Differentiating syndrome of inappropriate ADH, reset osmostat, cerebral/renal salt wasting using fractional urate excretion.

OBJECTIVES: Clinical and laboratory data of reset osmostat (RO) and cerebral/renal salt wasting (C/RSW) mimic syndrome of inappropriate antidiuretic hormone (SIADH) and can pose diagnostic challenges because of significant overlapping between clinical and laboratory findings. Failure to correctly diagnose hyponatremia may result in increased mortality risk, longer hospital stay, and is cost-effective. We aim to illustrate clinical and laboratory similarities and difference among patients with hyponatremic disorders and discuss the diagnostic value of factional uprate excretion (FEurate) to differentiate SIADH from RO and C/RSW. CASE PRESENTATIONS: We report the use of FEurate in the evaluation of three patients with hyponatremia and elevated urine osmolality in the absence of edema or clinical evidence of dehydration to differentiate SIADH from RO and C/RSW. CONCLUSIONS: Measurement of FEurate may offset in part the diagnostic confusion imparted by the diagnoses of SIADH, RO, and C/RSW.

Clinical and laboratory features of female Gitelman syndrome and the pregnancy outcomes in a Chinese cohort.

AIM: Gitelman syndrome (GS) is a rare inherited salt-losing renal tubulopathy. Data on clinical features and the pregnancy outcome for female GS patients in a large cohort are lacking. The study was aimed to explore the phenotype and pregnant issue for female GS patients. METHODS: GS cases from the National Rare Diseases Registry System of China (NRSC) were collected, and detailed clinical, laboratory and genetic data were analysed. Articles on pregnancy in GS were also systemically reviewed. RESULTS: A total of 101 GS patients were included; among them, 42.6% were female and 79.2% showed hypomagnesaemia. A lower proportion of female patients presented before 18 years of age, with less frequently reported polyuria, higher serum potassium and less urine sodium and chloride excretions. There was no gender difference in the sodium-chloride cotransporter (NCC) dysfunction evaluated by hydrochlorothiazide test. Twelve of the 43 female GS patients delivered after disease symptom onset, and their pregnancies were generally uneventful. As a group, pregnant GS patients had lower potassium levels in the first-trimester (P = .002) requiring higher potassium supplementation. After delivery, serum potassium (P = .02) and magnesium (P = .03) increased significantly. Both caesarean section and vaginal delivery were safe. CONCLUSION: Female GS patients may have a less severe phenotype with generally favourable outcomes of pregnancy. Intensive monitoring and increased potassium supplementation are necessary during pregnancy, especially in the first-trimester.

Sodium Fate after Sodium Bicarbonate Infusion: Influence of Altered Acid-Base Status.

BACKGROUND: We have previously investigated the fate of administered bicarbonate infused as a hypertonic solution in animals with each of the 4 chronic acid-base disorders. Those studies did not address the fate of sodium, the coadministered cation. METHODS: We examined baseline total body water (TBW), Na+ space, HCO3- space, and urinary sodium and bicarbonate excretion after acute hypertonic NaHCO3 infusion (1-N solution, 5 mmol/kg body weight) in dogs with each of the 4 chronic acid-base disorders. Observations were made at 30, 60, and 90 min postinfusion. Retained sodium that remains osmotically active distributes in an apparent space that approximates TBW. Na+ space that exceeds TBW uncovers nonosmotic sodium storage. RESULTS: Na+ space approximated TBW at all times in normal and hyperbicarbonatemic animals (metabolic alkalosis and respiratory acidosis), but exceeded TBW by ~30% in hypobicarbonatemic animals (metabolic acidosis and respiratory alkalosis). Such osmotic inactivation was detected at 30 min and remained stable. The pooled data revealed that Na+ space corrected for TBW was independent of the initial blood pH but correlated with initial extracellular bicarbonate concentration (y = -0.01x + 1.4, p= 0.002). The fate of administered sodium and bicarbonate (internal distribution and urinary excretion) was closely linked. CONCLUSIONS: This study demonstrates that hypobicarbonatemic animals have a Na+ space that exceeds TBW after an acute infusion of hypertonic NaHCO3 indicating osmotic inactivation of a fraction of retained sodium. In addition to an expanded Na+ space, these animals have a larger HCO3- space compared with hyperbicarbonatemic animals. Both phenomena appear to reflect the wider range of titration of nonbicarbonate buffers (Δ pH) occurring during NaHCO3- loading whenever initial [HCO3-]e is low. The data indicate that the fate of administered bicarbonate drives the internal distribution and the external disposal of sodium, the co-administered cation, and is responsible for the early, but non-progressive, osmotic inactivation of a fraction of the retained sodium.

Tacrolimus-induced hypomagnesemia and hypercalciuria requires FKBP12 suggesting a role for calcineurin.

Calcineurin inhibitors (CNIs) are immunosuppressive drugs used to prevent graft rejection after organ transplant. Common side effects include renal magnesium wasting and hypomagnesemia, which may contribute to new-onset diabetes mellitus, and hypercalciuria, which may contribute to post-transplant osteoporosis. Previous work suggested that CNIs reduce the abundance of key divalent cation transport proteins, expressed along the distal convoluted tubule, causing renal magnesium and calcium wasting. It has not been clear, however, whether these effects are specific for the distal convoluted tubule, and whether these represent off-target toxic drug effects, or result from inhibition of calcineurin. The CNI tacrolimus can inhibit calcineurin only when it binds with the immunophilin, FKBP12; we previously generated mice in which FKBP12 could be deleted along the nephron, to test whether calcineurin inhibition is involved, these mice are normal at baseline. Here, we confirmed that tacrolimus-treated control mice developed hypomagnesemia and urinary calcium wasting, with decreased protein and mRNA abundance of key magnesium and calcium transport proteins (NCX-1 and Calbindin-D28k ). However, qPCR also showed decreased mRNA expression of NCX-1 and Calbindin-D28k , and TRPM6. In contrast, KS-FKBP12-/- mice treated with tacrolimus were completely protected from these effects. These results indicate that tacrolimus affects calcium and magnesium transport along the distal convoluted tubule and strongly suggests that inhibition of the phosphatase, calcineurin, is directly involved.

Natriuretic Response Is Highly Variable and Associated With 6-Month Survival: Insights From the ROSE-AHF Trial.

OBJECTIVES: This study sought to describe sodium excretion in acute decompensated heart failure (ADHF) clearly and to evaluate the prognostic ability of urinary sodium and fluid-based metrics. BACKGROUND: Sodium retention drives volume overload, with fluid retention largely a passive, secondary phenomenon. However, parameters (urine output, body weight) used to monitor therapy in ADHF measure fluid rather than sodium balance. Thus, the accuracy of fluid-based metrics hinges on the contested assumption that urinary sodium content is consistent. METHODS: Patients enrolled in the ROSE-AHF (Renal Optimization Strategies Evaluation-Acute Heart Failure) trial with 24-h sodium excretion available were studied (n = 316). Patients received protocol-driven high-dose loop diuretic therapy. RESULTS: Sodium excretion through the first 24 h was highly variable (range 0.12 to 19.8 g; median 3.63 g, interquartile range: 1.85 to 6.02 g) and was not correlated with diuretic agent dose (r = 0.06; p = 0.27). Greater sodium excretion was associated with reduced mortality in a univariate model (hazard ratio: 0.80 per doubling of sodium excretion; 95% confidence interval: 0.66 to 0.95; p = 0.01), whereas gross urine output (p = 0.43), net fluid balance (p = 0.87), and weight change (p = 0.11) were not. Sodium excretion of less than the prescribed dietary sodium intake (2 g), even in the setting of a negative net fluid balance, portended a worse prognosis (hazard ratio: 2.02; 95% confidence interval: 1.17 to 3.46; p = 0.01). CONCLUSIONS: In patients hospitalized with ADHF who were receiving high-dose loop diuretic agents, sodium concentration and excretion were highly variable. Sodium excretion was strongly associated with 6-month mortality, whereas traditional fluid-based metrics were not. Poor sodium excretion, even in the context of fluid loss, portends a worse prognosis.

Mitochondrial dysfunction and oxidative stress are involved in the mechanism of methotrexate-induced renal injury and electrolytes imbalance.

Methotrexate is a folate analog used against a wide range of diseases including malignancies and autoimmune disorders. On the other hand, clinical use of the MTX is associated with kidney injury and renal failure. There is no clear mechanism for MTX-induced renal injury. The current investigation was designed to evaluate the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of MTX-induced renal injury. Rats received MTX (a single dose of 20 or 30 mg/kg, i.p). Five days after MTX administration, serum biomarkers of kidney injury and tissue markers of oxidative stress were assessed. Moreover, kidney mitochondria were isolated, and several mitochondrial indices were determined. MTX-treated animals developed biochemical evidence of renal injury as judged by elevated serum blood urea nitrogen (BUN), creatinine (Cr) and along with hypokalemia, hypophosphatemia, hypocalcemia, and a decrease in serum glucose, and uric acid. Moreover, MTX caused an increase in kidney reactive oxygen species and lipid peroxidation. Renal glutathione reservoirs were also depleted, and tissue antioxidant capacity was decreased in MTX-treated animals. Kidney histopathological changes including interstitial inflammation, renal tubular degeneration, retraction glomeruli, and vascular congestion were also evident in MTX-treated rats. On the other hand, it was found that mitochondrial parameters including mitochondrial membrane potential, mitochondrial dehydrogenases activity, and mitochondrial glutathione and ATP content were decreased, while lipid peroxidation and mitochondrial permeabilization were increased with MTX treatment. These data suggest a role for mitochondrial dysfunction and oxidative stress in the mechanism of MTX nephrotoxicity.

Validating the use of bioimpedance spectroscopy for assessment of fluid status in children.

BACKGROUND: Bioimpedance spectroscopy (BIS) with a whole-body model to distinguish excess fluid from major body tissue hydration can provide objective assessment of fluid status. BIS is integrated into the Body Composition Monitor (BCM) and is validated in adults, but not children. This study aimed to (1) assess agreement between BCM-measured total body water (TBW) and a gold standard technique in healthy children, (2) compare TBW_BCM with TBW from Urea Kinetic Modelling (UKM) in haemodialysis children and (3) investigate systematic deviation from zero in measured excess fluid in healthy children across paediatric age range. METHODS: TBW_BCM and excess fluid was determined from standard wrist-to-ankle BCM measurement. TBW_D2O was determined from deuterium concentration decline in serial urine samples over 5 days in healthy children. UKM was used to measure body water in children receiving haemodialysis. Agreement between methods was analysed using paired t test and Bland-Altman method comparison. RESULTS: In 61 healthy children (6-14 years, 32 male), mean TBW_BCM and TBW_D2O were 21.1 ± 5.6 and 20.5 ± 5.8 L respectively. There was good agreement between TBW_BCM and TBW_D2O (R2 = 0.97). In six haemodialysis children (4-13 years, 4 male), 45 concomitant measurements over 8 months showed good TBW_BCM and TBW_UKM agreement (mean difference - 0.4 L, 2SD = ± 3.0 L). In 634 healthy children (2-17 years, 300 male), BCM-measured overhydration was - 0.1 ± 0.7 L (10-90th percentile - 0.8 to + 0.6 L). There was no correlation between age and OH (p = 0.28). CONCLUSIONS: These results suggest BCM can be used in children as young as 2 years to measure normally hydrated weight and assess fluid status.

Albuminuria in kidney transplant recipients is associated with increased urinary serine proteases and activation of the epithelial sodium channel.

Albuminuria predicts adverse renal outcome in kidney transplant recipients. The present study addressed the hypothesis that albuminuria is associated with increased urine serine proteases with the ability to activate the epithelial sodium channel (ENaC) and with greater extracellular volume and higher blood pressure. In a cross-sectional design, kidney transplant recipients with ( n = 18) and without ( n = 19) albuminuria were included for office blood pressure measurements, estimation of volume status by bioimpedance, and collection of spot urine and plasma samples. Urine was analyzed for serine proteases and for the ability to activate ENaC current in vitro. Urine exosome protein was immunoblotted for prostasin and γ-ENaC protein. In the present study, it was found that, compared with nonalbuminuria (8.8 mg/g creatinine), albuminuric (1,722 mg/g creatinine) kidney transplant recipients had a higher systolic and diastolic blood pressure, despite receiving significantly more antihypertensives, and a greater urinary total plasminogen, active plasmin, active urokinase-type plasminogen activator, and prostasin protein abundance, which correlated significantly with u-albumin. Fluid overload correlated with systolic blood pressure, urinary albumin/creatinine, and plasminogen/creatinine. Urine from albuminuric kidney transplant recipients evoked a greater amiloride- and aprotinin-sensitive inward current in single collecting duct cells (murine cell line M1). γENaC subunits at 50 and 75 kDa showed increased abundance in urine exosomes from albuminuric kidney transplant recipients when compared with controls. These findings show that albuminuria in kidney transplant recipients is associated with hypertension, ability of urine to proteolytically activate ENaC current, and increased abundance of γENaC. ENaC activity could contribute to hypertension and adverse outcome in posttransplant proteinuria.

Evaluation of Polyuria: The Roles of Solute Loading and Water Diuresis.

Polyuria, defined as daily urine output in excess of 3.0 to 3.5L/d, can occur due to solute or water diuresis. Solute-induced polyuria can be seen in hospitalized patients after a high solute load from exogenous protein administration or following relief of urinary obstruction. Similar clinical scenarios are rarely encountered in the outpatient setting. We describe a case of polyuria due to high solute ingestion and excessive water intake leading to a mixed picture of solute and water diuresis. Restriction of the daily solute load and water intake resulted in complete resolution of polyuria. Determination of the daily excreted urinary osmoles may yield important clues to the cause of polyuria and should be included in the routine workup of polyuria.

[Serum and urine osmolality: clinical and laboratory features]. / Osmolalità sierica ed urinaria: considerazioni cliniche e laboratoristiche.

Clinical practice is frequently challenged by limited funding and resources, which finally limit both clinical effectiveness and safety of some therapies. Electrolyte disorders represent serious problems in the clinical management. Nonetheless the osmometer, that is the reference instrument for routine assessment of osmolality, it is only available in a limited number of healthcare facilities. The diagnosis of the leading electrolyte disorders relies therefore on indirect criteria, frequently inaccurate, especially when inappropriately used. According to recent evidences emerged on prevalence, severity and therapeutic approach of patients with electrolyte disturbances such as hyponatremia, the diagnostic appropriateness is now regarded as an essential aspect of the clinical decision making. Recent multidisciplinary guidelines indicate that urinary osmolality is a mainstay in the differential diagnosis of hyponatremic states. Since hyponatremia is commonplace across a broad range of clinical conditions, it is noteworthy that accurate knowledge of the different equations that may be used for its calculation in serum or urine is not widespread among general and hospital physicians. To couple with these clinical issues, this article is aimed to briefly describe the epidemiology and clinics of osmolality disturbances and to suggest some equations that may be useful for its routine assessment in serum or urine, and which can be applied to different categories of patients. The usefulness and reliability of additional indirect methods used in the diagnostic approach of electrolyte disturbances, such as the assessment of urine specific gravity, will also be briefly discussed. The equations that will be proposed have been validated in small sample population studies, but are commonly used as a surrogate or replacement of direct osmolality assessment. A larger multicentric study is hence necessary to validate the clinical use of the equations used for the calculation of serum and urine osmolality.

Residual urinary volume is a predictor of overhydration in patients on peritoneal dialysis.

Fluid overload is linked to hypertension and cardiovascular diseases in patients on peritoneal dialysis (PD). It is important to monitor the residual urinary volume in patients with end-stage renal disease (ESRD). In fact, fluid overload and residual urinary volume have been considered the risk factors of mortality in ESRD patients on PD. However, the relationship between residual urinary volume and fluid overload was still controversial. Therefore, the objective of this cross-sectional study was to evaluate the association between residual urinary volume and the volume status of PD patients. Body composition was measured using a portable multifrequency whole-body bioimpedance assessment. Relative overhydration was defined when the ratio of overhydration to extracellular water was > 0.15. We examined 75 patients, with a mean age of 50.7 years and mean body mass index of 23.5 kg/m(2). Dialysis vintage was 46.5 months. The patients were divided into the anuric group (n = 30; urine output ≤ 100 mL/day) and the group of urine output > 100 mL/day (n = 45). The anuric group showed higher degree of relative overhydration compared to the patients with the urine output of > 100 mL/day (p = 0.020). In a multivariable linear regression analysis, anuria, diabetes, and serum albumin level were independently associated with relative overhydration. In conclusion, volume status should be closely monitored in anuric patients, and the preservation of residual urinary volume is one of important goals to maintain volume status in PD patients.

Magnesium excretion and hypomagnesemia in pediatric renal transplant recipients.

BACKGROUND: We investigated magnesium excretion and rate of hypomagnesemia in pediatric renal transplant recipients. METHOD: The medical records of 114 pediatric renal transplant recipients were retrospectively evaluated. After exclusion of 23 patients, 91 patients were included in the study. We recorded serum magnesium levels at the time of measurement of urine magnesium wasting. RESULTS: Mean serum magnesium levels were 1.73 ± 0.22 mg/dL and 38 of the patients (41%) had hypomagnesemia. There was a negative correlation between serum magnesium levels and estimated glomerular filtration rate and serum tacrolimus trough level (r=-0.215, p=0.040 and r=-0.409, p=0.000, respectively). Also, there was a statistically significant positive correlation between serum magnesium levels and transplantation duration (r=0.249, p=0.017). Mean fractional magnesium excretion was 5.9 ± 3.7% and 59 patients (65%) had high magnesium excretion. There was a significant negative correlation between fractional magnesium excretion and estimated glomerular filtration rate (r=-0.432, p=0.001). There was a significant positive correlation between fractional magnesium excretion and serum creatinine (r=0.379 p=0.003). CONCLUSION: Patients with higher tacrolimus trough blood levels, lower glomerular filtration rate and at early posttransplant period had risk of hypomagnesemia.

[Interpretation of volemia in acute kidney injury]. / Interprétation de la volémie dans l'insuffisance rénale aiguë.

Assessment of volume status is often challenging in daily clinical practice. One of the clinician's tasks is to prevent or to treat organ systems failures that arise from a mismatch between the transport of oxygen and metabolic needs. Renal failure is a frequently encountered in-hospital diagnosis that is known to alter significantly the prognosis. In patients with acute renal failure in particular, the consequences of an inadequate volume management further increase morbidity and mortality.

[Pitfalls in the interpretation of laboratory parameters-electrolytes, urea, creatinine]. / Pitfalls bei Laborwerten - Elektrolyte, Harnstoff und Kreatinin.

When it comes to interpret parameters of electrolyte balance and kidney function, it is important to keep pathophysiology and the theory on reference intervals in mind. Hyponatremia is most often caused by excess water. A low sodium concentration in urine should prompt a clinical evaluation of volume status. In case of suspected acute kidney failure, fractionated sodium excretion and fractionated urea excretion are able to provide insights on prerenal or renal origin of the disorder. Disruption in potassium homoeostasis can occur due to changes in supply or renal elimination as well as due to changes in the potassium balance between the extra- and intracellular compartments. The transtubular potassium gradient can help in the differential diagnosis of hyperkalemia. Evaluation of kidney function should begin with determination of serum creatinine, accompanied by an estimate of the glomerular filtration rate, as calculated by the CKD-EPI equation. As a consequence of non-renal determinants of serum creatinine, this equation has been shown to overestimate true GFR in elderly and hospitalized patients. This can result in overdosing of renally-cleared drugs. Clearance determinations can be of use in this context.

Prevalence and risk factors of fluid overload in Southern Chinese continuous ambulatory peritoneal dialysis patients.

BACKGROUND: Fluid overload is frequently present in CAPD patients and one of important predictors of mortality. The aim of this study is to investigate the prevalence and associated risk factors in a cohort study of Southern Chinese CAPD patients. METHODS: The patients (receiving CAPD 3 months and more) in our center were investigated from January 1, 2008 to December 31, 2009. Multi-frequency bioelectrical impedance analysis was used to assess the patient's body composition and fluid status. RESULTS: A total of 307 CAPD patients (43% male, mean age 47.8±15.3 years) were enrolled, with a median duration of PD 14.6 (5.9-30.9) months. Fluid overload (defined by Extracellular water/Total body water (ECW/TBW)≥0.40) was present in 205 (66.8%) patients. Univariate analysis indicated that ECW/TBW were inversely associated with body mass index (r = -0.11, P = 0.047), subjective global assessment score (r = -0.11, P = 0.004), body fat mass (r = -0.15, P = 0.05), serum albumin (r = -0.32, P<0.001), creatinine (r = -0.14, P = 0.02), potassium (r = -0.15, P = 0.02), and residual urine output (r = -0.14, P = 0.01), positively associated with age (r = 0.27, P<0.001), Chalrlson Comorbidity Index score (r = 0.29, P<0.001), and systolic blood pressure (r = 0.22, P<0.001). Multivariate linear regression showed that lower serum albumin (ß = -0.223, P<0.001), lower body fat mass (ß = -0.166, P = 0.033), old age (ß = 0.268, P<0.001), higher systolic blood pressure (ß = 0.16, P = 0.006), less residual urine output (ß = -0.116, P = 0.042), and lower serum potassium (ß = -0.126, P = 0.03) were independently associated with higher ECW/TBW. After 1 year of follow-up, the cardiac event rate was significantly higher in the patients with fluid overload (17.1% vs 6.9%, P = 0.023) than that of the normal hydrated patients. CONCLUSIONS: The prevalence of fluid overload was high in CAPD patients. Fluid overload in CAPD patients were independently associated with protein-energy wasting, old age, and decreased residual urine output. Furthermore, CAPD patients with fluid overload had higher cardiac event rate than that of normal hydrated patents.

Comparison between blood and urinary fluid balance indices during dehydrating exercise and the subsequent hypohydration when fluid is not restored.

Blood serum osmolality (S (OSM)) is the gold standard to assess body fluid balance. Urine specific gravity (U (SG)) is also a body fluid balance index but it is not invasive. However, U (SG) capability to detect the minimal level of dehydration that affects athletic performance (i.e., 2 %) remains untested. We collected urine and blood samples in eighteen euhydrated trained athletes in the morning and that evening while dehydrating by 1, 2, and 3 % of body mass by cycling (60 % VO2peak) in the heat (32 °C, 46 % rh, 2.5 m s(-1) air flow). At 9:00 pm, subjects left the laboratory and went to bed after ingesting 0.7 ± 0.2 L of a sports drink. The next morning, subjects awoke 3 % hypohydrated, and blood and urine samples were collected and test terminated. We found that 2 % dehydration increased S (OSM) and U (SG) above exercise-baseline values (P < 0.05). The next morning, S (OSM) and U (SG) remained elevated compared to the first morning while euhydrated (287 ± 5 vs. 282 ± 3 mOsmol kg(-1) H(2)O and 1.028 ± 0.003 vs. 1.017 ± 0.005, respectively, P < 0.05). However, when comparing 3 % dehydration (end of exercise) to 3 % hypohydration (next morning), U (SG) increased (1.025 ± 0.003 to 1.028 ± 0.003; P < 0.05) while S (OSM) decreased (295 ± 5 to 287 ± 5 mOsmol kg(-1) H(2)O; P < 0.05). In summary, during exercise-induced dehydration, U (SG) is as sensitive as S (OSM) to detect low levels of dehydration (i.e., 2 %). Both indices maintain the ability to detect a 3 % overnight hypohydration although S (OSM) approaches euhydration values, while U (SG) remains a superior index to detect hypohydration.