Renal Tubular Reabsorption Research Articles

Long-term adefovir therapy may induce Fanconi syndrome: A report of four cases.

Fanconi syndrome is a rare disease characterized by dysfunction of the proximal renal tubules as a result of various pathogenic events. Drug-induced Fanconi syndrome may be neglected or misdiagnosed, which increases the level of suffering. The aim of the present study was to conduct an investigation into the effects of adefovir (ADV)-induced Fanconi syndrome. Four typical cases of Fanconi syndrome caused by long-term ADV therapy (2-9 years) were diagnosed at our hospital. A complete medical and therapy history was collected from all four patients prior to a physical examination. Laboratory and diagnostic examinations were also conducted. Following this, the patients were diagnosed and a treatment regimen was decided upon. Outcomes of the treatment regimen were observed. Common manifestations of all the four patients were: Renal tubular reabsorption dysfunction; imbalanced electrolyte acid-base ratio; elevated cystatin C levels; severe hypophosphatemia and diffused systemic pain; osteoporosis; and difficultly walking. When ADV was replaced with supportive treatment, all the four patients exhibited symptom relief. These findings indicate that long-term ADV therapy may induce Fanconi syndrome. For patients with a history of such therapy, the possibility of Fanconi syndrome should be assessed and monitored closely for indicators, including altered glomerular and renal tubular function. Once diagnosed, the agent should be immediately discontinued and prompt symptomatic treatment should be administered.

Calcium Mediates the Phosphaturia in Hypercalcemia of Malignancy

Background: Humoral hypercalcemia of malignancy (HHM) is claimed to be caused by circulating parathyroid hormone like peptide (PTHrP) that shares several of the cardinal biochemical and skeletal histological features with hyperparathyroidism (HPT). Both syndromes are characterized by hypercalcemia from increased renal tubular reabsorption of filtered calcium, increased urinary cyclic AMP, renal phosphate wasting and hypophosphatemia, in contrast to low 1,25(OH)2D levels, metabolic alkalosis, and uncoupled bone formation-resorption rate in HHM. The aim of the study was to reassess if phosphaturia of HHM can be attributed to hypercalcemia rather than to humoral effect of PTHrP. Methods: A prospective study was conducted at Mount Sinai Services at Queens Hospital Center, NY. Results: Nine (four females and five males) out of 20 patients with hypercalcemia of malignancy documented having elevated PTHrP, normal renal function, and low PTH levels were finalized for the study. Serum calcium, phosphate, creatinine, albumin, and PTHrP concentration were determined. On the initiation of hydration, 24 h urine for creatinine, calcium and phosphorous were also collected. Blood and urine tests were repeated after serum calcium levels had been decreased by at least 1.5 mg/dL. All patients received vigorous intravenous hydration with normal saline at 200 cc/h. After the first 24 h, small doses of furosemide were given to two out of nine patients for 48 - 72 h. Hydration has shown statistically significant decrease in serum calcium concentration (13.9 ± 2.1 to 10.8 ± 1.48 mg/dL; P < 0.001) and increase in tubular reabsorption of phosphate (TRP) (69.54±8.16% to 77.85±12.24%; P < 0.01). However, PTHrP levels have shown no statistically significant difference on hydration therapy. Conclusion: Improvement of hypercalcemia by hydration reverses phosphaturia without reducing PTHrP levels. It is being proposed that in HHM, PTHrP can lead to hypercalcemia from uncoupled bone formation-resorption rate through a local autocrine or paracrine action produced by bony micrometastases that could not be demonstrated radiologically, rather than from PTHrP’s humoral effect. J Endocrinol Metab. 2017;7(2):55-60 doi: https://doi.org/10.14740/jem402w

A rare case of multiple phosphaturic mesenchymal tumors along a tendon sheath inducing osteomalacia

BackgroundTumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by renal phosphate wasting, hypophosphatemia, reduction of 1,25-dihydroxyl vitamin D, and bone calcification disorders. Tumors associated with TIO are typically phosphaturic mesenchymal tumors that are bone and soft tissue origin and often present as a solitary tumor. The high production of fibroblast growth factor 23 (FGF23) by the tumor is believed to be the causative factor responsible for the impaired renal tubular phosphate reabsorption, hypophosphatemia and osteomalacia. Complete removal of the tumors by surgery is the most effective procedure for treatment. Identification of the tumors by advanced imaging techniques is difficult because TIO is small and exist within bone and soft tissue. However, systemic venous sampling has been frequently reported to be useful for diagnosing TIO patients.Case presentationWe experienced a case of 39-year-old male with diffuse bone pain and multiple fragility fractures caused by multiple FGF23-secreting tumors found in the hallux. Laboratory testing showed hypophosphatemia due to renal phosphate wasting and high levels of serum FGF23. Contrast-enhanced MRI showed three soft tissue tumors and an intraosseous tumor located in the right hallux. Systemic venous sampling of FGF23 revealed an elevation in the right common iliac vein and external iliac vein, which suggested that the tumors in the right hallux were responsible for overproduction of FGF23. Thereafter, these tumors were surgically removed and subjected to histopathological examinations. The three soft tissue tumors were diagnosed as phosphaturic mesenchymal tumors, which are known to be responsible for TIO. The fourth tumor had no tumor structure and was consisting of hyaline cartilage and bone tissue. Immediately after surgery, we noted a sharply decrease in serum level of FGF23, associated with an improved hypophosphatemia and a gradual relief of systematic pain that disappeared within two months of surgery.ConclusionThe authors reported an unusual case of osteomalacia induced by multiple phosphaturic mesenchymal tumors located in the hallux. Definition of tumors localization by systemic venous sampling led to successful treatment and cure this patient. The presence of osteochondral tissues in the intraosseous tumor might be developed from undifferentiated mesenchymal cells due to high level of FGF23 produced by phosphaturic mesenchymal tumors.

Update on recent progress in vitamin D research. Vitamin D treatment for hypoparathyroidism.

The patients with hypoparathyroidism have been treated with active vitamin D(ie, alfacalcidol and calcitriol). Parathyroid hormone(PTH)increases extracellular calcium concentration partly through the activation of vitamin D, and active vitamin D corrects hypocalcemia mainly by increasing intestinal calcium abosorption. PTH coordinately increases blood calcium level with vitamin D in bone and kidney, however, renal tubular reabsorption of calcium is regulated by PTH-dependent mechanism. Hypercalciuria is an complication of long-term vitamin D treatment for PTH-deficient hypoparathyroidism.

Calcium and phosphorus metabolism and nutrition of poultry: are current diets formulated in excess?

Calcium (Ca) and phosphorus (P) are important nutrients in poultry diet formulations. In the present review, we discuss recent advances in our understanding of the metabolism of Ca and P in poultry. Recent data are provided in support of the proposition that current poultry diets are formulated in excess for Ca and P. The quantities of Ca and P available for metabolism reflect rates of intestinal absorption, bone accretion and resorption, glomerular filtration, renal tubular reabsorption, and intestinal endogenous losses. Ca and P homeostasis is largely under endocrine control. Parathyroid hormone and the hormonal form of vitamin D3 are the two hormones credited with this role. However, a novel hormonal axis involving Fibroblast Growth Factor 23 and Klotho has been recently delineated, which, in conjunction with parathyroid hormone and vitamin D3, tightly regulates Ca and P homeostasis. Recent studies have suggested that current commercial diets for both broilers and layers contain excess Ca and P, the content of which could be reduced without affecting production or bird welfare. The challenge in reducing Ca and P concentrations in poultry diets is the uncertainty about what concentrations of Ca and P can be fed without compromising bird welfare. This is because there are limited data on the available P and Ca concentrations in poultry feedstuffs determined biologically. This is further complicated by the need for agreement on evaluation systems for evaluation of Ca and P bioavailability. We conclude that direct ileal or pre-caecal digestible Ca and P values are preferred.

Is the renal kallikrein-kinin system a factor that modulates hypercalciuria?

Renal tubular calcium reabsorption is one of the principal factors that determine serum calcium concentration and calcium excretion. Calcium excretion is regulated by the distal convoluted tubule and connecting tubule, where the epithelial calcium channel TRPV5 can be found, which limits the rate of transcellular calcium transport. The dynamic presence of the TRPV5 channel on the surface of the tubular cell is mediated by an endosomal recycling process. Different intrarenal factors are involved in calcium channel fixation in the apical membrane, including the anti-ageing hormone klotho and tissue kallikrein (TK). Both proteins are synthesised in the distal tubule and secreted in the tubular fluid. TK stimulates active calcium reabsorption through the bradykinin receptor B2 that compromises TRPV5 activation through the protein kinase C pathway. TK-deficient mice show hypercalciuria of renal origin comparable to that seen in TRPV5 knockout mice. There is a polymorphism with loss of function of the human TK gene R53H (allele H) that causes a marked decrease in enzymatic activity. The presence of the allele H seems to be common at least in the Japanese population (24%). These individuals have a tendency to greater calcium and sodium excretion in urine that is more evident during furosemide infusion. Future studies should analyse if manipulating the renal kallikrein-kinin system can correct idiopathic hypercalciuria with drugs other than thiazide diuretics.

The renal effects of SGLT2 inhibitors and a mini-review of the literature.

Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a new and promising class of antidiabetic agents which target renal tubular glucose reabsorption. Their action is based on the blockage of SGLT2 sodium-glucose cotransporters that are located at the luminal membrane of tubular cells of the proximal convoluted tubule, inducing glucosuria. It has been proven that they significantly reduce glycated hemoglobin (HbA1c), along with fasting and postprandial plasma glucose in patients with type 2 diabetes mellitus (T2DM). The glucosuria-induced caloric loss as well as the osmotic diuresis significantly decrease body weight and blood pressure, respectively. Given that SGLT2 inhibitors do not interfere with insulin action and secretion, their efficacy is sustained despite the progressive β-cell failure in T2DM. They are well tolerated, with a low risk of hypoglycemia. Their most frequent adverse events are minor: genital and urinal tract infections. Recently, it was demonstrated that empagliflozin presents a significant cardioprotective effect. Although the SGLT2 inhibitors' efficacy is affected by renal function, new data have been presented that some SGLT2 inhibitors, even in mild and moderate renal impairment, induce significant HbA1c reduction. Moreover, recent data indicate that SGLT2 inhibition has a beneficial renoprotective effect. The role of this review paper is to explore the current evidence on the renal effects of SGLT2 inhibitors.

Di- and tripeptide transport in vertebrates: the contribution of teleost fish models.

Solute Carrier 15 (SLC15) family, alias H+-coupled oligopeptide cotransporter family, is a group of membrane transporters known for their role in the cellular uptake of di- and tripeptides (di/tripeptides) and peptide-like molecules. Of its members, SLC15A1 (PEPT1) chiefly mediates intestinal absorption of luminal di/tripeptides from dietary protein digestion, while SLC15A2 (PEPT2) mainly allows renal tubular reabsorption of di/tripeptides from ultrafiltration, SLC15A3 (PHT2) and SLC15A4 (PHT1) possibly interact with di/tripeptides and histidine in certain immune cells, and SLC15A5 has unknown function. Our understanding of this family in vertebrates has steadily increased, also due to the surge of genomic-to-functional information from 'non-conventional' animal models, livestock, poultry, and aquaculture fish species. Here, we review the literature on the SLC15 transporters in teleost fish with emphasis on SLC15A1 (PEPT1), one of the solute carriers better studied amongst teleost fish because of its relevance in animal nutrition. We report on the operativity of the transporter, the molecular diversity, and multiplicity of structural-functional solutions of the teleost fish orthologs with respect to higher vertebrates, its relevance at the intersection of the alimentary and osmoregulative functions of the gut, its response under various physiological states and dietary solicitations, and its possible involvement in examples of total body plasticity, such as growth and compensatory growth. By a comparative approach, we also review the few studies in teleost fish on SLC15A2 (PEPT2), SLC15A4 (PHT1), and SLC15A3 (PHT2). By representing the contribution of teleost fish to the knowledge of the physiology of di/tripeptide transport and transporters, we aim to fill the gap between higher and lower vertebrates.

Tetany Secondary to the Use of a Proton-Pump Inhibitor

Introduction: Chronic PPI use has been reported to cause hypocalcemia, bone density loss and osteoporoticrelated fractures but an acute drop in serum calcium level with PPI use is rare. We present a rare case of symptomatic hypocalcemia with 2 weeks use of PPI. Case Report: 61-year-old female with past medical history of hypothyroidism and hypoparathyroidism secondary to thyroidectomy and parathyroidectomy came to the emergency department(ED) with complaints of spasm and twitching of her upper extremities associated with lethargy and difficulty ambulation. 2 weeks prior to this presentation patient had upper endoscopy done for dyspepsia which showed antral erythema and stomach biopsies came back positive for Helicobacter Pylori gastritis. Patient started taking omeprazole after the endoscopy and later she was given antibiotics treatment for Helicobacter Pylori which she started taking three days prior to the ED presentation. Prior to initiate the omeprazole patient's serum calcium was 8.1 mg/DL. The patient has been taking magnesium citrate 200 mg two times a day and calcium carbonate 1200 mg daily with meals since surgery. No recent change in the dosage of these medications. In ED, EKG done showed QT prolongation, serum calcium was 5.7 mg/DL, magnesium was 1.7 mg/DL and albumin was 3.3 g/DL Thyroid function was within normal limit and parathyroid hormone(PTH) was Discussion Gastric acidic PH is required for absorption of the calcium. Calcium carbonate is a widely use form of calcium supplement which become soluble in the gastric acidic PH and then get absorb in the small intestine. PPI increase the gastric PH so decrease the absorption of calcium which later can cause hypocalcemia. This effect is more seen in the patient with low PTH as it plays a key role in maintaining the serum calcium level within normal limit by stimulating bone resorption, renal tubular calcium reabsorption, and by enhancing gastrointestinal absorption of calcium. The patients with hypoparathyroidism when take PPI their serum calcium needs to be closely monitored to avoid the life threatening complication of hypocalcemia and should be advised to take calcium citrate as a calcium supplement which does not require gastric acidic PH.

Role of the renal sympathetic nerves in renal sodium/potassium handling and renal damage in spontaneously hypertensive rats.

Renal sympathetic nerve activity has an important role in renal disease-associated hypertension and in the modulation of fluid homeostasis. In the present study, changes in renal function and renal sodium/potassium handling were investigated in groups of 12-week-old male, spontaneously hypertensive rats with renal denervation (RDNX group) or sham denervation (sham group). The RDNX group excreted significantly more sodium than the sham group during the 2-week observation period (P<0.05). Following bilateral renal denervation, the fractional lithium excretion was elevated in the RDNX group compared with the sham group, but no significant effect was observed of renal denervation on the fractional distal reabsorption rate of sodium or the fractional excretion of potassium. Furthermore, the glomerular injury score and the wall-to-lumen ratio of the interlobular artery were significantly lower in the RDNX group than in the sham group (P<0.05). In conclusion, the present study indicates an involvement of the renal sympathetic nerves in the regulation of renal tubular sodium reabsorption in spontaneously hypertensive rats and in the renal damage associated with hypertension.

Abstract 050: mir-192-5p in the Kidney is Protective Against the Development of Hypertension

MicroRNAs (miRs) are short RNAs that primarily reduce protein abundance by base-paring with their target mRNA. The role of most miRs in the development of hypertension remains unknown. We performed a deep sequencing analysis of miR expression in human kidney biopsies with hypertensive nephrosclerosis or without any significant injury. miR-192-5p was one of the most abundant miRs detected and was down-regulated in hypertensive nephrosclerosis. Previous studies have shown that miR-192-5p targets the beta 1 subunit of Na/K-ATPase which drives renal tubular reabsorption. We hypothesized that miR-192-5p in the kidney protects against hypertension. We used the Dahl salt sensitive (SS) rat and a congenic rat SS.13BN26 (L26) with reduced salt sensitivity as well as Mir192 knockout mice (KO) to test this hypothesis. SS rats had a decreased level of abundance of miR-192-5p in the renal cortex compared to the L26 rats (n=9, p&lt;0.05). The protein abundance of the beta 1 subunit of Na/K-ATPase was higher in the SS rat compared to the L26 rat (n= 3, p&lt;0.05). Treatment with anti-miR-192-5p, delivered directly into the kidney through renal artery injection, in uninephrectomized L26 rats significantly exacerbated hypertension. Mean arterial blood pressure (MAP) of L26 rats treated with anti-miR-192-5p reached 151+/-5 mmHg at day 14 post anti-miR treatment and 4% NaCl (HS) diet, which was significantly higher than L26 rats treated with a control anti-miR and HS (135+/-5 mmHg, n=6 and 8, p&lt;0.05). Tissues were collected in additional groups of rats at 9 days after anti-miR injection, which was just before MAP became significantly different between the two groups, for analysis of Na/K-ATPase activity. Na/K-ATPase activity was increased in the renal cortex of rats treated with anti-miR-192-5p compared to control anti-miR (9.8 +/-1.8μmole/min/μg vs 7.2+/-1.3μmole/min/μg, n=5 and 6, p&lt;0.05). Furthermore, Mir192 KO mice treated with 1μg/Kg/min of Angiotensin II and HS for 14 days exhibited an increased MAP compared to wild-type (WT) mice (190+/-4 mmHg vs 167+/-12 mmHg; n= 3 WT and 5 KO, p&lt;0.05). In conclusion, miR-192, particularly miR-192-5p in the kidney, confers significant protection against the development of hypertension.

¿Es el sistema calicreína/quinina renal un factor modulador de la calciuria?

Renal tubular calcium reabsorption is one of the principal factors that determine serum calcium concentration and calcium excretion. Calcium excretion is regulated by the distal convoluted tubule and connecting tubule, where the epithelial calcium channel TRPV5 can be found, which limits the rate of transcellular calcium transport. The dynamic presence of the TRPV5 channel on the surface of the tubular cell is mediated by an endosomal recycling process. Different intrarenal factors are involved in calcium channel fixation in the apical membrane, including the anti-ageing hormone klotho and tissue kallikrein (TK). Both proteins are synthesised in the distal tubule and secreted in the tubular fluid. TK stimulates active calcium reabsorption through the bradykinin receptor B2 that compromises TRPV5 activation through the protein kinase C pathway. TK-deficient mice show hypercalciuria of renal origin comparable to that seen in TRPV5 knockout mice. There is a polymorphism with loss of function of the human TK gene R53H (allele H) that causes a marked decrease in enzymatic activity. The presence of the allele H seems to be common at least in the Japanese population (24%). These individuals have a tendency to greater calcium and sodium excretion in urine that is more evident during furosemide infusion. Future studies should analyse if manipulating the renal kallikrein-kinin system can correct idiopathic hypercalciuria with drugs other than thiazide diuretics.

Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis.

The prevalence of obesity-related glomerulopathy is increasing in parallel with the worldwide obesity epidemic. Glomerular hypertrophy and adaptive focal segmental glomerulosclerosis define the condition pathologically. The glomerulus enlarges in response to obesity-induced increases in glomerular filtration rate, renal plasma flow, filtration fraction and tubular sodium reabsorption. Normal insulin/phosphatidylinositol 3-kinase/Akt and mTOR signalling are critical for podocyte hypertrophy and adaptation. Adipokines and ectopic lipid accumulation in the kidney promote insulin resistance of podocytes and maladaptive responses to cope with the mechanical forces of renal hyperfiltration. Although most patients have stable or slowly progressive proteinuria, up to one-third develop progressive renal failure and end-stage renal disease. Renin-angiotensin-aldosterone blockade is effective in the short-term but weight loss by hypocaloric diet or bariatric surgery has induced more consistent and dramatic antiproteinuric effects and reversal of hyperfiltration. Altered fatty acid and cholesterol metabolism are increasingly recognized as key mediators of renal lipid accumulation, inflammation, oxidative stress and fibrosis. Newer therapies directed to lipid metabolism, including SREBP antagonists, PPARα agonists, FXR and TGR5 agonists, and LXR agonists, hold therapeutic promise.

Effect of four monthly doses of a human monoclonal anti-FGF23 antibody (KRN23) on quality of life in X-linked hypophosphatemia

X-linked hypophosphatemia (XLH) is characterized by lower extremity deformities that lead to bone and/or joint pain that result from decreased renal tubular reabsorption leading to hypophosphatemia caused by elevated levels of fibroblast growth factor 23 (FGF23). ObjectiveValidate the use of SF-36v2 Health Survey (SF-36v2) and the Western Ontario and McMaster Osteoarthritis Index (WOMAC) to measure previously unstudied health-related quality of life (HRQoL) in XLH patients and determine the change in HRQoL before and after treatment with KRN23, a human monoclonal anti-FGF23 antibody. MethodsTwenty-eight adult outpatients with XLH received up to four doses of KRN23 administered subcutaneously every 28days. General HRQoL was measured with the SF-36v2 and condition-related HRQoL with the WOMAC at baseline and study endpoint as a secondary outcome of a Phase 1/2, open-label, multicenter, dose-escalation trial. ResultsTesting for scale discriminant validity and convergent-divergent validity supported the use of these scales in the assessment of HRQoL in XLH. Both instruments indicated impairment of physical function at baseline with all mean scores showing a trend to improved health at study endpoint compared to baseline. When corrected for multiple comparisons, the score for Role Limitations due to physical health on the SF-36v2 which measures the patient's perception of their own chronic functional impairments due to poor physical health remained significantly improved (P<0.05), increasing to the mean score of US adults. For the WOMAC, Physical Functioning and Stiffness scores were significantly improved (P<0.05). ConclusionKRN23 administration was associated with significantly improved patient perception of their Physical Functioning and Stiffness due to their disease. This study demonstrates that the SF-36v2 and WOMAC are valid tools for assessing HRQoL in XLH.

Effects of exenatide on glycemia and renal water and ion excretion differ in frogs and rats

The aim of this study was to compare the effects of exenatide, a glucagon-like peptide-1 (GLP-1) mimetic, on glucose and water–salt homeostasis in animals with different levels of renal proximal tubular reabsorption, rats (Rattus norvegicus) and frogs (Rana temporaria). Following the glucose tolerance test, in rats exenatide promoted fast recovery of normoglycemia, whereas in frogs it delayed this process. In water-loaded rats, exenatide augmented solute-free water clearance and enhanced natriuresis in furosemide-treated animals. In frogs, exenatide did not alter the urinary flow rate, urinary sodium excretion and solute-free water clearance under water diuresis and furosemide treatment. It is suggested that the involvement of GLP-1 in regulation of water–salt homeostasis in mammals was preceded by a key evolutionary transformation, the increase in the glomerular filtration rate and proximal tubular reabsorption.

Renal Fanconi Syndrome Is Caused by a Mistargeting-Based Mitochondriopathy.

We recently reported an autosomal dominant form of renal Fanconi syndrome caused by a missense mutation in the third codon of the peroxisomal protein EHHADH. The mutation mistargets EHHADH to mitochondria, thereby impairing mitochondrial energy production and, consequently, reabsorption of electrolytes and low-molecular-weight nutrients in the proximal tubule. Here, we further elucidate the molecular mechanism underlying this pathology. We find that mutated EHHADH is incorporated into mitochondrial trifunctional protein (MTP), thereby disturbing β-oxidation of long-chain fatty acids. The resulting MTP deficiency leads to a characteristic accumulation of hydroxyacyl- and acylcarnitines. Mutated EHHADH also limits respiratory complex I and corresponding supercomplex formation, leading to decreases in oxidative phosphorylation capacity,mitochondrial membrane potential maintenance, and ATP generation. Activity of the Na(+)/K(+)-ATPase is thereby diminished, ultimately decreasing the transport activity of the proximal tubule cells.

Hypercalcemia of Malignancy: A New Twist on an Old Problem.

Hypercalcemia associated with malignancy is an old clinical problem, first described by Fuller Albright more than 50 years ago. It can cause significantmorbidity in patients with cancer and is associated with a poor prognosis in most patients. Thus, it is important to understand the pathophysiology to properly diagnosis and treat this important clinical syndrome. The accompanying article by Goldner presents a comprehensive review of this topic, which includes the latest addition to our therapeutic armamentarium to lower pathologic increases in serum calcium concentration: the receptor activator of nuclear factor k B–ligand antibody denosumab. Goldnermakes several important points in this review. First, the clinician must determine if the hypercalcemia is indeed a result of malignancy, rather than just associated with a nonmalignant cause of hypercalcemia such as primary hyperparathyroidism. After this has been established, treatment is directed against the cancer as well as thehypercalcemia. Tumor-produced systemic factors, such as parathyroid hormone–related peptide (PTHrP) or 1,25dihydroxyvitaminD, or locally active factors in bone, such as interleukin-6 or tumor necrosis factor-a, disrupt normal calcium homeostasis by excessive stimulation of osteoclastic bone resorption, in addition to lesser effects, to increase renal tubular reabsorption of calcium to result in hypercalcemia. As such, the mainstay of supportive care is to block pathologic osteoclast activity and maintain adequate hydration. For many years, this therapy consisted of bisphosphonates and fluid hydration, and for the most part was effective, particularly with the advent of the potent bisphosphonate zoledronic acid. As therapy evolved to include the most potent bisphosphonates, our understanding of the pathophysiology also evolved. The discovery thatmost tumor osteolytic factors, either humoral or local, stimulated bone resorption via receptor activator of nuclear factor k B–ligand led to more potent therapy to block osteoclastic bone resorption with the monoclonal antibody denosumab directed against this powerful stimulator of osteoclast formation and resorption. Indeed, recent reports indicate that denosumab is effective to reduce serum calcium concentration in the setting of bisphosphonate resistance and is more effective than zoledronic acid to prevent hypercalcemia associated with bone metastases. One downside to this new and more potent treatment is the increased risk of hypocalcemia. Thus, calcium should be closely monitored with the use of denosumab. Furthermore, because the studies describing denosumab use are small or retrospective analyses, further clinical studies using denosumab in the setting of hypercalcemia of malignancy are indicated. A future molecular target for the treatment of hypercalcemiaofmalignancy involvesPTHrPrelated antibodies. In an animal model, PTHrP antibodies corrected hypercalcemia and also suppressed the release of cytokines associated with malignancy. Taken together, insight into the pathogenesis of hypercalcemia ofmalignancy has resulted in new and better therapy for an old but difficult clinical problem.

Lipid-based nutrient supplements containing vitamins and minerals attenuate renal electrolyte loss in HIV/AIDS patients starting antiretroviral therapy: A randomized controlled trial in Zambia

Advanced HIV infection combined with undernutrition and antiretroviral therapy (ART) places HIV/AIDS patients at high risk of electrolyte abnormalities and increased morbidity and mortality. Here, in a sub-study of a large published randomized trial, we evaluated if nutritional supplements will help curtail renal electrolyte loss in HIV/AIDS patients starting ART. 130 malnourished HIV-positive patients referred for ART received lipid-based nutrient supplements alone (LNS, n=63) or together with vitamins and minerals (LNS-VM, n=67). Serum and spot urine samples were collected and assayed for creatinine, potassium, magnesium and phosphate concentrations at baseline and after 12 weeks of ART, and fractional excretion and reabsorption were calculated using standard equations. Eighteen (28.6%) patients from the LNS and 16 (23.9%) from LNS-VM groups died, most during the referral interval before starting ART. Phosphate excretion at baseline, was high in both LNS (mean±SD: 1.2±0.6mg/mg creatinine) and LNS-VM (1.1±0.8mg/mg creatinine) groups relative to normal physiological ranges. Phosphate excretion remained high in the LNS group (1.1±0.41mg/mg creatinine) but significantly decreased in the LNS-VM group (0.6±0.28mg/mg creatinine; p<0.001) after 12 weeks of ART. This difference is probably explained by increased renal tubular reabsorption of phosphate in the LNS-VM group (88.3±5.7%) compared to the LNS group (76.6±8.9%). The fractional excretion of potassium (FEK) was not significantly different at baseline between the two groups (p=0.69) but the values were above normal physiological ranges (i.e. >6.4%) reflecting renal potassium wasting. However, FEK was significantly lowered in the LNS-VM group (6.2±3.4%) but not in the LNS group (12.8±4.7%) after 12 weeks of ART (p<0.001). Finally, the fractional excretion of magnesium was not significantly different between the two groups at baseline (p=0.68) and remained unchanged within normal physiological ranges at 12 weeks of ART (p=0.82) in both groups. The LNS-VM regimen appeared to offer protection against phosphate and potassium loss during HIV/AIDS treatment. This offers potential opportunities to improve care and support of poorly nourished HIV-infected patients in resource-limited settings. www.pactr.org ID number: PACTR201106000300631.

Novel minimal physiologically-based model for the prediction of passive tubular reabsorption and renal excretion clearance

PurposeDevelop a minimal mechanistic model based on in vitro–in vivo extrapolation (IVIVE) principles to predict extent of passive tubular reabsorption. Assess the ability of the model developed to predict extent of passive tubular reabsorption (Freab) and renal excretion clearance (CLR) from in vitro permeability data and tubular physiological parameters. MethodsModel system parameters were informed by physiological data collated following extensive literature analysis. A database of clinical CLR was collated for 157 drugs. A subset of 45 drugs was selected for model validation; for those, Caco-2 permeability (Papp) data were measured under pH6.5–7.4 gradient conditions and used to predict Freab and subsequently CLR. An empirical calibration approach was proposed to account for the effect of inter-assay/laboratory variation in Papp on the IVIVE of Freab. ResultsThe 5-compartmental model accounted for regional differences in tubular surface area and flow rates and successfully predicted the extent of tubular reabsorption of 45 drugs for which filtration and reabsorption were contributing to renal excretion. Subsequently, predicted CLR was within 3-fold of the observed values for 87% of drugs in this dataset, with an overall gmfe of 1.96. Consideration of the empirical calibration method improved overall prediction of CLR (gmfe=1.73 for 34 drugs in the internal validation dataset), in particular for basic drugs and drugs with low extent of tubular reabsorption. ConclusionsThe novel 5-compartment model represents an important addition to the IVIVE toolbox for physiologically-based prediction of renal tubular reabsorption and CLR. Physiological basis of the model proposed allows its application in future mechanistic kidney models in preclinical species and human.

Thiazide-Associated Hypercalcemia: A Population-Based Study

Thiazide diuretics can increase renal tubular reabsorption of calcium, resulting in hypercalcemia. However, thiazide-associated hypercalcemia also can