Diuretic resistance in patients with kidney disease: Challenges and opportunities.

Edema caused by kidney disease is called renal edema. Edema is a common symptom of many human kidney diseases. Patients with renal edema often need to take diuretics.However, After taking diuretics, patients with kidney diseases are prone to kidney congestion, decreased renal perfusion, decreased diuretics secreted by renal tubules, neuroendocrine system abnormalities, abnormal ion transporter transport, drug interaction, electrolyte disorder, and hypoproteinemia, which lead to ineffective or weakened diuretic use and increase readmission rate and mortality. The main causes and coping strategies of diuretic resistance in patients with kidney diseases were described in detail in this report. The common causes of DR included poor diet (electrolyte disturbance and hypoproteinemia due to patients' failure to limit diet according to correct sodium, chlorine, potassium, and protein level) and poor drug compliance (the patient did not take adequate doses of diuretics. true resistance occurs only if the patient takes adequate doses of diuretics, but they are not effective), changes in pharmacokinetics and pharmacodynamics, electrolyte disorders, changes in renal adaptation, functional nephron reduction, and decreased renal blood flow. Common treatment measures include increasing in the diuretic dose and/or frequency, sequential nephron blockade,using new diuretics, ultrafiltration treatment, etc. In clinical work, measures should be taken to prevent or delay the occurrence and development of DR in patients with kidney diseases according to the actual situation of patients and the mechanism of various causes. Currently, there are many studies on DR in patients with heart diseases. Although the phenomenon of DR in patients with kidney diseases is common, there is a relatively little overview of the mechanism and treatment strategy of DR in patients with kidney diseases. Therefore, this paper hopes to show the information on DR in patients with kidney diseases to clinicians and researchers and broaden the research direction and ideas to a certain extent.

Urinary Diversion: Core Curriculum 2021.

Urinary diversion after cystectomy has been a historical standard for the treatment of numerous benign and malignant diseases of the bladder. Since the first published description in the early 1900s, improvements in surgical technique and a better understanding of the metabolic sequelae postoperatively have greatly enhanced patient outcomes. Both continent and incontinent diversions are available to patients after cystectomy. In appropriately selected patients, orthotopic neobladder reconstruction can offer preservation of body image and continence, and continent cutaneous diversions represent a reasonable alternative. Conduit diversion, which remains the most commonly performed diversion technique, is ideal for patients who would benefit from a less morbid surgical procedure that negates the need for self-catheterization. This installment of the Core Curriculum in Nephrology outlines numerous aspects of urinary diversion, in which a multidisciplinary approach to postoperative management at the intersection of nephrology and urology is required to effectively optimize patient outcomes. This article includes a discussion of the various reconstructive options after cystectomy as well as a comprehensive review of frequently encountered short-term and long-term metabolic abnormalities associated with altered electrolyte and acid-base homeostasis.

Alterações hidroeletrolíticas em pessoas com cirrose / Hydroelectrolytic alterations in cirrhotic patients

O objetivo deste estudo foi evidenciar e discutir as principais alterações hidroeletrolíticas em pessoas com cirrose. Trata-se de uma revisão integrativa, de natureza qualitativa. Os artigos foram selecionados por meio da plataforma Medical Literature Analysis and Retrievel System Online. Os principais achados identificados a partir dos artigos selecionados foram a ocorrência de hiponatremia, o mau prognóstico diante da presença de distúrbios hidroeletrolíticos em relação à sobrevida em pessoas com cirrose e a importância da albumina. Indivíduos com cirrose são suscetíveis ao desenvolvimento de distúrbios hidroeletrolíticos devido às mudanças fisiopatológicas da doença e às condições clínicas apresentadas. A hiponatremia e a hipocalemia são os mais recorrentes, destacando, porém, a necessidade de atenção aos demais distúrbios. (AU)

The objective of this study was to show and discuss the main hydroelectrolytic alterations in cirrhotic patients. This is an integrative review, a qualitative study, in which articles were selected at the Medical literature Analysis and Retrieval System Online. The main findings identified in the articles selected were the occurrence of hyponatremia, the poor prognostic, due to the presence of hydroelectrolytic disorders, regarding cirrhotic individuals survival and the importance of albumin. Individuals with cirrhosis are susceptible to the development of hydroelectrolytic disorders due to the pathophysiological alterations of the disease and because of the clinical status presented. Hyponatremia and hypokalemia are the most recurrent, but attention shall be given to the other disorders too. (AU)

Electrolyte imbalance in COVID-19 patients admitted to the Emergency Department: a case-control study.

In patients visiting the emergency department (ED), a potential association between electrolytes disturbance and coronavirus disease 2019 (COVID-19) has not been well studied. We aim to describe electrolyte disturbance and explore risk factors for COVID-19 infection in patients visiting the ED. We carried out a case-control study in three hospitals in France, including adult ED inpatients (≥ 18 years old). A total of 594 ED case patients in whom infection with COVID-19 was confirmed, were matched to 594 non-COVID-19 ED patients (controls) from the same period, according to sex and age. Hyponatremia was defined by a sodium of less than 135 mmol/L (reference range 135-145 mmol/L), hypokalemia by a potassium of less than 3.5 mmol/L (reference range 3.5-5.0 mmol/L), and hypochloremia by a chloride of less than 95 mmol/L (reference range 98-108 mmol/L). Among both case patients and controls, the median (IQR) age was 65 years (IQR 51-76), and 44% were women. Hyponatremia was more common among case patients than among controls, as was hypokalemia and hypochloremia. Based on the results of the multivariate logistic regression, hyponatremia, and hypokalemia were associated with COVID-19 among case patients overall, with an adjusted odds ratio of 1.89 [95% CI 1.24-2.89] for hyponatremia and 1.76 [95% CI 1.20-2.60] for hypokalemia. Hyponatremia and hypokalemia are independently associated with COVID-19 infection in adults visiting the ED, and could act as surrogate biomarkers for the emergency physician in suspected COVID-19 patients.

Pheochromocytoma crisis in a patient with newly diagnosed neurofibromatosis type 1.

Pheochromocytoma occasionally engenders catecholamine-induced hypertension crisis. Pheochromocytoma is clinically identified in 0.1%-5.7% of patients with neurofibromatosis type 1 (NF1), which is 10 times more frequently than in healthy individuals. This report describes a case of newly diagnosed NF1 presenting with pheochromocytoma crisis, with severe electrolyte depletion and deteriorating recurrent ventricular tachycardia storm. Characteristic skin lesions such as café-au-lait macules and neurofibromas contributed to the diagnosis of NF1 and pheochromocytoma. No recurrence of electrolyte depletion was found after the adrenalectomy. Primary care physicians must distinguish the characteristic skin lesions of NF1, such as café-au-lait macules and neurofibromas and recognise the risk for pheochromocytoma.

11C-Metomidate PET/CT Detected Multiple Ectopic Adrenal Rest Tumors in a Woman With Congenital Adrenal Hyperplasia.

CONTEXT: Women with congenital adrenal hyperplasia (CAH) may present with androgen excess that is difficult to control with conventional suppressive doses of glucocorticoids. Clinical management is challenging, and the woman is at great risk of developing steroid-induced complications. PATIENTS AND METHODS: A 32-year-old woman with salt-wasting CAH due to 21-hydroxylase deficiency underwent right-sided adrenalectomy because of a large myelolipoma. Over the years, androgens became increasingly difficult to suppress on prednisolone 5 + 0 + 2.5 mg daily, and at age 39 years the left adrenal with an enlarging myelolipoma was removed. A month later serum testosterone levels had increased from 4.1 preoperatively to 18.3 nmol/L (reference 0.2-1.8 nmol/L), and adrenocorticotropin levels from 32 to 283 pmol/L (reference < 14 pmol/L). No adrenal parenchyma was visualized on computed tomography (CT). In the further search for the source of the markedly elevated testosterone, positron emission tomography (PET) was performed with 2 different tracers, 18fluorodeoxyglucose (18FDG) reflecting glucose metabolism and 11C-metomidate, an inhibitor of 11-ß-hydroxylase targeting adrenocortical tissue. RESULTS: 18FDG-PET/CT with cosyntropin stimulation showed ovarian/paraovarian hypermetabolism, suggestive of adrenal rest tumors. Further characterization with 11C-metomidate PET/CT showed uptakes localized to the ovaries/adnexa, behind the spleen, and between the right crus diaphragmaticus and inferior vena cava. CONCLUSION: Adrenal rest tumors can give rise to high androgen levels in spite of suppressive supraphysiological glucocorticoid doses. This case illustrates, for the first time, the value of 11C-metomidate PET as a sensitive method in documenting adrenal rest tumors, currently considered rare in women with CAH.

Salt-Losing 21-Hydroxylase Deficiency Caused by Double Homozygosity for Two "Mild" Mutations.

CONTEXT: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency presents with different severities that correlate with the genotype. The salt-losing phenotype requires 2 alleles with "severe" mutations. CASE DESCRIPTION: We present a case of salt-losing 21-hydroxylase deficiency that was found to be homozygous for 2 "mild" pathogenic variants: V281L and S301Y. Both in silico and heterologous expression functional analysis demonstrated that co-occurrence of these 2 mutations in cis severely impairs the function of the 21-hydroxylase enzyme. CONCLUSIONS: This case has important implications for genetic counseling. Regarding this combination of 2 "mild" variants as having mild phenotypic effects could lead to inappropriate counseling of heterozygote carriers.

Overhydration Measured by Bioimpedance Spectroscopy and Urinary Serine Protease Activity Are Risk Factors for Progression of Chronic Kidney Disease.

BACKGROUND: Overhydration (OH) is common in chronic kidney disease (CKD) and might be related to the excretion of urinary serine proteases. Progression of CKD is associated with proteinuria; however, the interrelations of urinary serine proteases, OH, and progression of CKD remain unclear. METHODS: In n = 179 patients with stable nondialysis-dependent CKD of all stages, OH was measured using bioimpedance spectroscopy (Body Composition Monitor; Fresenius), and urinary serine protease activity was determined using the peptide substrate S-2302. After a median follow-up of 5.9 (IQR: 3.9-6.5) years, progression to end-stage renal disease (ESRD) was analyzed retrospectively. RESULTS: OH correlated with baseline MDRD-eGFR, urinary albumin creatinine ratio (ACR), and urinary aprotinin-sensitive serine protease activity. Progression to ESRD occurred in n = 33 patients (19%) and correlated with OH and urinary serine protease activity as well as MDRD-eGFR and ACR. Patients were divided into 2 groups determined by cutoff values from receiver operating characteristics for MDRD-eGFR (32 mL/min/1.73 m2), ACR (43 mg/g creatinine), urinary serine protease activity (0.9 RU/g creatinine), and OH (1 L/1.73 m2). Across these cutoff values, Kaplan-Meier curves for renal survival showed significant separations of the groups. In Cox regression adjusted for MDRD-eGFR, ACR, P-NT-pro-BNP, systolic blood pressure, and diabetes mellitus, patients with OH >1 L/1.73 m2 had a 3.32 (95% CI: 1.26-8.76)-fold higher risk for progression to ESRD. CONCLUSIONS: Our results corroborate that OH detected by bioimpedance spectroscopy in CKD patients is an independent risk factor for progression to ESRD in addition to GFR and albuminuria. Urinary serine protease activity is associated with OH and progression of CKD and provides a possible underlying mechanism.

Bundled care in acute kidney injury in critically ill patients, a before-after educational intervention study.

BACKGROUND: Acute kidney injury (AKI) often occurs in critically ill patients. AKI is associated with mortality and morbidity. Interventions focusing on the reduction of AKI are suggested by the Kidney Disease: Improving Global Outcomes guideline. We hypothesized that these educational interventions would improve outcome in patients admitted to the Intensive Care Unit (ICU). METHODS: This was a pragmatic single-centre prospective observational before-after study design in an ICU in a tertiary referral hospital. All consecutive patients admitted to the ICU irrespective their illness were included. A 'Save the Kidney' (STK) bundle was encouraged via an educational intervention targeting health care providers. The educational STK bundle consisted of optimizing the fluid balance (based on urine output, serum lactate levels and/or central venous oxygen saturation), discontinuation of diuretics, maintaining a mean arterial pressure of at least 65 mmHg with the potential use of vasopressors and critical evaluation of the indication and dose of nephrotoxic drugs. The primary outcome was the composite of mortality, renal replacement therapy (RRT), and progression of AKI. Secondary outcomes were the components of the composite outcome the severity of AKI, ICU length of stay and in-hospital mortality. MAIN RESULTS: The primary outcome occurred in 451 patients (33%) in the STK group versus 375 patients (29%) in the usual care group, relative risk (RR) 1.16, 95% confidence interval (CI) 1.03-1.3, p < 0.001. Secondary outcomes were, ICU mortality in 6.8% versus 5.6%, (RR 1.22, 95% CI 0.90-1.64, p = 0.068), RRT in 1.6% versus 3.6% (RR 0.46, 95% CI 0.28-0.76, p = 0.002), and AKI progression in 28% versus 24% (RR 1.18, 95% CI 1.04-1.35, p = 0.001). CONCLUSIONS: Providing education to uniformly apply an AKI care bundle, without measurement of the implementation in a non-selected ICU population, targeted at prevention of AKI progression was not beneficial.

Identification of compound mutations of SLC12A3 gene in a Chinese pedigree with Gitelman syndrome exhibiting Bartter syndrome-liked phenotypes.

BACKGROUND: Gitelman syndrome is a rare salt-losing renal tubular disorder associated with mutation of SLC12A3 gene, which encodes the Na-Cl co-transporter (NCCT). Gitelman syndrome is characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and renin-angiotensin-aldosterone system (RAAS) activation. Different SLC12A3 variants may lead to phenotypic variability and severity. METHODS: In this study, we reported the clinical features and genetic analysis of a Chinese pedigree diagnosed with Gitelman syndrome. RESULTS: The proband exhibited hypokalaemia, hypomagnesemia, metabolic alkalosis, but hypercalciuria and kidney stone formation. The increased urinary calcium excretion made it confused to Bartter syndrome. The persistent renal potassium wasting resulted in renal tubular lesions, and might affect urinary calcium reabsorption and excretion. Genetic analysis revealed mutations of SLC12A3 gene with c.433C > T (p.Arg145Cys), c.1077C > G (p.Asn359Lys), and c.1666C > T (p.Pro556Ser). Potential alterations of structure and function of NCCT protein due to those genetic variations of SLC12A3 are predicted. Interestingly, one sibling of the proband carried the same mutant sites and exhibited similar clinical features with milder phenotypes of hypokalemia and hypomagnesemia, but hypocalciuria rather than hypercalciuria. Family members with at least one wild type copy of SLC12A3 had normal biochemistry. With administration of spironolactone, potassium chloride and magnesium supplement, the serum potassium and magnesium were maintained within normal ranges. CONCLUSIONS: In this study, we identified compound mutations of SLC12A3 associated with varieties of clinical features. Further efforts are needed to investigate the diversity in clinical manifestations of Gitelman syndrome and its correlation with specific SLC12A3 mutations.

Serum levels of protein carbonyl, a marker of oxidative stress, are associated with overhydration, sarcopenia and mortality in hemodialysis patients.

BACKGROUND: Increased oxidative stress in end-stage renal disease is regarded as one of the important mechanisms in the atherosclerosis and muscle wasting. However, studies examining the clinical significance of oxidative stress by direct measurement of these markers and its association with volume status and sarcopenia are limited. METHODS: A follow-up cross-sectional study was performed in stable hemodialysis (HD) patients and serum protein carbonyl levels were measured as a biomarker of oxidative stress. Additionally, multi-frequency body composition analysis, handgrip strength (HGS) and nutritional assessments were performed at baseline. RESULTS: Eighty-eight patients undergoing HD were included and 30 (34.1%) patients died during a mean follow-up of 5.2 years. The mean patient age was 60.6 ± 13.5 years, and the mean HD duration was 50.8 ± 41.3 months. In total, 16 patients (18.2%) were overhydrated, 49 (55.7%) had low HGS and 36 (40.9%) had low muscle mass. Serum protein carbonyl levels were associated with serum levels of albumin, prealbumin and transferrin, hydration status and low HGS. Overhydration (odds ratio [OR] 7.01, 95% CI 1.77-27.79, p = 0.006), prealbumin (OR 0.91, 95% CI 0.83-0.99, p = 0.030), subjective global assessment (OR 3.52, 95% CI 1.08-11.46, p = 0.037) and sarcopenia (OR 3.41, 95% CI 1.02-11.32, p = 0.046) were significantly related to increased serum protein carbonyl levels. Multivariate analysis showed that the serum levels of protein carbonyl (Hazard ratio [HR] 2.37, 95% CI 1.02-5.55, p = 0.036), albumin (HR 0.17, 95% CI 0.06-0.46, p = 0.003), prealbumin (HR 0.86, 95% CI 0.80-0.92, p = 0.001), overhydration (HR 2.31, 95% CI 1.26-8.71, p = 0.015) and sarcopenia (HR 2.72, 95% CI 1.11-6.63, p = 0.028) were independent determinants of all-cause mortality. CONCLUSIONS: Serum protein carbonyl was significantly associated with overhydration, nutritional status and sarcopenia, and could be a new predictor of mortality in patients undergoing HD.

Markers of potassium homeostasis in salt losing tubulopathies- associations with hyperaldosteronism and hypomagnesemia.

BACKGROUND: Renal loss of potassium (K+) and magnesium (Mg2+) in salt losing tubulopathies (SLT) leads to significantly reduced Quality of Life (QoL) and higher risks of cardiac arrhythmia. The normalization of K+ is currently the most widely accepted treatment target, however in even excellently designed RCTs the increase of K+ was only mild and rarely normalized. These findings question the role of K+ as the ideal marker of potassium homeostasis in SLT. Aim of this hypothesis-generating study was to define surrogate endpoints for future treatment trials in SLT in terms of their usefulness to determine QoL and important clinical outcomes. METHODS: Within this prospective cross-sectional study including 11 patients with SLTs we assessed the biochemical, clinical and cardiological parameters and their relationship with QoL (RAND SF-36). The primary hypothesis was that QoL would be more dependent of higher aldosterone concentration, assessed by the transtubular-potassium-gradient (TTKG). Correlations were evaluated using Pearson's correlation coefficient. RESULTS: Included patients were mainly female (82%, mean age 34 ± 12 years). Serum K+ and Mg2+ was 3.3 ± 0.6 mmol/l and 0.7 ± 0.1 mmol/l (mean ± SD). TTKG was 9.5/3.4-20.2 (median/range). While dimensions of mental health mostly correlated with serum Mg2+ (r = 0.68, p = 0.04) and K+ (r = 0.55, p = 0.08), better physical health was associated with lower aldosterone levels (r = -0.61, p = 0.06). TTKG was neither associated with aldosterone levels nor with QoL parameters. No relevant abnormalities were observed in neither 24 h-ECG nor echocardiography. CONCLUSIONS: Hyperaldosteronism, K+ and Mg2+ were the most important parameters of QoL. TTKG was no suitable marker for hyperaldosteronism or QoL. Future confirmatory studies in SLT should assess QoL as well as aldosterone, K+ and Mg2+.

Sensing of tubular flow and renal electrolyte transport.

The kidney is a remarkable organ that accomplishes the challenge of removing waste from the body and simultaneously regulating electrolyte and water balance. Pro-urine flows through the nephron in a highly dynamic manner and adjustment of the reabsorption rates of water and ions to the variable tubular flow is required for electrolyte homeostasis. Renal epithelial cells sense the tubular flow by mechanosensation. Interest in this phenomenon has increased in the past decade since the acknowledgement of primary cilia as antennae that sense renal tubular flow. However, the significance of tubular flow sensing for electrolyte handling is largely unknown. Signal transduction pathways regulating flow-sensitive physiological responses involve calcium, purinergic and nitric oxide signalling, and are considered to have an important role in renal electrolyte handling. Given that mechanosensation of tubular flow is an integral role of the nephron, defective tubular flow sensing is probably involved in renal disease. Studies investigating tubular flow and electrolyte transport differ in their methodology, subsequently hampering translational validity. This Review provides the basis for understanding electrolyte disorders originating from altered tubular flow sensing as a result of pathological conditions.

Presentation, Treatment, and Outcome of Survivors of In-Hospital Versus Out-of-Hospital Sudden Cardiac Arrest.

We examined the baseline characteristics, rates of implantable cardioverter defibrillator implantation, and long-term all-cause mortality for survivors of in-hospital (IHSCA) versus out-of-hospital (OHSCA) sudden cardiac arrest (SCA). A total of 1,433 SCA survivors (807 IHSCA and 626 OHSCA) from 2002 to 2012 were followed through February 2017. Baseline characteristics and potential triggers of SCA, including significant electrolyte and metabolic abnormalities and acute myocardial infarction and ischemia, were collected. Adjusted survival analyses were performed using a multivariate Cox model. The presence of SCA triggers was similar between IHSCA and OHSCA patients (39% vs 35%, p = 0.3), but OHSCA was more likely associated with cardiac ischemia and drug abuse, whereas IHSCA was more associated with new antiarrhythmic drugs (p <0.05). OHSCA survivors were more likely to receive an implantable cardioverter defibrillator (38% vs 18%, p <0.001). Over a median follow-up of 3.6 years, 674 (47%) patients died. After adjusting for unbalanced baseline characteristics, survival was similar between IHSCA and OHSCA survivors (hazard ratio 1.1, 95% confidence interval 0.9 to 1.3, p = 0.4). In conclusion, survivors of IHSCA and OHSCA differed in baseline characteristic, potential SCA triggers, and treatment interventions but their adjusted survival was comparable.

Bioimpedance spectroscopy for fluid status assessment in patients with decompensated liver cirrhosis: Implications for peritoneal dialysis.

Bioimpedance spectroscopy (BIS) is routinely used in peritoneal dialysis patients and might aid fluid status assessment in patients with liver cirrhosis, but the effect of ascites volume removal on BIS-readings is unknown. Here we determined changes in BIS-derived parameters and clinical signs of fluid overload from before to after abdominal paracentesis. Per our pre-specified sample size calculation, we studied 31 cirrhotic patients, analyzing demographics, labs and clinical parameters along with BIS results. Mean volume of the abdominal paracentesis was 7.8 ± 2.6 L. From pre-to post-paracentesis, extracellular volume (ECV) decreased (20.2 ± 5.2 L to 19.0 ± 4.8 L), total body volume decreased (39.8 ± 9.8 L to 37.8 ± 8.5 L) and adipose tissue mass decreased (38.4 ± 16.0 kg to 29.9 ± 12.9 kg; all p < 0.002). Correlation of BIS-derived parameters from pre to post-paracentesis ranged from R² = 0.26 for body cell mass to R² = 0.99 for ECV. Edema did not correlate with BIS-derived fluid overload (FO ≥ 15% ECV), which occurred in 16 patients (51.6%). In conclusion, BIS-derived information on fluid status did not coincide with clinical judgement. The changes in adipose tissue mass support the BIS-model assumption that fluid in the peritoneal cavity is not detectable, suggesting that ascites (or peritoneal dialysis fluid) mass should be subtracted from adipose tissue if BIS is used in patients with a full peritoneal cavity.

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.

Principles and Practice of Oral Rehydration.

PURPOSE OF REVIEW: An understanding of fluid and electrolyte losses from diarrhea and mechanisms of solute cotransport led to development of oral rehydration solution (ORS), representing a watershed in efforts to reduce diarrheal disease morbidity and mortality. This report reviews the scientific rationale and modifications of ORS and barriers to universal application. RECENT FINDINGS: Solutions with osmolality and electrolyte composition different from original ORS for routine and unique pathophysiology such as in malnutrition have met with varying success. Following the conceptual rationale of sodium-glucose cotransportation to facilitate water absorption, other cotransporters and formulations have been explored with the aim to improve ORS efficacy and acceptance. ORS remains the anchor of acute watery diarrhea and dehydration management worldwide. Despite development of different formulations, the current standard solution is the mainstay of treatment for nearly all situations. Efforts to improve oral hydration solution and to increase acceptance and usage are ongoing.

Positive Fluid Balance is Associated with Poor Clinical Outcomes in Paediatric Severe Sepsis and Septic Shock.

INTRODUCTION: Growing evidence suggests there is potential harm associated with excess fluid in critically ill children. This study aimed to evaluate the association between percentage fluid overload (%FO) and paediatric intensive care unit (PICU) mortality in children with severe sepsis and septic shock. MATERIALS AND METHODS: Patients with severe sepsis and septic shock admitted to the PICU were identified through discharge codes. Data on clinical characteristics, fluid input and output were collected. %FO was calculated as: (total daily input - total daily output [L]/admission body weight [kg]) × 100. The primary outcome was PICU mortality. Secondary outcomes were 28-day ventilator-free days (VFD), intensive care unit-free days (IFD) and inotrope-free days (InoFD). Multivariate analysis adjusting for presence of comorbidities, Pediatric Index of Mortality (PIM) 2 score and multiorgan dysfunction were used to determine the association between cumulative %FO over 5 days and outcomes. RESULTS: A total of 116 patients were identified, with a mortality rate of 28.4% (33/116). Overall median age was 105.9 (23.1-157.2) months. Cumulative %FO over 5 days was higher in non-survivors compared to survivors (median [interquartile range], 15.1 [6.3-27.1] vs 3.6 [0.7-11.1]%; P <0.001). Cumulative %FO was associated with increased mortality (adjusted odds ratio 1.08, 95% confidence interval 1.03-1.13; P = 0.001) and decreased VFD, IFD and InoFD (adjusted mean difference -0.37 [-0.53 - -0.21] days, -0.34 [-0.49 - -0.20] days, and -0.31 [-0.48 - -0.14] days, respectively). CONCLUSION: Cumulative %FO within the first 5 days of PICU stay was consistently and independently associated with poor clinical outcomes in children with severe sepsis and septic shock. Future studies are needed to test the impact of restrictive fluid strategies in these children.

Progression of diabetic kidney disease in T2DN rats.

Diabetic kidney disease (DKD) is one of the leading pathological causes of decreased renal function and progression to end-stage kidney failure. To explore and characterize age-related changes in DKD and associated glomerular damage, we used a rat model of type 2 diabetic nephropathy (T2DN) at 12 wk and older than 48 wk. We compared their disease progression with control nondiabetic Wistar and diabetic Goto-Kakizaki (GK) rats. During the early stages of DKD, T2DN and GK animals revealed significant increases in blood glucose and kidney-to-body weight ratio. Both diabetic groups had significantly altered renin-angiotensin-aldosterone system function. Thereafter, during the later stages of disease progression, T2DN rats demonstrated a remarkable increase in renal damage compared with GK and Wistar rats, as indicated by renal hypertrophy, polyuria accompanied by a decrease in urine osmolarity, high cholesterol, a significant prevalence of medullary protein casts, and severe forms of glomerular injury. Urinary nephrin shedding indicated loss of the glomerular slit diaphragm, which also correlates with the dramatic elevation in albuminuria and loss of podocin staining in aged T2DN rats. Furthermore, we used scanning ion microscopy topographical analyses to detect and quantify the pathological remodeling in podocyte foot projections of isolated glomeruli from T2DN animals. In summary, T2DN rats developed renal and physiological abnormalities similar to clinical observations in human patients with DKD, including progressive glomerular damage and a significant decrease in renin-angiotensin-aldosterone system plasma levels, indicating these rats are an excellent model for studying the progression of renal damage in type 2 DKD.