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Hemodialysis (HD) patients are at high risk for infectious complications such as spondylodiscitis. The aim of this retrospective study was to evaluate the cases of infective spondylodiscitis occurred between May 2005 and October 2019 among HD patients at our center. In 14 years, there were 9 cases (mean age 69±12 years). The main comorbidities found were diabetes mellitus (55.6% of patients), hypertension (55.6%), bone diseases (22.2%), cancer (11.1%) and rheumatoid arthritis treated with steroids (11.1%). The clinical onset included back pain (100% of cases), fever (55.6%), neurological deficits (33.4%), leukocytosis (55.6%) and elevated CRP level (88.9%). Most cases were diagnosed by magnetic resonance imaging (66.7%) with more frequent involvement of lumbar region (77.8%). Blood cultures were positive in five patients (mostly for S. aureus); three of them used catheters as vascular access and, in two cases, their removal was necessary. The mean time interval between the onset of symptoms and the diagnosis was 34±42 days. All patients received antibiotic treatment for a mean duration of 6 weeks; most cases were initially treated with vancomycin or teicoplanin plus ciprofloxacin. Most patients (77.8%) recovered after a mean of 3.5 months; one patient had a relapse after 2 years and one patient had long-term neurologic sequelae. Infective spondylodiscitis in HD must be suspected in the presence of back pain, even in the absence of fever or traditional risk factors. An early diagnosis could improve the outcome. Close monitoring of vascular access, disinfection procedures and aseptic techniques are important to avoid this complication.

Pleuro-peritoneal leakage is an uncommon complication of peritoneal dialysis (PD). In this study, we report the case of a male patient (age 83), treated with PD (daytime single-exchange). In October 2019, hospitalization was necessary due to dyspnoea and a reduction of peritoneal ultrafiltration. A right pleural leakage resulted at chest x-ray. A regression of the pleural leakage was immediately observed after interrupting PD. It was then performed a pleuro-peritoneal CT scan at baseline, followed by a second scan performed 4 hours after the injection of 2 L of isotonic solution with 100ml of contrast medium, which evidenced a pleuro-peritoneal communication. It was then decided to perform a video-assisted thoracoscopic surgery (VATS), that showed no evidence of diaphragm communication. It was then executed a pleurodesis using sterile talcum. The patient was released on the 3rd day, with a conservative therapy and a low-protein diet. After 2 weeks a new pleuro-peritoneal CT scan with contrast medium was executed. This time the scan evidenced the absence of contrast medium in the thoracic cavity. The patient then resumed PD therapy, with 3 daily exchanges with isotonic solution (volume 1.5 L), showing no complications. Concerning the treatment of pleuro-peritoneal leakage, VATS allows both the patch-repairing of diaphragmatic flaws and the instillation of chemical agents. In our case, VATS allowed the chemical pleurodesis which in turn enabled, in just 2 weeks of conservative treatment, the resuming of PD. In conclusion, this methodology is a valid option in the treatment of pleuro-peritoneal leakage in PD patients.

Background and Aims Hemodialysis (HD) patients represent a risk category for infections and for their possible complications, in particular infective spondylodiscitis. Although this is a serious complication, only few cases have been reported in the literature and it is not clear which is the best clinical management. The aim of this retrospective study was to evaluate the cases of infective spondylodiscitis that occurred among HD patients of our center. Method We collected the cases of spondylodiscitis that occurred at our center between May 2005 and October 2019. We focused in particular on the time interval between onset of symptoms and diagnosis, often delayed. The possible risk factors related to the onset of this disease were also considered. The diagnosis of infective spondylodiscitis was based on clinical data, laboratory results and diagnostic imaging tests. Results Over more than 10 years, there were 9 cases. The mean age was 69 ± 12 years. 55.6% of patients were affected by diabetes mellitus, 55.6% by hypertension, 22.2% by bone diseases, 11.1% by cancer and 11.1% by rheumatoid arthritis in chronic treatment with low-dose steroids and azathioprine (Table 1). All patients had back pain as an initial symptom, 55.6% had fever, while 33.4% had neurological symptoms. At hospital admission 55.6% of patients had leukocytosis and 88.9% of patients had elevated CRP level (Table 2). Six patients (66.7%) had their diagnoses confirmed by magnetic resonance imaging (MRI), while two patients had performed CT prior to MRI and one patient had his diagnosis confirmed by CT (Table 2). The lumbar region was the most common site of infection (77.8%) (Figure 1). The mean dialytic age was 33 ± 38 months. Four patients used an arteriovenous fistula as vascular access for HD, one patient used an arteriovenous graft, three patients used a tunneled cuffed catheter, and one patient used a temporary catheter (Table 3). Two patients had experienced thrombosis of the arteriovenous fistula requiring endovascular surgery. Blood culture were positive in five patients (four for S. aureus and one for S. agalactiae) and negative in four patients. Three of the patients with positive coltures used a catheter for HD and in two cases it was necessary its removal. Bone biopsy (performed in three cases) confirmed the diagnosis of S. aureus spondylodiscitis in one patient (Table 3). The mean time interval between onset of symptoms and diagnosis was 34 ± 42 days (Table 3). All patients received antibiotic treatment for a mean duration of 6 weeks. In most of the cases it was used vancomycin or teicoplanin plus ciprofloxacin as initial antibiotics (Table 4). One patients had recurrent infective spondylodiscitis within 2 years; one patient had long-term neurologic sequelae despite surgical treatment. The others 7 cases underwent resolution after a mean of 3.5 months. Conclusion Infective spondylodiscitis is a disease to be suspected in the presence of back pain among HD patients, even in the absence of fever or traditional risk factors. It is important to get an early diagnosis, to improve the outcome of patients, avoiding diagnostic delays. Close monitoring of vascular access, paying attention to disinfection procedures and aseptic techniques, is important to avoid this complication. Figure 1. MRI of the lumbosacral spine without gadolinium contrast showing discitis at the L4–L5 level (Patient n. 6). Table 1. Characteristics of the patients with infective spondylodiscitis in care at our center. Table 2. Initial clinical presentation, initial laboratory results, diagnostic tools, location of infection. Table 3. Dialytic age, vascular access for hemodialysis, culture results, time interval between onset of symptoms and diagnosis. Table 4. Treatments and outcome of patients.

BACKGROUND Tunnelled femoral catheters with their tip in the lower inferior vena cava (IVC) are proposed only in few cases, but they often provide less than optimal blood flows and frequently have complications. The aim of this prospective observational study is to evaluate the use of 70-cm-long tunnelled cuffed femoral twin Tesio catheters with their tip in the upper IVC for haemodialysis. METHODS Between May 2007 and May 2009, 25 tunnelled femoral catheters (fCVC) have been placed in 25 patients (77.7 +/- 10.8 years) with exhausted thoracic venous accesses or old patients with several comorbidities. Two 10 Fr carbothane 70-cm-long Tesio catheters with a Dacron cuff at 45 cm from the tip were placed in the femoral vein of each patient and then tunnelled; tips were in the upper third of the IVC. fCVCs were removed for either malfunction (Qb < 200 ml/min) or infection that did not resolve with antibiotics. RESULTS Technical success of placement was 100%. The 6- and 12-month assisted primary patency rate were respectively 67 +/- 13% and 54 +/- 17%. The mean session Kt/V was 1.45 +/- 0.19, and the blood flow was 270 +/- 17 ml/min. Six fCVCs have been removed: three for infection, one for accidental damaging and two for the making of a different vascular access. The main complications were 2 catheter tip thrombi, 3 tunnel infections and 11 fCVC-related bacteraemia (1.77 episodes per 1000 CVC-days). CONCLUSION The placement of twin fCVCs with their tip in the high IVC can provide an adequate dialysis and can be considered for patients with no remaining thoracic accesses.

Long-term exposure to high glucose up-regulates VCAM-induced endothelial cell adhesiveness to PBMC. Background The changes induced on endothelial cells by a long-term exposure to high glucose, a situation that mimics the hyperglycemia of diabetics, have not yet been determined. We compared short- and long-term effects of elevated glucose on macrovascular and microvascular endothelial cells. Methods Endothelial cells were grown in high-glucose media for 24 hours and for 8 weeks. Cell proliferation was evaluated by cell counting, apoptosis and expression of adhesion molecules by flow cytometry; nitric oxide (NO) by measuring the concentration of nitrite/nitrate in the cell supernatant; α2(IV) collagen mRNA and protein by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The adhesion of peripheral blood mononuclear cells (PBMCs) to endothelial cells was evaluated by adhesion assay. In some experiments, endothelial cells were preincubated with anti-vascular cell adhesion molecule-1 (VCAM-1) and anti-receptor for advanced glycation end product (RAGE) blocking antibodies. Results At 24 hours, but not at 8 weeks, high glucose increased endothelial cell proliferation and apoptosis. High glucose did not modify NO synthesis at 24 hours and 8 weeks. Collagen production and expression were increased only after eight weeks. VCAM-1 but not intercellular adhesion molecule-1 was up-regulated after 8 weeks, a change not observed after 24 hours. The adhesion of PBMCs was significantly increased at eight weeks and was completely abrogated by anti-VCAM-1 and by anti-RAGE antibodies. After 24 hours, there was a modest increase of PBMC adhesion that was not blunted by anti-RAGE antibodies. Conclusions Increased adhesion of PBMCs, caused by up-regulation of VCAM-1 with a mechanism involving advanced glycation end product (AGE) adducts, and augmented collagen deposition are critical effects of long-term high glucose on endothelial cells, and may eventually promote the atherosclerotic process.

Cyclosporine induces different responses in human epithelial, endothelial and fibroblast cell cultures. Background Nephrotoxicity, accelerated atherosclerosis, and graft vascular disease are common complications of cyclosporine long-term treatment characterized by a wide disruption of organ architecture with increased interstitial areas and accumulation of extracellular matrix (ECM). How cyclosporine induces these changes is not clear, but it is conceivable that they are the sum of changes induced at the cell level. Methods We studied the effects of cyclosporine on human endothelial (HEC), epithelial (HK-2), and fibroblast (MRC5) cells. Cell proliferation was evaluated by cell counting, apoptosis and collagen production by enzyme-linked immunosorbent assay, and nitric oxide by measuring the concentration of nitrite/nitrate in the cell supernatant. (α1)I and (α2)IV collagen, matrix metalloprotease-9 (MMP9), and tissue inhibitors of metalloprotease-1 (TIMP-1) mRNA levels were measured by reverse transcription-polymerase chain reaction. Proteolytic activity was evaluated by zymography. Results Cyclosporine showed a marked antiproliferative and proapoptotic effect on endothelial and epithelial cells. Fibroblast growth was not affected by cyclosporine. Nitric oxide was up-regulated by cyclosporine in epithelial cells and fibroblasts but not in endothelial cells. (α1)I and (α2)IV collagen synthesis was increased in cyclosporine-treated endothelial and epithelial cells, respectively. Proteolytic activity was increased in endothelial and epithelial cells. TIMP-1 mRNA was up-regulated by cyclosporine in fibroblasts. Conclusions Our results demonstrate that cyclosporine exhibits an antiproliferative effect on endothelial and epithelial cells. This effect is associated with induction of apoptosis probably via nitric oxide up-regulation in epithelial cell cultures. Cyclosporine treatment induces ECM accumulation by increasing collagen synthesis in endothelial and epithelial cells and reducing its degradation by up-regulating TIMP-1 expression in fibroblasts. We conclude that cyclosporine affects cell types differently and that the disruption of organ architecture is the result of multiple effects at the cell level.

Aging is characterized by a decline in renal function and by a susceptibility to renal diseases. However it is not clear whether the observed changes are solely hemodynamic, structural or both. We evaluated renal function, functional reserve (RFR) and morphology in healthy elderly individuals.Healthy participants (n=19) were divided into young (n=6, age range 25-37 years), middle-aged (n=6, 44-74 years) and elderly (n=7, 81-96 years). Nitric oxide (NO), plasma renin activity (PRA) and aldosterone, renal plasma flow (RPF) by p-aminohippurate clearance (CPAH) and glomerular filtration rate (GFR) by inulin clearance (CIN) were determined before and during maximal vasodilating stimuli, induced with the infusion of dopamine and amino acids. Glomerular sclerosis, lumen area and wall thickness of afferent arterioles were determined by kidney biopsy from 36 healthy kidney donors and from 6 nephrectomies for renal carcinoma.GFR and RPF were slightly reduced in elderly individuals whereas filtration fraction (FF) was increased. GFR and RPF did not increase in the elderly after maximal vasodilating stimuli as in young and middle-aged subjects suggesting a reduction of RFR. NO, increased at baseline, did not increase further after vasodilating stimuli; while on the contrary, PRA, similar in the 3 groups at baseline, was not reduced by vasodilating stimuli in the elderly. Sclerotic glomeruli but not glomerular volume were significantly increased by aging. Afferent arteriole lumens were reduced by aging whereas wall thickness was unchanged.Renal function is preserved with aging in healthy subjects at the expense of a complete reduction of RFR. RFR may be wasted to compensate for the increased number of sclerotic glomeruli. Vascular changes, suggested by reduced arteriolar lumen, may be so advanced that even in the presence of high levels of vasodilatory molecules, kidneys are not responsive anymore to maximal vasoactive stimuli.

Introduction Although chronic cyclosporine toxicity is mainly characterized by tubular atrophy and interstitial fibrosis, glomerular injury with expansion of mesangial matrix and sclerosis is not uncommon. Tacrolimus is a newer calcineurin inhibitor that has been used in renal transplant recipients as primary or rescue therapy. Clinical trials suggest an improved long-term graft survival among patients treated with tacrolimus. Recently we have shown that tacrolimus and cyclosporine have similar effects on extracellular matrix turnover in cultured cells. The present study was performed to investigate the effects of the calcineurin inhibitors on whole glomeruli extracellular matrix turnover. Methods Human glomeruli isolated from kidney biopsies just before transplantation were incubated with culture media containing either cyclosporine (200 ng/mL) or tacrolimus (10 ng/mL) for 24 hours. Glomeruli incubated only with culture medium were used as control. Results The expressions of (α2)IV collagen, metalloprotease 9 (MMP9), tissue inhibitors of metalloproteases 2 (TIMP-2), and TGFβ were evaluated by in situ reverse transcription and polymerase chain reactions (RT-PCR). β-actin was used as a control gene. Cyclosporine (but not tacrolimus) increased the expression of (α2)IV collagen and TIMP2 in isolated glomeruli. TGF-β was markedly increased by cyclosporine. MMP9 expression was not affected by the calcineurin inhibitors. By light microscopy kidney biopsies did not show pathologic changes. Conclusion Cyclosporine treatment modulates extracellular matrix turnover in isolated human glomeruli, inducing an imbalance between synthesis and degradation. This effect, not observed in tacrolimus-treated human glomeruli, may induce the extracellular matrix deposition and sclerosis characteristic of chronic cyclosporine toxicity.

Hepatocyte growth factor (HGF) modulates matrix turnover in human glomeruli Background The imbalance between synthesis and degradation of mesangial matrix causes glomerulosclerosis and leads to renal failure. Hepatocyte growth factor (HGF) has been shown to reduce the progression in murine models of chronic renal failure. The present study evaluated the effect of HGF on the extracellular matrix turnover and on c-met receptor in human glomeruli. Methods Human glomeruli microdissected from donor kidney biopsies before transplantation were incubated with culture media containing HGF (50 ng/mL). After 24 and 48 hours, the expression of c-met, (α2) IV collagen, transforming growth factor-β (TGF-β), metalloprotease (MMP) 2 and 9 and of the inhibitor of MMP-2, tissue inhibitors of metalloprotease-1 (TIMP-1), was evaluated by polymerase chain reaction (PCR). β-actin was used as housekeeping gene. The production of collagen type IV and TGF-β was evaluated by enzyme-linked immunosorbent assay (ELISA) and Western blotting and the activity of MMP by zymography. Results (α2) IV collagen, TGF-β, and TIMP-1 mRNA levels were markedly decreased in glomeruli treated with HGF at 24 and 48 hours. The expression of c-met was up-regulated by HGF treatment. HGF reduced the production of collagen type IV and TGF-β. MMP-2 but not MMP-9 mRNA level was increased in HGF-treated glomeruli, although the gelatinolytic activity of the supernatant was not changed. By light microscopic examination kidney biopsies neither showed glomerular hypercellularity nor mesangial expansion. Conclusion HGF reduced expression and synthesis of TGF-β and collagen type IV and increased MMP-2 mRNA level in normal human glomeruli. These results suggest an antifibrotic effect of HGF on glomerular cells and may explain its beneficial role in glomerulosclerosis.