Faculty Bibliography

A knowledge gap may exist when attempting to identify the pathogenetic mechanisms resulting in the syndrome of inappropriate antidiuretic hormone (SIADH) or hypotonic hyponatremia. Ectopic secretion of antidiuretic hormone [ADH] is the classic cause of SIADH. But another form of inappropriate secretion of ADH occurs when interleukin 6 is activated. Hypotonic hyponatremia can also occur in patients with cerebral salt wasting, but the secretion of ADH is appropriate, responding to volume depletion induced by excessive natriuresis. Reset osmostat (RO) is another cause of hypotonic hyponatremia caused by an unknown anomaly in the hypothalamus. This review discusses the pathophysiology of and the identical laboratory findings found in classic ectopic ADH secretion, interleukin 6-mediated ADH secretion, cerebral salt wasting-induced ADH secretion, and RO. This review also discusses potential methods to discern which hypotonic hyponatremic syndrome is present and current recommendations for treatment.

Idiopathic edema (IE) is a disease that occurs predominantly in women. It is characterized by increasing weight gain of >1.4 kg from morning to night, increasing edema, increasing truncal and abdominal girth with bloating when assuming an upright position and nocturia that is unrelated to menses. There is an increase in morbidity but not mortality. Increased capillary membrane leakage appears to be the underlying pathophysiologic abnormality that explains the myriad of clinical presentations. We present 2 cases of life-threatening complications of IE that resulted in seizures related to acute hyponatremia in one and extreme postural dizziness and fainting induced by postural hypotension in the other. The first patient was successfully treated with salt restriction, timely use of furosemide and limitation of water intake; the other was successfully treated by use of support hose. Treatment of these patients required a fundamental understanding of the intricate pathophysiological consequences of a leaky capillary membrane, an understanding of Starling forces and detailing the effectiveness of a low salt diet, use of diuretics and limited water intake in one and why support hose would be beneficial in the other patient. Both patients experienced significant physical and emotional benefits that substantially improved quality of life.

The subject of hyponatremia is undergoing significant changes after developing a more pathophysiologic approach that is superior to the ineffective volume approach and can more effectively identify the different causes of hyponatremia. This new approach identified cerebral salt wasting (CSW) in 24 (38%) of 62 hyponatremic patients from the medical wards of the hospital with 21 showing no evidence of cerebral disease to support our proposal to change CSW to renal salt wasting (RSW). RSW had to be differentiated from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) because of diametrically opposite therapeutic goals of water-restricting water-logged patients with SIADH or administering salt water to volume-depleted patients with RSW. Both syndromes present with identical clinical parameters that require a difficult protocol to make such a differentiation possible. We describe rat clearance studies demonstrating natriuretic activity in the plasma of patients with neurosurgical and Alzheimer diseases (AD) and eventually identify the protein as haptoglobin-related protein without signal peptide, which can serve as a biomarker to simplify diagnosis of RSW and delivery of the proper management to improve clinical outcomes. We also discuss the introduction of a new syndrome of RSW in AD and its implications. The high prevalence of RSW and identification of the natriuretic factor have created debates over the existence of RSW with none questioning or addressing the pathophysiologic data that identified patients with RSW. We also discuss the potentially large group of patients with RSW who are normonatremic.

The application of pathophysiologic tenets has created significant changes in our approach to hyponatremia and hyponatremia-related conditions. This new approach incorporated the determination of fractional excretion (FE) of urate before and after the correction of hyponatremia and the response to isotonic saline infusion to differentiate the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from renal salt wasting (RSW). FEurate simplified the identification of the different causes of hyponatremia, especially the diagnosis of a reset osmostat and Addison's disease. Differentiating SIADH from RSW has been extremely difficult because both syndromes present with identical clinical parameters, which could be overcome by successfully carrying out the difficult protocol of this new approach. A study of 62 hyponatremic patients from the general medical wards of the hospital identified 17 (27%) to have SIADH, 19 (31%) with reset osmostat, and 24 (38%) with RSW with 21 of these RSW patients presenting without clinical evidence of cerebral disease to warrant changing the nomenclature from cerebral to renal salt wasting. The natriuretic activity found in the plasma of 21 and 18 patients with neurosurgical and Alzheimer's disease, respectively, was later identified as haptoglobin-related protein without signal peptide (HPRWSP). The high prevalence of RSW creates a therapeutic dilemma of deciding whether to water-restrict water-logged patients with SIADH as compared to administering saline to volume-depleted patients with RSW. Future studies will hopefully achieve the following: 1. Abandon the ineffective volume approach; 2. Develop HPRWSP as a biomarker to identify hyponatremic and a projected large number of normonatremic patients at risk of developing RSW, including Alzheimer's disease; 3. Facilitate differentiating SIADH from RSW on the first encounter and improve clinical outcomes.

Our understanding of hyponatremic conditions has undergone major alterations. There is a tendency to treat all patients with hyponatremia because of common subtle symptoms that include unsteady gait that lead to increased falls and bone fractures and can progress to mental confusion, irritability, seizures, coma and even death. We describe a new approach that is superior to the ineffectual volume approach. Determination of fractional excretion (FE) of urate has simplified the diagnosis of a reset osmostat, Addison"™s disease, edematous causes such as congestive heart failure, cirrhosis and nephrosis, volume depletion from extrarenal salt losses with normal renal tubular function and the difficult task of differentiating the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from cerebral/renal salt wasting (C/RSW). SIADH and C/RSW have identical clinical and laboratory parameters but have diametrically opposite therapeutic goals of water-restricting water-loaded patients with SIADH or administering salt water to dehydrated patients with C/RSW. In a study of nonedematous patients with hyponatremia, we utilized FEurate and response to isotonic saline infusions to differentiate SIADH from C/RSW. Twenty-four (38%) of 62 hyponatremic patients had C/RSW with 21 having no clinical evidence of cerebral disease to support our important proposal to change cerebral to renal salt wasting (RSW). Seventeen (27%) had SIADH and 19 (31%) had a reset osmostat. One each from hydrochlorothiazide and Addison"™s disease. We demonstrated natriuretic activity in the plasma of patients with neurosurgical and Alzheimer diseases (AD) in rat clearance studies and have now identified the natriuretic protein to be haptoglobin related protein without signal peptide (HPRWSP). We introduce a new syndrome of RSW in AD that needs further confirmation. Future studies intend to develop HPRWSP as a biomarker to simplify the diagnosis of RSW in hyponatremic and normonatremic patients and explore other clinical applications that can improve clinical outcomes.

BACKGROUND:Idiopathic edema (IE), a disorder of females, is characterized by edema and weight gains exceeding 1.4 kg while assuming an upright position followed by nocturia and returning to a non-edematous baseline weight in the morning. There is no successful treatment of IE and the importance of nocturia needs to be emphasized. The major underlying abnormality is an increase in vascular membrane permeability (VMP). We present four cases with differing degrees of IE who were successfully managed by manipulating Starling's forces. While we could not alter the increase in VMP, manipulating oncotic and hydrostatic pressures between both compartments were untenable except to decrease intravascular hydrostatic pressure by sodium restriction. All four cases virtually eliminated daily weight gains and nocturia to improve quality of life considerably, two with the assistance of daily hydrochlorothiazide (HCTZ) and all four by furosemide to accelerate recovery from the weight gain to permit occasional dietary indiscretions to improve quality of life. Two cases with milder forms of IE did not quantify sodium intake as meticulously as cases one and four, who appeared to have greater increases in VMP. IE can be treated successfully by sodium restriction with or without use of HCTZ and furosemide to eliminate the distressing edema, weight gain and nocturia with marked improvement in emotional instability after understanding that the weight gains and nocturia were linked to dietary intake of sodium.

Background/UNASSIGNED:Patients on maintenance hemodialysis are particularly vulnerable to infection and hospitalization from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to immunocompromised patients and the clustering that occurs in outpatient dialysis units, the seroprevalence of COVID-19 antibodies in this population is unknown and has significant implications for public health. Also, little is known about their risk factors for hospitalization. Methods/UNASSIGNED:nasopharyngeal, real-time, reverse-transcriptase PCR (RT-PCR); SARS-CoV-2 IgG seropositivity; hospitalization; and mortality. Results/UNASSIGNED:<0.001) compared with those who tested negative. Higher positivity rates were also observed among those who took taxis and ambulettes to and from dialysis, compared with those who used personal transportation. Antibodies were detected in all of the patients with a positive PCR result who underwent serologic testing. Of those that were seropositive, 32% were asymptomatic. The hospitalization rate on the basis of either antibody or PCR positivity was 35%, with a hospital mortality rate of 33%. Aside from COPD, no other variables were more prevalent in patients who were hospitalized. Conclusions/UNASSIGNED:We observed significant differences in rates of COVID-19 infection within three outpatient dialysis units, with universal seroconversion. Among patients with ESKD, rates of asymptomatic infection appear to be high, as do hospitalization and mortality rates.

BACKGROUND:The most vexing problem in hyponatremic conditions is to differentiate the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from cerebral/renal salt wasting (C-RSW). Both have identical clinical parameters but diametrically opposite therapeutic goals of water- restricting water-logged patients with SIADH or administering salt and water to dehydrated patients with C-RSW. While C-RSW is considered a rare condition, the report of a high prevalence of C-RSW in the general hospital wards creates an urgency to differentiate one syndrome from the other on first encounter. We decided to identify the natriuretic factor (NF) we previously demonstrated in plasma of neurosurgical and Alzheimer diseases (AD) who had findings consistent with C-RSW. METHODS:We performed the same rat renal clearance studies to determine natriuretic activity (NA) in serum from a patient with a subarachnoid hemorrhage (SAH) and another with AD and demonstrated NA in their sera. The sera were subjected to proteomic and SWATH (Sequential Windowed Acquisition of All) analyses which identified increased levels of haptoglobin related protein (Hpr) without signal peptide (Hpr-WSP). RESULTS:Recombinant Hpr with His tag at the N terminus had no NA. Hpr-WSP had a robust NA in a dose-dependent manner when injected into rats. Serum after recovery from C-RSW in the SAH patient had no NA. CONCLUSIONS:Hpr-WSP may be the NF in C-RSW which should be developed as a biomarker to differentiate C-RSW from SIADH on first encounter, introduces a new syndrome of C-RSW in AD and can serve as a proximal diuretic to treat congestive heart failure.

PURPOSE OF REVIEW/OBJECTIVE:The topic of hyponatremia is in a state of flux. We review a new approach to diagnosis that is superior to previous methods. It simplifies identifying the causes of hyponatremia, the most important issue being the differentiation of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from cerebral/renal salt wasting (RSW). We also report on the high prevalence of RSW without cerebral disease in the general wards of the hospital. RECENT FINDINGS/RESULTS:We applied our new approach to hyponatremia by utilizing sound pathophysiologic criteria in 62 hyponatremic patients. Seventeen (27%) had SIADH, 19 (31%) had a reset osmostat, 24 (38%) had RSW with 21 having no evidence of cerebral disease, 1 had Addison's disease, and 1 was because of hydrochlorothiazide. Many had urine sodium concentrations (UNa) less than 30 mmol/l. SUMMARY/CONCLUSIONS:RSW is much more common than perceived in the general wards of the hospital. It is important to change the terminology from cerebral to RSW and to differentiate SIADH from RSW. These changes will improve clinical outcomes because of divergent therapeutic goals of water-restricting in SIADH and administering salt and water to a dehydrated patient with RSW. The present review will hopefully spur others to reflect and act on the new findings and different approaches to hyponatremia.