Evaluation and management of hypernatremia in adults: clinical perspectives

Hypernatremia is an occasionally encountered electrolyte disorder, which may lead to fatal consequences under improper management. Hypernatremia is a disorder of the homeostatic status regarding body water and sodium contents. This imbalance is the basis for the diagnostic approach to hypernatremia. We summarize the eight diagnostic steps of the traditional approach and introduce new biomarkers: exclude pseudohypernatremia, confirm glucose-corrected sodium concentrations, determine the extracellular volume status, measure urine sodium levels, measure urine volume and osmolality, check ongoing urinary electrolyte free water clearance, determine arginine vasopressin/copeptin levels, and assess other electrolyte disorders. Moreover, we suggest six steps to manage hypernatremia by replacing water deficits, ongoing water losses, and insensible water losses: identify underlying causes, distinguish between acute and chronic hypernatremia, determine the amount and rate of water administration, select the type of replacement solution, adjust the treatment schedule, and consider additional therapy for diabetes insipidus. Physicians may apply some of these steps to all patients with hypernatremia, and can also adapt the regimens for specific causes or situations.

Evidence-based hyponatremia management in liver disease

Hyponatremia is primarily a water balance disorder associated with high morbidity and mortality. The pathophysiological mechanisms behind hyponatremia are multifactorial, and diagnosing and treating this disorder remains challenging. In this review, the classification, pathogenesis, and step-by-step management approaches for hyponatremia in patients with liver disease are described based on recent evidence. We summarize the five sequential steps of the traditional diagnostic approach: 1) confirm true hypotonic hyponatremia, 2) assess the severity of hyponatremia symptoms, 3) measure urine osmolality, 4) classify hyponatremia based on the urine sodium concentration and extracellular fluid status, and 5) rule out any coexisting endocrine disorder and renal failure. Distinct treatment strategies for hyponatremia in liver disease should be applied according to the symptoms, duration, and etiology of disease. Symptomatic hyponatremia requires immediate correction with 3% saline. Asymptomatic chronic hyponatremia in liver disease is prevalent and treatment plans should be individualized based on diagnosis. Treatment options for correcting hyponatremia in advanced liver disease may include water restriction; hypokalemia correction; and administration of vasopressin antagonists, albumin, and 3% saline. Safety concerns for patients with liver disease include a higher risk of osmotic demyelination syndrome.

Incident dementia in kidney transplantation recipients: a matched comparative nationwide cohort study in South Korea

Recent studies have shown that patients with end-stage renal disease (ESRD) are at elevated risk of dementia. However, whether kidney transplantation (KT) lowers the risk for incident dementia remains unclear. Methods: From the Korean National Health Insurance Service database, we identified incident KT recipients aged ≥40 years without any history of dementia between 2007 and 2015. We also established a pair of age-, sex-, and inclusion year-matched control cohorts of patients with incident dialysis-dependent ESRD and members of the general population (GP) without a history of dementia, respectively. Cases of incident all-cause dementia, including Alzheimer disease (AD), vascular dementia (VD), and other kinds of dementia, were obtained from baseline until December 31, 2017. Results: We followed 8,841 KT recipients, dialysis-dependent ESRD patients, and GP individuals for 48,371, 28,649, and 49,149 patient- years, respectively. Their mean age was 52.5 years, and 60.6% were male. Over the observation period, 55/43/19 KT recipients, 230/188/75 dialysis-dependent ESRD patients, and 38/32/14 GP individuals developed all-cause dementia/AD/VD. The risks of incident all-cause dementia, AD, and VD in KT recipients were similar to those in GP (hazard ratio: 0.74 [p = 0.20], 0.74 [p = 0.24], and 0.59 [p = 0.18], respectively) and significantly lower than those in dialysis-dependent ESRD patients (hazard ratio: 0.17 [p < 0.001], 0.16 [p < 0.001], and 0.16 [p < 0.001], respectively). Older age and diabetes mellitus at the time of KT were risk factors for incident all-cause dementia and AD in KT recipients. Conclusion: This is the first study to show a beneficial impact of KT on incident dementia compared to dialysis dependency.

Risk factors for overcorrection of severe hyponatremia: a post hoc analysis of the SALSA trial

Hyponatremia overcorrection can result in irreversible neurologic impairment such as osmotic demyelination syndrome. Few prospective studies have identified patients undergoing hypertonic saline treatment with a high risk of hyponatremia overcorrection. Methods: We conducted a post hoc analysis of a multicenter, prospective randomized controlled study, the SALSA trial, in 178 patients aged above 18 years with symptomatic hyponatremia (mean age, 73.1 years; mean serum sodium level, 118.2 mEq/L). Overcorrection was defined as an increase in serum sodium levels by >12 or 18 mEq/L within 24 or 48 hours, respectively. Results: Among the 178 patients, 37 experienced hyponatremia overcorrection (20.8%), which was independently associated with initial serum sodium level (≤110, 110–115, 115–120, and 120–125 mEq/L with 7, 4, 2, and 0 points, respectively), chronic alcoholism (7 points), severe symptoms of hyponatremia (3 points), and initial potassium level (<3.0 mEq/L, 3 points). The NASK (hypoNatremia, Alcoholism, Severe symptoms, and hypoKalemia) score was derived from four risk factors for hyponatremia overcorrection and was significantly associated with overcorrection (odds ratio, 1.41; 95% confidence interval, 1.24–1.61; p < 0.01) with good discrimination (area under the receiver-operating characteristic [AUROC] curve, 0.76; 95% CI, 0.66–0.85; p < 0.01). The AUROC curve of the NASK score was statistically better compared with those of each risk factor. Conclusion: In treating patients with symptomatic hyponatremia, individuals with high hyponatremia overcorrection risks were predictable using a novel risk score summarizing baseline information.

Association between copeptin levels and treatment responses to hypertonic saline infusion in patients with symptomatic hyponatremia: a prospective cohort study

Background@#Copeptin is secreted in equimolar amounts as arginine vasopressin, main hormone regulating body fluid homeostasis. A recent study reported a copeptin-based classification of osmoregulatory defects in syndromes of inappropriate antidiuresis that may aid in prediction of therapeutic success. We investigated usefulness of copeptin for differentiating etiologies of hyponatremia and predicting efficacy and safety of hypertonic saline treatment in hyponatremic patients. @*Methods@#We performed a multicenter, prospective cohort study of 100 inpatients with symptomatic hyponatremia (corrected serum sodium [sNa] ≤ 125 mmol/L) treated with hypertonic saline. Copeptin levels were measured at baseline and 24 hours after treatment initiation, and patients were classified as being below or above median of copeptin at baseline or at 24 hours, respectively. Correlations between target, under correction, and overcorrection rates of sNa within 24 hours/24–48 hours and copeptin levels at baseline/24 hours were analyzed. @*Results@#Mean sNa and median copeptin levels were 117.9 and 16.9 pmol/L, respectively. Ratio of copeptin-to-urine sodium allowed for an improved differentiation among some (insufficient effective circulatory volume), but not all hyponatremia etiologic subgroups. Patients with below-median copeptin levels at baseline achieved a higher target correction rate in 6/24 hours (odds ratio [OR], 2.97; p = 0.02/OR, 6.21; p = 0.006). Patients with below-median copeptin levels 24 hours after treatment showed a higher overcorrection rate in next 24 hours (OR, 18.00, p = 0.02). @*Conclusion@#There is a limited diagnostic utility of copeptin for differential diagnosis of hyponatremia. However, copeptin might be useful for predicting responses to hypertonic saline treatment in hyponatremic patients.

Circulating renalase predicts all-cause mortality and renal outcomes in patients with advanced chronic kidney disease

BACKGROUND/AIMS@#Patients with chronic kidney disease (CKD) have been found to show markedly increased rates of end-stage renal disease, major adverse cardiovascular and cerebrovascular events (MACCEs), and mortality. Therefore, new biomarkers are required for the early detection of such clinical outcomes in patients with CKD. We aimed to determine whether the level of circulating renalase was associated with CKD progression, MACCEs, and all-cause mortality, using data from a prospective randomized controlled study, Kremezin STudy Against Renal disease progression in Korea (K-STAR; NCT 00860431).@*METHODS@#A retrospective analysis of the K-STAR data was performed including 383 patients with CKD (mean age, 56.4 years; male/female, 252/131). We measured circulating renalase levels and examined the effects of these levels on clinical outcomes.@*RESULTS@#The mean level of serum renalase was 75.8 ± 34.8 μg/mL. In the multivariable analysis, lower hemoglobin levels, higher serum creatinine levels, and diabetes mellitus were significantly associated with a higher renalase levels. Over the course of a mean follow-up period of 56 months, 25 deaths and 61 MACCEs occurred. Among 322 patients in whom these outcomes were assessed, 137 adverse renal outcomes occurred after a mean follow-up period of 27.8 months. Each 10-μg/mL increase in serum renalase was associated with significantly greater hazards of all-cause mortality and adverse renal outcomes (hazard ratio [HR] = 1.112, p = 0.049; HR = 1.052, p = 0.045). However, serum renalase level was not associated with the rate of MACCEs in patients with CKD.@*CONCLUSIONS@#Our results indicated that circulating renalase might be a predictor of mortality and adverse renal outcomes in patients with CKD.

Optimal systolic blood pressure in noncritically ill patients with acute kidney injury: A retrospective cohort study

BACKGROUND: Few data showed the optimal blood pressure (BP) in noncritically ill patients with acute kidney injury (AKI) relative to mortality or severe AKI. We therefore sought to analyze the data that exist for the ideal target range for BP in noncritically ill patients with AKI. METHODS: We performed a retrospective cohort study involving 1,612 hospitalized patients who were diagnosed with AKI using the Kidney Disease: Improving Global Outcomes definition based on serum creatinine measurements for a period of 1 year. The average systolic BP (SBP) was categorized into 10-mmHg increments (within 48 hours after the development of AKI). The primary outcome was a composite of severe AKI or 90-day mortality. RESULTS: The composite outcome rate in patients was 18.7% (302/1,612). The relationship between BP and the composite outcome followed a U-shaped curve, with an increased event rate observed at both low and high BP values. The average SBP after AKI predicted the composite outcome after adjusting for baseline variables (reference SBP: 120–129 mmHg; < 100 mmHg: hazard ratio [HR] 1.84, P = 0.015; 100–109 mmHg: HR 1.56, P = 0.038; 110–119 mmHg: HR 1.15, P = 0.483; 130–139 mmHg: HR 1.51, P = 0.045; ≥ 140 mmHg: HR 1.73, P = 0.005). CONCLUSION: Among noncritically ill patients with AKI, a U-shaped curve association was observed between the average SBP within 48 hours after AKI and the composite primary outcome of this study, with the lowest event rate for SBP ranging from approximately 110 to 129 mmHg.

Predialysis hyponatremia and mortality in elderly patients beginning to undergo hemodialysis

BACKGROUND/AIMS: Predialysis hyponatremia has been recently reported to be associated with mortality in incident hemodialysis patients. However, whether hyponatremia is associated with unfavorable outcomes in elderly patients remains unknown. We hypothesized that nephrology referral inf luences hyponatremia, and aimed to define how nephrology referral affects the association between hyponatremia and mortality in the elderly. METHODS: We retrospectively assessed mortality in 599 incident hemodialysis patients aged ≥ 70 at a tertiary university hospital, between 2000 and 2010. We analyzed 90-day and 1-year all-cause mortality (ACM) in relation to predialysis serum sodium (sNa). We divided the patients into two groups according to predialysis glucose-corrected sNa: hyponatremia (< 135 mmol/L) and normonatremia (135 to 145 mmol/L). RESULTS: Low estimated glomerular filtration rate, high phosphorus, low albumin, nonpreparation of arteriovenous fistula or graft, and late referral were associated with a low sNa in the elderly. Among 599 patients, 106 and 174 patients died at the 90-day and 1-year follow-ups, respectively. Each 10-mmol/L increase in predialysis sNa tended to be associated with lower 90-day and 1-year ACM. When patients were stratified by nephrology referral, hyponatremia was associated with increased mortality in early referral group (90-day ACM: hazard ratio [HR] = 2.335, p = 0.041; 1-year ACM: HR = 1.790, p = 0.024). However, hyponatremia was not associated with mortality in late referral group. CONCLUSIONS: Predialysis hyponatremia at hemodialysis initiation is associated with late referra

An Acute Medical Unit in a Korean Tertiary Care Hospital Reduces the Length of Stay and Waiting Time in the Emergency Department

A hospitalist-run acute medical unit (AMU) opened at a tertiary care hospital on August 2015 for the first time in Korea. Patients visiting the emergency department (ED) with acute medical problems are admitted to the AMU. They stay in that unit for less than 72 hours and are discharged or transferred to specialty wards if longer treatment is necessary. We reviewed 19,450 medical admissions through the ED from January 2014 to September 2016. The median length of stay (LOS) significantly decreased from 10.0 days (interquartile range [IQR], 5.5–16.7) to 9.1 days (IQR, 5.1–15.0) (P < 0.001) after the establishment of the AMU. The median waiting time in the ED significantly shortened by 40% (P < 0.001). Future studies on the impact of AMU on in-patient morbidity, mortality, re-admission rate, and patient or staff satisfaction are necessary.

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) Associated with Mediastinal Schwannoma

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of euvolemic hypo-osmotic hyponatremia. There are several etiologies of SIADH including neuroendocrine tumor, pulmonary disease, infection, trauma, and medications. Here, we report a case of SIADH associated with a schwannoma involving the mediastinum in a 75-year-old woman who presented with nausea, vomiting, and general weakness. Laboratory testing showed hypo-osmolar hyponatremia, with a serum sodium level of 102mmol/L, serum osmolality of 221mOsm/kg, urine osmolality of 382mOsm/kg, urine sodium of 55 mmol/L, and plasma antidiuretic hormone (ADH) of 4.40 pg/mL. Chest computed tomography identified a 1.5-cm-sized solid enhancing nodule in the right lower paratracheal area. A biopsy specimen was obtained by video-assisted thoracoscopic surgery, which was diagnosed on pathology as a schwannoma. The hyponatremia was completely resolved after schwannoma resection and plasma ADH level decreased from 4.40 pg/mL to 0.86 pg/mL. This case highlights the importance of suspecting and identifying the underlying cause of SIADH when faced with refractory or recurrent hyponatremia, and that on possibility is mediastinal schwannoma

Long-term Prognosis of Anti-Neutrophil Cytoplasmic Antibody-Negative Renal Vasculitis: Cohort Study in Korea

Few studies have reported on the long-term prognosis of anti-neutrophil cytoplasmic antibody (ANCA)-negative renal vasculitis. Between April 2003 and December 2013, 48 patients were diagnosed with renal vasculitis. Their ANCA status was tested using indirect immunofluorescence and enzyme-linked immunosorbent assays. During a median (interquartile range) follow-up duration of 933.5 (257.5-2,079.0) days, 41.7% of patients progressed to end stage renal disease (ESRD) and 43.8% died from any cause. Of 48 patients, 6 and 42 were ANCA-negative and positive, respectively. The rate of ESRD within 3 months was higher in ANCA-negative patients than in ANCA-positive patients (P = 0.038). In Kaplan-Meier survival analysis, ANCA-negative patients showed shorter renal survival than did ANCA-positive patients (log-rank P = 0.033). In univariate Cox-proportional hazard regression analysis, ANCA-negative patients showed increased risk of ESRD, with a hazard ratio 3.190 (95% confidence interval, 1.028-9.895, P = 0.045). However, the effect of ANCA status on renal survival was not statistically significant in multivariate analysis. Finally, ANCA status did not significantly affect patient survival. In conclusion, long-term patient and renal survival of ANCA-negative renal vasculitis patients did not differ from those of ANCA-positive renal vasculitis patients. Therefore, different treatment strategy depending on ANCA status might be unnecessary.

Predictive Value of Echocardiographic Parameters for Clinical Events in Patients Starting Hemodialysis

Echocardiographic parameters can predict cardiovascular events in several clinical settings. However, which echocardiographic parameter is most predictive of each cardiovascular or non-cardiovascular event in patients starting hemodialysis remains unresolved. Echocardiography was used in 189 patients at the time of starting hemodialysis. We established primary outcomes as follows: cardiovascular events (ischemic heart disease, cerebrovascular disease, peripheral artery disease, and acute heart failure), fatal non-cardiovascular events, all-cause mortality, and all combined events. The most predictable echocardiographic parameter was determined in the Cox hazard ratio model with a backward selection after the adjustment of multiple covariates. Among several echocardiographic parameters, the E/e' ratio and the left ventricular end-diastolic volume (LVEDV) were the strongest predictors of cardiovascular and non-cardiovascular events, respectively. After the adjustment of clinical and biochemical covariates, the predictability of E/e' remained consistent, but LVEDV did not. When clinical events were further analyzed, the significant echocardiographic parameters were as follows: s' for ischemic heart disease and peripheral artery disease, LVEDV and E/e' for acute heart failure, and E/e' for all-cause mortality and all combined events. However, no echocardiographic parameter independently predicted cerebrovascular disease or non-cardiovascular events. In conclusion, E/e', s', and LVEDV have independent predictive values for several cardiovascular and mortality events.

Renal adverse effects of sunitinib and its clinical significance: a single-center experience in Korea

BACKGROUND/AIMS: Sunitinib is an oral multitargeted tyrosine kinase inhibitor used mainly for the treatment of metastatic renal cell carcinoma. The renal adverse effects (RAEs) of sunitinib have not been investigated. The aim of this study was to determine the incidence and risk factors of RAEs (proteinuria [PU] and renal insufficiency [RI]) and to investigate the relationship between PU and antitumor efficacy. METHODS: We performed a retrospective review of medical records of patients who had received sunitinib for more than 3 months. RESULTS: One hundred and fifty-five patients (mean age, 58.7 +/- 12.6 years) were enrolled, and the mean baseline creatinine level was 1.24 mg/dL. PU developed in 15 of 111 patients, and preexisting PU was aggravated in six of 111 patients. Only one patient developed typical nephrotic syndrome. Following discontinuation of sunitinib, PU was improved in 12 of 17 patients but persisted in five of 17 patients. RI occurred in 12 of 155 patients, and the maximum creatinine level was 3.31 mg/dL. RI improved in two of 12 patients but persisted in 10 of 12 patients. Risk factors for PU were hypertension, dyslipidemia, and chronic kidney disease. Older age was a risk factor for RI. The median progression-free survival was significantly better for patients who showed PU. CONCLUSIONS: The incidence of RAEs associated with sunitinib was lower than those of previous reports. The severity of RAEs was mild to moderate, and partially reversible after cessation of sunitinib. We suggest that blood pressure, urinalysis, and renal function in patients receiving sunitinib should be monitored closely.

Effect of Bilirubin on Triglyceride Synthesis in Streptozotocin-Induced Diabetic Nephropathy

We aimed to elucidate the effect of bilirubin on dyslipidemia and nephropathy in a diabetes mellitus (DM) type I animal model. Sprague-Dawley rats were separated into control, DM, and bilirubin-treated DM (Bil) groups. The Bil group was injected intraperitoneally with 60 mg/kg bilirubin 3 times per week and hepatoma cells were cultured with bilirubin at a concentration of 0.3 mg/dL. The Bil group showed lower serum creatinine levels 5 weeks after diabetes onset. Bilirubin treatment also decreased the amount of mesangial matrix, lowered the expression of renal collagen IV and transforming growth factor (TGF)-beta1, and reduced the level of apoptosis in the kidney, compared to the DM group. These changes were accompanied by decreased tissue levels of hydrogen superoxide and NADPH oxidase subunit proteins. Bilirubin decreased serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), free fatty acids, and triglycerides (TGs), as well as the TG content in the liver tissues. Bilirubin suppressed protein expression of LXRalpha, SREBP-1, SCD-1, and FAS, factors involved in TG synthesis that were elevated in the livers of DM rats and hepatoma cells under high-glucose conditions. In conclusion, bilirubin attenuates renal dysfunction and dyslipidemia in diabetes by suppressing LXRalpha and SREBP-1 expression and oxidative stress.

Small Increases in Plasma Sodium Are Associated with Higher Risk of Mortality in a Healthy Population

Elevated blood pressure (BP) is the most common cause of cardiovascular disease. Salt intake has a strong influence on BP, and plasma sodium (pNa) is increased with progressive increases in salt intake. However, the associations with pNa and BP had been reported inconsistently. We evaluated the association between pNa and BP, and estimated the risks of all-cause-mortality according to pNa levels. On the basis of data collected from health checkups during 1995-2009, 97,009 adult subjects were included. Positive correlations between pNa and systolic BP, diastolic BP, and pulse pressure (PP) were noted in participants with pNa > or =138 mM/L (P or =50 yr, SBP, DBP, and PP were positively associated with pNa. In participants with metabolic syndrome components, the differences in SBP and DBP according to pNa were greater (P or =50 yr during the median 4.2-yr-follow-up (P or =145 mM/L was related to mortality. The positive correlation between pNa and BP is stronger in older subjects, women, and subjects with metabolic syndrome components. The incidence and adjusted risks of mortality increase with increasing pNa in women aged > or =50 yr.

A Case of Chronic Renal Failure Associated with Systemic Capillary Leak Syndrome / 영남의대학술지

Systemic capillary leak syndrome (SCLS) is an unusual entity characterized by hypovolemic shock, hemoconcentration, and hypo-albuminemia associated with paraproteinemia as a result of marked capillary hyperpermeability. Complications of this syndrome can include compartment syndromes, pulmonary edema, thrombosis, and acute kidney injury. This paper reports a case of severe SCLS accompanied by acute tubular necrosis caused by hypoperfusion and myoglobinuria secondary to rhabdomyolysis, which resulted in chronic kidney disease that necessitated hemodialysis. However, there have been rare data of residual end-organ damage after acute attacks in Korea. Therefore, this paper reports a case of complicated SCLS enough to hemodialysis and that developed into chronic kidney disease.

The Usefulness of Urinary Angiotensinogen as a Biomarker of Renal Progression in Autosomal Dominant Polycystic Kidney Disease / 대한신장학회지

PURPOSE: The renin-angiotensin-aldosterone system activation has been suggested as a potential risk factor for renal progression in autosomal dominant polycystic kidney disease (ADPKD). This study was performed to evaluate urinary angiotensinogen as a biomarker of renal progression in ADPKD. METHODS: Patients with estimated glomerular filtration rate (eGFR) > or =30 mL/min/1.73m2 were enrolled in the study. Specimens (blood and urine) and computed tomography (CT) were taken from each subject. The eGFR was calculated by 4-variable MDRD equation and total kidney volume (TKV) was measured from CT images by modified ellipsoid method. Urinary angiotensinogen (AGT) and neutrophil gelatinaseassociated lipocalin (NGAL) were measured by ELISA. The concentration of AGT was adjusted with random urine creatinine (Cr). The association between urinary biomarkers, TKV and eGFR were evaluated. RESULTS: A total of 59 (M:F=31:28) subjects were enrolled in the study and their mean age was 46 years. The eGFR and TKV at the enrollment were 77.3+/-15.6 mL/min/1.73m2 and 1389.8+/-925.1 mL, respectively. Log AGT/Cr was associated with TKV (r2=0.117, p=0.01) in the earlier stage of disease (TKV<3,000 mL). However, it did not show significant correlation with eGFR. Log NGAL was not associated with either TKV or eGFR. Urinary AGT/Cr was closely related to the number of anti-hypertensive medication, TKV, and the presence of albuminuria, although there was no correlation with plasma renin activity or aldosterone level. CONCLUSION: Urinary angiotensinogen may be a useful biomarker of disease progression in ADPKD patients.