Renal health in horses encompasses the study of kidney function, disorders, and their management in equine species. The kidneys are vital organs responsible for filtering waste products from the blood, regulating fluid balance, and maintaining electrolyte levels. Renal disorders in horses can arise from various causes, including dehydration, toxins, infections, and congenital abnormalities. Common conditions affecting equine renal health include acute kidney injury and chronic kidney disease. Diagnostic methods often involve blood tests, urinalysis, and imaging techniques to assess kidney function and structure. This page gathers peer-reviewed research studies and scholarly articles that explore the physiology, pathology, and therapeutic approaches related to renal health in horses.
Zapata GL, Britos RM, Pintos ME, Dreizzen E, Lausada NB, Arauz S.The objective of this paper was to determine the physiological values of urea nitrogen and creatinine in tears, and to compare the results with those obtained from serum. Thirty healthy thoroughbred horses were included in the study. Tear fluid samples were obtained using a glass capillary tube placed in lower conjunctival cul-de-sac. Blood samples were taken from the jugular vein. Tear and serum urea nitrogen and creatinine levels were quantitatively analyzed by an enzymatic colorimetric method. Urea nitrogen values were 4.22+/-1.84 mmol/l in tears and 4.44+/-1.78 mmol/l in serum, whereas cre...
Meyer C, Guthrie AJ, Stevens KB.Haematological variables and selected serum indices, particularly those affected by changes in renal and hepatic function, were examined in 6 healthy ponies following 4 intramuscular doses of 4 mg/kg imidocarb dipropionate administered every 72 hours. This treatment regime has been reported to sterilise experimental Babesia equi infections in horses and may have value in preventing the spread of this disease during exportation of possible carrier horses to non-endemic countries. Serum bile acids and serum gamma glutamyltransferase activity were measured to evaluate the effect of this treatment...
Gallatin LL, Couëtil LL, Ash SR.A 15-year-old Paso Fino gelding was evaluated because of acute renal failure following an episode of exertional rhabdomyolysis. The horse was azotemic and treated conservatively at another referral practice with no improvement in the azotemia. With conservative treatment and intermittent peritoneal dialysis, the horse had minimal improvement. Continuous-flow peritoneal dialysis (CFPD) was instituted on day 7 and continued for 3 consecutive days. Dramatic changes in the horse's attitude and serum creatinine concentration were detected within the first 24 hours of CFPD treatment. The horse remai...
van der Harst MR, Bull S, Laffont CM, Klein WR.The aminoglycoside gentamicin is often used in equine practice. Despite its clinical use, concerns remain regarding the potential toxic side-effects, such as nephrotoxicity, in equine patients, particularly after repeated dosing. The aim of the study was to investigate first in vitro the mechanisms contributing to the renal toxicity of gentamicin and to identify sensitive biomarkers indicating proximal tubule damage. To this end, the kidney-derived cell lines LLC-PKI and MDCK were treated with gentamicin at different concentrations. Toxicity was assessed by measuring the release of gamma-gluta...
Mitchell KJ, Dowling BA, Hughes KJ, Dart AJ.A 2-day-old Warmblood colt foal was referred for evaluation of progressive abdominal distension and lethargy. Haemoperitoneum was diagnosed and a ventral midline laparotomy revealed capsular rupture, sub capsular haematoma and haemorrhage of the left kidney. Unilateral nephrectomy was performed and the foal recovered uneventfully, with no reported complications 1 year later.
Johansson AM, Gardner SY, Levine JF, Papich MG, Lafevers DH, Goldman RB, Sheets MK, Atkins CE.Furosemide is the most common diuretic drug used in horses. Furosemide is routinely administered as IV or IM bolus doses 3-4 times a day. Administration PO is often suggested as an alternative, even though documentation of absorption and efficacy in horses is lacking. This study was carried out in a randomized, crossover design and compared 8-hour urine volume among control horses that received placebo, horses that received furosemide at 1 mg/kg PO, and horses that received furosemide at 1 mg/kg IV. Blood samples for analysis of plasma furosemide concentrations, PCV, and total solids were obta...
Bosken JM, Tobin T, Mundy GD, Fisher M, Gantz MG, Banks RO.Postrace urine samples from thoroughbred horses were examined to compare osmolality and specific gravity between horses treated with furosemide and those not treated. Samples were assigned to groups in relation to reported medication (furosemide) status, race finish position, and distance of race. Urine osmolality was significantly (P <.05) lower in samples from horses treated with furosemide when compared with untreated horses. Specific gravity determinations are less precise at measuring urine osmolality at lower levels (1.01 g/ml or less). The measurement of osmolality is a superior meth...
Magdesian KG, Wilson WD, Mihalyi J.To determine disposition kinetics of amikacin in neonatal foals administered high doses at extended intervals. Methods: 7 neonatal foals. Methods: Amikacin was administered (21 mg/kg, i.v., q 24 h) for 10 days. On days 1, 5, and 10, serial plasma samples were obtained for measurement of amikacin concentrations and determination of pharmacokinetics. Results: Mean +/- SD peak plasma concentrations of amikacin extrapolated to time 0 were 103.1 +/- 23.4, 102.9 +/- 9.8, and 120.7 +/- 17.9 microg/mL on days 1, 5, and 10, respectively. Plasma concentrations at 1 hour were 37.5 +/- 6.7, 32.9 +/- 2.6, ...
Gonda KC, Wilcke JR, Crisman MV, Ward DL, Robertson JL, Finco DR, Braselton WE.To determine whether pharmacokinetic analysis of data derived from a single i.v. dose of iohexol could be used to predict creatinine clearance and evaluate simplified methods for predicting serum clearance of iohexol with data derived from 2 or 3 blood samples in clinically normal foals. Methods: 10 healthy foals. Methods: Serum disposition of iohexol and exogenous creatinine clearance was determined simultaneously in each foal (5 males and 5 females). A 3-compartment model of iohexol serum disposition was selected via standard methods. Iohexol clearance calculated from the model was compared ...
Johansson AM, Gardner SY, Levine JF, Papich MG, LaFevers DH, Fuquay LR, Reagan VH, Atkins CE.Continuous rate infusion (CRI) of furosemide in humans is considered superior to intermittent administration (IA). This study examined whether furosemide CRI, compared with IA, would increase diuretic efficacy with decreased fluid and electrolyte fluctuations and activation of the renin-angiotensin-aldosterone system (RAAS) in the horse. Five mares were used in a crossover-design study. During a 24-hour period, each horse received a total of 3 mg/kg furosemide by either CRI (0.12 mg/kg/h preceded by a loading dose of 0.12 mg/kg IV) or IA (1 mg/kg IV q8h). There was not a statistically signific...
Keoughan CG, Rodgerson DH, Brown MP.To describe a hand-assisted, laparoscopic technique to remove the left kidney in standing horses. Methods: Prospective evaluation. Methods: Eight horses. Methods: Food was withheld for a minimum of 12 hours. Horses were sedated with detomidine hydrochloride (0.01-0.02 mg/kg, intravenously) and restrained in standing stocks. The left paralumbar fossa was prepared for surgery, and the surgical site was infiltrated with 2% mepivacaine. Hand-assisted, laparoscopic removal of the left kidney was performed through an incision in the center of the paralumbar fossa; the surgeon's hand was used to isol...
Estepa JC, Garfia B, Gao PR, Cantor T, Rodriguez M, Aguilera-Tejero E.Parathyroid hormone (PTH) plays a critical role in the regulation of mineral metabolism in mammals. Until recently, the standard method for PTH measurement has been the 2nd generation intact-PTH (I-PTH) assay. Current evidence indicates that the I-PTH assay binds to the PTH molecule and to an inactive N-terminally truncated PTH fragment that tends to accumulate in the blood of uraemic patients. Therefore, a new 3rd generation PTH assay that detects only the whole PTH molecule (W-PTH; cyclase-activating PTH [CAP]) has been developed. Objective: To validate this more specific W-PTH assay for mea...
McKenzie EC, Valberg SJ, Godden SM, Pagan JD, Carlson GP, MacLeay JM, DeLaCorte FD.To determine daily variation in urinary clearance and fractional excretion (FE) of electrolytes and minerals within and between horses and to compare volumetric and single-sample urine collection for determining FE values of diets with a range of dietary cation-anion balance (DCAB). Methods: 5 Thoroughbred and 6 mixed-breed mares. Methods: 3 isocaloric diets with low, medium, and high DCAB values (85, 190, and 380 mEq/kg of dry matter, respectively) were each fed for 14 days. Daily blood samples, single urine samples collected by using a urinary catheter (5 mares), and volumetric urine collect...
O'Connor SJ, Fowden AL, Holdstock N, Giussani DA, Forhead AJ.Angiotensin-converting enzyme (ACE) has an active role in the control of blood pressure and body fluid homeostasis both before and after birth. This study investigated the ontogeny of pulmonary and renal ACE concentrations in fetal and neonatal horses. Fetal pulmonary ACE concentration increased from 250 days towards term (c. 335 days). Newborn foals showed significantly higher mean concentrations of pulmonary ACE (4.40 +/- 0.62 nmol min(-1) mg protein(-1)) than both fetuses during late gestation (1.23 +/- 0.51 nmol min(-1) mg protein(-1)) and animals aged 1 day to 2 weeks of postnatal age (0....
Aleman M, Gillis CL, Nieto JE, Renaudin CD, Bea J.Knowledge of normal renal parameters, as documented in mature horses, is essential for the accurate evaluation of abnormal kidneys. Although the ultrasonographic appearance and location of the abdominal organs in foals and the renal dimensions in neonates have been reported, there is currently no information available for the assessment of normal organ growth in foals. The objectives of the study were to describe the ultrasonographic characteristics, location and variations of the thoracic and abdominal organs with relation to age, height and weight; and provide a growth table for comparison w...
Driessen B, Zarucco L, Steffey EP, McCullough C, Del Piero F, Melton L, Puschner B, Stover SM.The volatile anaesthetic sevoflurane is degraded to fluoride (F-) and a vinyl ether (Compound A), which have the potential to harm kidney and liver. Whether renal and hepatic injuries can occur in horses is unknown. Cardiopulmonary, biochemical and histopathological changes were studied in six healthy thoroughbred horses undergoing 18 h of low-flow sevoflurane anaesthesia. Serum F- concentrations were measured and clinical laboratory tests performed to assess hepatic and renal function before and during anaesthesia. Necropsy specimens of kidney and liver were harvested for microscopic examinat...
Zeyner A, Kirbach H, Fürll M.Feeding a high-fat diet may have potential advantages by maintaining pH homeostasis during intense exercise; conversely, effects including elevated PCV and increased plasma concentration of total protein may indicate effects detrimental to performance by reducing perfusion of tissues and organs. Six horses were used to determine the effects of an replacement of starch (diet '0.00') with 0.33, 0.67, 1.00 and 1.33 g soybean oil/kg bwt/day (diets '033', '0.67', '1.00' and '1.33') on venous and renal acid-base status and fractional clearance (FC) of electrolytes in a postprandial state but prior t...
McKeever KH, Scali R, Geiser S, Kearns CF.The purpose of the present study was to determine whether the training-induced hypervolaemic response seen in the horse is associated with aldosterone-mediated renal mechanisms affecting sodium conservation during the first days of training. Five healthy, Standardbred mares (weight 450-500 kg, age 4-8 years) that were unfit, but accustomed to running on the treadmill, were used to test the hypothesis that repeated submaximal exercise would alter plasma aldosterone (ALDO) concentration and renal excretion of electrolytes in horses within the first 3 days of training. The experiment consisted of...
Belgrave RL, Hines MT, Keegan RD, Wardrop KJ, Bayly WM, Sellon DC.The development of ultrapurified hemoglobin-based oxygen carriers has eliminated many problems associated with whole-blood transfusions in other species. We hypothesized that the administration of polymerized ultrapurified bovine hemoglobin (PUBH) would result in improved hemodynamic parameters in ponies with normovolemic anemia without adverse effects on renal function or coagulation times. Normovolemic anemia was induced in 6 healthy adult ponies. Over a 3-day period, at least 45 mL/kg of whole blood was withdrawn from each pony until a target PCV of <12% was attained. Plasma was separate...
Watson ZE, Steffey EP, VanHoogmoed LM, Snyder JR.To characterize the effect of general anesthesia and minor surgery on renal function in horses. Methods: 9 mares with a mean (+/- SE) age and body weight of 9+/-2 years and 492+/-17 kg, respectively. Methods: The day before anesthesia, urine was collected (catheterization) for 3 hours to quantitate baseline values, and serum biochemical analysis was performed. The following day, xylazine (1.1 mg/kg, IV) was administered, and general anesthesia was induced 5 minutes later with diazepam (0.04 mg/kg, IV) and ketamine (2.2 mg/kg, IV). During 2 hours of anesthesia with isoflurane, Paco2 was maintai...
Cohen ND, Peck KE, Smith SA, Ray AC.The distribution of specific gravity values for 2,599 urine samples collected from racing Thoroughbred horses that were known to have received furosemide prior to racing was compared with that for 1,669 urine samples from racing Thoroughbred horses that reportedly had not received furosemide. Values of specific gravity for furosemide-treated horses were significantly lower (P < 0.001) than those for horses that had not received furosemide, and the proportion of horses with urine specific gravity either <1.010 or <1.012 was significantly greater (P < 0.001) among the furosemide-trea...
Kisthardt KK, Schumacher J, Finn-Bodner ST, Carson-Dunkerley S, Williams MA.Case records of 7 horses diagnosed with pyelonephritis were reviewed to determine common features that might aid in diagnosis, treatment, and prognosis of this disease. All 7 horses had been admitted for evaluation of hematuria. During cystoscopy of 5 horses, hemorrhage was observed from one or both ureters. Renal biopsy of 1 horse, laboratory analysis of ureteral discharge of 2 horses, and renal ultrasonography of all horses indicated that pyelonephritis was the cause of hemorrhage. Sonographic renal changes included decreased length, increased echogenicity, abnormal outline, loss of corticom...
Erkert RS, Macallister CG.Isoxsuprine hydrochloride has been suggested for use in horses for treatment of navicular syndrome and laminitis. The drug has been shown to be a beta-adrenoreceptor antagonist with beta-adrenoreceptor agonistic properties, with both characteristics contributing to vasodilation and uterine relaxation. In addition, the drug is capable of decreasing blood viscosity and platelet aggregation. Studies have shown i.v. isoxsuprine to have a plasma half-life of <3 h with a large apparent volume of distribution. Cardiovascular effects resolve rapidly following i.v. administration, but are absent wit...
Morisset S, Hawkins JF, Frank N, Sojka JE, Berg D, Blevins WE.A 2-day-old male foal developed uroperitoneum. Initial exploration of the abdomen via ventral midline celiotomy failed to localize the source of uroperitoneum. Bilateral nephropyelocentesis and antegrade urography were performed, and a defect in the right ureter and stenosis of the left ureter were identified. With the foal in dorsal recumbency in the Trendelenburg position, ureterorrhaphy was performed on the right ureter. After ureterorrhaphy, a ureteral catheter was maintained as a stent. The stenotic left ureter was transected, and ureteroneocystostomy was performed using a drop-in mucosal...
Casteel SW.The ubiquity and stability of metals in the environment make them unique as a pollutant or an essential dietary component. Metals are neither created nor destroyed by chemical processes but are redistributed in the environment. In combination with other elements, metal compounds and alloys are essential materials of the contemporary world. Inappropriate use or distribution in the environment leads to adverse health effects on all biologic systems, including horses. Gastrointestinal upset is a common feature of acute toxicosis with metals in general. Among the metals discussed, arsenic and inor...
Saam D.A 9-year-old, quarter horse gelding with obstructive urethrolithiasis was treated with a perineal urethrostomy. The horse's condition deteriorated and abdominocentesis confirmed septic uroperitonitis. The horse was euthanized and postmortem examination revealed peritonitis, a tear in the lateral wall of the bladder, and a nephrolith within the left renal pelvis.
Erkert RS, Macallister CG.Isoxsuprine hydrochloride has been suggested for use in horses for treatment of navicular syndrome and laminitis. The drug has been shown to be a beta-adrenoreceptor antagonist with beta-adrenoreceptor agonistic properties, with both characteristics contributing to vasodilation and uterine relaxation. In addition, the drug is capable of decreasing blood viscosity and platelet aggregation. Studies have shown i.v. isoxsuprine to have a plasma half-life of <3 h with a large apparent volume of distribution. Cardiovascular effects resolve rapidly following i.v. administration, but are absent wit...
Ruoff WW, Sams RA.The pharmacokinetics and bioavailability of cephalothin given to 6 horse mares at a dosage level of 11 mg/kg of body weight IV or IM were investigated. The disposition of cephalothin given IV was characterized by a rapid disposition phase with a mean half-life of 2.89 minutes and a subsequent slower elimination phase with a mean half-life of only 14.7 minutes. The mean residence time of cephalothin was 10.6 +/- 2.11 minutes. The total plasma clearance of cephalothin averaged 13.6 ml/min/kg and was caused by metabolism and renal elimination. Renal clearance of cephalothin averaged 1.32 ml/min/k...
Bolat D, Bahar S, Tipirdamaz S, Selcuk ML.The aims of this study were to determine the total volume of the horse kidney and volume fractions of its functional subcomponents (cortex, medulla, renal pelvis) using stereological methods and investigate any possible difference in the functional subcomponents of the right and left kidneys that may arise from differences in shape. The study was carried out on the kidneys of 5 horses of different breed and sex. The weight of the kidneys was measured by a digital scale, and kidney volume was calculated by Archimedes' principle. Total kidney volume and volume fractions of subcomponents of the r...
Kohn CW, Strasser SL.Urine samples were obtained from 6 healthy mares. During a 2-day acclimation period, mares were kept in stalls, fed sweet feed and mixed grass hay, and allowed free access to water and trace mineral salt. The mares were crosstied in their stalls within reach of hay, salt, and water for 24 hours during which urine was obtained by constant flow via indwelling Foley catheters. Twenty-four-hour urine production was 7,649 to 11,904 ml/day (mean = 9,212 +/- 1,9285) or 14.7 to 25.1 mlĝ/day. (mean = 19.3 +/- 4.1). Urinary excretion and clearance of electrolytes and protein were determined from aliquo...
Habershon-Butcher J, Bowen M, Hallowell G.A reliable method for obtaining renal ultrasonographic measurements in the horse is important for diagnosis and monitoring of clinical renal disease. The aims of this prospective study were to develop and validate a novel translumbar ultrasound technique for measuring renal dimensions in horses. Six Thoroughbred or Thoroughbred part bred horses were recruited. All horses were scheduled for euthanasia due to reasons unrelated to the kidneys. Two observers recorded renal length, width, and depth; and dimensions of the cortex, medulla, pyramids, and pelvis for both kidneys in each horse using nov...
Johansson AM, Gardner SY, Levine JF, Papich MG, Lafevers DH, Goldman RB, Sheets MK, Atkins CE.Furosemide is the most common diuretic drug used in horses. Furosemide is routinely administered as IV or IM bolus doses 3-4 times a day. Administration PO is often suggested as an alternative, even though documentation of absorption and efficacy in horses is lacking. This study was carried out in a randomized, crossover design and compared 8-hour urine volume among control horses that received placebo, horses that received furosemide at 1 mg/kg PO, and horses that received furosemide at 1 mg/kg IV. Blood samples for analysis of plasma furosemide concentrations, PCV, and total solids were obta...
Johansson AM, Gardner SY, Levine JF, Papich MG, LaFevers DH, Fuquay LR, Reagan VH, Atkins CE.Continuous rate infusion (CRI) of furosemide in humans is considered superior to intermittent administration (IA). This study examined whether furosemide CRI, compared with IA, would increase diuretic efficacy with decreased fluid and electrolyte fluctuations and activation of the renin-angiotensin-aldosterone system (RAAS) in the horse. Five mares were used in a crossover-design study. During a 24-hour period, each horse received a total of 3 mg/kg furosemide by either CRI (0.12 mg/kg/h preceded by a loading dose of 0.12 mg/kg IV) or IA (1 mg/kg IV q8h). There was not a statistically signific...
McKeever KH, Hinchcliff KW, Schmall LM, Muir WW.Exercise-induced changes in renal function were examined during steady-state submaximal treadmill exercise in six unfit mares. Horses were randomly assigned to either an exercise or parallel control (no exercise) trial on day 1 and the alternate trial 1 wk later. The mares ran on a treadmill, set at a 6 degrees incline, for 1 h at 55-60% of maximal heart rate. Exercise significantly (P less than 0.05) increased plasma osmolality, plasma [K+], urine flow (+ 45%), Na+ excretion (+ 371%), K+ excretion (+ 57%), osmotic clearance (+ 32%), Na+ clearance (+ 391%), K+ clearance (+ 33%), and fractional...
Lewis N, Racklyeft DJ.The clinical course of toxic envenomation of a mare and her foal after an attack by a swarm of bees in the Upper Hunter Valley of New South Wales is described. Early agitation and urticaria were followed by more severe systemic clinical signs within 18 h. There was severe, generalised angioedema, rhabdomyolysis, hypovolaemia, gastrointestinal stasis and renal injury. A particular feature in the mare was almost maniacal behaviour during the first 48 h. Clinical pathological examination showed evidence of haemoconcentration, intravascular haemolysis, thrombocytopenia, azotaemia, rhabdomyolysis a...
Sprayberry KA, Madigan J, LeCouteur RA, Valentine BA.A Thoroughbred-Percheron crossbred gelding developed a fulminant cascade of sequelae following a severe episode of rhabdomyolysis. Complications may occur with rhabdomyolysis of any etiology. In warmblood horses with Percheron bloodlines, rhabdomyolysis may be secondary to polysaccharide storage disease, and aggressive therapy should be undertaken promptly to avoid the complications.
James K, Pullar DM, Morton JB, Dalton RG, Nolan B, Woodruff MF.Methods are described for the intravenous administration of equine antilymphocytic globulin (ALG) to renal transplant recipients. The development of circulating antibodies to the equine IgG has been investigated using primary and secondary immunological procedures. The need for primary immunoassay procedures to assess both the immune response and induction of tolerance to equine IgG in ALG treated patients is extensively discussed.
Scala E, van Galen G, Skärlina EM, Durie I.Pyelonephritis is a serious condition that is rarely described in horses. In contrast, urinary tract infections are common in humans and small animals, and multi-drug-resistant urinary infections are an emerging threat. In this report, we describe a horse with unilateral pyelonephritis caused by extended-spectrum beta-lactamase-producing bacteria belonging to the Enterobacter cloacae complex. [Correction added on 9 August 2023, after first online publication: The preceding sentence was corrected.] An 11-year-old Swedish warmblood gelding was diagnosed with a cystolith and a cystotomy through a...
Lo HC, Winter JC, Merle R, Gehlen H.Acute dehydration caused by a variety of diseases in horses can lead to acute kidney injury. However, current renal biomarkers usually indicate renal damage late in the course of the disease. A novel biomarker would be helpful to diagnose renal disease earlier. Objective: (1) To estimate the correlation of serum symmetric dimethylarginine (SDMA) concentrations with the degree of dehydration, traditional renal biomarkers and renal function analysis, and (2) to determine the value of SDMA as a prognostic and early biomarker of renal injury in horses. Methods: Prospective cohort. Methods: Serum S...
Sturgeon BP, Bassett H.This research article presents the case of a five-month-old foal showing intense thirst and excessive urination, which was found to be associated with renal helminthiasis – a rare condition characterized […]
Tomlinson JE, Farnsworth K, Sage AM, Turner TA, Wilson JH.Ultrasound-guided percutaneous pyelography has previously been used in dogs to diagnose ectopic ureter. To the authors' knowledge its use has never been reported in the horse. This paper reports the technique used in a three-week-old filly with a suspected ectopic ureter. Pyelography can be performed under sedation and is a relatively simple, safe procedure. The technique enables assessment of individual renal function through collection and analysis of urine from each renal pelvis.
Steffey EP, Giri SN, Dunlop CI, Cullen LK, Hodgson DS, Willits N.Six healthy horses were anaesthetised with halothane (1.2 times the horse minimal alveolar concentration) in oxygen for more than 12 hours. Serum bilirubin, aspartate aminotransferase, alkaline phosphatase and L-iditol dehydrogenase values were significantly (P < 0.05) increased for up to nine days after anaesthesia. These changes suggest an anaesthesia related liver dysfunction. Creatine kinase increased to an average of more than 1400 IU litre-1 24 hours after anaesthesia and this change is indicative of muscle cell disruption. Renal-associated biochemical results, (that is serum creatinine ...
Arroyo LG, Stämpfli HR.Renal tubular disorders have been sporadically reported in horses. Only three types of tubular defects have been recognized: (1) nephrogenic diabetes insipidus, attributable to unresponsiveness of the renal tubules to antidiuretic hormone; (2) distal renal tubular acidosis (RTA; type I); and (3) proximal RTA (type II). The following review focuses on RTA and nephrogenic diabetes insipidus.