A pragmatic, open-label, randomized controlled trial of Plasma-Lyte-148 versus standard intravenous fluids in children receiving kidney transplants (PLUTO).

Acute electrolyte and acid-base imbalance is experienced by many children following kidney transplant. This is partly because doctors give very large volumes of artificial fluids to keep the new kidney working. When severe, fluid imbalance can lead to seizures, cerebral edema and death. In this pragmatic, open-label, randomized controlled trial, we randomly assigned (1:1) pediatric kidney transplant recipients to Plasma-Lyte-148 or standard of care perioperative intravenous fluids (predominantly 0.45% sodium chloride and 0.9% sodium chloride solutions). We then compared clinically significant electrolyte and acid-base abnormalities in the first 72 hours post-transplant. The primary outcome, acute hyponatremia, was experienced by 53% of 68 participants in the Plasma-Lyte-148 group and 58% of 69 participants in the standard fluids group (odds ratio 0·77 (0·34 - 1·75)). Five of 16 secondary outcomes differed with Plasma-Lyte-148: hypernatremia was significantly more frequent (odds ratio 3·5 (1·1 - 10·8)), significantly fewer changes to fluid prescriptions were made (rate ratio 0·52 (0·40-0·67)), and significantly fewer participants experienced hyperchloremia (odds ratio 0·17 (0·07 - 0·40)), acidosis (odds ratio 0·09 (0·04 - 0·22)) and hypomagnesemia (odds ratio 0·21 (0·08 - 0·50)). No other secondary outcomes differed between groups. Serious adverse events were reported in 9% of participants randomized to Plasma-Lyte-148 and 7% of participants randomized to standard fluids. Thus, perioperative Plasma-Lyte-148 did not change the proportion of children who experienced acute hyponatremia compared to standard fluids. However fewer fluid prescription changes were made with Plasma-Lyte-148, while hyperchloremia and acidosis were less common.

Patient-Specific Risk Factors Associated With the Development of Hyperchloremia in a Neurocritical Care Intensive Care Unit.

BACKGROUND: Hypertonic sodium chloride (HTS) is used in intensive care unit (ICU) settings to manage cerebral edema, intracranial hypertension, and for the treatment of severe hyponatremia. It has been associated with an increased incidence of hyperchloremia; however, there is limited literature focusing on hyperchloremic risk in neurologically injured patients. Objective: The primary objective of this study was to determine risk factors associated with development of hyperchloremia in a neurocritical care (NCC) ICU population. METHODS: This was a retrospective case-control study performed in an adult NCC ICU and included patients receiving HTS. The primary outcome was to evaluate patient characteristics and treatments associated with hyperchloremia. Secondary outcomes included acute kidney injury and mortality. RESULTS: Overall, 133 patients were identified; patients who were hyperchloremic were considered cases (n = 100) and patients without hyperchloremia were considered controls (n = 33). Characteristics and treatments were evaluated with univariate analysis and a logistic regression model. In the multivariate model, APACHE II Score, initial serum osmolality, total 3% saline volume, and total 23.4% saline volume were significant predictors for hyperchloremia. In addition, patients with a serum chloride greater than 113.5 mEq/L were found to have a higher risk of acute kidney injury (AKI) (adjusted OR 3.15; 95% CI 1.10-9.04). CONCLUSIONS: This study demonstrated APACHE II Score, initial serum osmolality, and total 3% and 23.4% saline volumes were associated with developing hyperchloremia in the NCC ICU. In addition, hyperchloremia is associated with an increased risk of AKI.

Comprehensive and Safe Decongestion in Acutely Decompensated Heart Failure.

PURPOSE OF THE REVIEW: Progressive intravascular, interstitial, and alveolar fluid overload underlies the transition from compensated to acutely decompensated heart failure and loop diuretics are the mainstay of treatment. Adverse effects and resistance to loop diuretics received much attention while the contribution of a depressed cardiac output to diuretic resistance was downplayed. RECENT FINDINGS: Analysis of experience with positive inotropic agents, especially dobutamine, indicates that enhancement of cardiac output is not consistently associated with increased renal blood flow. However, urinary output and renal sodium excretion increase likely due to dobutamine-mediated decrease in renal and systemic reduced activation of sympathetic nervous- and renin-angiotensin-aldosterone system. Mechanical circulatory support with left ventricular assist devices ascertained the contribution of low cardiac output to diuretic resistance and the pathogenesis and progression of kidney disease in acutely decompensated heart failure. Diuretic resistance commonly occurs in acutely decompensated heart failure. However, failure to resolve fluid overload despite high doses of loop diuretics should alert to the presence of a low cardiac output state.

Severe Electrolyte Disturbances Due to Proton Pump Inhibitor Therapy: An Underrecognized Problem with Potentially Severe Sequelae.

BACKGROUND Proton pump inhibitors are increasingly being recognized as a cause of multiple electrolyte disturbances, including hypomagnesemia, hypocalcemia, hypophosphatasemia, hypokalemia and hyponatremia, particularly in persons on long-term therapy. The mechanisms, consequences, and management of these electrolyte disturbances are discussed below. CASE REPORT A 55-year-old woman was seen by various clinicians, with a variety of clinical presentations, over the space of a couple of years. During each visit, she had electrolyte disturbances and was on proton pump inhibitor therapy, which were either continued or changed to a different proton pump inhibitor. She had presented variously with diarrhea and weight loss due to microscopic colitis, confusion, and grand mal seizures on separate occasions. Changing the proton pump inhibitor did not alleviate her profound electrolyte disturbances, which completely resolved shortly after stopping drug therapy. CONCLUSIONS It is important for clinicians to be aware of the electrolyte disturbances that can be caused by these medications, and to actively monitor patients on long-term therapy for these disturbances, thus avoiding potentially severe consequences. Electrolyte disturbances are more likely to arise in patients who are prescribed concomitant diuretic treatment or who overuse alcohol. The incidental finding of hypocalcemia in persons on proton pump inhibitors may be secondary to hypomagnesemia, and hypomagnesemia may be a consequence of an underlying otherwise symptomless genetic disorders. Clinicians should be encouraged to deprescribe these drugs after 4 weeks of treatment in patients with mild symptoms or mild disease.

Diuretics in States of Volume Overload: Core Curriculum 2022.

Volume overload, defined as excess total body sodium and water with expansion of extracellular fluid volume, characterizes common disorders such as congestive heart failure, end-stage liver disease, chronic kidney disease, and nephrotic syndrome. Diuretics are the cornerstone of therapy for volume overload and comprise several classes whose mechanisms of action, pharmacokinetics, indications, and adverse effects are essential principles of nephrology. Loop diuretics are typically the first-line treatment in the management of hypervolemia, with additional drug classes indicated in cases of diuretic resistance and electrolyte or acid-base disorders. Separately, clinical trials highlight improved outcomes in some states of volume overload, such as loop diuretics and sodium/glucose cotransporter 2 inhibitors in patients with congestive heart failure. Resistance to diuretics is a frequent, multifactorial clinical challenge that requires creative and physiology-based solutions. In this installment of AJKD's Core Curriculum in Nephrology, we discuss the pharmacology and therapeutic use of diuretics in states of volume overload and strategies to overcome diuretic resistance.

Electrolyte and Acid-Base Disorders Associated with Cancer Immunotherapy.

Novel immunotherapy drugs have changed the landscape of cancer medicine. Immune checkpoint inhibitors and chimeric antigen receptor T cells are being used and investigated in almost all types of cancers. Immune-related adverse events have been associated with immunotherapies. AKI has been the most commonly associated kidney adverse event. In this review, we showcase the several associated electrolyte disorders seen with immunotherapy. Immune checkpoint inhibitors can lead to hyponatremia by several mechanisms, with the syndrome of inappropriate antidiuresis being the most common. Endocrine causes of hyponatremia are rare. Hypokalemia is not uncommon and is associated with both proximal and distal renal tubular acidosis. Hypercalcemia associated with immune checkpoint inhibitors has led to some interesting observations, including immune checkpoint inhibitor-induced parathyroid hormone-related peptide production, sarcoid-like granulomas, and hyperprogression of the disease. Hypocalcemia and hyperphosphatemia may be seen with immune checkpoint inhibitor-induced tumor lysis syndrome. Chimeric antigen receptor T cell therapy-associated electrolyte disorders are also common. This is associated chiefly with hyponatremia, although other electrolyte abnormalities can occur. Early recognition and prompt diagnosis may help providers manage the mechanistically varied and novel electrolyte disorders associated with immunotherapy.

Electrolyte Disorders Common in Thiazide Diuretic Users.

According to this study: Hyponatremia and hypokalemia occur in approximately 20% of patients who take thiazide diuretics.

Characterizing the impact of magnesium and potassium-supplemented hydration with cisplatin and the subsequent electrolyte replacement requirements.

BACKGROUND: Cisplatin-associated electrolyte dysregulation is a prevalent therapy-related adverse effect. There are numerous electrolyte-supplemented hydration regimens that have been evaluated, however these studies focused on the development of nephrotoxicity. The objective of this study was to characterize the impact of magnesium and potassium-supplemented hydration during cisplatin administration on subsequent magnesium and potassium imbalances. METHODS: A single-region retrospective study from central Texas at Baylor Scott & White Cancer Clinics who were treated with two or more cycles of cisplatin were included. Standard hydration for this study was defined as normal saline before and after cisplatin along with potassium chloride 10 mEq and magnesium sulfate 1 g added to the cisplatin bag. RESULTS: A total of 477 patients were included in the study with376 patients receiving the standard hydration. Overall, 17 percent of patients experienced a potassium level below 3.5 mEq/L, but no major depletion was observed. Thirty-three percent of the patients experienced a magnesium level below 1.8 mg/dL, and time to first rescue magnesium supplementation was 4 weeks. CONCLUSION: Our study demonstrated despite routine magnesium and potassium supplementation in hydration, magnesium imbalances were observed. Potassium levels post cisplatin administration were maintained with minimal routine supplementation in hydration.

Gitelman-like syndrome: A rare complication of using aminoglycosides in tuberculosis - A case report.

Aminoglycosides are known to cause electrolyte disturbances. Approximately 8-26% of patients who receive an aminoglycoside for several days develop mild renal impairment that is almost always reversible (Brunton et al., 2013). A 46 year old male with multi-drug-resistant pulmonary tuberculosis with resistance to kanamycin is being presented, who was on injectable Capreomycin, Levofloxacin, Ethionamide, Cycloserine, pyrazinamide, linezolid and clofazamine for a period of four months. He presented to us with generalised weakness and pain in the lower limb muscles. Investigation revealed hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalceuria and hypocalcemia. This features mimic Gitelman's syndrome which is an autosomal recessive disorder affecting kidneys causing electrolyte disturbances. The drug was immediately withdrawn and electrolyte correction was given and the condition reversed gradually.

Fluid overload is associated with use of a higher number of antihypertensive drugs in hemodialysis patients.

INTRODUCTION: Hypertension is multifactorial, highly prevalent in the hemodialysis (HD) population and its adequate control requires, in addition to adequate volume management, often the use of multiple antihypertensive drugs. We aimed to describe the use of antihypertensive agents in a group of HD patients and to evaluate the factors associated with the use of multiple classes (≥3) of antihypertensives. METHODS: We analyzed the baseline data from the HDFit study. Clinically stable patients with HD vintage between 3 and 24 months without any severe mobility limitation were recruited from sites throughout southern Brazil. Fluid status was measured pre-dialysis with the Body Composition Monitor (BCM; Fresenius, Germany). Fluid overload (FO) was considered when the overhydration index (OH) was greater than 7% of extracellular water (OH/ECW > 7%) and overweight was defined as a body mass index (BMI) greater than 25 kg/m2 . Prescriptions of antihypertensive drugs were obtained from participants' reports and medical records. Logistic regression was employed to determine factors associated with excessive use of antihypertensive medication (≥3 classes). FINDINGS: Of 195 studied patients, 171 with complete data were included (70% male, 53 ± 15 years old, 57% of them with FO). Pre-dialysis systolic blood pressure (SBP) was 150 ± 24 mmHg and patients used a median of 2 (1-3) antihypertensive drugs. Vasodilators (20%) were of lowest prevalence, use of other classes varied from 40% to 53%. Sixty-two (36%) subjects used ≥3 classes and presented a higher prevalence of diabetes and FO, lower prevalence of overweight, and higher SBP. In a logistic regression model age, BMI <25 kg/m2 , and OH/ECW > 7% were associated with excessive drug use. DISCUSSION: More than one-third of participants used ≥3 classes of antihypertensive drugs, and it was associated with older age, BMI <25 kg/m2 and FO. Strategies that better manage FO may aid better blood pressure control and avoid the use of multiple antihypertensive medications.

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.

Toxicity profile of chemotherapy agents used in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal surface malignancies.

INTRODUCTION: Morbidity associated with cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is due to the synergistic effect of cytoreduction, effect hyperthermia and the cytotoxic agents used for HIPEC. This study was done to analyse the postoperative morbidity in relation to the chemotherapy agent used in patients undergoing CRS-HIPEC for peritoneal surface malignancy (PSM) in Indian set up. MATERIALS AND METHODS: Patient with PSM, underwent CRS-HIPEC as per the institutional protocol. Patients were stratified as per the chemotherapy drug used during HIPEC & perioperative outcome were documented. RESULTS: 163 patients underwent CRS-HIPEC for PSM: 67.4% were of ovarian primary. Others were colorectal, appendicular, gastric primary and rare tumors.Cisplatin was the most common drug used: as alone (57.05%) or in combination with Adriamycin (12.88%). Mitomycin-C (MMC) was used in 20% and oxaliplatin in 10%.Grade 3-5 morbidity in the whole cohort was 44.8% and grade 1-2 was 74%.Grade 1-2 electrolyte abnormality was the most common morbidity overall and grade 3-4 hematological toxicity was the most common severe morbidity. Frequency of grade 3-5 morbidity were 38.7%, 48.5%,50% and 61.9% for Cisplatin alone, MMC, oxaliplatin and Adriamycin + cisplatin respectively. None of the patients had grade 3-4 nephrotoxicity as sole complication. All major complications were highest in the group who received Adriamycin. Cisplatin was associated with higher rate of electrolyte imbalance, oxaliplatin with post-operative bleeding. Rates of other complications did not differ significantly. CONCLUSION: Cisplatin followed by MMC were the well tolerated drugs during HIPEC and tolerance to Adriamycin combination regimen in Indian patients was poor.

Endocrinological Toxicity Secondary to Treatment of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs).

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are increasingly recognized, characterized by prolonged survival even with metastatic disease. Their medical treatment is complex involving various specialties, necessitating awareness of treatment-related adverse effects (AEs). As GEP-NENs express somatostatin receptors (SSTRs), long-acting somatostatin analogs (SSAs) that are used for secretory syndrome and tumor control may lead to altered glucose metabolism. Everolimus and sunitinib are molecular targeted agents that affect glucose and lipid metabolism and may induce hypothyroidism or hypocalcemia, respectively. Chemotherapeutic drugs can affect the reproductive system and water homeostasis, whereas immunotherapeutic agents can cause hypophysitis and thyroiditis or other immune-mediated disorders. Treatment with radiopeptides may temporarily lead to radiation-induced hormone disturbances. As drugs targeting GEP-NENs are increasingly introduced, recognition and management of endocrine-related AEs may improve compliance and the quality of life of these patients.

Main challenges of electrolyte imbalance in older patients with coronavirus disease and risk of QT prolongation / Principales desafíos del desequilibrio electrolítico en pacientes geriátricos con COVID-19 y riesgo de prolongación del intervalo QT

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Effect of the methanol extract of the red cultivar Allium cepa L. on the serum biochemistry and electrolytes of rats following sub-chronic oral administration.

Background In traditional medicine, Allium cepa Linnaeus is used for the treatment of several disease conditions. Whilst reports abound on the effects of several cultivars of A. cepa L on biochemical parameters, similar information on the red cultivar is scarce. This study examines the effects of the methanol extract of the red cultivar A. cepa L on some serum biochemical parameters in experimental Wistar rats. Materials and methods Fifty-five Wistar rats were divided into three groups (A, B and C), which include 25, 25 and 5 rats, respectively. The rats in Groups A and B were sub-divided into 5 groups of 5 rats. Each rat was administered a certain dose of methanol extract of the red cultivar A. cepa L for 14 days (Group A) or 28 days (Group B). Group C rats served as the control and were administered with distilled water (10 mL/kg). Results A. cepa L administration resulted in dyslipidaemia, hyponatremia, hypokalaemia and hyperchloraemia; a significant (p < 0.05) decrease in hepatic enzymes and a significant (p < 0.05) increase in serum bicarbonate, bilirubin and its fractions. Conclusions These biochemical results indicate that the excessive and prolonged medicinal consumption of A. cepa L products beyond 7 days may induce moderate hepatic injury and mild renal dysfunction and may complicate disease conditions, such as hypertension and diabetes. Thus, in order to minimize its toxic effects, it is recommended that A. cepa L products should not be used for more than seven consecutive days or beyond a dosage of 90 mg/kg.

A phase 2 study of panitumumab with irinotecan as salvage therapy in chemorefractory KRAS exon 2 wild-type metastatic colorectal cancer patients.

BACKGROUND: Targeted agents are standard treatment for RAS wild-type metastatic colorectal cancer in the first- and second-line settings. This phase 2 study determined the benefit of targeting the epidermal growth factor receptor (EGFR) with panitumumab plus irinotecan in irinotecan-refractory patients. METHODS: KRAS exon-2 wild-type patients failing prior irinotecan received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). KRAS exon-2 status was evaluated centrally, along with NRAS, BRAF mutations, epiregulin, amphiregulin, PTEN and EGFR copy number status, and correlated with efficacy. RESULTS: Sixty-one patients were treated. Among the 46 wild-type RAS patients, the ORR was 15.2% (seven partial responses), with median PFS of 3.8 months (95% CI 2.7-4.3) and median OS of 12.5 months (95% CI 6.7-15.9). Wild-type BRAF patients showed a 13.0% response rate. No significant correlations between response and baseline biomarker expression were identified. Common grade 3-4 adverse events were diarrhoea and rash (18.0% each), hypomagnesaemia and asthenia (8.2% each). CONCLUSIONS: The addition of panitumumab to irinotecan as salvage therapy is feasible but has limited activity in irinotecan-refractory metastatic colorectal cancer. No biomarkers predictive of response were identified.

[Retrospective Investigation of the Risk Factors for Severity in Panitumumab-Induced Hypomagnesemia].

Hypomagnesemia caused by panitumumab can often lead to severe adverse effects, such as arrhythmia. However, the risk factors are still controversial. To clarify the risk factors and time to onset of panitumumab-induced hypomagnesemia, we retrospectively investigated the records of 30 patients who had received panitumumab. They were divided into Grade B2 hypomagnesemia and non-Grade B2 hypomagnesemia groups, according to their serum magnesium levels, and we compared patients' backgrounds, laboratory values, and concomitant drugs between the 2 groups. Univariate analysis revealed that hypocalcemia and non-administration of an oral magnesium preparation were significantly associated with Grade B2 hypomagnesemia induced by panitumumab. Incipient grade 1 hypocalcemia was observed after incipient Grade 1 hypomagnesemia in both groups. The occurrence of these complications was significant in the Grade B2 hypomagnesemia group. Thereafter, in all patients of the Grade B2 hypomagnesemia group that exhibited both complications, hypomagnesemia developed to Grade 2 or higher. The development of Grade 3 and Grade 4 hypomagnesemia without the development of Grade 2 hypomagnesemia was observed in 2 patients each. Thus, aggravation of hypomagnesemia can be expected upon the administration of panitumumab, and therefore, not only serum magnesium levels, but also serum calcium levels need to be monitored.