminal narrowing of >or=50%) were detected, 12 of whom had high grade (>or=70%) RAS, and two subjects had significant RAS without CAD. Patients with RAS were older (67+/-8 vs 61+/-11 years, mean+/-SD;P =0.004), had higher systolic blood pressure (150+/-15 vs 138+/-20 mmHg;P =0.005), a lower glomerular filtration rate (GFR; 61+/-16 vs 80+/-22 ml.min(-1), P<0.001) and more often diabetes mellitus (69% vs 30%; P=0.004). In multivariate analysis a low GFR and the extent of CAD were independent predictors of RAS. The presence of >2 significant coronary lesions predicted RAS (sensitivity 0.84, specificity 0.77, positive predictive value 0.30, negative predictive value 0.98). CONCLUSION: Screening for RAS in patients with >2 diseased coronary segments has a high diagnostic yield, which is even greater in the presence of a reduced GFR, diabetes mellitus, and elevated systolic blood pressure.