Urea-induced Osmotic Diuresis Research Articles

THU112 Effect Of Protein Supplementation On Plasma Sodium Levels And Urinary Urea Excretion In Patients With Chronic Siad—A Monocentric Open-Label Proof-Of-Concept Study—The Treasure Study

Abstract Disclosure: S. Monnerat: None. C. Atila: None. F.E. Baur: None. M. Dickenmann: None. M. Christ-Crain: None. INTRODUCTION The syndrome of inappropriate antidiuresis (SIAD) is the most common cause of euvolemic hyponatremia. Besides fluid restriction, increasing free-water clearance is an effective treatment approach that can be achieved through osmotic diuresis by administering oral urea. However, oral urea has a very peculiar taste that impedes long-term compliance. Dietary proteins are metabolized into soluble excretable urea by the liver. We hypothesized that dietary protein could increase free water clearance through urea-induced osmotic diuresis and therefore aimed to investigate the effect of high-protein supplementation on plasma sodium levels in outpatients with chronic SIAD. METHODS This is an interim analysis of a monocentric open-label proof-of-concept trial conducted at the University Hospital of Basel since October 2021. Adult outpatients with chronic SIAD of any etiology were eligible. Patients received 90g protein daily for 7 days in the form of protein powder dissolved in a maximum of 1L of liquid of choice. After a wash-out period of at least a week, patients received 30g of oral urea daily for 7 days. Patients were asked to keep their baseline fluid intake unchanged throughout the study. The primary endpoint was the increase in sodium levels from baseline to the end of the 7-day protein supplementation. RESULTS Thirteen patients, 10 females and 3 males, with chronic SIAD were included. Median [IQR] age was 63 [61, 80] and the median [IQR] duration of hyponatremia was 33 months [12, 42]. At baseline, median [IQR] plasma sodium concentration was 130 mmol/L [129, 133]. Eight patients had mild hyponatremia (130-134 mmol/L), 4 had moderate hyponatremia (125-129 mmol/L), and 1 patient had profound hyponatremia (<125 mmol/L). After 7 days of 90g daily protein supplementation (n = 13), sodium levels increased by a median [IQR] of 3 mmol/L [0, 5], blood urea nitrogen increased by a median [IQR] of 4.3 mmol/L [1.7, 5.1] and urinary urea corrected for urine creatinine increased by a median [IQR] of 26.0 mmol/mmol [17.1, 32.3]. After 7 days of oral urea (n = 8), sodium levels increased by a median [IQR] of 2 mmol/L [1, 3], blood urea nitrogen increased by a median [IQR] of 8.5 mmol/L [3.8, 10.2] and urinary urea corrected for urine creatinine increased by a median [IQR] of 31 mmol/mmol [21.1, 39.8]. CONCLUSION This interim analysis suggests that high-protein supplementation with protein powder increases plasma sodium levels in patients with chronic SIAD. The increase in urea concentration in both plasma and urine upon protein supplementation is comparable to the increase upon oral urea administration, which supports protein-induced ureagenesis to be the underlying mechanism of action. Presentation: Thursday, June 15, 2023

ICU-Acquired Hypernatremia Is Associated with Persistent Inflammation, Immunosuppression and Catabolism Syndrome.

Developing hypernatremia while on intensive care unit (ICU) is a common problem with various undesirable effects. A link to persistent inflammation, immunosuppression and catabolism syndrome (PICS) can be established in two ways. On the one hand, hypernatremia can lead to inflammation and catabolism via hyperosmolar cell stress, and on the other, profound catabolism can lead to hypernatremia via urea-induced osmotic diuresis. In this retrospective single-center study, we examined 115 patients with prolonged ICU stays (≥14 days) and sufficient renal function. Depending on their serum sodium concentrations between ICU day 7 and 21, allocation to a hypernatremic (high) and a nonhypernatremic group (low) took place. Distinct signs of PICS were detectable within the complete cohort. Thirty-three of them (28.7%) suffered from ICU-acquired hypernatremia, which was associated with explicitly higher signs of inflammation and ongoing catabolism as well as a prolonged ICU length of stay. Catabolism was discriminated better by the urea generation rate and the urea-to-creatinine ratio than by serum albumin concentration. An assignable cause for hypernatremia was the urea-induced osmotic diuresis. When dealing with ICU patients requiring prolonged treatment, hypernatremia should at least trigger thoughts on PICS as a contributing factor. In this regard, the urea-to-creatinine ratio is an easily accessible biomarker for catabolism.

Could Evening Dietary Protein Intake Play a Role in Nocturnal Polyuria?

Urea is the most abundant and the largest contributing factor for urine osmolality. Urinary urea excretion is highly interrelated with dietary protein intake. Accordingly, an increase of urinary urea excretion due to high protein diet may lead to urea-induced osmotic diuresis. This study aims to explore the association between nocturnal polyuria (NP) and urea. This is a post hoc analysis of a prospective observational study of subjects who completed a renal function profile between October 2011 and February 2015 (n = 170). Each subject underwent a 24 h urine collection, which included 8 urine samples collected at 3 h intervals. Urine volume, osmolality, creatinine, urea and sodium were determined. Urinary urea excretion was used to estimate dietary protein intake. Compared to the control group, subjects with NP exhibited significantly higher nighttime urea and sodium excretion. Estimated evening dietary protein intake was correspondingly significantly higher amongst the NP subgroup. Nighttime diuresis rate was positively associated with age and nighttime free water clearance, creatinine clearance, sodium excretion, and urea excretion in NP subjects. Therefore, increased nocturnal urinary urea excretion may reflect an additional important mediator of nocturia owing to excess nocturnal urine production.

Hypernatremia due to Urea-Induced Osmotic Diuresis: Physiology at the Bedside.

Hypernatremia secondary to urea-induced solute diuresis is due to the renal excretion of electrolyte-free water. This concept is explained here step-wise physiologically with the help of a clinical vignette.

Urea transporter knockout mice and their renal phenotypes.

Urea transporter gene knockout mice have been created for the study of the urine-concentrating mechanism. The major findings in studies of the renal phenotype of these mice are as follows: (1) Urea accumulation in the inner medullary interstitium is dependent on intrarenal urea recycling mediated by urea transporters; (2) urea transporters are essential for preventing urea-induced osmotic diuresis and thus for water conservation; (3) NaCl concentration in the inner medullary interstitium is not significantly affected by the absence of IMCD, descending limb of Henle and descending vasa recta urea transporters. Studies in urea transporter knockout mouse models have highlighted the essential role of urea for producing maximally concentrated urine.

Urea may regulate urea transporter protein abundance during osmotic diuresis.

Rats with diabetes mellitus have an increase in UT-A1 urea transporter protein abundance and absolute urea excretion, but the relative amount (percentage) of urea in total urinary solute is actually decreased due to the marked glucosuria. Urea-specific signaling pathways have been identified in mIMCD3 cells and renal medulla, suggesting the possibility that changes in the percentage or concentration of urea could be a factor that regulates UT-A1 abundance. In this study, we tested the hypothesis that an increase in a urinary solute other than urea would increase UT-A1 abundance, similar to diabetes mellitus, whereas an increase in urine urea would not. In both inner medullary base and tip, UT-A1 protein abundance increased during NaCl- or glucose-induced osmotic diuresis but not during urea-induced osmotic diuresis. Next, rats undergoing NaCl or glucose diuresis were given supplemental urea to increase the percentage of urine urea to control values. UT-A1 abundance did not increase in these urea-supplemented rats compared with control rats. Additionally, both UT-A2 and UT-B protein abundances in the outer medulla increased during urea-induced osmotic diuresis but not in NaCl or glucose diuresis. We conclude that during osmotic diuresis, UT-A1 abundance increases when the percentage of urea in total urinary solute is low and UT-A2 and UT-B abundances increase when the urea concentration in the medullary interstitium is high. These findings suggest that a reduction in urine or interstitial urea results in an increase in UT-A1 protein abundance in an attempt to restore inner medullary interstitial urea and preserve urine-concentrating ability.

Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct.

To investigate the role of inner medullary collecting duct (IMCD) urea transporters in the renal concentrating mechanism, we deleted 3 kb of the UT-A urea transporter gene containing a single 140-bp exon (exon 10). Deletion of this segment selectively disrupted expression of the two known IMCD isoforms of UT-A, namely UT-A1 and UT-A3, producing UT-A1/3(-/-) mice. In isolated perfused IMCDs from UT-A1/3(-/-) mice, there was a complete absence of phloretin-sensitive or vasopressin-stimulated urea transport. On a normal protein intake (20% protein diet), UT-A1/3(-/-) mice had significantly greater fluid consumption and urine flow and a reduced maximal urinary osmolality relative to wild-type controls. These differences in urinary concentrating capacity were nearly eliminated when urea excretion was decreased by dietary protein restriction (4% by weight), consistent with the 1958 Berliner hypothesis stating that the chief role of IMCD urea transport in the concentrating mechanism is the prevention of urea-induced osmotic diuresis. Analysis of inner medullary tissue after water restriction revealed marked depletion of urea in UT-A1/3(-/-) mice, confirming the concept that phloretin-sensitive IMCD urea transporters play a central role in medullary urea accumulation. However, there were no significant differences in mean inner medullary Na(+) or Cl(-) concentrations between UT-A1/3(-/-) mice and wild-type controls, indicating that the processes that concentrate NaCl were intact. Thus, these results do not corroborate the predictions of passive medullary concentrating models stating that NaCl accumulation in the inner medulla depends on rapid vasopressin-regulated urea transport across the IMCD epithelium.

Effects of chronic, urea-induced osmotic diuresis on kidney weight and function in rats

To study the effects of chronic osmotic diuresis which were not associated with hyperglycaemia on the rat kidney, osmotic diuresis was induced by i.v. infusion of urea. A 5 mol/l urea solution was continuously infused at a rate of 100 ml.kg-1 x day-1 on the basis of body weight on day 0. Duration of infusion was 2, 6, 10 or 14 days. Control rats received continuously infused Ringer's solution. Urea-treated groups developed osmotic diuresis (urine flow = about 0.04 ml.min-1 x 100 g body weight-1) comparable to that in rats with experimental diabetes mellitus induced by i.v. streptozotocin (55 mg/kg), however urea-induced osmotic diuresis was not associated with blood glucose level increases. Compared with their controls, rats receiving urea for 2-14 days had markedly increased kidney weight. Rats receiving urea for 10 days showed greatest kidney weight increase, 0.565 +/- 0.044 g/100 g body weight (mean +/- SD), representing a 53% increase compared with the control (0.369 +/- 0.034 g/100 g body weight). Kidney weight was associated with increases in kidney protein content. In contrast, none of control kidney weight values differed significantly from day 0 values (= normal rats; 0.387 +/- 0.028 g/100 g body weight). Creatinine clearance values in urea-treated groups were also higher than those in controls. The maximum value, 0.65 +/- 0.17.ml-min-1 x 100 g body weight-1, was recorded in the 14-day group and was significantly higher than the corresponding control value (0.34 +/- 0.07 ml.min-1 x 100 g body weight-1) (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of chronic, urea-induced osmotic diuresis on kidney weight and function in rats

Effects of chronic, urea-induced osmotic diuresis on kidney weight and function in rats

The Acid Truth and Basic Facts—With a Sweet Touch, an EnLYTEnment

This deLYTEful ring-bound handbook stands out clearly among the many texts and learning aids that attempt to teach us and our students more about renal and electrolyte disturbances. Dr Mitchell Halperin's expertise in this field is widely acknowledged and is only equaled by his enthusiasm in teaching others concepts he has perceived in the mass of laboratory data that is modern medicine. Each of the text's six chapters has pearls of wisdom, clinical classifications and syndromes, and, finally, elements of differential diagnosis. Each chapter is accompanied by at least one clinical case applicable to the metabolic abnormality discussed, eg, hypernatremia after a skull fracture in a patient who, after all, did not have diabetes insipidus but, rather, urea-induced osmotic diuresis. Both at the beginning of the book and at intervals thereafter, Halperin defines and discusses the transtubular potassium gradient (TTKG), with emphasis on practicality. The TTKG reflects urine potassium/plasma potassium

Micropuncture study of effects of urea infusion in tubular reabsorption in the rat.

ARTICLESMicropuncture study of effects of urea infusion in tubular reabsorption in the ratML Kauker, WE Lassiter, and CW GottschalkML Kauker, WE Lassiter, and CW GottschalkPublished Online:01 Jul 1970https://doi.org/10.1152/ajplegacy.1970.219.1.45MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByMild Chronic Hyponatremia in the Ambulatory SettingClinical Journal of the American Society of Nephrology, Vol. 10, No. 12Diuretics: a review10 July 2012 | Annals of Clinical Biochemistry: International Journal of Laboratory Medicine, Vol. 49, No. 5Effects of chronic, urea-induced osmotic diuresis on kidney weight and function in ratsDiabetologia, Vol. 37, No. 3Renal Handling of Urea1 January 2011Renal tubular transport of 3H-digoxin in saline diuresis in rats.Circulation Research, Vol. 38, No. 3Factors influencing sodium and water excretion in uremic manKidney International, Vol. 7, No. 2Defect in proximal and distal sodium transport in post-obstructive diuresisKidney International, Vol. 2, No. 6Alterations in renal tubular sodium and water reabsorption in chronic renal disease in manKidney International, Vol. 2, No. 3Glomerular filtration changes during renal artery infusion of various hypertonic solutions in the dogPfl�gers Archiv European Journal of Physiology, Vol. 337, No. 1FUNCTIONAL ASPECTS OF COMPENSATORY RENAL GROWTHPharmaceutical Sciences—1970: Literature Review of PharmaceuticsJournal of Pharmaceutical Sciences, Vol. 60, No. 7The relation between the reabsorption of urea and of water in the distal tubule of the rat kidneyPfl�gers Archiv European Journal of Physiology, Vol. 329, No. 2 More from this issue > Volume 219Issue 1July 1970Pages 45-50 Copyright & PermissionsCopyright © 1970 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1970.219.1.45PubMed5424857History Published online 1 July 1970 Published in print 1 July 1970 Metrics

Micropuncture studies of the recovery phase of myohemoglobinuric acute renal failure in the rat.

Micropuncture studies of the recovery phase of glycerol-induced myohemoglobinuric acute renal failure were performed in rats whose blood urea nitrogen (BUN) had fallen at least 20% below its peak value. The glomerular filtration rate (GFR) of individual nephrons in a single kidney in the recovery period generally either was in the normal range or minimal. Each animal's BUN concentration at the time of the study was inversely related to the proportion of functioning surface nephrons, but did not correlate with individual nephron GFR values. Proximal tubule fractional water absorption was significantly depressed as manifested by both depressed inulin (TF/P) values and supernormal volumes of collections, a finding which, in the absence of a urea-induced osmotic diuresis, suggests impaired sodium transport by the damaged nephron. The mean proximal tubule hydrostatic pressure in recovery was normal and there was little variation in pressure among functioning nephrons. It is concluded that recovery from this model of acute renal failure reflects the progressive recruitment of increasing numbers of functioning nephrons. The recovery of individual nephron glomerular filtration, once begun, was rapid and complete. No evidence could be adduced that the gradual return of renal function towards normal reflects a slow release of tubular obstruction or repair of disrupted tubular epithelium. Rather, recovery appeared to be directly attributable to the return of an adequate effective glomerular filtration pressure. Significant limitation in proximal tubule water absorption persisted after individual nephron GFR had returned to normal or supernormal values in this model of experimental acute renal failure in the rat, a finding which readily accounts for the diuresis associated with the recovery phase of this syndrome.