Idiopathic Calcium Oxalate Nephrolithiasis: A Cellular Disease

Physico-chemical, metabolic and hormonal theories regarding the pathogenesis of calcium oxalate nephrolithiasis do not sufficiently explain many features of this disease. The recent findings of an abnormally faster oxalate self-exchange and higher phosphorylation of band 3 in erythrocytes of idiopathic calcium oxalate stone formers suggest the hypothesis that nephrolithiasis may be a cellular disease, characterized by a defect in the function of the anion-exchange. The cellular anomaly seems genetically controlled. Band 3 anion exchanger function seems to be biochemically regulated through modulation of band 3 phosphorylation, which depends on cyclic AMP- and phospholipid-sensitive Ca2+ independent protein kinases. In this light, a reduced glycosaminoglycan concentration in the erythrocyte membranes of stone formers might play a role, as these molecules exert a strong inhibitory effects on band 3 phosphorylation and anion transport in vitro and in vivo. An in vivo trial was performed in which stone formers were administered glycosaminoglycans orally. A reduction in oxalate excretion, and oxalate renal clearance, and a simultaneous correction of the abnormal RBC oxalate flux and band 3 phosphorylation were observed. These data suggest the existence of a link between the erythrocyte abnormality and oxalate transport by the kidney and gut

Serum Potassium Disorders Predict Subsequent Kidney Injury: A Retrospective Observational Cohort Study of Hospitalized Patients

Introduction: Electrolyte disorders are common findings in kidney diseases and might represent a useful biomarker preceding kidney injury. Serum potassium [K+] imbalance is still poorly investigated for association with acute kidney injury (AKI), and most evidence came from intensive care units. The aim of our study was to comprehensively investigate this association in a large, unselected cohort of hospitalized patients. Methods: We performed a retrospective observational cohort study on the inpatient population admitted to Fondazione Policlinico Universitario A. Gemelli IRCCS between January 1, 2010 and December 31, 2014, with inclusion of adult patients with at least 2 [K+] and 3 serum creatinine measurements who did not develop AKI during an initial 10-day window. The outcome of interest was in-hospital AKI. The exposures of interest were [K+] fluctuations and hypo (HoK) and hyperkalemia (HerK). [K+] variability was evaluated using the coefficient of variation. Cox proportional hazards regression models were used to obtain hazard ratios and 95% confidence intervals of the association between the exposures of interest and development of AKI. Results: About 21,830 hospital admissions from 18,836 patients were included in our study. During a median follow-up of 5 (interquartile range [IQR] 7) days, AKI was observed in 555 hospital admissions (2.9%); median time for AKI development was 5 (IQR 7) days. Higher [K+] variability was independently associated with increased risk of AKI with a statistically significant linear trend across groups (p value = 0.012). A significantly higher incidence of AKI was documented in patients with HerK compared with normokalemia. No statistically significant difference was observed between HoK and HerK (p value = 0.92). Conclusion: [K+] abnormalities including fluctuations even within the normal range are associated with development of AKI

Heparanase: A Multitasking Protein Involved in Extracellular Matrix (ECM) Remodeling and Intracellular Events

Heparanase (HPSE) has been defined as a multitasking protein that exhibits a peculiar enzymatic activity towards HS chains but which simultaneously performs other non-enzymatic functions. Through its enzymatic activity, HPSE catalyzes the cutting of the side chains of heparan sulfate (HS) proteoglycans, thus contributing to the remodeling of the extracellular matrix and of the basal membranes. Furthermore, thanks to this activity, HPSE also promotes the release and diffusion of various HS-linked molecules like growth factors, cytokines and enzymes. In addition to being an enzyme, HPSE has been shown to possess the ability to trigger different signaling pathways by interacting with transmembrane proteins. In normal tissue and in physiological conditions, HPSE exhibits only low levels of expression restricted only to keratinocytes, trophoblast, platelets and mast cells and leukocytes. On the contrary, in pathological conditions, such as in tumor progression and metastasis, inflammation and fibrosis, it is overexpressed. With this brief review, we intend to provide an update on the current knowledge about the different role of HPSE protein exerted by its enzymatic and non-enzymatic activity

Nephroprotective action of glycosaminoglycans: why the pharmacological properties of sulodexide might be reconsidered

A relatively large body of evidence supports the notion that glomerular capillary wall and mesangial alterations in diabetic nephropathy involve biochemical alterations of glycoproteins in these structures. Evidence in experimental animals rendered diabetic reveals that the administration of heparin and other anionic glycoproteins can effectively prevent the biochemical alterations that promote albuminuria. Moreover, angiotensin II inhibits heparan sulfate synthesis, while heparins modulate angiotensin II signaling in glomerular cells, inhibiting aldosterone synthesis and lowering proteinuria in diabetes patients. Sulodexide, a mixture of heparin and dermatan sulfate, appears to be a promising treatment for diabetic proteinuria partially resistant to renin–angiotensin system blocking agents. Sulodexide prevents heparan sulfate degradation, thus allowing reconstruction of heparan sulfate content and restoration of glomerular basement membrane ionic permselectivity. The antiproteinuric effect appears to be mainly related to the basal proteinuria and consequently to the duration of treatment in a relatively large number of small clinical trials. On the other hand, several sulodexide pharmacodynamic properties could improve the prognosis of chronic kidney disease patients, also independently from its antiproteinuric effect. However, sulodexide development as an antiproteinuric drug needs to be continued, in order to define which kind of patients could better respond to this treatment

Luci Ed Ombre di Una Metanalisi Sul Trattamento Medico Della Nefrolitiasi

Abstract non disponibil

Low level exposure to cadmium increases the risk of chronic kidney disease: analysis of the NHANES 1999-2006

BACKGROUND: Environmental factors have been associated with the outbreak of chronic kidney disease (CKD). We evaluated the association of Cadmium (Cd) exposure with the risk of CKD in U.S. adults who participated in the 1999-2006 National Health and Nutrition Examination Surveys (NHANES). METHODS: 5426 subjects > or = 20 years were stratified for values of urinary and blood Cd and a multivariate logistic regression was performed to test the association between blood and urinary Cd, CKD and albuminuria (ALB) after adjustment for age, gender, race/ethnicity, body mass index and smoking habits. RESULTS: Subjects with urinary Cd > 1 mcg/g and subjects with blood Cd > 1 mcg/L showed a higher association with ALB (OR 1.63, 95% CI 1.23, 2.16; P = 0.001). Subjects with blood Cd > 1 mcg/L showed a higher association with both CKD (OR 1.48, 95% CI 1.01, 2.17; P = 0.046) and ALB (OR 1.41, 95% CI 1.10, 1.82; P = 0.007). An interaction effect on ALB was found for high levels of urinary and blood Cd (P = 0.014). CONCLUSIONS: Moderately high levels of urinary and blood Cd are associated with a higher proportion of CKD and ALB in the United States population

Heparanase and Renal Fibrosis

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Improvement of Urinary Stones Analysis Combining Morphological Analysis and Infrared Spectroscopy

Daudon et al. have developed a complex morphoconstitutional classification of renal stone in six different morphological types and several subtypes. According to this classification, a precise correspondence exists between causes of renal stones and subtypes with a great clinical relevance and can be considering a sort of shortcut for the metabolic diagnosis in renal stone patients. Now the diagnosis of causes of renal stones generally requires repeated biochemical investigations on urine and blood samples and usually remains presumptive. We analyzed 150 urinary stones both by stereoscopic microscopy and Fourier transform infrared spectroscopy. The comparison of 150 stones did not reveal any disagreement. We have only 20 partial agreement, and clinicians agreed that the imprecise information obtained with morphological analysis alone would have missed an important clinical finding only in 3 cases. In conclusion, in our opinion, the analysis of urinary stone must combine two different analytical techniques: morphological analysis by stereomicroscope and biochemical analysis with the FT-IR

Sphingomyelin and medullary sponge kidney disease: a biological link identified by omics approach

Background: Molecular biology has recently added new insights into the comprehension of the physiopathology of the medullary sponge kidney disease (MSK), a rare kidney malformation featuring nephrocalcinosis and recurrent renal stones. Pathogenesis and metabolic alterations associated to this disorder have been only partially elucidated.Methods: Plasma and urine samples were collected from 15 MSK patients and 15 controls affected by idiopathic calcium nephrolithiasis (ICN). Plasma metabolomic profile of 7 MSK and 8 ICN patients was performed by liquid chromatography combined with electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS). Subsequently, we reinterrogated proteomic raw data previously obtained from urinary microvesicles of MSK and ICN focusing on proteins associated with sphingomyelin metabolism. Omics results were validated by ELISA in the entire patients' cohort.Results: Thirteen metabolites were able to discriminate MSK from ICN (7 increased and 6 decreased in MSK vs. ICN). Sphingomyelin reached the top level of discrimination between the two study groups (FC: -1.8, p < 0.001). Ectonucleotide pyrophophatase phosphodiesterase 6 (ENPP6) and osteopontin (SPP1) resulted the most significant deregulated urinary proteins in MSK vs. ICN (p < 0.001). ENPP6 resulted up-regulated also in plasma of MSK by ELISA.Conclusion: Our data revealed a specific high-throughput metabolomics signature of MSK and indicated a pivotal biological role of sphingomyelin in this disease

Association analysis of 10 candidate genes causing Mendelian calcium nephrolithiasis in the INCIPE study: a South European general population cohort

Background: Idiopathic calcium nephrolithiasis (ICN) is a common condition with a complex phenotype influenced by both environmental and genetic factors. In our study we investigated the association of allelic variants with the history of nephrolithiasis. Methods: We genotyped and selected 10 candidate genes potentially related to ICN from 3046 subjects participating in the INCIPE survey cohort (Initiative on Nephropathy, of relevance to public health, which is Chronic, possibly in its Initial stages, and carries a Potential risk of major clinical End-points), a study enrolling subjects from the general population in the Veneto region in Italy. Results: Overall, 66 224 variants mapping on the 10 candidate genes were studied. A total of 69 and 18 variants in INCIPE-1 and INCIPE-2, respectively, were significantly associated with stone history (SH). Only two variants, rs36106327 (chr20:54 171 755, intron variant) and rs35792925 (chr20:54 173 157, intron variant) of the CYP24A1 gene were observed to be consistently associated with ICN. Neither variant has been previously reported in association with renal stones or other conditions. Carriers of CYP24A1 variants showed a significant increase in the ratio of 1,25 (OH)2 vitamin D to 25 (OH) vitamin D compared with controls (P = .043). Although not associated with ICN in this study, the rs4811494 CYP24A1 variant that was reported to be causative of nephrolithiasis was very prevalent in heterozygosity (20%). Conclusion: Our data suggest a possible role for CYP24A1 variants in the risk of nephrolithiasis. Genetic validation studies in larger sample sets will be necessary to confirm our findings