Occult hepatitis B infection in a hemodialysis population in Guilan province, northern Iran

Hemodialysis (HD) patients are vulnerable to transfusion-transmitted infections such as hepatitis B virus (HBV). HBV infection with undetectable hepatitis B surface antigens (HBsAg) is described as occult HBV and can lead to serious complications. The aim of this study was to evaluate the prevalence of occult HBV and concomitant factors in HD patients. Using a cross-sectional design, clinical and epidemiological data were obtained from May to September 2009 in 11 different HD units in Guilan province in northern Iran. After serological testing for HBV surface antigens in 514 HD patients using a third-generation enzyme-linked immunosorbent assay kit (Diapro, Milano, Italy), HBsAg-negative patients were tested for HBV DNA using a Qiagen PCR kit (Artus Qiagen GmbH, Hilden, Germany). After omission of seven HBsAg-positive patients, 507 patients were included in the study, 280 (55.2%) of whom were male and 227 (44.8%) were female. Patients ranged in age from 16 to 66 years (mean 53.2 years). No HBV DNA was detected in HBsAg-negative patients. Some 59 patients (11.6%) were anti-hepatitis C virus positive and 32 (6.3%) were hepatitis C virus positive according to polymerase chain reaction. The study results indicate that occult HBV infection is not a significant health problem in HD patients in Guilan province.     

Occult hepatitis B among patients with chronic renal failure on hemodialysis from a capital city in northeast Brazil

Occult hepatitis B (OHB) is characterized by the presence of HBV‐DNA in the absence of HBsAg in the serum of patients. Hemodialysis patients are at high risk for hepatitis B virus and there are few data on the prevalence of OHB in this population, mainly in Brazil. Thus, the aim of this study was to determine the prevalence of OHB in patients undergoing hemodialysis. A cross‐sectional study was performed, including 301 patients on chronic hemodialysis at two dialysis centers in São Luís (Maranhão), northeast Brazil. Serological tests were performed for HBsAg, anti‐HBc, anti‐HBs, and anti‐HCV using enzyme immunoassays (ELISA); HBV‐DNA and HCV‐RNA were studied by real‐time PCR. The mean age was 49 ± 15 years, and 128 (42%) were female. Serological tests confirmed that all samples were HBsAg negative. Anti‐HBc was positive in 114 (38%) patients, anti‐HBc and anti‐HBs were simultaneously positive in 104 (35%), and anti‐HBc alone was positive in 10 (3%). Tests were negative for anti‐HBc and anti‐HBs in 55 patients (18%). Anti‐HBs was the only positive marker in 132 (44%) patients. Anti‐HCV was positive in 15 (5%) patients with HCV‐RNA present in 14 of them (93%). HBV‐DNA was positive in seven cases (2.3%). There was no association of HBV‐DNA with age, gender, time on dialysis, previous kidney transplant, or HBV serological pattern, but there was a positive correlation with the presence of anti‐HCV (P < 0.001). OHB in chronic renal failure patients on hemodialysis appears to be a relevant finding, suggesting that studying HBV‐DNA in this population using sensitive molecular tests should be a recommended course of action, especially in candidates for renal transplant.     

A rare case of Actinomyces skin and soft tissue infection in an end‐stage kidney disease patient with a review of the literature

End‐stage kidney disease (ESKD) patients are a commonly overlooked immunocompromised population that places them at risk for rare infections. We describe the case of a 78‐year‐old man with a history of ESKD managed with thrice weekly in‐center hemodialysis who had a prolonged episode of left elbow pain and drainage and was eventually found to have a skin and soft tissue infection from Actinomyces radingae. We review the bacteriology of Actinomyces spp. and the experiences of other providers who have treated actinomycosis in individuals with ESKD. The anatomic sites and demographics of these individuals are heterogeneous, but they all generally require a long antibiotic course with a beta‐lactam and portend to a good prognosis. High index of suspicion is needed to identify rare and atypical infections in the ESKD population.     

Outcomes of patients with end‐stage renal disease (ESRD) under chronic hemodialysis requiring continuous renal replacement therapy (CRRT) and patients without ESRD in acute kidney injury requiring CRRT: A single‐center study

In most continuous renal replacement therapy (CRRT) studies, end‐stage renal disease (ESRD) patients were excluded and the outcomes of patients with ESRD treated with chronic hemodialysis (HD) were unknown. The purposes of this study were to (1) evaluate short‐term patient survival and (2) compare the survival of conventional HD patients needing CRRT with the survival of non‐ ESRD patients in acute kidney injury (AKI) requiring CRRT. We evaluated adults (>18 years) requiring CRRT who were treated in the intensive care unit (ICU) at Kosin University Gospel Hospital from January 1, 2009 to December 31, 2010. A total of 100 (24 ESRD, 76 non‐ESRD) patients underwent CRRT during the study period. Patients were divided into two major groups: patients with ESRD requiring chronic dialysis and patients without ESRD (non‐ESRD) with AKI. We compared the survival of conventional HD patients requiring CRRT with the survival of non‐ ESRD patients in AKI requiring CRRT. For non‐ESRD patients, the 90‐day survival rate was 41.6%. For ESRD patients, the 90‐day survival rate was 55.3%. Multivariate Cox proportional hazards analyses demonstrated that conventional HD was not a significant predictor of mortality (hazard ratio [HR]: 0.334, 95% confidence interval [CI]: 0.063–1.763, P = 0.196), after adjustment for age, gender, presence of sepsis, APACHE score, use of vasoactive drugs, number of organ failures, ultrafiltration rate, and arterial pH. The survival rates of non‐ESRD and ESRD patients requiring CRRT did not differ; ESRD with conventional HD patients may be not a significant predictor of mortality.     

Comparison of ultrasound echo‐tracking technology and pulse wave velocity for measuring carotid elasticity among hemodialysis patients

This study aims to investigate the correlation between carotid elasticity in hemodialysis patients as evaluated by ultrasound echo‐tracking technology and aortic pulse wave velocity. A total of 103 patients with end‐stage renal disease who underwent stable hemodialysis were enrolled. An ultrasonic echo‐tracking method was used to evaluate the elastic modulus and the stiffness index (β), which were compared with pulse wave velocity (PWV). Blood glucose, blood lipids, and serum creatinine were also tested. These indices were analyzed to determine the independent factor for arterial elasticity. The carotid elastic modulus and β were in good correlation with PWV among hemodialysis patients (P = 0.000). Diabetes and age are independent risk factors for arterial elasticity among hemodialysis patients. Ultrasound echo‐tracking technology is a sensitive and accurate method for evaluating arterial elasticity and is a good alternative to traditional PWV.     

Chronic obstructive pulmonary disease in patients with end‐stage kidney disease on hemodialysis

The objectives of this study were to assess the prevalence of chronic obstructive pulmonary disease (COPD) in hemodialysis patients with spirometry and to examine the effects of fluid removal by hemodialysis on lung volumes. Patients ≥18 years at two Danish hemodialysis centers were included. Forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), and FEV₁/FVC ratio were measured with spirometry before and after hemodialysis. The diagnosis of COPD was based on both the GOLD criteria and the lower limit of normal criteria. There were 372 patients in treatment at the two centers, 255 patients (69%) completed spirometry before dialysis and 242 of these (65%) repeated the test after. In the initial test, 117 subjects (46%) had airflow limitation indicative of COPD with GOLD criteria and 103 subjects (40.4%) with lower limit of normal criteria; COPD was previously diagnosed in 24 patients (9%). Mean FVC and FEV₁ decreased mildly after dialysis (FVC: 2.84 to 2.79 L, P < 0.01. FEV₁: 1.97 to 1.93 L, P < 0.01) Hemodialysis did not affect the FEV₁/FVC ratio or number of subjects with airflow limitation indicative of COPD (113 vs. 120, P = 0.324; n = 242). COPD is a frequent and underdiagnosed comorbidity in patients on chronic hemodialysis. Spirometry should be considered in all patients on dialysis in order to address dyspnea adequately. Hemodialysis induced a small fall in mean FEV₁ and FVC, which was more pronounced in patients with little or no fluid removal, but the FEV₁/FVC ratio and the number of subjects with airflow limitation indicative of COPD were not affected by dialysis.     

Role of T‐regulatory cells in the response to hepatitis B vaccine in hemodialysis patients

Human disease elicits a complex array of biological processes that results in long‐term protective immunological memory to infectious agents. Chronic kidney disease is known to impair induction of sustained immunological memory to hepatitis B vaccine (HBVax) antigens. We asked the question: Does end‐stage renal disease promote changes in subtypes of regulatory T (Treg) cells that correlate with diminished amnestic response to HBVax antigen compared to healthy controls? The study design and setting was a prospective observational cohort at a veterans affairs medical center. End‐stage renal disease patients on hemodialysis (HD) were compared with individuals with self‐reported normal kidney function. All subjects received HBVax. Peripheral blood was sampled for assessment for Treg cells pre and post vaccination. CD4+ FOXP3 Treg numbers were similar between HD and healthy subjects during a 14‐day time period post vaccination. HD subjcts had lower anti‐HBSag antibody than CON (control) subjects (330 ± 108.7 vs. 663.1 ± 129.7 IU/mL; P = 0.063). Hemodialysis subjects with resting Tregs higher than the median value in our cohort demonstrated a significantly lower change in HBsAB at 30 days post booster vaccination (P = 0.030). No such relationship was found for the activated Treg subset among HD subjects, or either subset among CON subsets. In our limited comparison study of 11 HD and 8 CON subjects, Treg subsets did not differ between the two groups; but differences in the suppressive Treg numbers in the HD group could explain the altered antibody response to HBVax and is worthy of further study.     

End-stage renal disease patients on hemodialysis: a study from a tertiary care center in a developing country

The exact number of patients with chronic renal failure requiring renal replacement therapy in developing world is not known. Unlike the developed world, most developing countries lack renal registries. This study was initiated to know demographic and clinical data of end-stage renal disease (ESRD) patients presenting to maintenance hemodialysis (MHD) at a government funded tertiary care centre in a developing country. A prospective analysis of all new ESRD patients attending to hemodialysis at our centre from 2004 to 2007 had been done. There were 237 new hemodialysis patients during a three-year period. Males were 153 and females were 84, with the mean age 44.92 years. Diabetes mellitus (31.22%) was the most common cause of ESRD. Only 29.95% of patients had education on renal replacement therapy. 65.40% patients had emergency hemodialysis. Internal jugular catheter was the most common form of vascular access at initiation of hemodialysis. Arteriovenous fistula was secured in 29.95% of patients at presentation. Catheter-related infection appeared in 13.55% of patients on catheter. The most common infection in dialysis patients was urinary tract infection (37.14%). Renal transplantation was opted by 9.7% patients and continuous ambulatory peritoneal dialysis in 20.25% and 103 (43.45%) were lost to follow up. The rest (8.86%) continued on MHD. There were 42 (17.72%) deaths over a three-year period. The present study provided the information of the practice of hemodialysis, its population characteristics and outcomes from a developing country.     

Incidence of hepatitis C virus infection in patients on hemodialysis: A systematic review and meta‐analysis

Hepatitis C virus infection is a perennial concern for hemodialysis units because the prevalence of hepatitis C is significantly higher there than in the general population. Through a systematic review and meta‐analysis, we aim to assess the incidence rate of hepatitis C virus infection in hemodialysis units and explore its potential risk factors. Five electronic databases were used to search articles from 1990 to 2012, including PubMed, Embase, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and Wanfang. A random‐effects analysis was used to estimate the overall incidence rate of hepatitis C virus infection. A subgroup analysis and meta‐regression analysis were conducted to explore factors associated with heterogeneity between studies. Twenty‐two eligible articles were found, including 23 incidence rate estimates. The overall incidence rate of hepatitis C virus infection was 1.47 per 100 patient‐years (95% confidence interval [CI] 1.14 to 1.80). In the subgroup analysis, the pooled incidence rate was 4.44 (CI 2.65, 6.23) per 100 patient‐years in the developing world and 0.99 (CI 0.66, 1.29) per 100 patient‐years in the developed world. [Correction added on 2 November 2012, after first online publication: Pooled incidence rate in the developed world has been changed.] In addition, in hemodialysis units with higher prevalence, the incidence rate of hepatitis C virus infection also tended to be higher. Meta‐regression analysis showed that the country's development level and initial HCV prevalence combined could explain 67.91% of the observed heterogeneity. The incidence rate of hepatitis C virus infection among patients on hemodialysis was significantly high. Efforts should be taken to control hepatitis C virus infection in hemodialysis units, especially in developing countries.     

Clinical epidemiology of parathyroidectomy in hemodialysis patients: the USRDS waves 1, 3, and 4 study

Despite advances in the medical management of secondary hyperparathyroidism, parathyroidectomy remains necessary in some end-stage renal disease patients. Observational studies may help with the design of intervention trials. We linked the retrospective Waves 1, 3, and 4 Dialysis Morbidity and Mortality Study datasets to Medicare claims data to identify incident parathyroidectomy in 10,588 Medicare patients receiving hemodialysis in the United States on December 31, 1993. The mean age was 60.0 years, and the mean follow-up 3.6 years. De novo parathyroidectomy incidence was 14.2/1000 patient-years. Considered as quintiles (Q), higher levels of standard bone metabolism variables were associated (p<0.0001) with parathyroidectomy stepwise, such that adjusted hazards ratios (AHR) for Q5 (vs. Q1) were, for calcium (>10.3 mg/dL), 5.09 (3.64-7.10); for phosphorus (>7.5 mg/dL), 2.92 (2.06-4.15); for calcium-phosphorus product (>71 mg2/dL2), 3.32 (2.27-4.85); and for parathyroid hormone (PTH; >480 pg/mL), 13.81 (7.47-25.55). Other antecedent associations included younger age, lower hemoglobin, and longer dialysis vintage, while transplantation, as a time-dependent covariate, was associated with lower hazards ratios. Using interval Poisson analysis, parathyroidectomy was associated with higher mortality risk ratios in the first year, and progressively lower risk ratios subsequently. Demographic variables may modify the risk of parathyroidectomy. Younger patients on long-term hemodialysis may be at a special risk. Parathyroidectomy risk increases stepwise with alterations in bone metabolism variables, suggesting that a single-threshold management approach may not be ideal.     

Both pelvic radiography and lateral abdominal radiography correlate well with coronary artery calcification measured by computed tomography in hemodialysis patients: A cross‐sectional study

Introduction Lateral abdominal radiograph is suggested as an alternative to coronary artery computed tomography (CT) in evaluating vascular calcification. Simple scoring systems including pelvic radiograph scoring and abdominal scoring system were utilized to study their correlation with coronary artery calcification. Methods In 106 MHD patients, coronary artery CT, lateral abdominal, and pelvic radiograph were taken. The Agatston scoring system was applied to evaluate the degree of coronary artery calcification which was categorized according to Agatston coronary artery calcification score (CACS) ≥ 30, ≥100, ≥400, and ≥1000. Abdominal aortic calcification was scored by 4‐scored and 24‐scored systems. Pelvic artery calcification was scored by a 4‐scored system. Sensitivities and specificities of abdominal aortic calcification scores and pelvic artery calcification scores to predict different categories of coronary artery calcification were analyzed. We studied the diagnostic capability of abdominal aorta calcification and pelvic artery calcification to predict different CACS categories by calculating likelihood ratios. Receiver operator characteristic curves were used to determine the area under the curve for each of these testing procedures. Findings The prevalence was 48(45.3%), 15 (14.2%), 11 (10.4%), 11 (10.4%), and 11 (10.4%) for CACs > 0, ≥30, ≥100, ≥400, and ≥1000, respectively. The degree of CACs was positively correlated with patient age, prevalence of diabetes, abdominal aorta scores, and pelvic calcification scores. The areas under the curves for different CACS by all X‐ray scoring systems were above 0.70 except pelvic 4‐scored system for diagnosing CACS ≥30, without significant difference (P > 0.05). Discussion Both lateral abdominal and pelvic plain radiographs were demonstrated as acceptable alternatives to CT in evaluating vascular calcification.     

D‐dimer levels in maintenance hemodialysis patients: High prevalence of positive values also in the group without predisposing diseases

We aimed to estimate the prevalence of elevated D‐dimer levels in all chronic hemodialysis patients and those without additional disease, and to identify factors associated with increased D‐dimer. In 167 chronic hemodialysis patients from our center, D‐dimer was measured before dialysis. The effects of age, C‐reactive protein (CRP), recent acute illness, vascular access, anticoagulation type, dialysis vintage, and chronic diseases, considered to predispose for increased D‐dimer levels, were analyzed. The median D‐dimer in the whole group was 966 (inter‐quartile range [IQR] 524–1947) μg/L and was positive (>500 μg/L) in 75% of cases. D‐dimer was positive in 91% of patients with acute illness, 76% of those with predisposing chronic diseases, but was still positive in 52% of patients without additional disease (i.e., acute illness or predisposing chronic diseases) – median D‐dimer was 538.5 (IQR 359–966) μg/L. D‐dimer was correlated to patients' age, but not dialysis vintage. In univariate analysis, the D‐dimer levels were significantly higher in patients with atrial fibrillation, ischemic heart disease, recent acute illness, increased CRP, dialyzed over a catheter, and on citrate anticoagulation. Multivariate logistic regression showed that only age >65 years (odds ratio [OR] 2.93), catheter (OR 4.86), and positive CRP (OR 4.07) were independently associated with positive D‐dimer at 500 μg/L cut‐off, while the significance of age disappeared at 2000 μg/L cut‐off. To conclude, the high prevalence of positive D‐dimer values even in hemodialysis patients without additional disease limits the use of D‐dimer for exclusion of thromboembolic diseases in hemodialysis patients.     

Acute hemodialysis complications in end‐stage renal disease patients: The burden and implications for the under‐resourced Sub‐Saharan African health systems

Little is known about the challenges of routine renal replacement therapy in Sub‐Saharan Africa. We investigated the fatal and nonfatal acute hemodialysis (HD) complications in patients with end‐stage renal disease (ESRD) in two main dialysis centers in Cameroon. 1000 consecutive HD sessions incurred over a 4‐month period by 129 patients (96 men, 74%) with ESRD, receiving two weekly HD sessions of 4 hours each, were considered. Personal and clinical profiles before, during, and within 24 hours after HD sessions were used to diagnose complications. Participants were aged 7 to 80 years (mean 46 years). In all, 452 acute complications were recorded in 411 (41%) of the 1000 HD sessions. Of the 11 types of complications, hypotension (25%), muscular cramps (22%), hypertensive crisis (14%), pruritus (10%), and fever (7%) were the most frequent. Three hundred and six complications (67.7%) occurred during understaffed nighttime. The vascular access was the main bleeding site with 64%. Being diabetic and ultrafiltration rate >1000 mL/h were associated with hypotension and muscle cramps. The shorter duration in dialysis was associated with the risk of bleeding and the disequilibrium syndrome while longer duration was associated with muscle cramps. Four deaths (three from bleeding and one from disequilibrium syndrome) occurred, all during nighttime. Nearly half of dialysis sessions in these settings are associated with acute complications, some of which are fatal. Those complications occurred mostly during understaffed periods. Urgent strategies are needed to quickly solve the human capital crisis in the health care sector.     

Clinical and psychosocial factors predicting health‐related quality of life in hemodialysis patients

Many patients with end‐stage renal disease have significant impairment in health‐related quality of life (HRQoL). Most previous studies have focused on clinical factors; however, quality of life can also be affected by psychosocial factors. The aim of this study was to identify the possible predictors of HRQoL among clinical and psychosocial factors in hemodialysis (HD) patients. The study included 101 patients who were undergoing HD. Psychosocial factors were evaluated using the Hospital Anxiety and Depression Scale, Multidimensional Scale of Perceived Social Support, Montreal Cognitive Assessment, and Pittsburgh Sleep Quality Index. We also assessed laboratory and clinical factors, including albumin, Kt/V as a marker of dialysis adequacy, normalized protein catabolic rate, and duration of HD. The Euro Quality of Life Questionnaire 5‐Dimensional Classification (EQ‐5D) was used to evaluate HRQoL. The mean EQ‐5D index score was 0.704 ± 0.199. The following variables showed a significant association with the EQ‐5D index: age (P < 0.001), depression (P < 0.001), anxiety (P < 0.001), support from friends (P < 0.001), cognitive function (P < 0.001), duration of HD (P = 0.034), triglyceride (P = 0.031), total iron‐binding capacity (P = 0.036), and phosphorus (P = 0.037). Multiple regression analysis showed that age (95% confidence interval [CI] ?0.008 to ?0.002), anxiety (95% CI ?0.025 to ?0.009), and support from friends (95% CI 0.004 to 0.018) were independent predictors of impaired HRQoL. This study explored determinants of impaired HRQoL in HD patients. We found that impaired HRQoL was independently associated with age, anxiety, and support from friends. We should consider psychosocial as well as clinical factors when evaluating ways to improve HRQoL in HD patients.     

Cardiac autonomic dysfunction in hemodialysis patients: The value of heart rate turbulence

Patients with end-stage renal disease (ESRD) are likely to have cardiac autonomic dysfunction, which is related with an increased risk of sudden death. The aim of this study is to detect cardiac autonomic dysfunction in patients with ESRD and to evaluate the possible acute effects of hemodialysis (HD) on cardiac autonomic functions measured by heart rate variability (HRV) and heart rate turbulence (HRT). Thirty-one (mean age 50 ± 13 years, 15 males) with ESRD on regular HD program and 31 healthy volunteers (mean age 51 ± 12 years, 15 males) were included in the study. Twenty-four-hour ambulatory electrocardiogram recordings were taken from the subjects before and after HD and from the control group. Heart rate variability and HRT parameters were calculated from these recordings. All of the HRV and HRT parameters were found to be significantly blunted in patients in comparison with healthy individuals. There were significant differences in HRV after HD, but similar differences were not observed in HRT parameters. Cardiac autonomic functions were significantly altered in patients with ESRD. Heart rate turbulence parameters seemed to be less affected from HD and may be more useful in the evaluation of cardiac autonomic functions in the ESRD population.     

Piperacillin/tazobactam‐induced neurotoxicity in a hemodialysis patient: A case report

Antibiotics are potentially a cause of neurotoxicity in dialysis patients, the most common are the beta‐lactams as ceftazidime and cefepime, and few cases have been reported after piperacillin/tazobactam use. This report presents a case of a hypertensive and diabetic 67‐year‐old woman in regular hemodialysis, which previously had a stroke. She was hospitalized presenting pneumonia, which was initially treated with cefepime. Two days after treatment, she presented dysarthria, left hemiparesis, ataxia, and IX and X cranial nerves paresis. Computed tomography showed no acute lesions and cefepime neurotoxicity was hypothesized, and the antibiotic was replaced by piperacillin/tazobactam. The neurologic signs disappeared; however, 4 days after with piperacillin/tazobactam treatment, the neurological manifestations returned. A new computed tomography showed no new lesions, and the second antibiotic regimen withdrawn. After two hemodialysis sessions, the patient completely recovered from neurological manifestations. The patient presented sequentially neurotoxicity caused by two beta‐lactams antibiotics. This report meant to alert clinicians that these antibiotics have dangerous neurological effects in chronic kidney disease patients.     

Association of bioimpedance spectroscopy‐based volume estimation with postdialysis hypotension in patients receiving hemodialysis

Clinical examination to determine the dry weight of patients on hemodialysis (HD) has been problematic, with studies showing discordance between physician assessment and objective measures of volume status.We studied the association between predialysis bioimpedance spectroscopy (BIS)‐based estimates of fluid overload and postdialysis hypotension in 635 patients in the United States Renal Data System ACTIVE/ADIPOSE (A Cohort study To Investigate the Value of Exercise/Analyses Designed to Investigate the Paradox of Obesity and Survival in ESRD) study receiving HD in 2009–2011. We recorded predialysis and postdialysis weight and blood pressures over 3 consecutive HD sessions and performed BIS before a single session. Using a previously reported method of estimating normohydration weight, we estimated postdialysis fluid overload (FO_post) in liters. We used logistic regression with extracellular water/total body water (ECW/TBW) or estimated FO_post as the primary predictor and 1 or more postdialysis systolic blood pressures less than 110 mmHg as the dependent variable. Models were adjusted for age, sex, race, ultrafiltration rate per kilogram of body weight, end‐stage renal disease vintage, diabetes mellitus, heart failure, and albumin. Higher ECW/TBW was associated with lower odds of postdialysis hypotension (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.15–0.84 per 0.1, P = 0.02). Every liter of FO_post was associated with lower adjusted odds of postdialysis hypotension (OR 0.86, 95% CI 0.79–0.95, P = 0.003). Prospective studies are needed to determine whether this application of BIS could improve current clinical efforts to minimize episodes of postdialysis hypotension without leading to volume overload.