Salinity-dependent expression of calcium-sensing receptors in Atlantic salmon (Salmo salar) tissues.

Multiple reports suggest that calcium-sensing receptors (CaSRs) are involved in calcium homeostasis, osmoregulation, and/or salinity sensing in fish (Loretz 2008, Herberger and Loretz 2013). We have isolated three unique full-length CaSR cDNAs from Atlantic salmon (Salmo salar) kidney that share many features with other reported CaSRs. Using anti-CaSR antibodies and PCR primers specific for individual salmon CaSR transcripts we show expression in osmoregulatory, neuroendocrine and sensory tissues. Furthermore, CaSRs are expressed in different patterns in salmon tissues where mRNA and protein expression are modified by freshwater or seawater acclimation. For example, in seawater, CaSR mRNA and protein expression is increased significantly in kidney as compared to freshwater. Electrophysiological recordings of olfactory responses produced upon exposure of salmon olfactory epithelium to CaSR agonists suggest a role for CaSRs in chemoreception in this species consistent with other freshwater, anadromous, and marine species where similar olfactory responses to divalent and polyvalent cations have been reported. These data provide further support for a role of CaSR proteins in osmoregulatory and sensory functions in Atlantic salmon, an anadromous species that experiences a broad range of environmental salinities in its life history.

Hernia prevention: practice patterns and surgeons' attitudes about abdominal wall closure and the use of prophylactic mesh.

PURPOSE: The penetration of hernia prevention techniques into surgical practice remains unknown. METHODS: A survey about knowledge/attitudes on hernia prevention was sent to the members of hernia societies. RESULTS: The 497 respondents were mostly from the US (47%) or Europe (40%). Most reported practicing, but not measuring their suture-to-wound length closure of > 4:1 (63%) and practicing but not measuring the number of stitches (58%). Reasons for not using short stitch closure were: does not apply to patient population (19%), not familiar enough with methods to correctly execute (25%), takes too long (13%), not reimbursed (4%), concerned about closure-related complications (27%), and other (22%). Regarding prophylactic mesh, respondents stated they were not familiar with literature (11%), familiar with literature but would not use (24%), familiar with literature and interested in use (45%), familiar with literature and using (15%), and other (5%). CONCLUSIONS: There appears to be some application of hernia prevention principles related to fascial closure; however, the use of prophylactic mesh still appears to be controversial.

An estimation of inguinal hernia epidemiology adjusted for population age structure in Tanzania.

PURPOSE: Surgical conditions represent a significant source of global disease burden. Little is known about the epidemiology of inguinal hernia in resource-poor settings. We present a method to estimate inguinal hernia disease burden in Tanzania. METHODS: Using data from the United States National Health and Nutrition Examination Survey (NHANES) prospective cohort study and Tanzanian demographic figures, we calculated inguinal hernia incidence and prevalence in Tanzanian adults under three surgical rate scenarios. Gender-specific incidence figures from NHANES data were adjusted according to Tanzanian population age structure. Hernia duration was adjusted for Tanzanian life expectancy within each age group. RESULTS: The prevalence of inguinal hernia in Tanzanian adults is 5.36% while an estimated 12.09% of men had hernias. Today, 683,904 adults suffer from symptomatic inguinal hernia in Tanzania. The annual incidence of symptomatic hernias in Tanzanian adults is 163 per 100,000 population. At Tanzania's current hernia repair rate, a backlog of 995,874 hernias in need of repair will develop over 10 years. 4.4 million disability-adjusted life-years would be averted with repair of prevalent symptomatic hernias in Tanzania. CONCLUSIONS: Our data indicate the extent of inguinal hernia disease burden in Tanzania. By adjusting our figures for the age structure of Tanzania, we have demonstrated that while the incidence of symptomatic cases may be lower than previously thought, prevalence of inguinal hernia in Tanzania remains high. This approach provides an update to our previously described methodology for calculation of inguinal hernia epidemiology in resource-poor settings that may be used in multiple country contexts.

A critical review of biologic mesh use in ventral hernia repairs under contaminated conditions.

PURPOSE: We used an evidence-based approach to determine whether the promotions and claims of superiority of biologic mesh over synthetic mesh use in ventral hernia repairs (VHRs) under contaminated conditions were sound and valid. METHODS: We searched the Medline database to specifically identify review articles relating to biologic mesh and VHR and critically reviewed these studies using an evidence-based approach. RESULTS: For the past 45 years, four clinical reviews and one systematic review have included biologic meshes as part of a larger discussion on available prosthetics for VHR. All reviews supported biologic mesh use, especially in the setting of contaminated fields. Yet, the primary literature included in these reviews and served as the basis for these conclusions consisted entirely of case series and case reports, which have the lowest level of evidence in determining scientific validity. Furthermore, the FDA has neither cleared nor approved this particular use. CONCLUSIONS: The cumulative data regarding biologic mesh use in VHRs under contaminated conditions does not support the claim that it is better than synthetic mesh used under the same conditions. The highly promoted and at least moderately utilized practice of placing biologic mesh in contamination is being done outside of the original intended use, and a re-evaluation of or possible moratorium on biologic mesh use in hernia surgery is seriously warranted. Alternatively, an industry-sponsored national registry of patients in whom ventral hernia repairs involved biologic mesh would substantively add to our understanding regarding how these intriguing biomaterials are being used and their overall clinical efficacy.

Electrokinesis is a microbial behavior that requires extracellular electron transport.

We report a previously undescribed bacterial behavior termed electrokinesis. This behavior was initially observed as a dramatic increase in cell swimming speed during reduction of solid MnO(2) particles by the dissimilatory metal-reducing bacterium Shewanella oneidensis MR-1. The same behavioral response was observed when cells were exposed to small positive applied potentials at the working electrode of a microelectrochemical cell and could be tuned by adjusting the potential on the working electrode. Electrokinesis was found to be different from both chemotaxis and galvanotaxis but was absent in mutants defective in electron transport to solid metal oxides. Using in situ video microscopy and cell tracking algorithms, we have quantified the response for different strains of Shewanella and shown that the response correlates with current-generating capacity in microbial fuel cells. The electrokinetic response was only exhibited by a subpopulation of cells closest to the MnO(2) particles or electrodes. In contrast, the addition of 1 mM 9,10-anthraquinone-2,6-disulfonic acid, a soluble electron shuttle, led to increases in motility in the entire population. Electrokinesis is defined as a behavioral response that requires functional extracellular electron transport and that is observed as an increase in cell swimming speeds and lengthened paths of motion that occur in the proximity of a redox active mineral surface or the working electrode of an electrochemical cell.

Necrotizing pancreatitis: a surgical approach independent of documented infection.

BACKGROUND: Strategies for the management of patients with necrotizing pancreatitis remain controversial. While consensus opinion supports operative necrosectomy for the treatment of infected pancreatic necrosis, the timing for surgical intervention is not completely resolved. Further, the indication for the surgical management of sterile pancreatic necrosis is also subject to debate. METHODS: The objective of this study was to evaluate outcome measures for the surgical management of necrotizing pancreatitis, independent of documented infection. A retrospective review was undertaken between 1994 and 2002 at a single county hospital. RESULTS: Twenty-one patients with CT-documented necrotizing pancreatitis underwent operative pancreatic necrosectomy with laparostomy within 21 days of initial diagnosis and had an average of three reoperations. Average length of stay (LOS) in the ICU was 36 days and in the hospital 67 days. Ten patients had documented infected necrosis based on initial intra-operative cultures, while I I had sterile necrosis. Overall, 95% (20/21) of the patients had a complication, with an average of three complications per patient. Common complications included ARDS (71%), sepsis (33%), renal failure (24%), and pneumonia (24%). The overall mortality rate was 14% (3/21), with a mean follow-up of 469 days. DISCUSSION: The surgical management of acute necrotizing pancreatitis, independent of documented infection, can be undertaken within 3 weeks of diagnosis with an acceptable morbidity and a low mortality rate. Creation of a laparostomy to enable ready, atraumatic debridement of the retroperitoneum is a safe alternative to standard repeat laparotomies and thus represents a useful adjunct to the surgical management of necrotizing pancreatitis.

Polyvalent cation receptor proteins (CaRs) are salinity sensors in fish.

To determine whether calcium polyvalent cation-sensing receptors (CaRs) are salinity sensors in fish, we used a homology-based cloning strategy to isolate a 4.1-kb cDNA encoding a 1,027-aa dogfish shark (Squalus acanthias) kidney CaR. Expression studies in human embryonic kidney cells reveal that shark kidney senses combinations of Ca(2+), Mg(2+), and Na(+) ions at concentrations present in seawater and kidney tubules. Shark kidney is expressed in multiple shark osmoregulatory organs, including specific tubules of the kidney, rectal gland, stomach, intestine, olfactory lamellae, gill, and brain. Reverse transcriptase-PCR amplification using specific primers in two teleost fish, winter flounder (Pleuronectes americanus) and Atlantic salmon (Salmo salar), reveals a similar pattern of CaR tissue expression. Exposure of the lumen of winter flounder urinary bladder to the CaR agonists, Gd(3+) and neomycin, reversibly inhibit volume transport, which is important for euryhaline teleost survival in seawater. Within 24-72 hr after transfer of freshwater-adapted Atlantic salmon to seawater, there are increases in their plasma Ca(2+), Mg(2+), and Na(+) that likely serve as a signal for internal CaRs, i.e., brain, to sense alterations in salinity in the surrounding water. We conclude that CaRs act as salinity sensors in both teleost and elasmobranch fish. Their tissue expression patterns in fish provide insights into CaR functions in terrestrial animals including humans.

AQP2 is a substrate for endogenous PP2B activity within an inner medullary AKAP-signaling complex.

We have demonstrated that inner medullary collecting duct (IMCD) heavy endosomes purified from rat kidney IMCD contain the type II protein kinase A (PKA) regulatory subunit (RII), protein phosphatase (PP)2B, PKCzeta, and an RII-binding protein (relative molecular mass ~90 kDa) representing a putative A kinase anchoring protein (AKAP). Affinity chromatography of detergent-solubilized endosomes on cAMP-agarose permits recovery of a protein complex consisting of the 90-kDa AKAP, RII, PP2B, and PKCzeta. With the use of small-particle flow cytometry, RII and PKCzeta were localized to an identical population of endosomes, suggesting that these proteins are components of an endosomal multiprotein complex. (32)P-labeled aquaporin-2 (AQP2) present in these PKA-phosphorylated endosomes was dephosphorylated in vitro by either addition of exogenous PP2B or by an endogenous endosomal phosphatase that was inhibited by the PP2B inhibitors EDTA and the cyclophilin-cyclosporin A complex. We conclude that IMCD heavy endosomes possess an AKAP multiprotein-signaling complex similar to that described previously in hippocampal neurons. This signaling complex potentially mediates the phosphorylation of AQP2 to regulate its trafficking into the IMCD apical membrane. In addition, the PP2B component of the AKAP-signaling complex could also dephosphorylate AQP2 in vivo.

Pulmonary dysplasia, Denys-Drash syndrome and Wilms tumor 1 gene mutation in twins.

While a genetic basis for the association of developmental lung and kidney defects has been suspected, the involvement of specific genes in this process is under active investigation. We report such a possible genetic linkage present in identical twins with a mutant Wilms tumor (WT1) gene. Twin girls, born at 35 weeks gestation, manifested symptoms of congenital nephrotic syndrome, renal failure, and severe respiratory abnormalities refractory to assisted ventilation. Both died at 1 month of age. Renal biopsies and autopsy kidney tissue from both the girls revealed diffuse mesangial sclerosis (DMS). Autopsy lung tissue revealed pulmonary dysplasia and hypoplasia in both twins. The WT1 gene from renal tissue in both twins was analyzed for mutations using polymerase chain reaction (PCR) amplification and the single-strand conformation polymorphism (SSCP) technique. Both twins possessed an identical missense mutation in exon 8 of the WT1 gene, resulting in replacement of arginine by histidine at amino acid 366 (arg366his) in the WTI protein. This mutation has previously been described in Denys-Drash syndrome. The WT1 gene plays a role in mesenchymal epithelial (ME) interactions in the developing urogenital system, and possibly has a similar role during lung morphogenesis. We propose that this WT1 gene mutation contributes to both DMS and developmental pulmonary abnormalities by altering ME interactions in both organs.

Necrotizing pancreatitis during pregnancy: a rare cause and review of the literature.

Acute pancreatitis is an uncommon cause of abdominal pain during pregnancy, and rarely progresses to the necrotizing from of the disease in this clinical setting. Hyperlipidemia is an infrequent cause of acute pancreatitis. Whereas only 100 cases of hyperlipidemia-induced necrotizing pancreatitis have been reported in the literature to date, all of the cases were mild in severity and responsive to conservative medical management. Herein we present a case of life-threatening necrotizing pancreatitis, which developed in a hyperlipidemic pregnant woman and required multiple peripartum pancreatic necrosectomies. Additionally, we review the evaluation of pregnant patients with abdominal pain, the pathophysiology of hyperlipidemia-induced necrotizing pancreatitis, and the operative care of this challenging group of patients, revisiting an innovative technique for management of the retroperitoneum.

Cinematic nuclear scintigraphy reliably directs surgical intervention for patients with gastrointestinal bleeding.

HYPOTHESIS: Cinematic technetium Tc 99m red blood cell ((99m)Tc-RBC) scans, in which real-time scanning is performed and analyzed, can accurately localize gastrointestinal bleeding and thus direct selective surgical intervention. DESIGN: Retrospective medical record review with historical controls. SETTING: Large, university-affiliated public hospital in urban setting. PATIENTS: Twenty-six patients presenting with upper and lower gastrointestinal hemorrhage who underwent cinematic (99m)Tc-RBC scan examinations between 1990 and 1997 and required surgical intervention to control the bleeding. INTERVENTIONS: All patients with gastrointestinal bleeding underwent open surgical procedures to provide cessation of bleeding and resection of appropriate abnormalities. MAIN OUTCOME MEASURES: Patient outcome was based on correlation between preoperative RBC scans and intraoperative findings, surgical pathology, and postoperative clinical course. RESULTS: Twenty-five (96%) of 26 scans were interpreted as positive for gastrointestinal bleeding. In 22 of these 25 scans, the site of bleeding was correctly identified for a sensitivity of 88%. One or more additional diagnostic tests were performed on 19 (73%) of 26 patients, and included angiography and flexible endoscopy. The most common operation performed to control bleeding was a hemicolectomy (14/26). Diverticulosis was the most prevalent diagnosis (46%). Two patients (8%) experienced rebleeding after operation. The overall mortality rate was 19% (5/26). CONCLUSIONS: Cinematic (99m)Tc-RBC scintigraphy is a sensitive, noninvasive alternative to mesenteric angiography for accurately localizing the site of gastrointestinal hemorrhages. As such, this technique can be reliably used to direct selective surgical intervention.

Functional outcome of patients with femoral head fractures associated with hip dislocations.

Fracture of the femoral head after hip dislocation is a relatively rare injury often associated with a poor functional outcome. Twenty-six patients who sustained femoral head fractures were evaluated using radiographs, clinical examinations, and a validated outcome scoring system. The Short Form-12 was used to assess functional outcome. Patients whose fractures were stabilized with 3-mm cannulated screws and washers had a poor functional outcome. When evaluated with an odds ratio analysis, the use of Kocher-Langenbeck posterior approach was associated with a 3.2 times higher incidence of the patients having avascular necrosis develop when compared with the Smith-Petersen approach. A literature review combined with the current series confirms that the principles of early reduction of hip dislocation, early stabilization, anatomic reduction of the fracture, and rigid fixation are critical principles to attain good results. The Brumback classification system provides superior differentiation of different fracture types when compared with the Pipkin classification. The Smith-Petersen anterior surgical approach is recommended for the majority of patients with femoral head fractures. Three-millimeter cannulated screws with threaded washers are contraindicated for use in stabilizing femoral head fractures, and should not be used in any joint because of dissociation between the screw and the washer.

Extracellular matrix regulates the hepatocellular heat shock response.

BACKGROUND: Cirrhosis is characterized by the accumulation of collagen within the extracellular matrix (ECM) of the liver and progressive hepatocellular dysfunction. Since recent studies have shown that the ECM can modulate cellular function, we examined whether the ECM could contribute to hepatocellular dysfunction. To address this question we examined hepatocyte behavior in two different ECM environments. MATERIALS AND METHODS: Primary rat hepatocytes were cultured as a monolayer on collagen or as multicellular aggregates (spheroids) within a laminin-rich ECM. Hepatocytes were then compared for viability, response to proinflammatory cytokines, and their capacity to activate a heat shock response and adopt a thermotolerant phenotype. In addition, we compared the ability of prior heat shock exposure to protect hepatocytes from tumor necrosis factor (TNF) alpha/actinomycin-D-induced apoptosis in the two different ECM environments. RESULTS: Hepatocytes cultured as a monolayer on collagen exhibited decreased viability, underwent spontaneous apoptosis, and displayed an attenuated cytokine-stimulated nitric oxide production compared to hepatocytes cultured as spheroids. In response to heat, hepatocytes in both ECM environments expressed inducible heat shock protein 70 (hsp72). But, only the hepatocyte spheroids exhibited thermotolerance in response to a subsequent thermal challenge. In contrast to previous reports, induction of the heat shock response failed to protect hepatocytes against TNFalpha-induced apoptosis. CONCLUSIONS: These data demonstrate that the ECM can play an integral role in specific hepatocellular behaviors. Furthermore, the progressive deposition of collagen within the ECM, which is characteristic of fibrotic liver diseases, may directly contribute to the progressive hepatocellular dysfunction observed in cirrhosis. Hepatocellular viability, response to proinflammatory cytokines, heat shock response, and thermotolerance were all altered depending on the composition of the ECM. In contrast, TNFalpha-induced apoptosis was independent of the composition of the ECM.

Substance P dependence of endosomal fusion during bladder inflammation.

Urinary bladder instillation of ovalbumin into presensitized guinea pigs stimulates rapid development of local bladder inflammation. Substance P is an important mediator of this inflammatory response, as substance P antagonists largely reverse the process. Vacuolization of the subapical endosomal compartment of the transitional epithelial cells lining the bladder suggests that changes in endosomal trafficking and fusion are also part of the inflammatory response. To test directly for substance P mediation of changes in endosomal fusion, we reconstituted fusion of transitional cell endosomes in vitro using both cuvette-based and flow cytometry energy transfer assays. Bladders were loaded with fluorescent dyes by a hypotonic withdrawal protocol before endosomal isolation by gradient centrifugation. Endosomal fusion assayed by energy transfer during in vitro reconstitution was both cytosol and ATP dependent. Fusion was confirmed by the increase in vesicle size on electron micrographs of fused endosomal preparations compared with controls. In inflamed bladders, dye uptake was inhibited 20% and endosomal fusion was inhibited 50%. These changes are partly mediated by the neurokinin-1 (NK1) receptor (NK1R), as 4 mg/kg of CP-96,345, a highly selective NK1 antagonist, increased fusion in inflamed bladders but had no effect on control bladders. The receptor-mediated nature of this effect was demonstrated by the expression of substance P receptor mRNA in rat bladder lumen scrapings and by the detection of the NK1R message in guinea pig subapical endosomes by Western blot analysis. The NK1Rs were significantly upregulated following induction of an inflammatory response in the bladder. These results demonstrate that 1) in ovalbumin-induced inflammation in the guinea pig bladder, in vitro fusion of apical endosomes is inhibited, showing endocytotic processes are altered in inflammation; 2) pretreatment in vivo with an NK1R antagonist blocks this inhibition of in vitro fusion, demonstrating a role for NK1R in this process; and 3) the NK1R is present in higher amounts in apical endosomes of inflamed bladder, suggesting changes in translation or trafficking of the NK1R during the inflammatory process. This suggests that NK1R can change the fusion properties of membranes in which it resides.

The lipemia of sepsis: triglyceride-rich lipoproteins as agents of innate immunity.

Bacterial endotoxin (LPS) elicits dramatic responses in the host including elevated plasma lipid levels due to the increased synthesis and secretion of triglyceride (TG)-rich lipoproteins by the liver, and the inhibition of lipoprotein lipase. This cytokine-induced hyperlipoproteinemia, clinically termed the "lipemia of sepsis", was customarily thought to represent the mobilization of lipid stores to fuel the host response to infection. However, since lipoproteins can also bind and neutralize LPS, we hypothesize that TG-rich lipoproteins (VLDL and chylomicrons) are also components of an innate, non-adaptive host immune response to infection. Herein we review data demonstrating the capacity of lipoproteins to bind LPS, protect against LPS-induced toxicity, and modulate the overall host response to this bacterial toxin. Lastly, we propose a pathway whereby lipoprotein-bound LPS may represent a novel, endogenous mechanism for regulating the hepatic acute phase response.

Leukocytosis and free fluid are important indicators of isolated intestinal injury after blunt trauma.

BACKGROUND: The detection of isolated intestinal injuries after blunt trauma can be difficult because of subtle signs and symptoms, often leading to delayed diagnosis. We hypothesized that specific clinical indicators could be identified to assist in the diagnosis of these injuries. METHODS: Medical records of all patients with such injuries from 1988 to 1996 were reviewed. The patients were stratified into those operated on within 6 hours of presentation (apparent injury) and those operated on after 6 hours (occult injury), and the data were compared. RESULTS: Forty-six patients with isolated intestinal injuries were identified. There were no differences in the rate of peritonitis or free fluid on abdominal computed tomography, blood loss, intraoperative findings, or morbidity and mortality between groups. Leukocytosis (sensitivity, 84.8%; specificity, 55.2%; p = 0.01) and free fluid on computed tomography were frequently present, however, and their significance was underappreciated in the occult injury group. CONCLUSION: After blunt abdominal trauma in patients without obvious indications for invasive evaluation of the abdomen (e.g., peritoneal lavage, laparoscopy, laparotomy), leukocytosis can indicate an intestinal injury. Additionally, unexplained free fluid on abdominal computed tomography must be aggressively evaluated.

Modulation of vasopressin-elicited water transport by trafficking of aquaporin2-containing vesicles.

Vasopressin or AVP regulates water reabsorption by the kidney inner medullary collecting duct (IMCD) through the insertion and removal of aquaporin (AQP) 2 water channels into the IMCD apical membrane. AVP-elicited trafficking of AQP2 with the apical membrane occurs via a specialized population of vesicles that resemble synaptic vesicles in neurons. AQP2 vesicles and the IMCD apical membrane contain homologs of vesicle-targeting and signal transduction proteins found in neurons. Expression studies of AQP2, including human AQP2 mutants, suggest that the carboxyl-terminal domain of AQP2 is important in AQP2 trafficking, particularly as a site for cAMP-dependent protein kinase phosphorylation. These present data reveal that IMCD cells possess a complex integrated-signaling and vesicle-trafficking machinery that provides integration of AVP-elicited water transport with many other parameters within the IMCD cell as well as kidney.

Diet-induced protection against lipopolysaccharide includes increased hepatic NO production.

The host response to Gram-negative infection includes the elaboration of numerous proinflammatory agents, including tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO). A component of the hepatic response to infection is an elevation in serum lipids, the so-called "lipemia of sepsis," which results from the increased production of triglyceride (TG)-rich lipoproteins by the liver. We have postulated that these lipoproteins are components of a nonadaptive, innate immune response to endotoxin [lipopolysaccharide (LPS)] and have previously demonstrated the capacity of TG-rich lipoproteins to protect against endotoxicity in rodent models of sepsis. Herein we report the capacity of a high-fructose diet to protect against LPS, most likely by inducing high circulating levels of endogenous TG-rich lipoproteins. The protective phenotype included the increased production of NO by hepatic endothelial cells. Rats, made hypertriglyceridemic by fructose feeding, experienced decreased LPS-induced mortality (P < 0.03) and systemic TNFalpha levels (P < 0.05) as compared with normolipidemic (chow-fed) controls. The increased survival was associated with elevated levels of inducible NO synthase (NOS2) mRNA levels and NO production (82 +/- 26 vs 3 +/- 3 nmol nitrite/10(6) cells, P < 0.001) by hepatic endothelial cells. Nonselective NOS inhibitors reversed the protective phenotype in vivo and readily decreased NO production by cultured endothelial cells from hypertriglyceridemic rats in vitro. This study suggests that a high-fructose diet can protect against endotoxicity in part through induction of endogenous TG-rich lipoproteins and hepatic endothelial cell NO production. This is the first report of diet-induced hyperlipoproteinemia and subsequent protection against endotoxemia.

Recent insights into the coordinate regulation of body water and divalent mineral ion metabolism.

Traditionally, arginine vasopressin modulation of renal water, sodium, and urea excretion has been considered somewhat in isolation from factors that control divalent mineral ion homeostasis. Similarly, previous considerations of divalent mineral ion metabolism have focused mainly on the role of hormones, eg, parathyroid hormone and various forms of vitamin D, as principal modifiers of renal calcium handling. Recent data, however, have now suggested the existence of novel linkages that coordinate control of water and divalent mineral ion homeostasis. This article summarizes these data and highlights the fundamental roles of the extracellular calcium polyvalent cation-sensing receptor (CaR) as an integrator of water and divalent mineral ion homeostasis on a cellular, organ-specific, and whole-body basis. Organs where CaRs may integrate water and divalent mineral ion metabolism include endocrine tissues that express CaRs, the brain, various nephron segments of the kidney, bone, and the gastrointestinal tract. These new data suggest that considerable regulatory overlap exists between water and divalent mineral ion homeostasis.