Ionized hypercalcemia can resolve with nutritional modification in cats with idiopathic hypercalcemia or chronic kidney disease.

CASE SERIES SUMMARY: Cats with ionized hypercalcemia that were fed diets with either more than 200 mg calcium per 100 kilocalories (kcal), a calcium:phosphorus (Ca:P) ratio greater than 1.4:1 or both, based on diet history, were included in this case series. Ionized hypercalcemia was documented at least twice in all cats before enrollment. Cats were referred for evaluation of ionized hypercalcemia (n = 5) or were incidentally found to have ionized hypercalcemia (n = 5). After medical workups, cats were diagnosed with either idiopathic hypercalcemia (IHC; n = 7) or chronic kidney disease (n = 3). Cats receiving medications to treat IHC (eg, alendronate, corticosteroids) were excluded. Nutritional recommendations were made to transition the cats to diets with less thn 200 mg calcium per 100 kcal and a Ca:P ratio less than 1.4:1. Ionized calcium (iCa) concentrations were rechecked in all cats, with a median recheck time of 9 weeks (range 3-20). Of the 10 cats, nine (90%) had a decrease in iCa. Of the 10 cats, six (60%) became normocalcemic after the diet change, three (30%) had a partial response and one (10%) did not respond. Of the four cats that did not achieve normocalcemia with a change in diet, two (50%) received chia seeds (1-2 g per day), and at the next recheck, both cats' iCa concentrations had normalized. Three cats had a long-term follow-up. Ionized normocalcemia was maintained for at least two consecutive follow-up visits over a median follow-up period of 33 weeks (range 12-34). RELEVANCE AND NOVEL INFORMATION: Dietary calcium concentrations and the dietary Ca:P ratio appear to be important variables in considering nutritional approaches for hypercalcemic cats.

Interobserver reliability of canine urine specific gravity assessed by analog or digital refractometers.

Refractometry is utilized routinely to evaluate canine urine specific gravity (USG) in veterinary clinical settings. We aimed to determine if the magnitude of interobserver reliability when assessing canine USG via refractometry could impact clinical judgment. USG was determined in 38 dogs by 3 registered veterinary technicians (RVTs) using both an optical analog refractometer and a digital refractometer. Summary statistics were reported, interobserver reliability was assessed via intraclass correlation coefficient (ICC) analysis through a 2-way mixed-effects model, and agreement between RVT pairs was compared through Bland-Altman plots. The median analog refractometer USG measurement was 1.018 (range: 1.004-1.040) and for the digital refractometer was 1.0176 (1.0035-1.0357). The analog refractometer average measure ICC was 0.995 (95% CI: 0.992, 0.997; p < 0.001). The digital refractometer average measure ICC was 0.999 (95% CI: 0.999, 1.000; p < 0.001). Strong agreement between all pairs of RVTs was seen via Bland-Altman plots for both analog and digital refractometers, with 95% CIs spanning no more than 0.002 in either the positive or negative direction for all pairings. The interobserver variability in canine USG measurements by RVTs was trivial and did not impact clinical judgment and decision-making.

Short-term efficacy of epidural pain management in dogs undergoing cystoscopy.

BACKGROUND: The effects of epidural anesthesia in dogs undergoing cystoscopy are unknown. OBJECTIVE: To investigate the effect of epidural analgesia on postcystoscopy pain in dogs. ANIMALS: Twenty-six dogs undergoing routine cystoscopy for lower urinary tract disease. METHODS: Prospective, randomized, blinded observational study. Dogs were assigned either to a treatment group that received epidural anesthesia (preservative free morphine sulfate, 0.09 mg/kg; 1% ropivacaine, 0.2 mg/kg; total volume delivered, 1 mL/4.5 kg of body weight to a maximum of 10 mL; n = 9) or to a nonepidural control group (n = 13). Vital signs were monitored for 24 hours, and sedation and pain scores, behavioral assessments, and presence or absence of complications was evaluated for 5 days postprocedure. RESULTS: All dogs tolerated the epidural without complications. Four dogs were removed from the study because of status unblinding, lack of patient cooperation, or incomplete follow-up. No significant differences were noted in postprocedural pain scores in dogs that received epidural analgesia. Significant differences in postprocedural pain scores were noted in the nonepidural control group. No significant differences were noted in vital signs, behavioral assessments, or the proportion of dogs with a 50% increase in pain scores between the epidural and nonepidural groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Epidural anesthesia was well-tolerated. Dogs not receiving the epidural had poor postprocedural pain control. A consistent benefit for the epidural vs nonepidural group could not be identified. Additional studies are required to better assess the impact and efficacy of epidural anesthesia for cystoscopic procedures.

Effects of calcifediol supplementation on markers of chronic kidney disease-mineral and bone disorder in dogs with chronic kidney disease.

BACKGROUND: Chronic kidney disease-mineral and bone disorder (CKD-MBD) in dogs is associated with hypovitaminosis D, increased parathyroid hormone (PTH), and increased fibroblast growth factor-23 (FGF-23) concentrations. Best practice for vitamin D metabolite supplementation in CKD-MBD remains unknown. OBJECTIVE: To provide an extended-release calcifediol supplement to dogs with CKD and to measure its effects on variables indicative of CKD-MBD. ANIMALS: Ten dogs with International Renal Interest Society stages 2 and 3 CKD. METHODS: In a prospective study, dogs received a calcifediol supplement for 84 days. Serum 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH]2 D), 24,25-dihydroxyvitamin D (24,25[OH]2 D), creatinine, calcium, phosphorus, PTH, plasma FGF-23 concentrations, and urine profiles were measured monthly during supplementation. Urine calcium to creatinine (UCa/Cr) ratios and fractional excretion of calcium, phosphorus, and sodium were determined. RESULTS: All serum vitamin D metabolite concentrations increased significantly by day 84 (P < .001): [25(OH)D (median 249.9 ng/mL; range, 149.7-469.9 ng/mL) compared to baseline (median 50.2 ng/mL; range, 31.3-66.0 ng/mL); 1,25(OH)2 D (median 66.1 pg/mL; range, 56.9-88.1 pg/mL) compared to baseline (median 37.3 pg/mL; range, 29.3-56.7 pg/mL); 24,25(OH)2 D (median 81.4 ng/mL; range, 22.1-151.7 ng/mL) compared to baseline (median 15.4 ng/mL; range, 6.9-40.6 ng/mL)]. There were no significant differences in calcium, phosphorus, PTH concentrations, UCa/Cr or fractional excretion of calcium. No dog developed ionized hypercalcemia. Plasma FGF-23 concentrations increased by day 84 (median 1219 pg/mL; range, 229-8824 pg/mL) compared to baseline (median 798 pg/mL; range, 103-4.145 pg/mL) (P < .01). CONCLUSIONS AND CLINICAL IMPORTANCE: Calcifediol supplementation for 84 days was well-tolerated in dogs with IRIS stages 2 and 3 CKD. It remains to be determined how long-term supplementation would affect CKD progression and QOL.

Association between vitamin D metabolites, vitamin D binding protein, and proteinuria in dogs.

BACKGROUND: Proteinuria has been associated with progression of renal disease and increased morbidity and mortality in dogs and people. In people, proteinuria also has been associated with hypovitaminosis D. Little is known about the relationship between vitamin D metabolism and proteinuria in dogs. OBJECTIVES: To further elucidate vitamin D status in dogs with protein-losing nephropathy (PLN) and minimal to no azotemia. We hypothesized that vitamin D metabolites would be lower in dogs with PLN compared to healthy dogs. ANIMALS: Twenty-three client-owned adult dogs with PLN and 10 healthy control dogs. METHODS: Serum 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH]2 D), 24,25-dihydroxyvitamin D (24,25[OH]2 D), serum vitamin D binding protein (VDBP), and urine 25(OH)D concentrations were measured. RESULTS: Compared to healthy dogs, dogs with PLN had lower concentrations of all vitamin D metabolites (P < .01). Correlations (rho; 95% confidence interval [CI]) in dogs with PLN are reported. Serum 25(OH)D and 24,25(OH)2 D concentrations were positively correlated with albumin (r = 0.47; 0.07-0.74), and 24,25(OH)2 D was negatively correlated with urine protein-to-creatinine ratio (UPC; r = -0.54; -0.78 to -0.16). Urine 25(OH)D-to-creatinine ratio was negatively correlated with serum albumin concentration (r = -0.77; -0.91 to -0.50) and positively correlated with UPC (r = 0.79; 0.53-0.91). Serum VDBP concentration was positively correlated with serum albumin concentration (r = 0.53; 0.05-0.81). CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with PLN have decreased serum concentrations of vitamin D metabolites. Urine 25(OH)D-to-creatinine ratio and UPC are correlated in PLN dogs. Future studies are needed to assess additional management strategies for dogs with PLN.

Determination of a serum total calcium concentration threshold for accurate prediction of ionized hypercalcemia in dogs with and without hyperphosphatemia.

BACKGROUND: Total serum calcium (tCa) concentrations are poorly predictive of ionized calcium (iCa) status in dogs. HYPOTHESIS: There is an optimal threshold of tCa concentration that is highly predictive of ionized hypercalcemia and this threshold is higher in hyperphosphatemic dogs as compared to nonhyperphosphatemic dogs. ANIMALS: Nonhyperphosphatemic (n = 1593) and hyperphosphatemic (n = 250) adult dogs. METHODS: Retrospective medical record review of paired tCa and iCa concentration measurements in dogs presented to a university teaching hospital over a 5-year period. Positive and negative predictive values, sensitivity, and specificity were calculated for tCa concentration thresholds of 11.0-15.0 mg/dL (upper limit of laboratory reference interval = 11.5 mg/dL) in nonhyperphosphatemic and hyperphosphatemic groups. RESULTS: In nonhyperphosphatemic dogs, an optimal tCa concentration threshold of 12.0 mg/dL resulted in a positive predictive value of 93% (95% confidence interval [CI], 84%-98%) and sensitivity of 52% (95% CI, 43%-61%) for ionized hypercalcemia. An optimal tCa concentration threshold was not identified for hyperphosphatemic dogs. The nonhyperphosphatemic dogs had a higher prevalence of ionized hypercalcemia than the hyperphosphatemic dogs (7 versus 3%, P = .04) and a lower prevalence of ionized hypocalcemia (23 versus 62%, respectively; P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: High tCa concentrations are strongly predictive of ionized hypercalcemia in nonhyperphosphatemic adult dogs and should prompt further diagnostic testing to determine the underlying cause of hypercalcemia. In this population, dogs without increased tCa concentrations rarely had ionized hypercalcemia, but iCa concentrations still should be evaluated in patients with tCa concentrations within the reference interval if there is clinical suspicion for calcium abnormalities.

Association of abdominal effusion with a single decompressive cystocentesis prior to catheterization in male cats with urethral obstruction.

OBJECTIVE: To evaluate the occurrence of abdominal effusion and its association with decompressive cystocentesis in male cats with urethral obstruction. DESIGN: Prospective observational clinical study. ANIMALS: Forty-five male neutered, client-owned cats with naturally occurring urethral obstruction. PROCEDURES: Laboratory testing and point-of-care ultrasonography were performed. Presence of abdominal effusion was evaluated using the Focused Assessment with Sonography for Trauma (FAST) technique at presentation. Decompressive cystocentesis was then performed prior to catheterization by a standardized technique. Repeat FAST examination was performed 15 minutes after cystocentesis and the following day to further assess for the presence of abdominal effusion. RESULTS: A mean volume of 92.3 ± 35.2 mL of urine was removed from each cat via cystocentesis prior to catheterization. At presentation, 15 of 45 (33%) had abdominal effusion (13/15 with scant effusion, 2/15 with mild), with an additional 7 cats developing scant effusion 15 minutes post-cystocentesis. By the following day, 4 cats still had scant effusion present. No significant complications secondary to cystocentesis were reported. No association was found between severity of azotemia, or volume removed by cystocentesis, and the presence of effusion at presentation or after decompressive cystocentesis was performed. CONCLUSIONS AND CLINICAL RELEVANCE: A single decompressive cystocentesis prior to catheterization did not lead to development of clinically significant abdominal effusion or other discernable complications and appears to be a safe procedure in this population of patients. Abdominal effusion may be found at presentation in cats with urethral obstruction. The significance of this effusion remains to be determined.

Variability among four refractometers for the measurement of urine specific gravity and comparison with urine osmolality in dogs.

BACKGROUND: Refractometry is often used in clinical veterinary medicine to estimate urine concentration. Variability among commonly-used refractometers has not been critically evaluated. OBJECTIVE: This study aimed to evaluate the variability of urine specific gravity (USG) among four refractometers and compare results of USG measurements with those of urine osmolality (Uosm ), the gold standard for determining urine concentrations. METHODS: USG was determined in 100 dogs using three optical refractometers, the American Optical Abbe refractometer 10450, Reichert TS 400 refractometer, and Heska Veterinary refractometer 2737-E02, and one digital refractometer, the Misco Palm Abbe Digital refractometer #PA203. Results were compared between each pair of refractometers and between each refractometer and urine osmolality determined by freezing point depression using a Multi-Osmette 2430E osmometer. Results were analyzed with Bland-Altman plots and Passing-Bablok regression analysis. RESULTS: The Reichert, Heska, and Misco refractometers provide USG measurements that can be used interchangeably based on small differences, consistently less than 0.002, between the USG measurements. The AO refractometer measured USG values with much larger differences, which were deemed clinically significant by the study parameters. None of the refractometers were able to accurately predict Uosm or vice versa within a clinically acceptable range. CONCLUSIONS: Varying degrees of differences were seen in the USG measurements among the different refractometers. These differences were refractometer-dependent, and the results from one instrument could affect clinical decisions.

Incidence of bacteriuria at presentation and resulting from urinary catheterization in feline urethral obstruction.

OBJECTIVE: To determine the incidence of bacteriuria at the time of presentation and as a result of indwelling urethral catheterization in naturally occurring feline urethral obstruction (UO). DESIGN: Prospective observational study. SETTING: University teaching hospital. ANIMALS: A population of 34 male cats with UO admitted for standard medical care. INTERVENTIONS: A presenting urine sample was obtained by cystocentesis (precatheterization). After catheterization (performed under strict aseptic technique), a urine sample was obtained through the urinary catheter every 24 hours, as well as just prior to catheter removal. Urine was applied to culture media within 30 minutes of collection or refrigerated immediately at 4°C for subsequent culture the following morning. Samples positive for growth (defined as > 104 colony forming units/mL) had bacterial identification and susceptibility testing performed. MEASUREMENTS AND MAIN RESULTS: All 34 cats enrolled had initial culture performed. Of these, 1 patient died and 2 were euthanized within 24 hours and therefore subsequent cultures were obtained. The remaining 31 cats had median catheterization time of 42 hours (range 20-110 hours). No urine cultures yielded growth at presentation (0/34). A total of 4 of 31 patients (13%) subsequently had bacterial cultures that yielded growth. In these cases, all yielded growth by the 24-hour time point, and all had the same organism identified on subsequent cultures. Identified bacteria included Streptococcus spp. (3) and Pasteurella spp. (1). CONCLUSIONS: The male cats with UO in this study did not have bacteriuria at the time of presentation. The overall incidence of acquired bacteriuria was found to be 13% and could represent a transient bacterial population or true bacterial urinary tract infection. Based on these findings, empirical administration of antibiotics is not warranted in male cats with UO.

Vitamin D metabolism in dogs with and without hypercalciuric calcium oxalate urolithiasis.

BACKGROUND: There are abnormalities in vitamin D metabolism in people with calcium nephrolithiasis, but limited data are available on vitamin D status in dogs with calcium oxalate (CaOx) urolithiasis. OBJECTIVE: To compare serum concentrations of vitamin D metabolites in dogs with and without hypercalciuric CaOx urolithiasis. ANIMALS: Thirty-eight dogs with (n = 19) and without (n = 19) a history of CaOx urolithiasis and hypercalciuria. METHODS: Retrospective cross-sectional study. Serum 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2 D], and 24,25-dihydroxyvitamin D [24,25(OH)2 D] were measured. The ratios of 25(OH)D/24,25(OH)2 D and 1,25(OH)2 D/25(OH)D were compared between cases and controls. RESULTS: There were no significant differences between cases and controls when comparing 25(OH)D, 24,25(OH)2 D, 1,25(OH)2 D, or 1,25(OH)2 D/25(OH)D. Cases had higher 25(OH)D/24,25(OH)2 D (median = 1.40, range = 0.98-1.58) compared to controls (median = 1.16, range = 0.92-2.75; P = .01). There was overlap in the ranges for 25(OH)D/24,25(OH)2 D between cases and controls, but 6 cases (32%) had ratios above the control dog range. There was a moderate positive correlation between the ratio of 25(OH)D/24,25(OH)2 D and urinary calcium-to-creatinine ratios (r = 0.40, 95% confidence interval = 0.10-0.64; P = .01). CONCLUSIONS AND CLINICAL IMPORTANCE: These data suggest that decreased conversion of 25(OH)D to 24,25(OH)2 D occurs in a subset of dogs with CaOx urolithiasis. Abnormalities in vitamin D metabolism might contribute to stone risk in dogs.

Medication-related osteonecrosis of the jaw after long-term bisphosphonate treatment in a cat.

A 12-year-old, neutered female, domestic medium hair cat was evaluated for a nonhealing, oral mucosal ulceration. The cat had a history of idiopathic hypercalcemia that had been treated with a bisphosphonate for 41 months. Oral examination identified exposed maxillary bone adjacent to a previous extraction site. Histopathology of the exposed bone and associated mucosa was most consistent with medication-related osteonecrosis of the jaw. Treatment involved both medical and surgical interventions. Oral mucosal healing occurred after 6 months of treatment.

Factors associated with survival in dogs with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is associated with morbidity and mortality in dogs. Plasma fibroblast growth factor-23 (FGF-23) concentration is an independent predictor of CKD progression and survival in cats and people with CKD. OBJECTIVES: To investigate the relationship among FGF-23, parathyroid hormone (PTH), vitamin D metabolites, and other clinical variables with survival time in dogs with CKD. ANIMALS: Twenty-seven azotemic CKD dogs. METHODS: Dogs were recruited prospectively into the study and followed until death or study conclusion. Dogs were International Renal Interest Society (IRIS) staged into stage 2 (n = 9), stage 3 (n = 12), and stage 4 (n = 6) CKD. Survival times were calculated from the date of study inclusion. Univariable Cox regression was used to assess variables associated with survival including body condition score (BCS), muscle condition score, hematocrit, creatinine, CKD stage, serum phosphorus, urine protein:creatinine ratio (UPC), calcium phosphorus product (CaPP), PTH, 25-hydroxyvitamin D, 1,25--dihydroxyvitamin D, and FGF-23 concentrations. RESULTS: Significant hazard ratios (hazard ratio; 95% confidence interval; P value) were as follows: BCS < 4/9 (1.579; 1.003-2.282; P = .05), muscle atrophy (2.334; 1.352-4.030; P = .01), increased creatinine (1.383; 1.16-1.64; .01), hyperphosphatemia (3.20; 1.357-7.548; P = .005), increased UPC (3.191; 1.310-7.773; P = .01), increased CaPP (4.092; 1.771-9.454; P = .003), and increased FGF-23 (2.609; 1.090-6.240; P = .05). Survival times for each IRIS CKD stage were significantly different (P = .01). CONCLUSIONS AND CLINICAL IMPORTANCE: Multiple variables, including FGF-23, were associated with duration of survival in CKD dogs. FGF-23 could be a prognostic marker in dogs with CKD.

Effect of blood contamination on results of dipstick evaluation and urine protein-to-urine creatinine ratio for urine samples from dogs and cats.

OBJECTIVE To evaluate effects of blood contamination on dipstick results, specific gravity (SG), and urine protein-to-urine creatinine ratio (UPCR) for urine samples from dogs and cats. SAMPLE Urine samples collected from 279 dogs and 120 cats. PROCEDURES Urine pools were made for each species (dogs [n = 60] and cats [30]). Blood was added to an aliquot of a pool, and serial dilutions were prepared with the remaining urine. Color and dipstick variables were recorded, and SG and UPCR were measured. For cats, 1 set of pools was used; for dogs, 2 sets were used. Comparisons were made between undiluted urine and spiked urine samples for individual colors. Repeated-measures ANOVA on ranks was used to compare dipstick scores and UPCR results; χ2 tests were used to compare proteinuria categorizations (nonproteinuric, borderline, or proteinuric). RESULTS Any blood in the urine resulted in significantly increased dipstick scores for blood. In both species, scores for bilirubin and ketones, pH, and SG were affected by visible blood contamination. No significant difference for the dipstick protein reagent results was evident until a sample was visibly hematuric. The UPCR was significantly increased in dark yellow samples of both species. Proteinuria categorizations differed significantly between undiluted urine and urine of all colors, except light yellow. CONCLUSIONS AND CLINICAL RELEVANCE Any degree of blood contamination affected results of dipstick analysis. Effects depended on urine color and the variable measured. Microscopic blood contamination may affect the UPCR; thus, blood contamination may be a differential diagnosis for proteinuria in yellow urine samples.

Bilateral patellar fractures and increased cortical bone thickness associated with long-term oral alendronate treatment in a cat.

CASE SUMMARY: A 14-year-old cat presented with bilateral patellar fractures and radiographically thickened tibial cortices. This cat had been treated with alendronate for 8 years prior to presentation. To remove the subjectivity of the radiographic evaluation, tibial radiographs from 35 apparently healthy geriatric cats were used for comparison. Cortical and diaphyseal thickness were measured at the proximal and distal thirds of the tibia. Our cat had increased cortical bone thickness compared to that of the control cats. RELEVANCE AND NOVEL INFORMATION: Treatment with bisphosphonates can lead to brittle bones and fractures after prolonged use in humans. This is the first description of fractures and cortical bone changes that may have been associated with prolonged bisphosphonate use in a cat. Radiographic measurements of cortical bone thickness may identify cats that are at increased risk for bone pathology secondary to prolonged alendronate use.

Safety of Benazepril in 400 Azotemic and 110 Non-Azotemic Client-Owned Cats (2001-2012).

This retrospective study examined cats after initiation of benazepril therapy to determine the frequency of systemic hypotension or elevations in serum creatinine and/or potassium. Medical records review identified azotemic and non-azotemic cats prescribed benazepril. Blood pressure was recorded at the first available time after initiation of therapy. No cats experienced documented systolic systemic hypotension (<90 mmHg). Serum creatinine, and potassium when available, were recorded at baseline and in time windows after initiation of treatment: 1-30 days and 31-60 days. Blood chemistry results were screened for hyperkalemia (≥6.0 mEq/L). During the first 2 mo after starting benazepril therapy, there was a low incidence (3.7%) and clinically insignificant magnitude of hyperkalemia. Serum creatinine increases of greater than 30% from baseline were noted. This change was found in 11.0% of cats during the first 30 days of therapy and in 13.7% of cats from days 31-60 after initiation of therapy. The long-term survival of the cats that had >30% increases in creatinine from baseline was not statistically different from the survival of those that did not experience these increases, which suggests this finding may not be a reason to discontinue therapy. Benazepril appeared safe in a heterogeneous population of cats.

Update on Feline Ionized Hypercalcemia.

Hypercalcemia in cats is recognized with increased frequency, especially idiopathic hypercalcemia, which is the most common cause. Idiopathic hypercalcemia seems to be unique to the cat, not occurring in the dog as a specific syndrome. There are many causes of hypercalcemia, and diagnosis relies on evaluation of clinical signs, physical examination, diagnostic imaging, serum biochemistry, urinalysis, and evaluation of calcium metabolic hormones. With an accurate diagnosis, treatment options can be tailored to the individual.

A Quick Reference on Hypocalcemia.

Primary hypoparathyroidism should be considered in dogs with vague signs, including tremors, facial rubbing, and seizures. Ionized hypocalcemia should be considered in dogs with protein-losing enteropathy, especially lymphangiectasia caused by hypovitaminosis D. Ionized hypocalcemia typically occurs only in advanced chronic kidney disease.

A Quick Reference on Hypercalcemia.

In dogs, neoplasia is the most common cause of hypercalcemia, followed by primary hyperparathyroidism, chronic kidney disease, and hypoadrenocorticism. In cats, idiopathic hypercalcemia is the most common cause, followed by chronic kidney disease and then neoplasia. Prognosis and treatment ultimately depend on the cause of the hypercalcemia.