A case-based narrative review of pregnancy-associated atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy.

Atypical hemolytic uremic syndrome is a complement-mediated thrombotic microangiopathy caused by uncontrolled activation of the alternative complement pathway in the setting of autoantibodies to or rare pathogenic genetic variants in complement proteins. Pregnancy may serve as a trigger and unmask atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy (aHUS/CM-TMA), which has severe, life-threatening consequences. It can be difficult to diagnose aHUS/CM-TMA in pregnancy due to overlapping clinical features with other thrombotic microangiopathy syndromes including hypertensive disorders of pregnancy. However, the distinction among thrombotic microangiopathy etiologies in pregnancy is important because each syndrome has specific disease management and treatment. In this narrative review, we discuss 2 cases to illustrate the diagnostic challenges and evolving approach in the management of pregnancy-associated aHUS/CM-TMA. The first case involves a 30-year-old woman presenting in the first trimester who was diagnosed with aHUS/CM-TMA and treated with eculizumab from 19 weeks' gestation. Genetic testing revealed a likely pathogenic variant in CFI. She successfully delivered a healthy infant at 30 weeks' gestation. In the second case, a 22-year-old woman developed severe postpartum HELLP syndrome, requiring hemodialysis. Her condition improved with supportive management, yet investigations assessing for aHUS/CM-TMA remained abnormal 6 months postpartum consistent with persistent complement activation but negative genetic testing. Through detailed case discussion describing tests assessing for placental health, fetal anatomy, complement activation, autoantibodies to complement regulatory proteins, and genetic testing for aHUS/CM-TMA, we describe how these results aided in the clinical diagnosis of pregnancy-associated aHUS/CM-TMA and assisted in guiding patient management, including the use of anticomplement therapy.

Management of Patients With Glomerulonephritis During the COVID-19 Pandemic: Recommendations From the Canadian Society of Nephrology COVID-19 Rapid Response Team.

PURPOSE OF PROGRAM: This article will provide guidance on how to best manage patients with glomerulonephritis (GN) during the COVID-19 pandemic. SOURCES OF INFORMATION: We reviewed relevant published literature, program-specific documents, and guidance documents from international societies. An informal survey of Canadian nephrologists was conducted to identify practice patterns and expert opinions. We hosted a national webinar with invited input and feedback after webinar. METHODS: The Canadian Society of Nephrology (CSN) Board of Directors invited physicians with expertise in GN to contribute. Specific COVID-19-related themes in GN were identified, and consensus-based recommendations were made by this group of nephrologists. The recommendations received further peer input and review by Canadian nephrologists via a CSN-sponsored webinar. This was attended by 150 kidney health care professionals. The final consensus recommendations also incorporated review by Editors of the Canadian Journal of Kidney Health and Disease. KEY FINDINGS: We identified 9 areas of GN management that may be affected by the COVID-19 pandemic: (1) clinic visit scheduling, (2) clinic visit type, (3) provision of multidisciplinary care, (4) blood and urine testing, (5) home-based monitoring essentials, (6) immunosuppression, (7) other medications, (8) patient education and support, and (9) employment. LIMITATIONS: These recommendations are expert opinion, and are subject to the biases associated with this level of evidence. To expedite the publication of this work, a parallel review process was created that may not be as robust as standard arm's length peer review processes. IMPLICATIONS: These recommendations are intended to provide optimal care during the COVID-19 pandemic. Our recommendations may change based on the evolving evidence.

Drug-induced Thrombotic Microangiopathy with Concurrent Proteasome Inhibitor Use in the Treatment of Multiple Myeloma: A Case Series and Review of the Literature.

Thrombotic microangiopathy (TMA) is a life-threatening clinical syndrome characterized by hemolytic anemia, thrombocytopenia, and microvascular thrombosis, resulting in ischemia and organ damage. Multiple myeloma (MM) is a neoplasm arising from clonal plasma cells within the bone marrow. The treatment frequently includes multi-agent immunochemotherapy, often with the use of proteasome inhibitors (PIs) such as bortezomib, carfilzomib, or ixazomib. There are increasing reports of TMA in association with PI exposure. This review summarizes the epidemiology, pathogenesis, and diagnosis of PI-related drug-induced TMA. We will outline the definition and diagnosis of TMA and explore an important cause of hemolysis in patients with MM: drug-induced TMA after PI exposure, an increasingly recognized therapeutic complication. This will be emphasized through the description of 3 novel cases of TMA. These illustrative cases occurred after treatment with high-dose weekly carfilzomib, cyclophosphamide, and dexamethasone as part of the MCRN003/MYX1 phase II clinical trial (NCT02597062) in relapsed MM.

Relationship of coronary artery calcification with renal function decline and mortality in predialysis chronic kidney disease patients.

BACKGROUND: Patients with chronic kidney disease (CKD) have higher levels of coronary artery calcification (CAC) compared with the general population. The role of CAC in renal function decline is not well understood. METHODS: In this prospective cohort study of Stages 3-5 CKD patients with CAC scores kidney function decline, development of end-stage kidney disease (ESKD) and all-cause mortality were determined at 5 and 10 years. Baseline variables included markers of CKD and chronic kidney disease mineral and bone disorder (CKD-MBD), demographics and comorbidities. Multivariable analyses identified predictors of outcomes, and survival curves demonstrated the association of CAC score with ESKD and mortality. RESULTS: One hundred and seventy-eight patients were enrolled between 2005 and 2007. Independent predictors of ESKD at 5 years were estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR); at 10 years, eGFR was no longer a predictor, but CAC was now significant. Those who developed ESKD at the fastest rate either had the highest CAC score (≥400 AU) or were youngest and had the lowest calcidiol, and highest serum phosphate, UACR and percentage change in CAC per year. Predictors of eGFR decline over 5 years were UACR, parathyroid hormone and CAC score. Predictors of mortality at 5 years were age, diabetes and eGFR and at 10 years also included CAC score. CONCLUSIONS: In Stages 3-5 CKD patients, CAC is an independent predictor of both ESKD and mortality at 10 years. Those who developed ESKD at the fastest rate either had the highest CAC score or the worst CKD-MBD derangements.

Elevated body mass index as a risk factor for chronic kidney disease: current perspectives.

Chronic kidney disease (CKD) is defined by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative as the presence of reduced kidney function or kidney damage for a period of 3 months or greater. Obesity is considered a risk factor for CKD development, but its precise role in contributing to CKD and end stage kidney disease is not fully elucidated. In this narrative review, the objectives are to describe the pathogenesis of CKD in obesity, including the impact of altered adipokine secretion in obesity and CKD, and to provide an overview of the clinical studies assessing the risk of obesity and CKD development.

Sequence variation in vitamin K epoxide reductase gene is associated with survival and progressive coronary calcification in chronic kidney disease.

OBJECTIVE: Sequence variations in the gene(s) encoding vitamin K epoxide reductase complex subunit 1 (VKORC1), the enzyme target of warfarin, have been associated with increased cardiovascular disease in the general population. Coronary artery calcification (CAC) is a prevalent form of cardiovascular disease in chronic kidney disease. We tested the hypothesis that the VKORC1 rs8050894 CC genotype would be associated with mortality and progression of CAC ≤ 4 years. APPROACH AND RESULTS: This study is an observational, prospective study of 167 individuals with stages 3 to 5 chronic kidney disease. Survival ≤ 4 years was assessed in all participants, and CAC progression was measured in a subset of 86 patients. Participants with the CG/GG genotype of VKORC1 had higher baseline CAC scores (median score, 112 versus 299; P=0.036). Of those 86 patients who had a 4-year CAC score, those with the CG/GG genotype had an increased risk of progressive CAC (adjusted for age, diabetes mellitus, estimated glomerular filtration rate, and hypertension) compared with those with the CC genotype. Four-year mortality risk was 4 times higher for individuals with the CG/GG genotypes compared with individuals with the CC genotype (odds ratio, 3.8; 95% confidence interval, 1.2-12.5; P=0.02), adjusted for age, sex, diabetes mellitus, estimated glomerular filtration rate, baseline CAC, and hypertension. CONCLUSIONS: Patients with the CG/GG genotype of VKORC1 had a higher risk of CAC progression and a poorer survival. These data provide new perspectives on the potential extrahepatic role of VKORC1 in individuals with chronic kidney disease.

Insulin resistance is associated with Fibroblast Growth Factor-23 in stage 3-5 chronic kidney disease patients.

AIM: To determine the associations between insulin resistance, fibroblast growth factor 23 (FGF-23), and coronary artery calcification (CAC) in chronic kidney disease (CKD) patients. INTRODUCTION: FGF-23 is associated with atherosclerosis and cardiovascular disease, but its association with insulin resistance in CKD has not been explored. SUBJECTS: Cross sectional study of 72 stage 3-5 CKD patients receiving care in Ontario, Canada. MATERIALS AND METHODS: Insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR), FGF-23 was measured by carboxyl terminal enzyme linked immunoassay (ctFGF-23) and CAC was measured by multi-slice computed tomography. RESULTS: Median HOMA-IR was 2.19µU/ml (interquartile range 1.19 to 3.94). Patients with HOMA-IR>2.2 had greater ctFGF-23 (179.7 vs 109.6; P=0.03), and 40% higher log CAC scores (2.09±0.87 vs 1.58±1.26; P=0.049). Multivariable linear regression adjusted for 1,25 dihydroxyvitamin D, kidney function, and parathyroid hormone revealed insulin resistance was a risk factor for greater log ctFGF-23 levels (log HOMA IR ß=0.37; 95% confidence interval 0.14 to 0.59; P=0.002). CONCLUSIONS: Insulin resistant CKD patients demonstrated higher FGF-23 levels, and increased CAC, while PO4 levels remained normal, suggesting a potential link between insulin resistance and PO4 homeostasis in CKD.

Associations of epicardial fat with coronary calcification, insulin resistance, inflammation, and fibroblast growth factor-23 in stage 3-5 chronic kidney disease.

BACKGROUND: Epicardial fat, quantified in a single multi-slice computed tomography (MSCT) slice, is a reliable estimate of total epicardial fat volume (EFV). We sought to determine risk factors for EFV detected in a single-slice MSCT measurement (ssEFV) in pre-dialysis chronic kidney disease (CKD) patients. Our primary objective was to determine the association between ssEFV and coronary artery calcification (CAC). METHODS: 94 pre-dialysis stage 3-5 CKD patients underwent MSCT to measure ssEFV and CAC. ssEFV was quantified at the level of the left main coronary artery. Measures of inflammation, traditional and kidney-related cardiovascular disease risk factors were collected. RESULTS: Mean age: 63.7 ± 14 years, 56% male, 39% had diabetes, and mean eGFR: 25.1 ± 11.9 mL/min/1.73 m2. Mean ssEFV was 5.03 ± 2.4 cm3. By univariate analysis, body mass index (BMI) (r = 0.53; P = <0.0001), abdominal obesity (r = 0.51; P < 0.0001), high density lipoprotein (HDL) cholesterol (r = - 0.39; P = <0.0001), insulin resistance (log homeostasis model assessment of insulin resistance (log HOMA-IR)) (r = 0.38, P = 0.001), log interleukin-6 (IL-6) (r = 0.34; P = 0.001), and log urinary albumin to creatinine ratio (UACR) (r = 0.30, P = 0.004) demonstrated the strongest associations with ssEFV. Log coronary artery calcification (log CAC score) (r = 0.28, P = 0.006), and log fibroblast growth factor-23 (log FGF-23) (r = 0.23, P = 0.03) were also correlated with ssEFV. By linear regression, log CAC score (beta =0.40; 95% confidence interval (CI), 0.01-0.80; P = 0.045), increasing levels of IL-6 (beta = 0.99; 95% CI, 0.38 - 1.61; P = 0.002), abdominal obesity (beta = 1.86; 95% CI, 0.94 - 2.8; P < 0.0001), lower HDL cholesterol (beta = -2.30; 95% CI, - 3.68 to -0.83; P = 0.002) and albuminuria (log UACR, beta = 0.81; 95% CI, 0.2 to 1.4; P = 0.01) were risk factors for increased ssEFV. CONCLUSIONS: In stage 3-5 CKD, coronary calcification and IL-6 and were predictors of ssEFV. Further studies are needed to clarify the mechanism by which epicardial fat may contribute to the pathogenesis of coronary disease, particularly in the CKD population.

Body mass index, coronary artery calcification, and kidney function decline in stage 3 to 5 chronic kidney disease patients.

OBJECTIVE: To determine whether body mass index (BMI) and coronary artery calcification (CAC) are risk factors for kidney function decline in predialysis chronic kidney disease (CKD) patients. DESIGN: Prospective cohort study of 125 stage 3 to 5 predialysis CKD patients. SUBJECTS AND SETTING: CKD patients receiving care in Kingston, Ontario, Canada. METHODS: BMI, CAC, and kidney function were measured at baseline. CAC was measured by multislice computed tomography scan. Kidney function was determined by the 4-variable reexpressed Modification of Diet in Renal Disease Study equation. At study end, kidney function decline among patients was compared according to baseline BMI and CAC. MAIN OUTCOME: Kidney function decline was defined as a 1-year decline in estimated glomerular filtration rate (eGFR) of ≥ 5%. RESULTS: Individuals with a decline in eGFR of ≥ 5% at 1 year had higher baseline BMI (33.5 ± 8.3 vs. 28.4 ± 4.9 kg/m(2); P = .0001) and higher baseline median CAC scores (239 vs. 25 Agatston units; P = .01) compared with subjects without such a decline. BMI (r = 0.35; P < .0001) and logarithmically transformed CAC score (r = 0.22; P = .01) correlated with an eGFR decline of ≥ 5%. Both crude and adjusted logistic regression analyses showed escalating CAC (with CAC reported in quintiles and CAC score = 0 Agatston unit as the reference group) was associated with an increased risk of eGFR decline of ≥ 5%. CONCLUSIONS: CAC and BMI were associated with kidney function decline over 1 year. The risk of kidney function decline was greater in those with increasing burden of CAC, which remained robust in the adjusted analysis accounting for the risk factors for CKD progression. Larger studies will be required for independent validation of the associations of BMI, CAC, and kidney function decline, and to investigate whether obesity and CAC treatment strategies are efficacious in attenuating kidney function decline in predialysis CKD patients.

FGF-23 is associated with cardiac troponin T and mortality in hemodialysis patients.

Fibroblast growth factor 23 (FGF-23) is elevated in patients with end-stage kidney disease and has been linked with mortality, vascular calcification, markers of bone turnover, and left ventricular hypertrophy. In this cohort study, we determined the correlates of FGF-23 (including cardiac troponin T [cTNT]) and determined its association with mortality over 3.5 years of follow-up in 103 prevalent hemodialysis patients. Mean age was 61.2 (15.5) and the mean dialysis vintage was 4.19 years (4.6). The median (interquartile range) FGF-23 was 1259 (491, 2885) RU/mL. Independent predictors (estimate standard error) of log-transformed FGF-23 concentrations included phosphorus (0.75 [0.237], P = 0.002) and cardiac troponin T (1.04 [0.41], P = 0.01). There were 57 deaths. In the fully adjusted model, the significant predictors of mortality included age and albumin. The independent association between FGF-23 and cTNT is a novel finding. Whether this relationship supports the possibility that a downstream effect of dysregulated phosphorous homeostasis may be enhanced cardiac remodeling requires further study.

Is the calcium correct? Measuring serum calcium in dialysis patients.

Abnormalities in calcium concentration are frequent in patients receiving dialysis therapy. Most cases of both hypo- and hypercalcemia are mild and asymptomatic. There is concern, however, that, on the one hand, hypocalcemia can drive hyperparathyroidism and eventually lead to gland hypertrophy and autonomous function. Hypercalcemia, on the other hand, can be associated with increased extraosseous calcium and phosphate deposition leading to vascular calcification with an attendant mortality and morbidity. Calcium exists in three main forms in the blood: the physiologically active free or ionized fraction (terms often used interchangeably), a protein bound fraction, and a fraction complexed to other anions. Although the ionized calcium can readily be measured using ion-specific electrodes, it is the total calcium that is most commonly measured because of sample handling and cost concerns. As it is the free or ionized form that is biologically active (and therefore of most relevance), a number of adjustment formulae have been derived to "correct" the total calcium for changes in albumin, protein, and complexing ion concentrations. These formulae show good statistical correlation with measured ionized calcium in populations studied as a whole, but are generally poor predictors of true ionized hypo- or hypercalcemia in individual patients. International guideline committees in nephrology recommend frequent assessment of calcium levels in dialysis patients and recommend that these levels be kept within the normal reference range. These guidelines are less clear on which measurement of calcium should be used to guide clinical decision making. This review examines the merits of making any adjustment to the total calcium measurement, and suggests when it is appropriate to measure the ionized or free calcium.

Vitamins K and D status in stages 3-5 chronic kidney disease.

BACKGROUND AND OBJECTIVES: Vitamin K, vitamin K-dependent proteins, and vitamin D may be involved in the regulation of calcification in chronic kidney disease (CKD). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Vitamin K and D status was measured as dietary intake, plasma phylloquinone, serum percent uncarboxylated osteocalcin (%ucOC), proteins induced by vitamin K absence (PIVKA-II), Vitamin K Epoxide Reductase single-nucleotide polymorphism, apolipoprotein E genotype, and plasma 25-hydroxyvitamin D (25(OH)D) in 172 subjects with stage 3 to 5 CKD. Nutritional status was determined by subjective global assessment. RESULTS: Subclinical vitamin K deficiency criteria was met by 6% (phylloquinone), 60% (%ucOC), and 97% (PIVKA-II) of subjects, whereas 58.3% and 8.6% had 25(OH)D insufficiency and deficiency, respectively. Dietary vitamin K intake was associated with higher phylloquinone and lower PIVKA-II. There were positive correlations between phylloquinone and the presence of stable weight, and the absence of subcutaneous fat loss or muscle wasting. 25(OH)D levels were positively associated with stable weight and albumin (P < 0.001). PIVKA-II levels were associated with apolipoprotein E genotype. Higher %ucOC and lower 25(OH)D were similarly associated with CKD stage, parameters of mineral metabolism, and urine albumin to creatinine ratio. CONCLUSIONS: These data indicate that a suboptimal vitamin K and D status is prevalent in patients with CKD. Sufficiency of both vitamins K and D was similarly predicted by measures of overall improved nutritional status. Proteinuria was associated with both a suboptimal vitamin D status as well as worse peripheral vitamin K status.

Prevalence and associations of coronary artery calcification in patients with stages 3 to 5 CKD without cardiovascular disease.

BACKGROUND: Patients with chronic kidney disease (CKD) have a high prevalence of coronary artery calcification, suggesting that CKD itself is a risk factor for its occurrence. Existing studies are confounded by the inclusion of patients who may not have CKD by means of diagnostic criteria and by failing to account for existing cardiovascular disease. STUDY DESIGN: Cross-sectional study. PARTICIPANTS & SETTING: 119 patients with CKD stages 3 to 5 (excluding dialysis) without known cardiovascular disease receiving care at a single center in Kingston, Ontario, Canada. PREDICTORS: Glomerular filtration rate was estimated (eGFR) by using the 4-variable Modification of Diet in Renal Disease Study equation. Traditional and nontraditional coronary artery calcification risk factors were defined a priori. OUTCOMES: Coronary artery calcification was measured by means of multislice computed tomographic scan. RESULTS: Mean and median coronary artery calcification scores were 566.5 +/- 1,108 and 111 (interquartile range, 2 to 631.5), respectively. A total of 32.8% of patients showed little calcification (score, 0 to 10). Calcification correlated with age (r = 0.44; P < 0.001), body mass index (r = 0.28; P = 0.002), high-density lipoprotein cholesterol level (r = -0.23; P = 0.01), diabetes mellitus (r = 0.23; P = 0.01), and cardiovascular risk score (r = 0.35; P < 0.001). By means of multivariable linear regression controlling for eGFR and diabetes mellitus, age (beta = 0.05; 95% confidence interval, 0.03 to 0.06; P < 0.001), body mass index (beta = 0.04; 95% confidence interval, 0.02 to 0.07; P = 0.001), and serum calcium level (beta = 0.9; 95% confidence interval, 0.15 to 1.6; P = 0.02), were risk factors for coronary artery calcification. LIMITATIONS: Inadequate sample size and uncontrolled confounding are possible limitations, but are unlikely to have changed the main study findings. CONCLUSIONS: In this study, traditional cardiovascular disease risk factors and serum calcium level were associated with coronary artery calcification. No association was shown with eGFR. Studies exploring protective mechanisms against coronary artery calcification are needed.

Warfarin and aortic valve calcification in hemodialysis patients.

BACKGROUND: This retrospective cohort study was designed to determine the association between long-term exposure to warfarin and severity of aortic valve (AV) calcification in hemodialysis (HD) patients. METHODS: One hundred and eight HD patients underwent a study-specific echocardiogram. A grading scheme was used to classify AV calcification as none, mild, moderate and severe. Demographic, biochemical and medication data were abstracted by chart review. RESULTS: One hundred and eight subjects were enrolled. A minority had no calcification (n=17, 15.7%), the majority had mild calcification (n=62, 57.4%), and fewer had calcification rated as moderate (n=16, 14.8%) or severe (n=13, 12%). Dialysis vintage was associated with severity of AV calcification (p=0.04). The 18 subjects with long-term warfarin exposure (36.7 +/- 19.7 months) were more likely to have severe AV calcification (p=0.04). The odds ratio of falling into a higher category of AV calcification following 18 months of warfarin was 3.77 (95% confidence ratio, 0.97-14.70; p=0.055). There was an association between lifetime months of warfarin exposure and severity of AV calcification (p=0.004) that was independent of dialysis vintage, calcium and calcitriol intake. CONCLUSIONS: The data suggest that warfarin may be associated with severity of AV calcification in HD patients and support the need for prospective studies.

Cardioprotective medication use in hemodialysis patients.

BACKGROUND: Cardiovascular disease is the leading cause of mortality in patients with renal failure, accounting for more than 50% of deaths in end-stage renal disease. Risk factor modification with the use of cardioprotective medications such as angiotensin-converting enzyme inhibitors (ACEIs), beta-adrenergic antagonists (beta-blockers), acetylsalicylic acid (ASA) and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has been shown to reduce mortality in the general population. OBJECTIVE: To determine the extent of use of these medications in a hemodialysis population. METHODS: This was a cross-sectional study of a cohort of 185 prevalent hemodialysis patients. The inclusion criterion was dialysis dependence and there were no exclusion criteria. Data collection was by chart review. Contraindications to individual medication classes were not obtained. RESULTS: There were 185 patients enrolled, the mean age was 63.42+/-15.1 years and 126 (68.1%) were male. Sixty-six (35.7%) patients had diabetes and 89 (48.1%) patients had established coronary artery disease (CAD). Forty-six (24.9%) patients were on ACEIs or angiotensin II receptor blockers, 59 (31.9%) were on beta-blockers, 70 (37.8%) were on ASA and 84 (45.4%) were on statins. Although these medications were used in fewer than 60% of patients, those with CAD were more likely to be prescribed an ACEI or an angiotensin II receptor blocker (P=0.026), a beta-blocker (P<0.001), ASA (P<0.001) or a statin (P=0.001) than those without CAD. There were no differences in the use of these medications between diabetic and nondiabetic patients. CONCLUSIONS: Many hemodialysis patients are not prescribed cardioprotective medications. Given the high cardiovascular mortality in this high-risk population, more attention to reducing cardiovascular risk is warranted.

Diabetes during diarrhea-associated hemolytic uremic syndrome: a systematic review and meta-analysis.

OBJECTIVE: To quantify the incidence of diabetes during the acute phase of diarrhea-associated hemolytic uremic syndrome (D + HUS) and to identify features associated with its development. RESEARCH DESIGN AND METHODS: A systematic review and meta-analysis of articles assessing diabetes during D + HUS was conducted. Relevant citations were identified from Medline, Embase, and Institute for Scientific Information Citation Index databases. Bibliographies of relevant articles were hand searched. All articles were independently reviewed for inclusion and data abstraction by two authors. RESULTS: Twenty-one studies from six countries were included. Only 2 studies reported a standard definition of diabetes; 14 defined diabetes as hyperglycemia requiring insulin. The incidence of diabetes during the acute phase of D + HUS could be quantified in a subset of 1,139 children from 13 studies (1966-1998, age 0.2-16 years) and ranged from 0 to 15%, with a pooled incidence of 3.2% (95% CI 1.3-5.1, random-effects model, significant heterogeneity among studies, P = 0.007). Children who developed diabetes were more likely to have severe disease (e.g., presence of coma or seizures, need for dialysis) and had higher mortality than those without diabetes. Twenty-three percent of those who developed diabetes acutely died, and 38% of survivors required long-term insulin (median follow-up 12 months). Recurrence of diabetes was possible up to 60 months after initial recovery. CONCLUSIONS: Children with D + HUS should be observed for diabetes during their acute illness. Consideration should be given to long-term screening of D + HUS survivors for diabetes.

Measurement of extravascular lung water in hemodialysis patients using blood ultrasound velocity and optical density dilution.

In hemodialysis patients, volume homeostasis is an important clinical problem. The aim is to have patients at an ideal "dry weight" postdialysis, but current methods for accurately measuring dry weight are disappointing. Krivitski et al. (ASAIO J 1998;44:M535-M540) have described a novel technique whereby extravascular lung water (EVLW) may be measured using blood ultrasound velocity and electrical impedance dilution. They have tested this method in animals and achieved agreement between obtained versus gravimetric measurements. Isotonic saline is used as a nondiffusible indicator and hypertonic (5%) saline is used as a diffusible indicator. By injecting these solutions and following their transits through the cardiopulmonary circulation, a theoretic basis for the calculation of EVLW may be derived from the cardiac output, the water transferred to blood, the amount of sodium chloride moved from blood to lung, and the increase in blood osmolality measured at the moment of osmotic equilibrium. We have used this new technique to measure EVLW for the first time in humans in 18 stable hemodialysis patients with no cardiac problems. Measurements were carried out twice in each patient, the first early in dialysis, the second toward the end of a dialysis session where fluid removal took place. The values for EVLW were 260+/-49 ml early in dialysis and 230+/-48 ml late in dialysis. This fall of 30+/-45 ml was statistically significant (p = 0.011). EVLW normalized to body weight was 3.29+/-1.0 ml/kg early and 3.02+/-1.04 ml/kg late in dialysis, a nonsignificant difference (p - 0.073). The normalized EVLW values are almost identical to those obtained in animals (3.1+/-1.4 ml/kg) by Krivitski et al. (see above). We conclude that this new technique can conveniently and noninvasively give an estimate of EVLW in hemodialysis patients. The clinical value of this measurement has now to be determined.

Are hemodialysis access flow measurements by ultrasound dilution the standard of care for access surveillance?

Maintenance of vascular access function is vital to the delivery of adequate hemodialysis therapy. Failure of function is associated with significant morbidity and cost. Thus, access surveillance programs are suggested. The most common cause for access dysfunction is stenosis formation within the graft fistula. This may lead to reduced blood flow. The measurement of access blood flow has thus been recommended as the preferred method for surveillance. This article reviews blood flow among other methods for the screening of access dysfunction, the techniques used to measure it, the predictability of access flow measurements in determining the presence of access stenosis and allowing successful; intervention and finally the cost-effectiveness of such surveillance. Review of available evidence would suggest that access flow measurements are the best tests currently available to screen for access dysfunction, and as preventative interventions, such as angioplasty and surgery, are successful, they should be regarded as the present standard of care. This would appear to be a cost-effective strategy. Furthermore, the method of choice for access flow measurement is by ultrasound dilution technology.