Faculty Bibliography

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.

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.

OBJECTIVE:Mycophenolate (MPA) and cyclosporin A (CsA) are two immunosuppressive agents currently used for the treatment of autoimmune diseases. However, reports regarding their effects on inflammation and lipid handling are controversial. Here, we compare the effect of these two drugs on the expression of proteins involved in cholesterol handling and lipid accumulation in a macrophage cell system utilizing M0, M1 and M2 human macrophages and in murine bone marrow-derived macrophages (BMDM). METHODS:. RESULTS:In M0 macrophages, MPA increased expression of ABCA1 and CXCL16 in a concentration-dependent manner. In M1 THP-1 macrophages, MPA caused a significant increase of 27-hydroxylase mRNA and CD36 and SR-A1 receptor mRNAs. Exposure of M2 macrophages to MPA also stimulated expression of 27-hydroxylase, while downregulating all evaluated scavenger receptors. In contrast, CsA had no impact on cholesterol efflux in M0 and M1 macrophages, but significantly augmented expression of ABCA1 and 27-hydroxylase in M2 macrophages. CsA significantly increased expression of the LOX1 receptor in naïve macrophages, downregulated expression of CD36 and SR-A1 in the M1 subpopulation and upregulated expression of all evaluated scavenger receptors. However, CsA enhanced foam cell transformation in M0 and M2 macrophages, while MPA had no effect on foam cell formation unless used at a high concentration in the M2 subtype. CONCLUSIONS:Our results clearly underline the importance of further evaluation of the effects of these drugs when used in atherosclerosis-prone patients with autoimmune or renal disease.

Mineral bone disease (MBD) is a common complication of chronic kidney disease (CKD) characterized by disruption of normal mineral homeostasis within the body. One or more of the following may occur: hypocalcemia, hyperphosphatemia, secondary hyperparathyroidism (SHPT), decreased vitamin D and vascular calcification (VC). The greater the decrease in renal function, the worse the progression of CKD-MBD. These abnormalities may lead to bone loss, osteoporosis and fractures. CKD-MBD is a major contributor to the high morbidity and mortality among patients with CKD. Another well-known complication of CKD is cardiovascular disease (CVD) caused by increased atherosclerosis and VC. CVD is the leading cause of morbidity and mortality in CKD patients. VC is linked to reduced arterial compliance that may lead to widened pulse pressure and impaired cardiovascular function. VC is a strong predicator of cardiovascular mortality among patients with CKD. Elevated phosphorus levels and increased calcium-phosphorus product promote VC. Controlling mineral disturbances such as hyperphosphatemia and SHPT is still considered among the current strategies for treatment of VC in CKD through restriction of calcium based phosphate binders in hyperphosphatemic patients across all severities of CKD along with dietary phosphate restriction and use of calciminetics. Additionally, Vitamin D insufficiency is common in CKD and dialysis patients. The causes are multifactorial and a serious consequence is SHPT. Vitamin D compounds remain the first-line therapy for prevention and treatment of SHPT in CKD. Vitamin D may also have atheroprotective effects on the arterial wall, but clinical studies do not show clear evidence of reduced cardiovascular mortality with vitamin D administration. This review discusses the issues surrounding CKD-MBD, cardiovascular disease and approaches to treatment.

BACKGROUND:The approach to hyponatremia is in a state of flux, especially in differentiating syndrome of inappropriate antidiuretic hormone secretion (SIADH) from cerebral-renal salt wasting (RSW) because of diametrically opposite therapeutic goals. Considering RSW can occur without cerebral disease, we determined the prevalence of RSW in the general hospital wards. METHODS:To differentiate SIADH from RSW, we used an algorithm based on fractional excretion (FE) of urate and nonresponse to saline infusions in SIADH as compared to excretion of dilute urines and prompt increase in serum sodium in RSW. RESULTS:Of 62 hyponatremic patients, (A) 17 patients (27%) had SIADH, 11 were nonresponsive to isotonic saline, and 5 normalized a previously high FEurate after correction of hyponatremia; (B) 19 patients (31%) had a reset osmostat based on normal FEurates and spontaneously excreted dilute urines; (C) 24 patients (38%) had RSW, 21 had no clinical evidence of cerebral disease, 19 had saline-induced dilute urines; 2 had undetectable plasma ADH levels when urine was dilute, 10 required 5% dextrose in water to prevent rapid increase in serum sodium, 11 had persistently increased FEurate after correction of hyponatremia and 10 had baseline urinary sodium < 20 mEq/L; (D) 1 patient had Addison disease with a low FEurate and (E) 1 patient (1.6%) had hyponatremia due to hydrochlorothiazide. CONCLUSIONS:Of the 24 patients with RSW, 21 had no cerebral disease, supporting our proposal to change cerebral-renal salt wasting to renal salt wasting. Application of established pathophysiological standards and a new algorithm based on determination of FEurate were superior to the volume approach for determination of urinary sodium when identifying the cause of hyponatremia.

Our evaluation of hyponatremic patients is in a state of confusion because the assessment of the volume status of the patient and determinations of urine sodium concentrations (UNa) >30-40 mEq/L have dominated our approach despite documented evidence of many shortcomings. Central to this confusion is our inability to differentiate cerebral/renal salt wasting (C/RSW) from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), syndromes with diametrically opposing therapeutic goals. The recent proposal to treat most or all hyponatremic patients makes differentiation even more important and reports of C/RSW occurring without cerebral disease leads to a clinically important proposal to change cerebral to renal salt wasting (RSW). Differentiating SIADH from RSW is difficult because of identical clinical parameters that characterize both syndromes. Determination of fractional urate excretion (FEurate) is central to a new algorithm, which has proven to be superior to current methods. We utilized this algorithm and differences in physiologic response to isotonic saline infusions between SIADH and RSW to evaluate hyponatremic patients from the general medical wards of the hospital. In 62 hyponatremic patients, 17 (27%) had SIADH, 19 (31%) had reset osmostat (RO), 24 (38%) had RSW, 1 due to HCTZ and 1 Addison's disease. Interestingly, 21 of 24 with RSW had no evidence of cerebral disease and 10 of 24 with RSW had UNa < 20 mEqL. We conclude that 1. RSW is much more common than is perceived, 2.the term cerebral salt wasting should be changed to RSW 3. RO should be eliminated as a subclass of SIADH, 4. SIADH should be redefined 5. The volume approach is ineffective and 6. There are limitations to determining UNa, plasma renin, aldosterone or atrial/brain natriuretic peptides. We also present data on a natriuretic peptide found in sera of patients with RSW and Alzheimer's disease.

Hyponatremia, serum sodium < 135 mEq/L, is the most common electrolyte abnormality and is in a state of flux. Hyponatremic patients are symptomatic and should be treated but our inability to consistently determine the causes of hyponatremia has hampered the delivery of appropriate therapy. This is especially applicable to differentiating syndrome of inappropriate antidiuresis (SIAD) from cerebral salt wasting (CSW) or more appropriately, renal salt wasting (RSW), because of divergent therapeutic goals, to water-restrict in SIAD and administer salt and water in RSW. Differentiating SIAD from RSW is extremely difficult because of identical clinical parameters that define both syndromes and the mindset that CSW occurs rarely. It is thus insufficient to make the diagnosis of SIAD simply because it meets the defined characteristics. We review the pathophysiology of SIAD and RSW, the evolution of an algorithm that is based on determinations of fractional excretion of urate and distinctive responses to saline infusions to differentiate SIAD from RSW. This algorithm also simplifies the diagnosis of hyponatremic patients due to Addison's disease, reset osmostat and prerenal states. It is a common perception that we cannot accurately assess the volume status of a patient by clinical criteria. Our algorithm eliminates the need to determine the volume status with the realization that too many factors affect plasma renin, aldosterone, atrial/brain natriuretic peptide or urine sodium concentration to be useful. Reports and increasing recognition of RSW occurring in patients without evidence of cerebral disease should thus elicit the need to consider RSW in a broader group of patients and to question any diagnosis of SIAD. Based on the accumulation of supporting data, we make the clinically important proposal to change CSW to RSW, to eliminate reset osmostat as type C SIAD and stress the need for a new definition of SIAD.