Regulation of the expression of the Cl-/anion exchanger pendrin in mouse kidney by acid-base status

BACKGROUND: Pendrin belongs to a superfamily of Cl-/anion exchangers and is expressed in the inner ear, the thyroid gland, and the kidney. In humans, mutations in pendrin cause Pendred syndrome characterized by sensorineural deafness and goiter. Recently pendrin has been localized to the apical side of non-type A intercalated cells of the cortical collecting duct, and reduced bicarbonate secretion was demonstrated in a pendrin knockout mouse model. To investigate a possible role of pendrin in modulating acid-base transport in the cortical collecting duct, we examined the regulation of expression of pendrin by acid-base status in mouse kidney. METHODS: Mice were treated orally either with an acid or bicarbonate load (0.28 mol/L NH4Cl or NaHCO3) or received a K+-deficient diet for one week. Immunohistochemistry and Western blotting was performed. RESULTS: Acid-loading caused a reduction in pendrin protein expression levels within one day and decreased expression to 23% of control levels after one week. Concomitantly, pendrin protein was shifted from the apical membrane to the cytosol, and the relative abundance of pendrin positive cells declined. Similarly, in chronic K+-depletion, known to elicit a metabolic alkalosis, pendrin protein levels decreased and pendrin expression was shifted to an intracellular pool with the relative number of pendrin positive cells reduced. In contrast, following oral bicarbonate loading pendrin was found exclusively in the apical membrane and the relative number of pendrin positive cells increased. CONCLUSIONS: These results are in agreement with a potential role of pendrin in bicarbonate secretion and regulation of acid-base transport in the cortical collecting duct.     

The interaction of pendrin and the epithelial sodium channel in blood pressure regulation

PURPOSE OF REVIEW: This review summarizes the contribution of the Cl-/HCO3- exchanger pendrin in the renal regulation of blood pressure. RECENT FINDINGS: Intercalated cells are found in the distal convoluted tubule, the connecting tubule and the collecting duct. These cells regulate acid-base balance by secreting or absorbing OH-/H- equivalents and regulate vascular volume and blood pressure by absorbing chloride ions. In type B and non-A, non-B intercalated cells chloride absorption and HCO3- secretion are accomplished through the apical sodium-independent Cl-/HCO3- exchanger pendrin. With increased circulating aldosterone, pendrin abundance and transport are upregulated. In the absence of functional pendrin (Slc26a4 (-/-) mice), aldosterone-stimulated chloride absorption is reduced, which attenuates the blood pressure response to this steroid hormone. Pendrin also regulates aldosterone-induced changes in epithelial sodium channel abundance and function through a kidney-specific mechanism that does not involve changes in concentration of a circulating hormone. In vitro, angiotensin II increases sodium chloride absorption in the collecting duct by increasing the driving force for pendrin-mediated chloride absorption and the epithelial sodium channel-mediated sodium absorption through greater electrogenic hydrogen secretion. SUMMARY: Aldosterone and angiotensin II modulate the renal regulation of blood pressure, in part, by regulating pendrin-mediated chloride absorption and the epithelial sodium channel-mediated sodium absorption. Pendrin also modulates stimulation of the epithelial sodium channel by aldosterone.     

Angiotensin II activates H+-ATPase in type A intercalated cells

We reported previously that angiotensin II (AngII) increases net Cl(-) absorption in mouse cortical collecting duct (CCD) by transcellular transport across type B intercalated cells (IC) via an H(+)-ATPase-and pendrin-dependent mechanism. Because intracellular trafficking regulates both pendrin and H(+)-ATPase, we hypothesized that AngII induces the subcellular redistribution of one or both of these exchangers. To answer this question, CCD from furosemide-treated mice were perfused in vitro, and the subcellular distributions of pendrin and the H(+)-ATPase were quantified using immunogold cytochemistry and morphometric analysis. Addition of AngII in vitro did not change the distribution of pendrin or H(+)-ATPase within type B IC but within type A IC increased the ratio of apical plasma membrane to cytoplasmic H(+)-ATPase three-fold. Moreover, CCDs secreted bicarbonate under basal conditions but absorbed bicarbonate in response to AngII. In summary, angiotensin II stimulates H(+) secretion into the lumen, which drives Cl(-) absorption mediated by apical Cl(-)/HCO(3)(-) exchange as well as generates more favorable electrochemical gradient for ENaC-mediated Na(+) absorption.     

Pendrin modulates ENaC function by changing luminal HCO3-

The epithelial Na(+) channel, ENaC, and the Cl(-)/HCO(3)(-) exchanger, pendrin, mediate NaCl absorption within the cortical collecting duct and the connecting tubule. Although pendrin and ENaC localize to different cell types, ENaC subunit abundance and activity are lower in aldosterone-treated pendrin-null mice relative to wild-type mice. Because pendrin mediates HCO(3)(-) secretion, we asked if increasing distal delivery of HCO(3)(-) through a pendrin-independent mechanism "rescues" ENaC function in pendrin-null mice. We gave aldosterone and NaHCO(3) to increase pendrin-dependent HCO(3)(-) secretion within the connecting tubule and cortical collecting duct, or gave aldosterone and NaHCO(3) plus acetazolamide to increase luminal HCO(3)(-) concentration, [HCO(3)(-)], independent of pendrin. Following treatment with aldosterone and NaHCO(3), pendrin-null mice had lower urinary pH and [HCO(3)(-)] as well as lower renal ENaC abundance and function than wild-type mice. With the addition of acetazolamide, however, acid-base balance as well as ENaC subunit abundance and function was similar in pendrin-null and wild-type mice. We explored whether [HCO(3)(-)] directly alters ENaC abundance and function in cultured mouse principal cells (mpkCCD). Amiloride-sensitive current and ENaC abundance rose with increased [HCO(3)(-)] on the apical or the basolateral side, independent of the substituting anion. However, ENaC was more sensitive to changes in [HCO(3)(-)] on the basolateral side of the monolayer. Moreover, increasing [HCO(3)(-)] on the apical and basolateral side of Xenopus kidney cells increased both ENaC channel density and channel activity. We conclude that pendrin modulates ENaC abundance and function, at least in part by increasing luminal [HCO(3)(-)] and/or pH.     

Otosclerosis involving the vestibular aqueduct and Menière's disease

The coexistence of otosclerosis and endolymphatic hydrops in the temporal bone have been described; however, the mechanism for the development of endolymphatic hydrops in otosclerosis remains unknown. Among 128 temporal bones with otosclerosis, involvement of the vestibular aqueduct by otosclerosis was observed in four temporal bones from two patients. In all four, the vestibular aqueduct was filled with active otosclerotic foci; the lumen of the endolymphatic duct and sac was narrowed as a result of fibrosis, and endolymphatic hydrops, more severe in the pars inferior than the pars superior, was observed. Collapse of the ductus reuniens and dilated saccule was seen in three temporal bones. Our study indicates that otosclerotic obstruction of the vestibular aqueduct may create a disturbance of the outflow and/or absorption of endolymph, leading to the development of endolymphatic hydrops and Meniere's disease, thus supporting the theory of longitudinal flow of endolymph.     

Treatment of endolymphatic hydrops with cochleosacculotomy. Clinical results and experimental findings

Cochleosacculotomy was performed on 25 patients with Meniere's syndrome. Long-term relief of vertigo was obtained in 19 out of 23 (82%). Postoperatively dead ears occurred in three cases. The same operation was performed on 12 guinea pigs in which hydrops had been surgically induced by blockage of the endolymphatic duct and sac. All fistulas were healed and cochleosacculotomy did not decrease or prevent the induced endolymphatic hydrops in these animals. Although histologic confirmation of persistent fistulas in human ears is lacking, the relief of vertigo in patients may not be caused by "drainage" but, rather, by a nonspecific effect on the inner ear. Cochleosacculotomy gives results comparable with other nondestructive surgical procedures performed to suppress vertigo in Meniere's syndrome.     

Distal renal tubular acidosis in mice lacking the AE1 (band3) Cl-/HCO3- exchanger (slc4a1)

Mutations in the human gene that encodes the AE1 Cl(-)/HCO(3)(-) exchanger (SLC4A1) cause autosomal recessive and dominant forms of distal renal tubular acidosis (dRTA). A mouse model that lacks AE1/slc4a1 (slc4a1-/-) exhibited dRTA characterized by spontaneous hyperchloremic metabolic acidosis with low net acid excretion and, inappropriately, alkaline urine without bicarbonaturia. Basolateral Cl(-)/HCO(3)(-) exchange activity in acid-secretory intercalated cells of isolated superfused slc4a1-/- medullary collecting duct was reduced, but alternate bicarbonate transport pathways were upregulated. Homozygous mice had nephrocalcinosis associated with hypercalciuria, hyperphosphaturia, and hypocitraturia. A severe urinary concentration defect in slc4a1-/- mice was accompanied by dysregulated expression and localization of the aquaporin-2 water channel. Mice that were heterozygous for the AE1-deficient allele had no apparent defect. Thus, the slc4a1-/- mouse is the first genetic model of complete dRTA and demonstrates that the AE1/slc4a1 Cl(-)/HCO(3)(-) exchanger is required for maintenance of normal acid-base homeostasis by distal renal regeneration of bicarbonate in the mouse as well as in humans.     

Pendrin regulation in mouse kidney primarily is chloride-dependent

Recent studies indicate that pendrin, an apical Cl-/HCO3- exchanger, mediates chloride reabsorption in the connecting tubule and the cortical collecting duct and therefore is involved in extracellular fluid volume regulation. The purpose of this study was to test whether pendrin is regulated in vivo primarily by factors that are associated with changes in renal chloride transport, by aldosterone, or by the combination of both determinants. For achievement of this goal, pendrin protein abundance was studied by semiquantitative immunoblotting in different mouse models with altered aldosterone secretion or tubular chloride transport, including NaCl loading, hydrochlorothiazide administration, NaCl co-transporter knockout mice, and mice with Liddle's mutation. The parallel regulation of the aldosterone-regulated epithelial sodium channel (ENaC) was examined as a control for biologic effects of aldosterone. Major changes in pendrin protein expression were found in experimental models that are associated with altered renal chloride transport, whereas no significant changes were detected in pendrin protein abundance in models with altered aldosterone secretion. Moreover, in response to hydrochlorothiazide administration, pendrin was downregulated despite a marked secondary hyperaldosteronism. In contrast, alpha-ENaC was markedly upregulated, and the molecular weight of a large fraction of gamma-ENaC subunits was shifted from 85 to 70 kD, consistent with previous results from rat models with elevated plasma aldosterone levels. These results suggest that factors that are associated with changes in distal chloride delivery govern pendrin expression in the connecting tubule and cortical collecting duct.     

It is chloride depletion alkalosis, not contraction alkalosis

Maintenance of metabolic alkalosis generated by chloride depletion is often attributed to volume contraction. In balance and clearance studies in rats and humans, we showed that chloride repletion in the face of persisting alkali loading, volume contraction, and potassium and sodium depletion completely corrects alkalosis by a renal mechanism. Nephron segment studies strongly suggest the corrective response is orchestrated in the collecting duct, which has several transporters integral to acid-base regulation, the most important of which is pendrin, a luminal Cl/HCO(3)(-) exchanger. Chloride depletion alkalosis should replace the notion of contraction alkalosis.     

Unraveling the molecular pathogenesis of isolated proximal renal tubular acidosis

Proximal renal tubular acidosis (pRTA) results from an impairment of bicarbonate (HCO(3)(-)) reabsorption in the renal proximal tubules and is characterized by a decreased renal HCO(3)(-) threshold. Proximal RTA most commonly occurs in association with multiple defects of proximal tubular transport (renal Fanconi syndrome). Although much more rare, pRTA may occur without other functional defects in proximal tubules (isolated pRTA). The presenting clinical symptom of isolated pRTA is usually growth retardation in infancy or early childhood. Three categories of isolated pRTA have been identified: (1) autosomal dominant pRTA; (2) autosomal recessive pRTA with ocular abnormalities; and (3) sporadic isolated pRTA. Autosomal dominant and autosomal recessive pRTA are usually permanent; life-long alkali therapy is needed. In contrast, sporadic isolated pRTA is transient; alkali therapy can be discontinued after several years without reappearance of symptoms. Recent genetic studies have begun to elucidate the molecular pathogenesis of inherited isolated pRTA. Studies in knockout mice have identified a candidate gene for autosomal dominant pRTA, SLC9A3, a gene encoding one of the five plasma membrane Na(+)/H(+) exchangers (NHE3). Patients with autosomal recessive pRTA and ocular abnormalities have recently been found to have mutations in the kidney type Na(+)/HCO(3)(-) cotransporter gene (SLC4A4). Identification of these gene mutations provides new insights into the molecular pathogenesis of pRTA.     

Molecular physiology of the renal chloride-formate exchanger

Renal apical chloride-base exchangers are essential to electrolyte and acid-base homeostasis. Different functional isoforms of apical anion exchangers have been identified in kidney proximal tubule and cortical collecting duct. Included amongst these are the following: chloride-formate, chloride-oxalate, and chloride-hydroxyl exchangers in proximal tubule; and chloride-bicarbonate exchanger in cortical collecting duct. Chloride-formate exchange, which was first identified in kidney proximal tubule, works in parallel with the apical sodium-hydrogen exchanger, and is thought to reabsorb the bulk of luminal chloride. Despite numerous studies, the molecular identities of apical chloride-base exchangers have remained unknown. Recent studies have identified a new class of anion exchangers, including pendrin (encoded by the PDS gene) and downregulated in adenoma (DRA, encoded by the DRA gene). Pendrin is expressed in the kidney, whereas DRA is not. Functional studies indicate that pendrin can function in chloride-formate and chloride-base exchange modes. It is unlikely that pendrin is the apical chloride-formate exchanger in the kidney proximal tubule. However, it is the only molecule that has been shown to mediate chloride-formate exchange. In the present review, recent studies regarding the renal distribution and membrane localization of pendrin, and its functional properties, including its roles in chloride reabsorption and base excretion, are addressed.     

The effect of cochleostomy on the development of endolymphatic hydrops--morphologic changes in the rabbit cochlea

The present study was designed to examine the effects of cochleostomy on the development of endolymphatic hydrops in the rabbit. Fistulization of the cochlear partition and simultaneous obstruction of the endolymphatic duct was performed in one group of animals (n = 13). Rabbits in two other groups underwent either cochleostomy (n = 6) or endolymphatic duct obstruction (n = 6) alone. Animals were terminated at 1-, 4-, and 6-week intervals and the cochleas were examined with the light microscope to document the presence or absence of hydrops, or were evaluated with the scanning electron microscope to assess sensory-cell damage. Hydrops was observed in 67% of the animals in the combined duct-obstruction/cochleostomy group, in 100% of the duct-obstruction alone group, and in 0% of the cochleostomy alone group. Widespread sensory-cell degeneration was observed with the scanning electron microscope in the combined and the cochleostomy alone groups.     

Molecular pathophysiology of SLC4 bicarbonate transporters

PURPOSE OF REVIEW: Acid-base (H and HCO3) transport in the kidney is crucial for maintaining blood pH, cellular pH and excreting metabolic acid. HCO3 transport in the kidney is mediated by HCO3 transporter proteins which occur in two gene families in humans, vertebrates and invertebrates (SLC4 and SLC26). Since SLC26 transporters have other, non-HCO3 transport functions, this review highlights the history and recent advances in the SLC4 transporters in the kidney. The SLC4 gene and protein family (10 genes) contains three types of HCO3 transporters: Cl-HCO3 exchangers, Na/HCO3 cotransporters and Na-driven Cl-HCO3 exchangers. Function and human chromosomal location have been determined for most members. RECENT FINDINGS: Human mutations in AE1 (SLC4A1) and NBCe1 (SLC4A4) are associated with distal and proximal renal tubular acidosis, respectively. Recent advances include the cellular and biophysical mechanisms by which AE1 and NBCe1 mutations lead to renal disease. Mutational and cellular trafficking studies have begun to elucidate the membrane topology and functional domains of AE1 and NBCe1. Knockout mice for AE2 and NBCn1 do not have obvious renal phenotypes. Recently, SLC4A11 (bicarbonate transporter 1) was shown to function as an electrogenic Na/borate cotransporter unable to transport HCO3 but involved in cell cycle control. SUMMARY: SLC4 HCO3 transporters play critical roles in systemic and cellular pH homeostasis. Most of the SLC4 members are present at some level in the kidney. Future studies will likely continue to make use of knockout animals, for example mice and zebrafish, human mutations or polymorphisms to elucidate the normal and pathophysiologic roles of these proteins.     

The vestibular aqueduct: site of origin of endolymphatic sac tumors

OBJECT: Although endolymphatic sac tumors (ELSTs) frequently destroy the posterior petrous bone and cause hearing loss, the anatomical origin of these neoplasms is unknown. To determine the precise topographic origin of ELSTs, the authors analyzed the imaging, operative, and pathological findings in patients with von Hippel-Lindau disease (VHL) and ELSTs. METHODS: Consecutive VHL patients with small (相似文献   

SLC26 chloride/base exchangers in the kidney in health and disease

Solute-linked carrier 26 (SLC26) isoforms are members of a large, conserved family of anion exchangers, many of which display highly restricted and distinct tissue distribution. Cloning experiments have identified 10 SLC26 genes or isoforms (SLC26A1-11). Except for SLC26A5 (prestin), all function as anion exchangers with versatility with respect to transported anions. Modes of transport mediated by SLC26 members include the exchange of chloride for bicarbonate, hydroxyl, sulfate, formate, iodide, or oxalate with variable specificity. Other anion exchange modes not involving chloride also have been reported for some of the members of this family. Several members of SLC26 isoforms are expressed in the kidney. These include SLC26A1 (SAT1), SLC26A4 (pendrin), SLC26A6 (putative anion transporter [PAT1] or chloride/formate exchange [CFEX]), SLC26A7, and SLC26A11. Each isoform displays a specific nephron segment distribution with a distinct subcellular localization. Coupled to expression studies and examination of genetically engineered mice deficient in various SLC26 isoforms, the evolving picture points to important roles for the SLC26 family in chloride absorption, vascular volume homeostasis, acid-base regulation, and oxalate excretion in the kidney. This review summarizes recent advances in the identification and characterization of SLC26 family members, with specific emphasis on their distribution and role in kidney physiology. Specifically, the roles of A4 (pendrin), A6 (PAT1), and A7 (PAT2) in chloride homeostasis, oxalate excretion, and acid-base balance are discussed.     

Chloride/bicarbonate exchanger SLC26A7 is localized in endosomes in medullary collecting duct cells and is targeted to the basolateral membrane in hypertonicity and potassium depletion

SLC26A7 is a Cl(-)/HCO(3)(-) exchanger that is expressed on the basolateral membrane and in the cytoplasm of two distinct acid-secreting epithelial cells: The A-intercalated cells in the kidney outer medullary collecting duct and the gastric parietal cells. The intracellular localization of SLC26A7 suggests the possibility of trafficking between cell membrane and intracellular compartments. For testing this hypothesis, full-length human SLC26A7 cDNA was fused with green fluorescence protein and transiently expressed in MDCK epithelial cells. In monolayer cells in isotonic medium, SLC26A7 showed punctate distribution throughout the cytoplasm. However, in medium that was made hypertonic for 16 h, SLC26A7 was detected predominantly in the plasma membrane. The presence of mitogen-activated protein kinase inhibitors blocked the trafficking of SLC26A7 to the plasma membrane. Double-labeling studies demonstrated the localization of SLC26A7 to the transferrin receptor-positive endosomes. A chimera that was composed of the amino terminal fragment of SLC26A7 and the carboxyl terminal fragment of SLC26A1, and a C-terminal-truncated SLC26A7 were retained in the cytoplasm in hypertonicity. In separate studies, SLC26A7 showed predominant localization in plasma membrane in potassium-depleted isotonic medium (0.5 or 2 mEq/L KCl) versus cytoplasmic distribution in normal potassium isotonic medium (4 mEq/L). It is concluded that SLC26A7 is present in endosomes, and its targeting to the basolateral membrane is increased in hypertonicity and potassium depletion. The trafficking to the cell surface suggests novel functional upregulation of SLC26A7 in states that are associated with hypokalemia or increased medullary tonicity. Additional studies are needed to ascertain the role of SLC26A7 in enhanced bicarbonate absorption in outer medullary collecting duct in hypokalemia and in acid-base regulation in conditions that are associated with increased medullary tonicity.     

Hydrostatic pressure measurements of endolymph and perilymph in a guinea pig model of endolymphatic hydrops

The primary histologic correlate of Menière's disease is endolymphatic hydrops. From this, many investigators have postulated the existence of endolymphatic hypertension, although there have been no measurements published to substantiate this concept. Seventy guinea pigs, surgically treated with right endolymphatic duct obstruction, were later assessed by use of a micro-electrode technique that measured their endolabyrinthine hydrostatic pressures. For 21 of these animals, the pressures of both scala tympani (Pst) and scala media (Psm) of both ears of each animal were successfully measured. Similar measurements were made in a control group of 25 guinea pigs that had not undergone any previous surgery. For normal ears--as well as those with hydrops-pressure differences between perilymph and endolymph (Psm - Pst) varied around 0 +/- 2.0 mm Hg. When only the right (obstructed) ears were considered, there appeared to be a slight, relative pressure elevation (p less than 0.05) in scala media during the first 7 days after endolymphatic duct obstruction-and in those ears with EP, less than 70 mV. The magnitude of this pressure difference that can be attributed to the state of endolymphatic hydrops-and not to natural variability-is calculated (within 95% confidence limits) to be less than 0.5 mm Hg.     

Effects of ammonia on acid-base transport by the B-type intercalated cell.

Ammonia, in addition to its role as a constituent of urinary net acid excretion, stimulates cortical collecting duct (CCD) net bicarbonate reabsorption. The current study sought to begin determining the cellular transport processes through which ammonia regulates bicarbonate reabsorption by testing whether ammonia stimulates B-type intercalated cell bicarbonate secretion, bicarbonate reabsorption, or both. The effects of ammonia on single CCD intercalated cells was studied by use of measurements of intracellular pH taken from in vitro microperfused CCD segments after luminal loading of the pH-sensitive fluorescent dye BCECF. These results showed, first, that ammonia inhibited B-cell unidirectional bicarbonate secretion and that this occurred despite no effect of ammonia on apical Cl(-)/HCO(3)(-) exchange activity. Second, ammonia increased the contribution of a SCH28080-sensitive apical H(+)-K(+)-ATPase to basal intracellular pH regulation and it stimulated basolateral Cl(-)/HCO(3)(-) exchange activity. Thus, ammonia activated both apical proton secretion and basolateral base exit, consistent with stimulation of unidirectional bicarbonate reabsorption. It was concluded that ammonia regulates CCD net bicarbonate reabsorption, at least in part, through the coordinated regulation of the separate processes of B-cell bicarbonate reabsorption and bicarbonate secretion. These effects do not reflect a general activation of ion transport but, instead, reflect coordinated and specific regulation of ion transport.     

De Novo Development and Progression of Endolymphatic Sac Tumour in von Hippel-Lindau Disease: An Observational Study and Literature Review

Endolymphatic sac tumors (ELST) are rare invasive lesions of the temporal bone that are commonly associated with von Hippel-Lindau disease. This report describes serial magnetic resonance imaging (MRI) and computed tomography (CT) findings over a period of 6 years in a 12-year-old patient who developed an ELST after 3.5 years surveillance for a cerebellar hemangioblastoma. A 1.5 × 8 mm tumor was identified on MRI within the endolymphatic duct when the patient presented with audiovestibular symptoms due to intralabyrinthine hemorrhage. The tumor demonstrated subsequent growth over 25 months until the patient agreed to undergo surgical resection by subtotal petrosectomy. De novo development and the natural history have been described only in six previous cases. MRI is regarded to be unreliable with respect to the ability to demonstrate an ELST in the presence of intralabyrinthine hemorrhage, with only two out of four previously reported patients demonstrating positive MRI findings. Little is known about the precise origin (endolymphatic duct versus sac), growth, and symptom correlation. This case highlights that new audiovestibular symptoms are a potential clinical clue and intralabyrinthine hemorrhage is a neuroimaging indicator for the presence of an ELST, which based on high-resolution MRI appears to originate in the endolymphatic duct rather than sac.     

Autoimmune endolymphatic hydrops: five-year review

This article reviews the authors' experience with autoimmune endolymphatic hydrops over the past 5 years. Twenty-seven of 52 patients with diagnosed autoimmune inner ear disease (52%) manifested endolymphatic hydrops, usually bilateral. Treatment consisted of low salt diet, diuretic, vestibular suppressant, and usually prednisone. Cytotoxic drugs and lymphocytoplasmapheresis were reserved for refractory cases. Audiometric followup (average, 23 months) was available in 12 patients. Using American Academy of Otolaryngology--Head and Neck Surgery guidelines, hearing improved or stabilized in at least one ear in nine patients and deteriorated bilaterally in three patients. Vestibular treatment results paralleled auditory treatment results. Autoimmune endolymphatic hydrops should be considered in the differential diagnosis when symptoms are bilateral and do not respond to conventional therapy or when immune laboratory tests are positive. In suspect patients, medical therapy with prednisone, and rarely cytotoxic drugs and lymphocytoplasmapheresis, should be recommended. Further research is needed to determine whether surgery should be performed in medically unresponsive cases.