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.

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.

Background/Objectives: Idiopathic edema (IE) in women is characterized by swelling of hands and face followed by increasing abdominal and truncal girth, bloating, edema, >1.4 kg weight gain when in upright posture, and nocturia that eliminates the retained fluid. A capillary leak is the primary pathophysiologic abnormality that induces different clinical presentations that were considered untreatable. Methods: We utilized different aspects of Starling forces of edema formation and treated four uncomplicated cases of IE by reducing salt intake with or without diuretics and two cases of life-threatening cases due to seizures and coma induced by acute hyponatremia in one and postural dizziness, fainting, and fractures and dislocations of joints in another. Results: All four uncomplicated cases of IE were treated by reducing salt intake with or without diuretics that eliminated the weight gain and nocturia. The patient with hyponatremia never developed hyponatremia by reducing water intake and signs and symptoms of IE by salt restriction and diuretic therapy and eliminated the postural hypotension, falls, and fainting by use of support hose that increased interstitial hydrostatic pressure to eliminate fluid shifting from intravascular to interstitial spaces. Conclusions: A leaky capillary induces pathophysiologic changes that activate different metabolic pathways. IE is now a treatable condition, following: 1. Salt restriction with or without diuretics for the cyclical weight gain, and 2. Water restriction for hyponatremia, hyponatremic seizures, and coma and 3. support hose for postural hypotension, postural dizziness, and fainting. IE is unrecognized and probably more common than it is perceived.

Idiopathic edema is a disease of unknown etiology in women characterized by swelling of hands and face followed by increasing abdominal and truncal girth, bloating, edema, > 1.4 kg weight gain when in upright posture and nocturia that eliminates the retained fluid to become edema-free on awakening. We review how a capillary leak was determined as the primary pathophysiologic abnormality that induces different clinical presentations. We eliminated weight gains and nocturia in 4 cases of IE by sodium restriction with or without diuretic therapy. We present a case of hyponatremia-induced seizure and coma due to undiagnosed IE from ages 18 to 81. It took nearly 2 years to convince her that she will never have a seizure or suffer from IE if she drank small amounts of water every 3 hours and reduced sodium intake with or without diuretics, respectively. We present a 42-year-old woman with an 8-year history of postural hypotension, dizziness and fainting that led to many bone fractures and dislocated joints. She was home-bound and mentioning nocturia led to a diagnosis of IE where the capillary leak was of such magnitude that she became severely intravascularly volume depleted when standing. Wearing support stockings eliminated the postural hypotension, dizziness and fainting and symptoms of IE with no weight gain or nocturia. Increased capillary leak induces diverse pathophysiologic changes that cause seemingly disparate clinical manifestations. IE is probably much more common than it is perceived to be with many remaining undiagnosed for many years.