Hyponatremia Demystified: Integrating Physiology to Shape Clinical Practice.

Hyponatremia is one of the most common problems encountered in clinical practice and one of the least-understood because accurate diagnosis and management require some familiarity with water homeostasis physiology, making the topic seemingly complex. The prevalence of hyponatremia depends on the nature of the population studied and the criteria used to define it. Hyponatremia is associated with poor outcomes including increased mortality and morbidity. The pathogenesis of hypotonic hyponatremia involves the accumulation of electrolyte-free water caused by either increased intake and/or decrease in kidney excretion. Plasma osmolality, urine osmolality, and urine sodium can help to differentiate among the different etiologies. Brain adaptation to plasma hypotonicity consisting of solute extrusion to mitigate further water influx into brain cells best explains the clinical manifestations of hyponatremia. Acute hyponatremia has an onset within 48 hours, commonly resulting in severe symptoms, while chronic hyponatremia develops over 48 hours and usually is pauci-symptomatic. However, the latter increases the risk of osmotic demyelination syndrome if hyponatremia is corrected rapidly; therefore, extreme caution must be exercised when correcting plasma sodium. Management strategies depend on the presence of symptoms and the cause of hyponatremia and are discussed in this review.

Spurious Electrolyte and Acid-Base Disorders in the Patient With Cancer: A Review.

Electrolyte and acid-base disorders are frequently encountered in patients with malignancy, either due to cancer itself or as a complication of its therapy. However, spurious electrolyte disorders can complicate the interpretation and management of these patients. Several electrolytes can be artifactually increased or decreased such that the serum electrolyte values do not correspond to their actual systemic levels, potentially resulting in extensive diagnostic investigations and therapeutic interventions. Examples of spurious derangements include pseudohyponatremia, pseudohypokalemia, pseudohyperkalemia, pseudohypophosphatemia, pseudohyperphosphatemia, and artifactual acid-base abnormalities. Correctly interpreting these artifactual laboratory abnormalities is imperative for avoiding unnecessary and potentially harmful interventions in cancer patients. The factors influencing these spurious results also must be recognized, along with the steps to minimize them. We present a narrative review of commonly reported pseudo electrolyte disorders and describe strategies to exclude erroneous interpretations of these laboratory values and avoid pitfalls. Awareness and recognition of spurious electrolyte and acid-base disorders can prevent unnecessary and harmful treatments.

Sodium and Potassium Dysregulation in the Patient With Cancer.

Sodium and potassium disorders are pervasive in patients with cancer. The causes of these abnormalities are wide-ranging, are often primary or second-order consequences of the underlying cancer, and have prognostic implications. The approach to hyponatremia should focus on cancer-related etiologies, such as syndrome of inappropriate antidiuretic hormone, to the exclusion of other causes. Hypernatremia in non-iatrogenic forms is generally due to water loss rather than excessive sodium intake. Debilitated or dependent patients with cancer are particularly vulnerable to hypernatremia. Hypokalemia can occur in patients with cancer due to gastrointestinal disturbances, resulting from decreased intake or increased losses. Renal losses can occur as a result of excessive mineralocorticoid secretion or therapy-related nephrotoxicity. The approach to hyperkalemia should be informed by historical and laboratory clues, and pseudohyperkalemia is particularly common in patients with hematological cancers. Hyperkalemia can be seen in primary or metastatic disease that interrupts the adrenal axis. It can also develop as a consequence of immunotherapy, which can cause adrenalitis or hypophysitis. Tumor lysis syndrome (TLS) is defined by the development of hyperkalemia and is a medical emergency. Awareness of the electrolyte abnormalities that can befall patients with cancer is vital for its prompt recognition and management.

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.

Hypomagnesemia in Patients With Cancer: The Forgotten Ion.

Magnesium is crucial for various cellular and enzymatic processes, yet it often is overlooked or underappreciated. Hypomagnesemia, a deficiency of magnesium in the blood, is a frequent problem in cancer patients and can lead to severe symptoms and morbidity. In this review, we provide an in-depth analysis of the physiology and regulation of magnesium, and signs and symptoms of hypomagnesemia in cancer patients. We also examine the causes and mechanisms of magnesium imbalances in cancer patients, specifically focusing on cancer-specific therapies that can lead to hypomagnesemia. Finally, we provide updates on the management of hypomagnesemia, including oral and parenteral supplementation, as well as the role of drugs in cases that are resistant to treatment. This review aims to raise awareness among health care providers caring for cancer patients about the significance of monitoring magnesium levels in cancer patients and function as a guide. Future clinical studies should focus on magnesium monitoring, its impact on cancer progression, and its potential for preventing acute kidney injury.

Hypophosphatemia in cancer patients.

Dysregulation of phosphorus homeostasis resulting in hypophosphatemia is common in cancer patients and can result in serious complications and impact outcomes. Several factors, including critical illness, nutritional status, cancer type and therapy, influence the development of hypophosphatemia. Hypophosphatemia can develop as a result of phosphaturic mesenchymal tumors or as a paraneoplastic phenomenon. The clinical presentation for hypophosphatemia varies depending on the duration and severity of the hypophosphatemia and affects several organ systems. Among other serious effects, hypophosphatemia can impair tissue oxygenation and can cause hemolysis, leukocyte and platelet dysfunction, encephalopathy, seizures, arrhythmias, cardiomyopathy, rhabdomyolysis and coma. Multiple studies have demonstrated that hypophosphatemia is an adverse prognostic marker in inpatients with increased in-hospital stay, mortality and postoperative complications. The phosphate level is homeostatically regulated and maintained in a narrow range by three main hormones: parathyroid hormone, fibroblast growth factor 23 and 1,25-dihydroxyvitaminD3. Together, these hormones regulate how the intestine, kidneys and bones traffic phosphorus. Several hematological malignancies and cancer therapies are associated with proximal tubular dysfunction (Fanconi syndrome), resulting in phosphaturia. Caution should be taken with parenteral administration of phosphate salts, because secondary complications can develop, principally due to hypocalcemia. The general approach to hypophosphatemia should target the underlying cause. Early recognition and prevention are essential and the approach to hypophosphatemia in the cancer patient, because of the nuances and complexity, should be multidisciplinary.

The detrimental association between fear of falling and motor performance in older cancer patients with chemotherapy-induced peripheral neuropathy.

BACKGROUND: Cancer patients with chemotherapy-induced peripheral neuropathy (CIPN) are at increased risk of falls and developing fear of falling (FoF). Although FoF may continue to impair motor performance and increase the risk of falling even further, this association remains unexplored in CIPN. RESEARCH QUESTION: Does high FoF in patients with CIPN further deteriorate motor performance beyond the impairment from CIPN-related sensory deficits? METHODS: In this secondary analysis of data collected from two clinical trials, gait parameters during habitual walking condition and postural sway parameters during 30-second quiet standing (eye-open and eyes-closed) were compared among older participants (≥ 65 years) with CIPN and high FoF (CIPN FoF+; n=16), older participants with CIPN and low FoF (CIPN FoF-; n=19) and normal older controls (i.e., non-cancer, non-diabetic, non-neurologic, and non-orthopedic; n=16). We measured gait and postural sway parameters using wearable sensors (BioSensics, Newton, MA, USA), and FoF severity using the Falls Efficacy Scale-International. RESULTS: The largest between-group differences were found in gait speed. The CIPN FoF + group had significantly slower gait speed (0.78 ± 0.21 m/s) than the CIPN FoF- (0.93 ± 0.17 m/s) and normal control groups (1.17 ± 0.13 m/s) (all p < .05; effect sizes = 0.79 and 2.23, respectively). We found a significant association between gait speed and FoF severity (R2 = 0.356; p < .001) across all participants with CIPN. Among participants with CIPN, no significant differences in postural sway parameters were found between the CIPN FoF+and CIPN FoF- groups. SIGNIFICANCE: Our results suggest that gait performance further deteriorates in patients with CIPN and high FoF beyond the impairment from CIPN-related sensory deficits. Our results also suggest further research is needed regarding FoF, and fall risk, as FoF is a simple tool that healthcare providers can use in clinical practice.

Harnessing digital health to objectively assess cancer-related fatigue: The impact of fatigue on mobility performance.

OBJECTIVE: Cancer-related fatigue (CRF) is highly prevalent among cancer survivors, which may have long-term effects on physical activity and quality of life. CRF is assessed by self-report or clinical observation, which may limit timely diagnosis and management. In this study, we examined the effect of CRF on mobility performance measured by a wearable pendant sensor. METHODS: This is a secondary analysis of a clinical trial evaluating the benefit of exercise in cancer survivors with chemotherapy-induced peripheral neuropathy (CIPN). CRF status was classified based on a Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score ≤ 33. Among 28 patients (age = 65.7±9.8 years old, BMI = 26.9±4.1kg/m2, sex = 32.9%female) with database variables of interest, twenty-one subjects (75.9%) were classified as non-CRF. Mobility performance, including behavior (sedentary, light, and moderate to vigorous activity (MtV)), postures (sitting, standing, lying, and walking), and locomotion (e.g., steps, postural transitions) were measured using a validated pendant-sensor over 24-hours. Baseline psychosocial, Functional Assessment of Cancer Therapy-General (FACT-G), Falls Efficacy Scale-International (FES-I), and motor-capacity assessments including gait (habitual speed, fast speed, and dual-task speed) and static balance were also performed. RESULTS: Both groups had similar baseline clinical and psychosocial characteristics, except for body-mass index (BMI), FACT-G, FACIT-F, and FES-I (p<0.050). The groups did not differ on motor-capacity. However, the majority of mobility performance parameters were different between groups with large to very large effect size, Cohen's d ranging from 0.91 to 1.59. Among assessed mobility performance, the largest effect sizes were observed for sedentary-behavior (d = 1.59, p = 0.006), light-activity (d = 1.48, p = 0.009), and duration of sitting+lying (d = 1.46, p = 0.016). The largest correlations between mobility performance and FACIT-F were observed for sitting+lying (rho = -0.67, p<0.001) and the number of steps per day (rho = 0.60, p = 0.001). CONCLUSION: The results of this study suggest that sensor-based mobility performance monitoring could be considered as a potential digital biomarker for CRF assessment. Future studies warrant evaluating utilization of mobility performance to track changes in CRF over time, response to CRF-related interventions, and earlier detection of CRF.

Hypomagnesemia in the Cancer Patient.

Hypomagnesemia is a common medical problem that contributes to the morbidity and mortality of patients with cancer. This review summarizes magnesium physiology and highlights the mechanisms underlying magnesium disturbances due to cancer and cancer treatment. The causes of hypomagnesemia can be categorized according to the pathophysiologic mechanism: decreased intake, transcellular shift, gastrointestinal losses, and kidney losses. Patients with cancer are at risk for opportunistic infections, frequently experience cardiovascular complications, and often receive classes of medications that cause or exacerbate hypomagnesemia. Also, cancer-specific therapies are responsible for hypomagnesemia, including platinum-based chemotherapy, anti-EGF receptor mAbs, human EGF receptor-2 target inhibitors (HER2), and calcineurin inhibitors. Urinary indices, such as the fractional excretion of magnesium, can provide useful information about the etiology. The management of hypomagnesemia depends on the magnitude of hypomagnesemia and the underlying cause. We recommended checking serum magnesium at the beginning of treatment and as part of routine monitoring throughout cancer treatment. Opportunities exist for potential research and practice improvement, including further characterization of hypomagnesemia regarding the clinical effect on cancer outcomes, preventing hypomagnesemia in patients receiving high-risk anticancer agents, and developing effective therapeutic strategies.

Hyponatremia in the cancer patient.

Hyponatremia is a common electrolyte disorder observed in a wide variety of malignancies and is associated with substantial morbidity and mortality. Newer cancer therapies have improved patient outcomes while contributing to new cases of hyponatremia. Patients should be monitored closely for the development of vasopressin- and non-vasopressin-mediated hyponatremia. Acute and symptomatic forms of hyponatremia require urgent intervention, and recent findings support the correction of chronic "asymptomatic" hyponatremia. Optimizing hyponatremia may reduce medical costs, and improve cancer survival likelihood and quality of life. In this article, we review the epidemiology, pathophysiology, etiology, diagnosis, and treatment of hyponatremia in the cancer patient.

Using wearables to screen motor performance deterioration because of cancer and chemotherapy-induced peripheral neuropathy (CIPN) in adults - Toward an early diagnosis of CIPN.

OBJECTIVE: An essential component for optimizing quality of life in adults with cancer is determining the degree to which therapy may negatively impact motor-performance, so that patients can maintain their quality of life and independence. This study examined whether instrumented gait and balance could determine the magnitude of deterioration in motor-performance from chemotherapy-induced peripheral neuropathy (CIPN). METHODS: We recruited 84 adults with cancer (age = 71.1 ±â€¯9.7 years old, BMI = 26.8 ±â€¯6.2 kg/m2, gender = 56%female) and 57 age-matched non-cancer patients (age = 69.5 ±â€¯9.8 years old, BMI = 27.1 ±â€¯6.0 kg/m2, gender = 79%female). Based on clinical screening, the group with cancer was classified into two groups: participants with CIPN (CIPN+) and without CIPN (CIPN-). Gait and balance were quantified using validated wearables. The Vibration Perception Threshold (VPT) test was used to stratify the CIPN+ group into mild (Mild-CIPN) and severe (Severe-CIPN) subgroups. RESULTS: All gait and balance parameters were deteriorated in the group with cancer compared to non-cancer group with the largest effects observed for stride-time (11%, Cohen's effect size d = 1.00, p < 0.001) and eyes-closed ankle sway (94%, d = 0.49, p = 0.001). The same trend was observed when the Severe-CIPN subgroup was compared to the Mild-CIPN. VPT correlates significantly with motor deterioration, with the largest correlation found in stride-time (Rho = 0.37, p = 0.007). Severe-CIPN subjects were significantly older and overall had more deterioration in the majority of motor-performance parameters after adjusting for age (p < 0.050). CONCLUSION: These results confirmed the negative impact of CIPN on motor-performance with the largest effects on ankle stability and stride-time. VPT is a predictor of motor deterioration and may be used to determine the severity of CIPN symptom.

Trends in the outcomes of end-stage renal disease secondary to human immunodeficiency virus-associated nephropathy.

BACKGROUND: Little is known about the trends in the incidence and outcomes of patients with end-stage renal disease (ESRD) attributed to human immunodeficiency virus-associated nephropathy (HIVAN). We sought to define relative incidence among ESRD patients, changes in mortality among patients with ESRD attributed to HIVAN, as well as changes in the excess mortality experienced by patients with ESRD attributed to HIVAN compared with otherwise similar ESRD patients with non-HIVAN causes. METHODS: We used the US Renal Data System to identify all individuals with reported HIVAN who initiated treatment for ESRD between 1989 and 2011. We plotted their counts and proportions among all incident ESRD patients and tabulated their characteristics across years. We then compared mortality within the HIVAN group across years using Cox regression. In addition, we studied the trends in relative mortality of HIVAN patients versus those with ESRD not reported as HIVAN. RESULTS: Overall, 14 719 individuals with HIVAN-ESRD were recorded, with significant reductions in recent years (893 in 2006; 525 in 2011). Compared with patients initiating dialysis between 1989 and 1992, mortality declined by 40% (HR = 0.60; 95% CI, 0.55-0.65) and 64% (HR = 0.36; 95% CI, 0.32-0.40) for patients initiating dialysis in 1999/2000 and 2009-11, respectively. The adjusted excess mortality of HIVAN-ESRD patients versus incident ESRD patients from other causes was >5-fold in 1989-92 (HR = 5.21; 95% CI, 4.84-5.60); this excess mortality has subsequently declined but remained at almost 3-fold in recent years (e.g. HR = 2.58; 95% CI, 2.37-2.80, 2009-11 incidence cohort). CONCLUSIONS: Concurrent with the increasing availability of highly active antiretroviral therapy (HAART), both the incidence of ESRD due to HIVAN and the mortality of such patients have decreased substantially. However, HIVAN patients reaching ESRD continue to experience substantial excess mortality compared with other ESRD patients even in the current era of modern HAART.

Review of muscle wasting associated with chronic kidney disease.

Muscle wasting increases the morbidity and mortality associated with chronic kidney disease (CKD) and has been attributed to malnutrition. In most patients, this is an incorrect diagnosis because simply feeding more protein aggravates uremia. Instead, there are complex mechanisms that stimulate loss of skeletal muscle, involving activation of mediators that stimulate the ATP-dependent ubiquitin-proteasome system (UPS). Identified mediators of muscle protein breakdown include inflammation, metabolic acidosis, angiotensin II, and neural and hormonal factors that cause defects in insulin/insulin-like growth factor I (IFG-I) intracellular signaling processes. Abnormalities in insulin/IGF-I signaling activate muscle protein degradation in the UPS and caspase-3, a protease that disrupts the complex structure of muscle proteins to provide substrates for the UPS. During the cleavage of muscle proteins, caspase-3 leaves behind a characteristic 14-kD actin fragment in the insoluble fraction of muscle, and characterization of this fragment identifies the presence of muscle catabolism. Thus, it could become a marker of excessive muscle wasting, providing a method for early detection of muscle wasting. Another consequence of activation of caspase-3 in muscle is stimulation of the activity of the proteasome, which increases the degradation of muscle proteins. Treatment strategies for blocking muscle wasting include correction of metabolic acidosis, which can suppress muscle protein losses in patients with CKD who are or are not being treated by dialysis. Correcting acidosis also improves bone metabolism in CKD and hence should be a goal of therapy. Exercise training is a potentially beneficial approach, but more information is needed to optimize exercise regimens. Replacing testosterone deficits can improve muscle mass in men, but dosing and side effects in women have not been adequately tested. Although insulin resistance occurs early in the course of CKD, there are no effective means of correcting it. Consequently, new therapies that can safely suppress muscle wasting are needed.

Development of a diagnostic method for detecting increased muscle protein degradation in patients with catabolic conditions.

Muscle atrophy in catabolic illnesses is due largely to accelerated protein degradation. Unfortunately, methods for detecting accelerated muscle proteolysis are cumbersome. The goal of this study was to develop a method for detecting muscle protein breakdown and assess the effectiveness of anticatabolic therapy. In rodent models of catabolic conditions, it was found that accelerated muscle protein degradation is triggered by activation of caspase-3. Caspase-3 cleaves actomyosin/myofibrils to form substrates for the ubiquitin-proteasome system and leaves a characteristic 14-kD actin fragment in the insoluble fraction of a muscle lysate. Muscle biopsies were obtained from normal adults and three groups of patients: 14 who were undergoing hip arthroplasty, 28 hemodialysis patients who were participating in exercise programs, and seven severely burned patients. In muscle of patients who were undergoing hip arthroplasty, the 14-kD actin fragment level was correlated (r = 0.787, P < 0.01) with the fractional rate of protein degradation. In muscle of hemodialysis patients who were undergoing endurance exercise training, the 14-kD actin fragment decreased to values similar to levels in normal adults; strength training did not significantly decrease the actin fragment. Severely burned patients had increased muscle protein degradation and actin fragment levels, but the two measures were not significantly correlated. The experimental results suggest that the 14-kD actin fragment in muscle biopsies is increased in catabolic states and could be used in conjunction with other methods to detect and monitor changes in muscle proteolysis that occur in patients with mild or sustained increases in muscle proteolysis.