[Show abstract][Hide abstract] ABSTRACT: Dent disease (DD) is a rare X-linked recessive renal tubulopathy characterised by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis and/or nephrolithiasis. DD is caused by mutations in both the CLCN5 and OCRL genes. CLCN5 encodes the electrogenic chloride/proton exchanger ClC-5 which is involved in the tubular reabsorption of albumin and LMW proteins, OCRL encodes the inositol polyphosphate 5-phosphatase, and was initially associated with Lowe syndrome. In approximately 25 % of patients, no CLCN5 and OCRL mutations were detected. The aim of our study was to evaluate whether calcium phosphate metabolism disorders and their clinical complications are differently distributed among DD patients with and without CLCN5 mutations. Sixty-four male subjects were studied and classified into three groups: Group I (with CLCN5 mutations), Group II (without CLCN5 mutations) and Group III (family members with the same CLCN5 mutation). LMWP, hypercalciuria and phosphaturic tubulopathy and the consequent clinical complications nephrocalcinosis, nephrolithiasis, bone disorders, and chronic kidney disease (CKD) were considered present or absent in each patient. We found that the distribution of nephrolithiasis, bone disorders and CKD differs among patients with and without CLCN5 mutations. Only in patients harbouring CLCN5 mutations was age-independent nephrolithiasis associated with hypercalciuria, suggesting that nephrolithiasis is linked to altered proximal tubular function caused by a loss of ClC-5 function, in agreement with ClC-5 KO animal models. Similarly, only in patients harbouring CLCN5 mutations was age-independent kidney failure associated with nephrocalcinosis, suggesting that kidney failure is the consequence of a ClC-5 dysfunction, as in ClC-5 KO animal models. Bone disorders are a relevant feature of DD phenotype, as patients were mainly young males and this complication occurred independently of age. The triad of symptoms, LMWP, hypercalciuria, and nephrocalcinosis, was present in almost all patients with CLCN5 mutations but not in those without CLCN5 mutations. This lack of homogeneity of clinical manifestations suggests that the difference in phenotypes between the two groups might reflect different pathophysiological mechanisms, probably depending on the diverse genes involved. Overall, our results might suggest that in patients without CLCN5 mutations several genes instead of the prospected third DD underpin patients' phenotypes.
[Show abstract][Hide abstract] ABSTRACT: Background
Proton pump inhibitors (PPIs) are a class of drugs that is extensively used for common gastrointestinal disorders and often prescribed long-term for years. Long-term PPI treatment is associated with an increased risk of fractures in the general population. Several studies have suggested a relationship between vascular calcification, which is a predictor of cardiovascular morbidity and mortality, impaired bone metabolism and fractures. In dialysis patients, vascular calcifications are widespread and are connected to bone health.
The aim of this study was to assess the association between the use of PPIs and vascular calcifications involving the aorta and iliac arteries in haemodialysis patients.
Between November 2008 and November 2009, 387 patients receiving long-term dialysis treatment (≥1 year) were enrolled in a multicentre (18 Dialysis Units), cross-sectional study. Overall, 76.2 % of patients were receiving long-term PPI treatment. The main outcome measure was calcification of the aorta and iliac arteries in relation to PPI use. Standardized radiographs were sent to the coordinating centre for centralized evaluation in duplicate by two physicians who were blind to PPI status.
Arterial calcifications were significantly more common in the PPI group (p < 0.01). Also, the rates of aortic and iliac calcifications considered separately were higher (+12.2 %, p = 0.0254; and +13.6 %, p = 0.0211, respectively). After correction for the propensity score, the odds ratios [ORs] (95 % CI) related to PPI use were aorta 1.89 (1.01–3.54), p = 0.048; iliac arteries 2.27 (1.31–3.92), p = 0.003; aorta and iliac arteries 2.59 (1.48–4.53), p = 0.008. The ORs (95 % CI) related to the association of warfarin + PPI were aorta 2.19 (0.95–5.00), p = 0.06; iliac arteries 2.90 (1.07–7.86), p = 0.036; aorta and iliac arteries 2.69 (1.03–6.96), p = 0.042.
In haemodialysis patients, long-term treatment with PPIs, especially in the presence of warfarin treatment, is associated with vascular calcifications.
[Show abstract][Hide abstract] ABSTRACT: Few studies have provided information on the prevalence of vertebral fractures (VFs) and their risk factors in hemodialysis patients. A multicenter, cross-sectional, observational study was carried out to assess the prevalence of VFs and vascular calcifications (VCs) in 387 hemodialysis patients (mean age 64.2 ± 14.1 years, 63 % males) and in a control group of 51 osteoporotic subjects. Biochemical tests included 25(OH) vitamin D, bone Gla protein (total and undercarboxylated), and total matrix Gla protein. Vertebral quantitative morphometry was carried out centrally for the detection of VF, defined as reduction by ≥20 % of one of the vertebral body dimensions. In the same radiograph, aortic and iliac VC scores were calculated. Prevalence of VF was 55.3 % in hemodialysis patients and 51.0 % in the control group. Multivariate analysis disclosed that male gender (59.8 vs. 47.6 %, p = 0.02; OR = 1.78, 95 % CI 1.15-2.75) and age (mean ± SD 66.7 ± 13.1 vs. 61.0 ± 14.7 years, p < 0.001; OR = 1.03, 95 % CI 1.01-1.05) were significantly associated with VF. The prevalence of aortic VC was significantly higher in hemodialysis patients than in controls (80.6 vs. 68.4 %, p = 0.001). The factors with the strongest association with VC, apart from atrial fibrillation, were serum 25(OH)vitamin D levels below 29 ng/mL for aortic VC (OR = 1.85, 95 % CI 1.04-3.29) and VF both for aortic (OR = 1.77, 95 % CI 1.00-3.14) and iliac (OR = 1.96, 95 % CI 1.27-3.04) VC. In conclusion, the prevalence of VF, especially in males, and VC, in both genders, is high in hemodialysis patients. VF is associated with VC. Vitamin D deficiency is also associated with VC. Further longitudinal studies are warranted to investigate fractures in renal patients.
Full-text · Article · Mar 2013 · Calcified Tissue International
[Show abstract][Hide abstract] ABSTRACT: Glomerular protein handling mechanisms have received much attention in studies of nephrotic syndrome. Histopathological findings in renal biopsies from severely proteinuric patients support the likelihood of protein endocytosis by podocytes. ClC-5 is involved in the endocytosis of albumin in the proximal tubule.
To investigate whether ClC-5 is expressed in the glomerular compartment and whether it has a role in proteinuric nephropathies. ClC-5 expression was studied using Real-time PCR in manually- and laser-microdissected biopsies from patients with type 2 diabetes (n 37) and IgA nephropathy (n 10); in biopsies of membranous glomerulopathy (MG) (n 14) immunohistochemistry for ClC-5 (with morphometric analysis) and for WT1 was done. Controls: cortical tissue (n 23) obtained from unaffected parts of tumor-related nephrectomy specimens.
ClC-5 was expressed at glomerular level in all biopsies. Glomerular ClC-5 levels were significantly higher in diabetic nephropaty and MG at both mRNA and protein level (p<0.002; p<0.01). ClC-5 and WT1 double-staining analysis in MG showed that ClC-5 was localized in the podocytes. ClC-5 ultrastructural immunolocalization was demonstrated in podocytes foot processes. Our study is the first to demonstrate that ClC-5 is expressed in human podocytes. The ClC-5 overexpression found in biopsies of proteinuric patients suggests that proteinuria may play a part in its expression and that podocytes are likely to have a key role in albumin handling in proteinuric states.
[Show abstract][Hide abstract] ABSTRACT: Introduction and Aims: Pauci-immune necrotizing glomerulonephritis (PINGN) with antineutrophil cytoplasmic autoantibody (ANCA) are observed in systemic
vasculitis (Microscopic polyangiitis [MPA] with or without granuloma) but can be isolated and considered as vasculitis limited
to the kidney. By immunofluorescence, very few immmunoglobulin deposits can be observed associated with some C3 deposits.
Recent studies in murine models indicate that complement alternative pathway is involved in the development of necrotizing
glomerulonephritis. We seeked to analyse the deposition of complement activation products in kidney biopsies of PINGN, using
immunohistochemistry (IHC) and immunofluorescence (IF) staining.
Methods: Renal biopsies from 11 patients with PR3-ANCA and 8 patients with MPO-ANCA (5 MPA without granuloma, 3 isolated PINGN) were
studied with anti-C3d (IHC), anti-C4d (IHC) and anti-C5b-9 (IF) antibodies and compared to C3c deposits observed with standard
IF in glomeruli. Control biopsies were 2 cases of PINGN without C3c deposits, 1 case of acute post infectious glomerulonephritis
with C3c granular deposits, and one normal kidney biopsy.
Results: 10 of 11 renal biopsies from patients with PR3-ANCA had a moderate segmental or diffuse granular C3d staining in 38,5% of
glomeruli, with identical localisation compared to C3c deposits. A C4d staining was noted in the same localization as C3d
but with milder intensity and in only 4 cases. C5b-9 studied in the 10 cases with IF available showed a moderate to intense
granular deposit in the flocculus (along glomerular basement membrane in 1 case). The 8 renal biopsies from patients with
MPO-ANCA had a strong granular C3d staining in 57% of glomeruli. As for PR3-ANCA biopsies, C4d was positive only in 5 of 8
renal biopsies. C5b-9 staining was positive in the 4 cases tested with IF available. The C5b-9 staining was similar in the
two groups, but in the MPO group, some segmental accumulation was observed in segmental lesions corresponding to crescents
and necrosis. In control biopsies, C5b-9 was absent in glomerulus floculus of normal kidney but had identical distribution
in acute post infectious glomerulonephritis.
Conclusions: Complement pathways activation products, including those of the classical alternative pathway, are detected in the glomeruli
of patients with PINGN. We have observed a more intense staining of C3d in patients with MPO-ANCA compared to patients with
PR3-ANCA, which may reflect the more chronic/subacute course of MPO-PINGN compared to PR3-PIGN.
Full-text · Article · May 2012 · Nephrology Dialysis Transplantation
[Show abstract][Hide abstract] ABSTRACT: Given the higher mortality rate of ICU patients with sepsis and AKI, we decided to investigate the possible correlation between serum biomarkers of organ damage, and endotoxin activity in ICU septic patients. Ninety-eight consecutive adult patients were enrolled in this study. Patients were divided in two groups depending on the presence of sepsis. Fifty-six patients had sepsis, while forty-two patients were nonseptic. Among septic patients, twenty-four subjects developed AKI, while thirty-two did not. AKI occurred in fourteen patients without sepsis as well. The levels of NGAL, BNP, and AOPP were significantly higher among septic patients compared with nonseptic subjects (P < 0.001). Among septic patients, subjects who developed AKI showed significant higher levels of NGAL and AOPP (P = 0.0425) and BNP (P = 0.0327). Among patients who developed AKI, a significant difference was found only in terms of AOPP levels between septic and nonseptic patients. The correlation between endotoxin activity and BNP in septic patients and the increase in the levels of NGAL, BNP, and AOPP in case of sepsis and AKI, in particular if they are associated, indicate a multiorgan involvement in these two conditions.
Full-text · Article · Feb 2012 · Critical care research and practice
[Show abstract][Hide abstract] ABSTRACT: The epithelial-mesenchymal transition (EMT) of proximal tubular epithelial cells (PTECs) into myofibroblasts contributes to the establishment of fibrosis that leads to end stage renal disease. FGF-2 induces EMT in PTECs. Because the interaction between FGF-2 and its receptor is mediated by heparan sulfate (HS) and syndecans, we speculated that a deranged HS/syndecans regulation impairs FGF-2 activity. Heparanase is crucial for the correct turnover of HS/syndecans. The aim of the present study was to assess the role of heparanase on epithelial-mesenchymal transition induced by FGF-2 in renal tubular cells. In human kidney 2 (HK2) PTEC cultures, although FGF-2 induces EMT in the wild-type clone, it is ineffective in heparanase-silenced cells. The FGF-2 induced EMT is through a stable activation of PI3K/AKT which is only transient in heparanase-silenced cells. In PTECs, FGF-2 induces an autocrine loop which sustains its signal through multiple mechanisms (reduction in syndecan-1, increase in heparanase, and matrix metalloproteinase 9). Thus, heparanase is necessary for FGF-2 to produce EMT in PTECs and to sustain FGF-2 intracellular signaling. Heparanase contributes to a synergistic loop for handling syndecan-1, facilitating FGF-2 induced-EMT. In conclusion, heparanase plays a role in the tubular-interstitial compartment favoring the FGF-2-dependent EMT of tubular cells. Hence, heparanase is an interesting pharmacological target for the prevention of renal fibrosis.
Preview · Article · Nov 2011 · Journal of Biological Chemistry
[Show abstract][Hide abstract] ABSTRACT: The epithelial-mesenchymal transition (EMT) of proximal tubular epithelial cells (PTEC) into myofibroblasts contributes to
the establishment of fibrosis that leads to end-stage renal disease. FGF-2 induces EMT in PTECs. Since the interaction between
FGF-2 and its receptor is mediated by HS and syndecans, we speculated that a deranged HS/syndecans regulation impairs FGF-2
activity. Heparanase is crucial for the correct turn-over of HS/syndecans. The aim of the present study was to asses the role
of heparanase on epithelial mesenchymal transition induced by FGF-2 in renal tubular cells. In human HK2 PTEC cultures, while
FGF-2 induces EMT in the wild-type clone, it is ineffective in heparanase-silenced cells. The FGF-2 induced-EMT is through
a stable activation of PI3K/AKT which is only transient in heparanase-silenced cells. In PTECs, FGF-2 induces an autocrine
loop which sustains its signal through multiple mechanisms (reduction in syndecan-1, increase in heparanase and matrix metalloproteinase
9). Thus, heparanase is necessary for FGF-2 to produce EMT in PTECs and to sustain FGF-2 intracellular signaling. Heparanase
contributes to a synergistic loop for handling syndecan-1, facilitating FGF-2 induced-EMT. In conclusion, heparanase plays
a role in the tubular-interstitial compartment favouring the FGF-2-dependent EMT of tubular cells. Hence, heparanase is an
interesting pharmacological target for the prevention of renal fibrosis.
No preview · Article · Nov 2011 · Journal of Biological Chemistry
[Show abstract][Hide abstract] ABSTRACT: The authors briefly describe the history of gout, mainly focusing their attention on the renal involvement. They report some works and theories on gout of great ancient physicians, such as Paracelsus, Sydenham, Boerhaave, Van Swieten and Morgagni.
[Show abstract][Hide abstract] ABSTRACT: Epidemiological studies have shown that the burden of chronic kidney disease (CKD) is huge. CKD is a non-specific diagnosis, however, and it is hard to say which renal disorders comprise the body of CKD diagnosed on the strength of the combination of albuminuria and estimated glomerular filtration rate (eGFR) in epidemiological studies, or just how efficient such studies are in detecting chronic nephropathies.
The INCIPE study identified 524 CKD cases (using the K/DOQI definition based on albuminuria and eGFR) in a random sample of 4000 Italians >40 years old, 262 of whom were randomly chosen to be investigated in order to confirm their CKD and complete a diagnostic workup. We a priori defined diagnostic algorithms for 14 renal conditions based on personal family history, medical records, urine tests, kidney ultrasound with colour-Doppler and other tests.
Among the subjects whose CKD was confirmed, a diagnosis of chronic nephropathy was reached in 68% of cases recognized as having either a specific (38%) or an undetermined (30%) kidney disease. Almost 50% of subjects with a specific chronic nephropathy had a diabetic or vascular renal disease. Abnormalities consistent with a chronic nephropathy were found in 50, 68, 70 and 100% of subjects with CKD Stages 1, 2, 3 and 4, respectively. Lone low eGFR and lone microalbuminuria were observed in 20 and 12%, respectively.
In Caucasians >40 years old with a confirmed CKD condition, (i) an impressive 68% of subjects have an underlying chronic nephropathy, so eGFR and albuminuria are very efficient in detecting renal diseases; (ii) in 32%, the only disclosed renal abnormalities were a glomerular filtration rate <60 mL/min/1.73 m(2) or microalbuminuria; follow-up studies are needed to clarify whether these abnormalities do really identify a chronic nephropathy or just a cardiovascular risk condition.
[Show abstract][Hide abstract] ABSTRACT: Vascular access care is a key topic for hemodialysis patients. The most cost-effective and lasting vascular access for chronic hemodialysis is the native arteriovenous fistula (AVF); however, bleeding after dialysis session from puncture site is a relevant problem. Achieving hemostasis is necessary and requires hand compression by the nurse or the patient if he or she is capable and cooperative.
We assessed a new vascular closure device, VITACLIP® (Serumwerk Bernburg Vertriebs GmbH) that is an adhesive silicone seal device, which can be set onto the skin and punctured by dialysis needle. After withdrawal of the needle, VITACLIP® prevents bleeding from the punctured vessels, making hand compression unnecessary.
We used this device in 5 chronic hemodialysis patients with native lateral-terminal AVFs. The patients' hemodialysis prescription and anticoagulants dose were not changed. This device allowed puncture of vascular access without complications such as bleeding at the end of hemodialysis; we did not observe any mechanical complications due to needle dislocation or any dermatological lesions at skin puncture site. However, the cannulation proved to be more difficult for the nurses with this device because the silicone hampers identification of the vessel for puncture for deeper AVFs.
This device helps patient management and improves patient safety by reducing the risk of AVF bleeding at the end of dialysis, decreasing the risk of staff contact with patients' blood, and theoretically eliminating the risk of massive bleeding in the case of an inadvertent needle dislodgement going unnoticed during treatment.
No preview · Article · Jul 2011 · The journal of vascular access
[Show abstract][Hide abstract] ABSTRACT: Introduction. Acute kidney injury (AKI) is common in the intensive care unit (ICU) and associated with poor outcome. Plasma B-type natriuretic peptide (BNP) is a biomarker related to myocardial overload, and is elevated in some ICU patients. There is a high prevalence of both cardiac and renal dysfunction in ICU patients. Aims. To investigate whether plasma BNP levels in the first 48 hours were associated with AKI in ICU patients. Methods. We studied a cohort of 34 consecutive ICU patients. Primary outcome was presence of AKI on presentation, or during ICU stay. Results. For patients with AKI on presentation, BNP was statistically higher at 24 and 48 hours than No-AKI patients (865 versus 148 pg/mL; 1380 versus 131 pg/mL). For patients developing AKI during 48 hours, BNP was statistically higher at 0, 24 and 48 hours than No-AKI patients (510 versus 197 pg/mL; 552 versus 124 pg/mL; 949 versus 104 pg/mL). Conclusion. Critically ill patients with AKI on presentation or during ICU stay have higher levels of the cardiac biomarker BNP relative to No-AKI patients. Elevated levels of plasma BNP may help identify patients with elevated risk of AKI in the ICU setting. The mechanism for this cardiorenal connection requires further investigation.
[Show abstract][Hide abstract] ABSTRACT: Secondary hyperparathyroidism (SHPT), known complication of chronic renal failure, in addition to effects on bone and cardiovascular systems, is associated with reduced response to erythropoietin (EPO). Calcimimetics such as cinacalcet are the latest generation of drugs used in the treatment of SHPT. Few studies have evaluated the effect of cinacalcet on anemia associated with SHPT in dialysis patients, while no study has compared this cinacalcet effect with that of vitamin D analogs such as paricalcitol.
Using a retrospective chart-based review of dialysis patients' records to identify patients being treated with either cinacalcet or paricalcitol alone, matched for the same EPO treatment, which had been followed for 1 year, we have evaluated the effect of cinacalcet on anemia compared to that of paricalcitol.
Ten patient records were found that fit the criteria, five treated with cinacalcet (Group 1) and five treated with paricalcitol (Group 2), all treated with the same dose of darbepoetin. Darbepoetin dosage was the only parameter that significantly changed between groups, decreasing in Group 1 (-33%, p = 0.009) while remaining unchanged in Group 2. PTH-level reduction, which was significant versus baseline in both groups, although not statistically different between groups, was higher with cinacalcet.
The combination of lower EPO dose in cinacalcet-treated patients compared with paricalcitol-treated patients, along with good SHPT control is a novel information and might have considerable benefits in dialysis patients not only preventing bone (fractures) and cardiovascular system (calcifications) damages but also in terms of cost savings via a reduction of EPO dosage.