John K. Maesaka

More on Renal Salt Wasting Without Cerebral Disease: Response to Saline Infusion

BACKGROUND AND OBJECTIVES The existence and prevalence of cerebral salt wasting (CSW) or the preferred term, renal salt wasting (RSW), and its differentiation from syndrome of inappropriate antidiuretic hormone (SIADH) have been controversial. This controversy stems from overlapping clinical and laboratory findings and an inability to assess the volume status of these patients. The authors report another case of RSW without clinical cerebral disease and contrast it to SIADH. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Three patients with hyponatremia, hypouricemia, increased fractional excretion (FE) of urate, urine sodium >20 mmol/L, and concentrated urines were infused with isotonic saline after collection of baseline data. RESULTS One patient with RSW had pneumonia without cerebral disease and showed increased plasma aldosterone and FEphosphate, and two patients with SIADH had increased blood volume, low plasma renin and aldosterone, and normal FEphosphate. The patient with RSW responded to isotonic saline by excretion of dilute urines, prompt correction of hyponatremia, and normal water loading test after volume repletion. Hypouricemia and increased FEurate persisted after correction of hyponatremia. Two patients with SIADH failed to dilute their urines and remained hyponatremic during 48 and 110 h of saline infusion. CONCLUSIONS The authors demonstrate appropriate stimulation of ADH in RSW. Differences in plasma renin and aldosterone levels and FEphosphate can differentiate RSW from SIADH, as will persistent hypouricemia and increased FEurate after correction of hyponatremia in RSW. FEphosphate was the only contrasting variable at baseline. The authors suggest an approach to treat the hyponatremic patient meeting criteria for SIADH and RSW and changing CSW to the more appropriate term, RSW

Prostaglandin D2 synthase induces apoptosis in PC12 neuronal cells.

Apoptosis of neuronal cells is a proposed cause of certain neurological disorders. Here, we report on a 5- to 6-fold increase in apoptosis by exposure to prostaglandin D2 synthase (PGD2S) in PC12 neuronal cells. Apoptosis was detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assay, and appears to be mediated via caspase-3 activation. Neutralization with anti-PGD2S antibody or pre-treatment with selenium, which inhibits PGD2S enzymatic activity, both significantly inhibited the PGD2S-induced apoptosis, however, neither had any effect on the apoptosis induced by the known neuronal apoptotic inducer, glutamate. In addition, prostaglandins E1, E2, and F2α all inhibited the PGD2S-induced apoptosis while prostaglandin H2 had no significant effect. Furthermore, PGD2S isolated from human serum was more effective at inducing apoptosis then recombinantly expressed protein, presumably due to glycosylation. This novel role of PGD2S, as an inducer of apoptosis, may have implications in PC12 differentiation and possibly some neurological disorders.

Differentiating SIADH from Cerebral/Renal Salt Wasting: Failure of the Volume Approach and Need for a New Approach to Hyponatremia.

Hyponatremia is the most common electrolyte abnormality. Its diagnostic and therapeutic approaches are in a state of flux. It is evident that hyponatremic patients are symptomatic with a potential for serious consequences at sodium levels that were once considered trivial. The recommendation to treat virtually all hyponatremics exposes the need to resolve the diagnostic and therapeutic dilemma of deciding whether to water restrict a patient with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or administer salt and water to a renal salt waster. In this review, we briefly discuss the pathophysiology of SIADH and renal salt wasting (RSW), and the difficulty in differentiating SIADH from RSW, and review the origin of the perceived rarity of RSW, as well as the value of determining fractional excretion of urate (FEurate) in differentiating both syndromes, the high prevalence of RSW which highlights the inadequacy of the volume approach to hyponatremia, the importance of changing cerebral salt wasting to RSW, and the proposal to eliminate reset osmostat as a subtype of SIADH, and finally propose a new algorithm to replace the outmoded volume approach by highlighting FEurate. This algorithm eliminates the need to assess the volume status with less reliance on determining urine sodium concentration, plasma renin, aldosterone and atrial/brain natriuretic peptide or the BUN to creatinine ratio.

Normal fractional urate excretion identifies hyponatremic patients with reset osmostat

BACKGROUND Reset osmostat (RO) occurs in 36% of patients with syndrome of inappropriate antidiuretic hormone secretion (SIADH) and is not often considered when evaluating hyponatremic patients. Patients with RO are not usually treated, but recent awareness that symptoms are associated with mild hyponatremia creates a therapeutic dilemma. We encountered patients with hyponatremia, hypouricemia and high urine sodium concentration (UNa), who had normal fractional excretion (FE) of urate and excreted dilute urines that were consistent with RO. We decided to test whether a normal FEurate in nonedematous hyponatremia irrespective of UNa or serum urate would identify patients with RO. METHODS We determined FEurate in nonedematous hyponatremic patients. A diagnosis of RO was made if urine osmolality (Uosm) was <200 mOsm/kg in a random urine. We performed a modified water-loading test in patients with a normal FEurate whose random Uosm was >200 mOsm/kg. RESULTS All nonedematous hyponatremic patients with FEurate of 4%-11% had RO, as determined by Uosm <200 mOsm/kg on a random urine collection in 8 patients, or after a modified water-loading test in 6 patients. Plasma antidiuretic hormone (ADH) in 4 patients was undetectable at <1 pg/mL during water-loading. Nine patients had baseline concentrated urine, 12 had UNa >20 mmol/L, 9 were hypouricemic, yet all had a normal FEurate. Comorbidities were similar to those reported in RO. CONCLUSIONS RO, a benign form of SIADH, occurs commonly. A normal FEurate in a nonedematous hyponatremic patient is highly suggestive of RO. Determining FEurate is superior to serum urate. The therapeutic dilemma for RO must be resolved.

Complexity of differentiating cerebral/renal salt wasting from SIADH: Emerging importance of determining fractional urate excretion

The current approach to the diagnosis and treatment of hyponatremia is in a state of flux, largely because of an unresolved controversy regarding the relative prevalence of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and cerebral salt wasting, or preferably renal salt wasting (RSW). The recent awareness that symptoms are now being attributed to even mild hyponatremia has led to recommendations to treat virtually all hyponatremics. (Arief et al, 1976; Berl et al, 2010; Decaux, 2006, 2009; Gankam Kegne et al, 2008; Hoorn et al, 2009; Renneboog et al, 2006; Sterns et al,2009; Schrier, 2010) This tendency to treat even mild hyponatremia introduces an urgency to resolve the diagnostic dilemma of differentiating two syndromes, SIADH and RSW, with divergent therapeutic goals, to water-restrict in SIADH or administer salt and water in RSW. We propose to define RSW by supporting data and review the pathophysiology of RSW, the derivation and evolution of the controversy over the relative prevalence of SIADH and RSW, and methods to differentiate SIADH from RSW. We will also review the emerging value of determining fractional excretion (FE) of urate in the evaluation of patients with hyponatremia by emphasizing our recent observations in reset osmostat, identify conditions that predispose to RSW, amplify the possibility that RSW might exist in patients with an increased FEurate without hyponatremia and propose an algorithm where FEurate is central to the evaluation of hyponatremia. We will also advocate and hopefully justify changing the designation, cerebral salt wasting, to renal salt wasting, and briefly discuss different strategies to treat hyponatremia.

A Method to Identify Microinjected Nephrons of Rat

This paper describes a technique for identifying individual nephrons that have been subjected to micropuncture. The general location of the nephron is marked on the surface of the kidney by implanting two micropipette tips on opposite sides of it two or three tubule diameters away. The tubule itself is marked by the injection into the lumen of a tracer material, for purposes of this account, a suspension of E. coli. After perfusion fixation the kidneys are removed and a block of tissue containing the extrapapillary portion of the nephron is excised. This block is cut into thin slices parallel to the surface of the kidney; these are embedded in plastic for subsequent sectioning. On sectioning, the marker material makes the nephron in question readily discernible under the microscope. A major advantage of this technique is that it allows the tubule of interest to be located as much as 48 hours later.

Application of established pathophysiologic processes brings greater clarity to diagnosis and treatment of hyponatremia

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.

Atypical Presentations of Diabetic Nephropathy and Novel Therapies

Diabetes mellitus is a leading cause of end stage renal failure and contributes to a diffuse arteriolopathy. Diabetic nephropathy (DN) has been typically characterized by progressive proteinuria associated with progressive renal insufficiency. However this typical pattern of DN and proteinuria may be inadequate for a complete definition of DN. While glucotoxicity has been classically considered to be the agent of renal injury, other “atypical” mediators of renal injury also contribute. In addition, the renal pathologic changes can also be atypical for a sizable population of diabetics. The dissociation of albuminuria from declining glomerular filtration rate and even from the renal pathologic changes suggests alternative mechanisms are responsible for renal injury. Diabetes could be considered a chronic inflammatory disease with nephropathy resulting from the interplay of inflammatory mediators and the immune system. There are other unusual or “atypical” associations of the kidney and diabetes, which will be discussed in this chapter.