Effects of temporary sacral nerve stimulation on gastrointestinal motility and function in patients with chronic refractory slow-transit constipation.

BACKGROUND: The efficacy of sacral nerve stimulation (SNS) on patients with chronic refractory slow-transit constipation is controversial and its mechanism of action on gastrointestinal motility and transit is not fully understood. The aim of this study was to document the effects of temporary SNS on the gastrointestinal and biliary tract motility and on gastrointestinal transit in patients with refractory slow-transit constipation. METHODS: This was a prospective interventional study. Patients with slow-transit chronic constipation, unresponsive to any conservative treatment, were enrolled between January 2013 and December 2018. Patients' quality of life [patient assessment of constipation quality of life (PAC-QOL) questionnaire], constipation scores (Cleveland Clinic Constipation Score) colonic transit time (CTT), orocecal transit time (OCTT), gastric and gallbladder kinetics, together with the assessment of the autonomic nerve function were evaluated before and during temporary SNS. RESULTS: 14 patients (12 females, median age 38 years, range 24-42 years) had temporary SNS. The Cleveland Clinic Constipation Score did not change compared to baseline (23 ± 3 vs 21.4; p = 070). The PAC-QOL did not improve significantly during the stimulation period. Gallbladder/stomach motility (half-emptying time) did not change significantly before and after SNS. OCTT was delayed at baseline, as compared to standard internal normal values, and did not change during SNS. CTT did not improve significantly, although in two patients it decreased substantially from 97 to 53 h, and from 100 to 65 h. CONCLUSIONS: Temporary SNS did not have any effect on upper/lower gastrointestinal motility and transit in patients with severe constipation.

Reproducibility and validity of the Italian version of the International Physical Activity Questionnaire in obese and diabetic patients.

PURPOSE: Aims of this study were to evaluate the agreement between the short and long versions of the International Physical Activity Questionnaire (IPAQ: Italian versions), their reproducibility (agreement and reliability) and construct validity (relative to pedometry) in a clinical population. METHODS: Ninety patients affected by obesity (N = 39), type 2 diabetes mellitus (N = 26) or both (N = 25) were recruited. They were asked to maintain their usual physical activity habits during two consecutive weeks and to fill the questionnaires twice (at the end of each week). They were also asked to wear a pedometer for 7 consecutive days after the first administration of the questionnaires. RESULTS: We found acceptable agreement between the IPAQ short and long versions (ICC2,1 values were 0.81 and 0.77 for the 1st and 2nd administration), uncertain reproducibility (acceptable reliability but poor agreement) and inadequate validity relative to pedometry (the correlation coefficients between all IPAQ scores and daily steps were <0.50) for both IPAQ short and IPAQ long. CONCLUSIONS: The IPAQ use may be justified in daily clinical practice and in clinical research (e.g., in cross-sectional studies) for a simple and rapid evaluation of the physical activity level for discriminative purposes. However, the use of these questionnaires does not appear suitable for prospective interventional studies in which the level of physical activity of the recruited patients has to be assessed over time.

Fecal microRNA profile in patients with colorectal carcinoma before and after curative surgery.

PURPOSE: The purpose of this study was to explore the potential role of deranged fecal microRNA (miRNA) pattern as a reliable warning signal of colorectal cancer (CRC), a subset of fecal CRC-related miRNAs was evaluated in CRC patients, before and after surgery, and in healthy controls. METHODS: Twenty CRC patients and 20 age/sex-matched healthy volunteers with negative colonoscopy entered the study. Cancer biopsy, colonic mucosa from the resected specimens, and fecal samples from patients and controls were screened for 13 miRNAs involved in CRC onset and progressions by reverse transcription quantitative PCR (RT-qPCR). Postoperative evaluation of fecal miRNAs was carried out after a median follow-up of 18 months (range 12-30). RESULTS: Two out 13 miRNAs (RNU6B, miR-16-3p) were used as internal controls leaving 11 available for analysis. Cancer tissue contained significantly higher expression of all miRNAs, compared to normal mucosa (p < 0.05). Expression of preoperative levels of five fecal miRNAs, (miR-19-b-3p, miR-20a-5p, miR-21-3p, miR92a-3p, miR141) was significantly higher in CRC patients compared to controls and significantly decreased after curative surgery. Three out of these five miRNAs (miR20a-5p, miR21-3p, and miR141) returned to values comparable to normal controls. CONCLUSIONS: A set of three specific fecal miRNAs is overexpressed before surgery, and return within the normal range after cancer removal could be considered as an appealing opportunity for a new reliable tool for CRC secondary prevention. However, their role needs to be explored in large prospective trials and compared with the existing screening tools.

Unexpected discovery of massive liver echinococcosis. A clinical, morphological, and functional diagnosis.

We report a case of symptomatic massive liver echinococcosis due to Echinococcus granulosus, unexpectedly found in a 34 year old woman living in Apulia, Italy. Based on size (max diameter 18 cm), clinical presentation, geographical area, and natural history of echinococcosis, we estimate that the initial infection should have occurred 9-20 yrs before. Presenting symptoms were those of typical mass effect with RUQ pain, pruritus, malaise, and recent weight loss. Abdominal ultrasound diagnosis of probable echinococcal cyst was subsequentely confirmed by positive serology and further detailed by radiological imaging. The cyst was massively occupying subdiaphragmatic liver segments and extending to the omentum and the stomach. The characteristics of the lesion were compatible with the WHO 2003 classification type CE2l, indicating a large active fertile cyst with daughter cysts. The cyst was successfully treated with medical therapy followed by surgery. The prevalence, diagnostic workup, management, and costs of echinococcosis are discussed in this case presentation.

The morphology and application of stem cells in digestive system surgery.

BACKGROUND: Stem cells constitute a group of cells which possess the ability to self-renew as well as the capacity to differentiate into a vast number of different cells within the human organism. Moreover, stem cells are able to undergo a potentially unlimited number of divisions and this characteristic is clinically essential. Specific fields of its application include treatment of diseases mainly in the field of haematology, orthopaedics, surgery, dentistry, and neurology. MATERIALS AND METHODS: In the following work, the current knowledge concerning mechanisms of stem cell treatment in different parts of the digestive system with its diseases as well as adjacent therapy for surgery has been revised. RESULTS: Stem cells therapy may be used in the treatment of various diseases of different parts of the digestive system. This also applies to the end part of the digestive tract (proctological diseases) because stem cells can be used to treat fistulas. Liposuction allows more recovery of mesenchymal stem cells, compared to previous bone marrow harvesting methods. Despite the application of stem cells in the treatment of different diseases used for many years so far, the therapeutic use for the regeneration of the gastrointestinal tract is still rare and unfamiliar. CONCLUSIONS: Regenerative medicine seems to be a promising tool in medical research, especially when insulated cells and designed biomaterials are taken into consideration. Major points of discussion include types of stem cells, their origin or differentiation for the treatment of many diseases.

Impact of adipokines and myokines on fat browning.

Since the discovery of leptin in 1994, the adipose tissue (AT) is not just considered a passive fat storage organ but also an extremely active secretory and endocrine organ that secretes a large variety of hormones, called adipokines, involved in energy metabolism. Adipokines may not only contribute to AT dysfunction and obesity, but also in fat browning, a process that induces a phenotypic switch from energy-storing white adipocytes to thermogenic brown fat-like cells. The fat browning process and, consequently, thermogenesis can also be stimulated by physical exercise. Contracting skeletal muscle is a metabolically active tissue that participates in several endocrine functions through the production of bioactive factors, collectively termed myokines, proposed as the mediators of physical activity-induced health benefits. Myokines affect muscle mass, have profound effects on glucose and lipid metabolism, and promote browning and thermogenesis of white AT in an endocrine and/or paracrine manner. The present review focuses on the role of different myokines and adipokines in the regulation of fat browning, as well as in the potential cross-talk between AT and skeletal muscle, in order to control body weight, energy expenditure and thermogenesis.

Medicinal treatments of cholesterol gallstones: old, current and new perspectives.

Cholesterol cholelithiasis is one of the most common and costly digestive diseases. Although gallstones are usually asymptomatic and no treatment is generally required, it is imperative to treat symptomatic gallstones with or without complicated conditions. Laparoscopic cholecystectomy is first-line therapy for symptomatic gallstones. By contrast, a cautious study on the natural history of the disease and costs of therapy, indicates that non-surgical treatment of gallstones is currently restricted to a subgroup of patients with mild symptoms or with small radiolucent cholesterol gallstones in a functioning gallbladder. Appropriate selection of patients suitable for medical therapy is therefore of key importance. Oral litholysis with the hydrophilic bile acid ursodeoxycholic acid induces cholesterol desaturation of bile and may lead to gallstone dissolution in patients with small, radiolucent, cholesterol-enriched stones in a functioning gallbladder with a patent cystic duct. Recent studies from experimental animal models and preliminary findings in humans also suggest that blocking intestinal absorption of cholesterol with the powerful, specific, and effective NPC1L1 inhibitor ezetimibe, may offer a novel and exciting strategy for the treatment of cholesterol gallstones. A similar possibility might arise from manipulation of specific nuclear receptors involved in cholesterol and bile acid homeostasis. Current views and perspectives on medicinal treatment of cholesterol gallstone disease are discussed here.

Biliary proteins and their redox status changes in gallstone patients.

BACKGROUND: Proteins might act as pronucleating agents of cholesterol crystallization in bile. However, little is known about the redox status of biliary proteins in humans and their interaction with crystallization of biliary cholesterol. MATERIALS AND METHODS: Gallbladder biles were obtained at cholecystectomy from 86 symptomatic patients with either cholesterol gallstones (32 multiple and 32 solitary stones) or pigment stones (n = 22), and studied for protein redox status [carbonyl and sulfhydryl (PSH) concentrations], total lipid and protein levels and cholesterol saturation index (CSI). First appearance of cholesterol crystals in ultrafiltered bile (crystal observation time, COT) was studied with polarizing light microscopy during 21 days. RESULTS: Patients with cholesterol stones had significantly shorter COT (3 days vs. >21 days, P < 0.05), higher CSI (149 +/- 10% vs. 97 +/- 7%, P < 0.05) and higher total biliary proteins (1.96 +/- 0.1 mg mL(-1) vs. 0.55 +/- 0.1 mg mL(-1), P < 0.05) than patients with pigment stones. Patients with cholesterol stones had significantly lower (P < 0.05) level of protein sulfhydryl concentrations (18 +/- 4 nmol mg(-1) protein vs. 49 +/- 16 nmol mg(-1) protein), while total lipid and carbonyl proteins concentrations were similar between cholesterol and pigment stone patients. Crystallization probability was influenced by the number/type of gallstones (multiple > solitary > pigment stones, P = 0.009) and total protein concentration (high > low levels, P = 0.004). COT was negatively correlated with total protein content (r = -0.45, P = 0.03). CONCLUSIONS: Biles with cholesterol stones show high CSI and total protein concentration, and rapid COT, which is even faster in patients with multiple stones and high protein concentration. Low PSH levels in cholesterol stone patients point to a biochemical shift, potentially able to affect cholesterol crystallization.

Aquaporins in the hepatobiliary tract. Which, where and what they do in health and disease.

The biological importance of the aquaporin family of water channels was recently acknowledged by the 2003 Nobel Prize for Chemistry awarded to the discovering scientist Peter Agre. Among the pleiotropic roles exerted by aquaporins in nature in both health and disease, the review addresses the latest acquisitions about the expression and regulation, as well as physiology and pathophysiology of aquaporins in the hepatobiliary tract. Of note, at least seven out of the thirteen mammalian aquaporins are expressed in the liver, bile ducts and gallbladder. Aquaporins are essential for bile water secretion and reabsorption, as well as for plasma glycerol uptake by the hepatocyte and its conversion to glucose during starvation. Novel data are emerging regarding the physio-pathological involvement of aquaporins in multiple diseases such as cholestases, liver cirrhosis, obesity and insulin resistance, fatty liver, gallstone formation and even microparasite invasion of intrahepatic bile ducts. This body of knowledge represents the mainstay of present and future research in a rapidly expanding field.

Severe liver steatosis correlates with nitrosative and oxidative stress in rats.

BACKGROUND: Little is known about nitric oxide (NO) metabolism and redox changes with hepatocyte adipocytic transformation. The aims of this study were to investigate the changes occurring in plasma and hepatic NO metabolites and redox balance in a rat experimental model of simple fatty liver, and to relate plasma with hepatic and mitochondrial changes at different degrees of steatosis. MATERIALS AND METHODS: Circulating and hepatic redox active and nitrogen regulating molecules thioredoxin, glutathione, protein thiols (PSH), mixed disulfides (PSSG), NO metabolites nitrosothiols, nitrite plus nitrate (NOx), and lipid peroxides (TBARs) were measured in rats fed a choline deprived (CD) diet for 30 days. RESULTS: At histology, the CD diet resulted in hepatocellular steatosis (75% of liver weight at day 30) with no signs of necro-inflammation. In plasma, thioredoxin, nitrosothiols and NOx were unchanged, while TBARs levels increased significantly and were positively related with hepatic TBARs (r = 0.87, P < 0.001) and lipid content (r = 0.90, P < 0.001). In the liver, glutathione initially increased (day 3) and then decreased. From day 14, PSH decreased and NO derivatives increased. Thioredoxin 1 had initially increased (days 7-14) and then decreased. In the mitochondria, on day 14, nitrosothiols were inversely related to thioredoxin 2 (r = 0.988, P < 0.05); on day 30, PSH were decreased by 70%, PSSG were doubled and related with nitrosothiols levels (r = 0.925, P < 0.001). CONCLUSION: Adipocytic transformation of hepatocytes is accompanied by major interrelated modifications of redox parameters and NO metabolism especially at mitochondrial level, suggesting an early adaptive protective response but also an increased predisposition towards pro-oxidant insults.

Beneficial effects of oral tilactase on patients with hypolactasia.

BACKGROUND: A lactose-free diet is commonly prescribed to subjects with hypolactasia. We tested the effectiveness of a single ingestion of tilactase (a beta-D-galactosidase from Aspergillus oryzae) in adults with hypolactasia, previously assessed by lactose H(2)-breath test. MATERIALS AND METHODS: After measurement of orocecal transit time (OCTT, by lactulose H(2)-breath test) and lactose H(2)-breath testing plus placebo, a total of 134 subjects were positive to hypolactasia and underwent lactose H(2)-breath testing plus either low (6750 U) or standard (11,250 U) doses of tilactase. The appearance of gastrointestinal symptoms during the tests was monitored. RESULTS: OCTT was longer in malabsorbers (subjects without bloating, abdominal pain and/or diarrhoea, n = 25) than in intolerants (bloating, abdominal pain and/or diarrhoea, n = 109, P < 0.02). Malabsorbers had longer time to H(2) peak (P < 0.03), lower H(2) peak levels (P < 0.002) and smaller integrated H(2) excretion levels (P < 0.005) than intolerants. After tilactase ingestion, integrated H(2) levels were decreased by 75% (low dose) and 87% (standard dose) in malabsorbers, and by 74% (low dose) and 88% (standard dose) in intolerants. In the latter group, total symptom score were decreased by 76% (low dose) and by 88% (standard dose) (P < 0.0001). CONCLUSION: A single oral administration of tilactase is highly effective in decreasing symptoms and hydrogen excretion of hypolactasia assessed by lactose H(2)-breath test. If confirmed by long-term observations, ingestion of tilactase might be a better option than exclusion diets in intolerant subjects with hypolactasia.

Current treatments of primary sclerosing cholangitis.

Primary Sclerosing Cholangitis (PSC) is a chronic cholestatic disease characterized by hepatic inflammation and obliterative fibrosis, resulting in both intra- and extra-hepatic bile duct strictures. End-stage liver disease and bile duct carcinoma represent frequent complications. Incidence and prevalence of PSC in USA have been recently estimated as 0.9 per 100,000 person-years, and 1-6 per 100,000 person-years, respectively. Major diagnostic criteria include the presence of multifocal strictures, beadings of bile ducts, and compatible biochemical profile, once excluded secondary causes of cholangitis. Since the aetiology of PSC remains poorly defined, medical therapy is currently limited to symptom improvement and prolonged survival. Ursodeoxycholic acid (UDCA), corticosteroids and immunosuppressants have been proposed alone or in combination to improve the clinical outcome. In selected cases, surgical or endoscopic procedures need to be considered. Orthotopic liver transplantation (OLT) is at the moment the only definitive approach although disease relapse has been reported. In this article the state of the art in PSC treatment and future promises in this field are reviewed.

The impact of single parathyroid gland autotransplantation during thyroid surgery on postoperative hypoparathyroidism: a multicenter study.

BACKGROUND: We compared the surgical outcomes in patients undergoing bilateral thyroid surgery with or without parathyroid gland autotransplantation (PTAT). METHODS: One thousand three hundred nine patients underwent surgery for treatment of various thyroid diseases at three Academic Departments of General Surgery and one Endocrine-Surgical Unit throughout Italy. A nonviable gland or difficulties in dissection of the parathyroid glands were encountered in 160 (13.7%) patients. The subjects were divided into two groups: (1) patients undergoing PTAT during thyroidectomy (n = 79) versus (2) control group (n = 81), patients not undergoing PTAT. RESULTS: Clinical manifestations occurred in 5.0% of PTAT patients and in 13.6% of control patients (P = NS). Total postoperative hypocalcemia was less among PTAT than control patients (17.7% and 48.1%, respectively; P = .0001). There was no significant difference between the two groups in terms of definitive hypocalcemia (0% vs 2.5% in PTAT and control, respectively). Transient postoperative hypocalcemia was less among PTAT than controls (17.7% vs 45.7%; P = .0002). PTAT was associated with decreased occurrence of hypocalcemia in the two subgroups of patients operated for benign euthyroid disease (P < .0001), as compared with the control group. CONCLUSIONS: PTAT is an effective procedure to reduce the incidence of permanent hypoparathyroidism. Transient hypoparathyroidism appears to not be influenced by PTAT. Moreover, we observed that damage to one parathyroid gland has more side effects (ie, transient hypocalcemia) among patients who were preoperatively at low rather than at high risk of postoperative hypocalcemia.

Gallstone disease: Symptoms and diagnosis of gallbladder stones.

The clinical aspects and the diagnostic features of gallstone disease are described. The natural history of silent gallstones is overviewed, and the risk of developing symptoms and complications is also discussed. The importance of colicky pain as a specific gallstone symptom is highlighted, and the role of both laboratory tests and diagnostic investigations for differential diagnosis is discussed. Finally, we describe the diagnostic features of gallbladder stone disease, including indications, sensitivity, specificity, and limitations of different test investigations under special circumstances.

[Acute pneumonia caused by aspiration of hydrocarbons in a fire-eater]. / Polmonite acuta da aspirazione di idrocarburi in un "mangiafuoco".

Accidental aspiration of fuel in fire eaters can cause an acute chemical pneumonitis known as 'fire-eater's pneumonia". We report a case in a 29 year-old fire-eater. Six hours after aspiration of kerosene, he developed fever up to 39,5 degrees C, dyspnea, cough and chest pain. Chest radiograph showed infiltrates in the middle and lower parts of the lungs and left pleural effusion. He was treated with an antibiotic and antipiretic therapy and then with corticosteroids. The acute stage lasted four weeks and the patient recovered without sequelae within 3 months. Hazard related to main fuels used for fire eating is discussed.

Colchicine, Biologic Agents and More for the Treatment of Familial Mediterranean Fever. The Old, the New, and the Rare.

Familial Mediterranean Fever (FMF) is a rare autosomal recessive autoinflammatory disorder involving the innate immunity and affecting almost exclusively populations with Mediterranean origin. Clinical features include recurrent episodes of fever, leukocitosis, serositis (peritonitis or pleuritis, arthritis), myalgia or erysipelas-like skin lesions, lasting 12-72 hrs. The MEFV gene mutations on chromosome 16p13.3 encodes the abnormal pyrin (marenostrin), a protein expressed in granulocytes, monocytes, serosal and synovial fibroblasts and involved in the activation of caspase-1 and the processing and release of active pro-inflammatory IL-1ß. Since the first report in 1972, maintenance therapy with colchicine, a tricyclic neutral alkaloid, remains the mainstay of treatment in symptomatic FMF patients since it reduces the disease activity and prevents the development of secondary amyloidosis and renal damage. Adjunctive symptomatic therapy to colchicine includes nonsteroideal antinflammatory drugs and corticosteroids. In a small group of colchicine-intolerant or colchicine-resistant FMF patients, alternative treatments must be considered. Evolving experiences have focussed on the potential effectiveness of biologic agents working as TNF-α inhibitors (etanercept, infliximab), IL-1 trap (Rilonacept), IL-1 inhibitors (Anakinra, Canakinumab) and IL-6 receptor antibody (Tocilizumab). Interferon-α and thalidomide have also been employed in FMF patients. Still, clinical trials are mainly uncontrolled and restricted to few cases, thus requiring definitive conclusions. Old, and new treatments are discussed in the rare FMF disease, with the concept that any ideal treatment has to stand the test of time.

Colon neoplasia in patients with type 2 diabetes on metformin: A meta-analysis.

BACKGROUND: A growing body of evidence has suggested that metformin potentially reduces the risk of cancer. OBJECTIVE: We performed a meta-analysis of available studies to better define the effect of metformin on colon neoplasia (cancer and polyps) in patients with type 2 diabetes. METHODS: Medical literature searches for human studies were performed through December 2015, using suitable keywords. Pooled estimates were obtained using fixed or random-effects models. Heterogeneity between studies was evaluated with the Cochran Q test whereas the likelihood of publication bias was assessed by constructing funnel plots. Their symmetry was estimated by the Begg and Mazumdar adjusted rank correlation test and by the Egger's regression test. In addition subgroup and sensitivity analyses were performed. RESULTS: A total number of 709,980 patients, with type 2 diabetes, were included in 17 studies eligible for meta-analysis [1 RCT and 16 observational studies (13 cohort and 3 case-controls)]. The risk of colon neoplasia was significantly lower among metformin users than controls (non-metformin users) [pooled RRs (95% CI)=0.75 (0.65-0.87), test for overall effect Z=-3.95, p<0.001]. This observation applied separately for colon cancer [0.79 (0.69-0.91), Z=-3.34, p<0.001] and for colon polyps [0.58 (0.42-0.80), Z=-3.30, p<0.001]. CONCLUSION: This meta-analysis shows that the use of metformin in patients with type 2 diabetes is associated with significantly lower risk of colon neoplasia.

Lack of endogenous cholecystokinin promotes cholelithogenesis in mice.

BACKGROUND: Celiac disease is an autoimmune enteropathy caused by a permanent intolerance to dietary gluten in genetically predisposed individuals. Cholecystokinin (CCK) release from the proximal small intestine and gallbladder emptying in response to a fatty meal are greatly reduced in celiac patients before they start the gluten-free diet, showing a genetic predisposition to gallstones. METHODS: To elucidate the complex pathophysiological mechanisms determining the biliary characteristic of celiac disease, we investigated the effect of the absence of endogenous CCK on cholesterol crystallization and gallstone formation in mice fed a lithogenic diet for 28 days. KEY RESULTS: Fasting gallbladder volumes were increased and the response of gallbladder emptying to the high-fat diet was impaired in CCK knockout (KO) mice compared to wild-type mice. Because of the absence of CCK, small intestinal transit time was prolonged and intestinal cholesterol absorption was increased. During 28 days of feeding, elevated biliary cholesterol concentrations and gallbladder stasis promoted the growth and agglomeration of solid cholesterol crystals into microlithiasis and stones. Thus, cholesterol crystallization and gallstone formation were accelerated in CCK KO mice. In contrast, daily intraperitoneal administration of CCK-8 reduced gallstone formation in CCK KO mice even on the lithogenic diet. CONCLUSIONS & INFERENCES: The lack of endogenous CCK enhances susceptibility to gallstones by impairing gallbladder contractile function and small intestinal motility function. These findings show that celiac disease is an important risk factor for gallstone formation and the gallbladder motility function should be routinely examined by ultrasonography and gallbladder stasis should be prevented in celiac patients.

Management of gallstones and its related complications.

The majority of gallstone patients remain asymptomatic; however, interest toward the gallstone disease is continuing because of the high worldwide prevalence and management costs and the development of gallstone symptoms and complications. For cholesterol gallstone disease, moreover, a strong link exists between this disease and highly prevalent metabolic disorders such as obesity, dyslipidemia, type 2 diabetes, hyperinsulinemia, hypertriglyceridemia and the metabolic syndrome. Information on the natural history as well as the diagnostic, surgical (mainly laparoscopic cholecystectomy) and medical tools available to facilitate adequate management of cholelithiasis and its complications are, therefore, crucial to prevent the negative outcomes of gallstone disease. Moreover, some risk factors for gallstone disease are modifiable and some preventive strategies have become necessary to reduce the onset and the severity of complications.

Simvastatin increases AQP2 urinary excretion in hypercholesterolemic patients: A pleiotropic effect of interest for patients with impaired AQP2 trafficking.

We previously reported that statins improve the symptoms of X-linked nephrogenic diabetes insipidus (X-NDI) in animal models. The aim of this study was to verify whether the pleiotropic effect of statins on AQP2 trafficking and kidney-concentrating ability, observed in rodents, was attainable in humans at therapeutic doses. We enrolled 24 naïve hypercholesterolemic patients and measured urine excretion of AQP2 (uAQP2) at baseline and during 12 weeks of treatment with simvastatin 20 mg/day. Simvastatin induced a rapid and significant increase of uAQP2, reduced the 24-hour diuresis, and increased urine osmolality. These effects were also maintained in patients chronically treated with statins for at least 1 year. This study strongly suggests that statins may effectively enhance the efficacy of current pharmacological treatment of patients with urine-concentrating defects caused by defective AQP2 plasma membrane trafficking, like X-NDI.