Long-Term Outcomes of Rituximab-Treated Adult Patients with Podocytopathies.

BACKGROUND: Long-term outcomes of rituximab-treated adult patients with podocytopathies (either minimal change disease or focal segmental glomerulosclerosis) are largely unknown. METHODS: A retrospective study at 30 nephrology departments from 15 countries worldwide included rituximab-treated adults with primary podocytopathies and a minimum clinical follow-up of 36 months. The primary outcome was relapse-free survival at 36 months. RESULTS: 183 adult patients (n=64 with focal segmental glomerulosclerosis and n=119 with minimal change disease) with difficult-to-treat nephrotic syndrome (68% steroid-dependent/frequently relapsing, 22% steroid-resistant, 85% previously treated with two or more lines of immunosuppressive therapy) were treated with rituximab as part of a remission induction regimen. Complete or partial remission at 6 months after rituximab treatment was achieved in 82%. Eighty-three of 151 (55%) initial responders achieved long-term relapse-free survival over three years. Maintenance therapy with rituximab was associated with a better relapse-free survival (HR 2.05, 95% CI: 1.07-3.91), irrespective of the dosing regimen. At 36 months, 61% of initial responders receiving maintenance therapy with rituximab achieved long-term relapse-free survival and withdrawal of all concomitant immunosuppressive medication compared to 36% of patients without maintenance treatment (OR 2.69, 95% CI: 1.27-5.73). Relapses per year were reduced from an annual relapse rate of 1.0 (95% CI: 1.0-1.7) before to 0.17 (95% CI: 0.00-0.24) relapses/year after rituximab initiation. Over the 36 months of follow-up, a stable course of estimated glomerular filtration rate (eGFR) was observed in those who initially responded with either complete or partial remission, whereas non-responders experienced a reduction in eGFR reaching -11 (95% CI: -18 to -8) mL/min/1.73m2 . CONCLUSIONS: Rituximab facilitated achievement of initial and long-term response in a majority of adult patients with difficult-to-treat podocytopathies. Maintenance treatment with rituximab further associated with long-term relapse-free survival over three years. Non-response to initial rituximab treatment was associated with poor kidney prognosis.

Sodium-glucose cotransporter 2 inhibition in primary and secondary glomerulonephritis.

BACKGROUND: The role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the management glomerular/systemic autoimmune diseases with proteinuria in real-world clinical settings is unclear. METHODS: This is a retrospective, observational, international cohort study. Adult patients with biopsy-proven glomerular diseases were included. The main outcome was the percentage reduction in 24-h proteinuria from SGLT2i initiation to 3, 6, 9 and 12 months. Secondary outcomes included percentage change in estimated glomerular filtration rate (eGFR), proteinuria reduction by type of disease and reduction of proteinuria ≥30% from SGLT2i initiation. RESULTS: Four-hundred and ninety-three patients with a median age of 55 years and background therapy with renin-angiotensin system blockers were included. Proteinuria from baseline changed by -35%, -41%, -45% and -48% at 3, 6, 9 and 12 months after SGLT2i initiation, while eGFR changed by -6%, -3%, -8% and -10.5% at 3, 6, 9 and 12 months, respectively. Results were similar irrespective of the underlying disease. A correlation was found between body mass index (BMI) and percentage proteinuria reduction at last follow-up. By mixed-effects logistic regression model, serum albumin at SGLT2i initiation emerged as a predictor of ≥30% proteinuria reduction (odds ratio for albumin <3.5 g/dL, 0.53; 95% CI 0.30-0.91; P = .02). A slower eGFR decline was observed in patients achieving a ≥30% proteinuria reduction: -3.7 versus -5.3 mL/min/1.73 m2/year (P = .001). The overall tolerance to SGLT2i was good. CONCLUSIONS: The use of SGLT2i was associated with a significant reduction of proteinuria. This percentage change is greater in patients with higher BMI. Higher serum albumin at SGLT2i onset is associated with higher probability of achieving a ≥30% proteinuria reduction.

Body composition indices as predictors of humoral response to mRNA vaccination against COVID-19 in patients on maintenance hemodialysis.

INTRODUCTION: Patients on maintenance hemodialysis show lower serological response to mRNA vaccines. Main causes that contribute to this phenomenon are uremic milieu and older age. However, there are no data on the impact of body composition parameters to humoral response. MATERIALS AND METHODS: In this retrospective study, we used data from adult patients on maintenance hemodialysis who received vaccination with 2 doses of BNT162b2. Quantitative determination of antibodies to SARS-CoV-2 spike (S) protein receptor binding domain was performed using the Elecsys immunoassay. Antibody levels higher than 0.8 and 264 U/mL were considered positive and protective, respectively. Body composition parameters were assessed using multifrequency bioelectrical impedance spectroscopy. RESULTS: Overall, 49 patients were included in the study. Three weeks after the 1st vaccination, 34% of patients, and 3 weeks and 3 months after the 2nd vaccination, 100% of patients had detectable titers. Protective titer was developed in 43% of patients 3 weeks after the 2nd vaccination and then decreased to 24% 3 months after the 2nd vaccination. More years on dialysis were correlated to the absence of protective titers. Higher prediction marker values correlated to poor antibody response, and phase angle was negatively associated with the development of protective titers. Patients with protective titers at 3 months after the 2nd vaccination had significantly lower prediction marker and higher phase angle values. CONCLUSION: Parameters of body composition correlate and affect antibody response in patients on hemodialysis. The main observation is that immunogenicity of mRNA vaccines is influenced by phase angle and prediction marker.

Soluble urokinase plasminogen activator receptor (suPAR) in children with obesity or type 1 diabetes as a marker of endothelial dysfunction: a cross-sectional study.

Pediatric obesity and type 1 diabetes mellitus (T1DM) represent two common chronic diseases associated with chronic inflammation, endothelial dysfunction and long-term complications. The aim of the present study was to assess the possible diagnostic and prognostic value of soluble urokinase plasminogen activator receptor (suPAR), a marker of inflammation and impaired endothelial function, in children with the diseases. In this cross-sectional study, children and adolescents with T1DM (N = 41) or obesity (N = 37), aged < 18 years old, and without proteinuria were included, together with children of similar age and without evident morbidity that served as controls (N = 42). Serum samples were obtained during standard outpatient follow up and the urokinase-type plasminogen activator receptor (suPAR) concentrations were measured using a commercially available sandwich ELISA kit (DUP00, R&D systems). Clinical and biochemical indices that were also assessed include body mass index (BMI) z-score, Tanner stages, glycosylated haemoglobin (HbA1c), fasting lipid profile and serum creatinine. Mean serum suPAR levels were significantly higher in patients with obesity compared to patients with T1DM and controls, while children with T1DM had similar suPAR levels to controls. Also, serum suPAR levels showed a negative correlation with age (Spearman rho -0.359, p < 0.001) and serum creatinine levels (Spearman rho -0.334, p = 0.005), and a positive correlation with BMI z-score (Spearman rho 0.354, p = 0.009) in the whole cohort.  Conclusion: Serum suPAR may be a useful predictive marker of inflammation or endothelial dysfunction for children with obesity and T1DM, as well as a promising therapeutic target. Further studies are needed in order to clarify whether the reported differences in suPAR levels could reflect a greater impairment of the inflammation status and endothelial function in children with obesity compared to children with T1DM. What is Known: • Paediatric obesity and type 1 diabetes are characterised by chronic inflammation and metabolic dysregulation. • Urokinase plasminogen activator receptor (uPAR) has been proposed as a useful biomarker for chronic inflammation and cardiovascular risk in adults. What is New: • Serum suPAR levels were increased in children and adolescents with obesity compared to those with T1DM and healthy controls; thus, obesity may affect the inflammatory status and endothelial function to a higher degree than T1DM during childhood. • Serum suPAR may serve as a diagnostic and predictive marker of inflammation and endothelial dysfunction for children and adolescents with obesity and T1DM.

Circulating Immune Complexes and Complement Activation in Sensitized Kidney Transplant Recipients.

Chronic antibody-mediated rejection in kidney transplantation is a common cause of graft loss in the late post-transplant period. In this process, the role of the classical complement activation pathway is crucial due to the formation of immune complexes between donor-specific antibodies (DSAs) and donor antigens and the attachment of the C1q complement fragment. This study aimed to determine the levels of circulating C1q immunocomplexes (CIC-C1q) and complement activation (CH50), in sensitized kidney transplant recipients (KTRs). In this cross-sectional study we used serum samples from KTRs with de novo or preformed DSAs (n = 14), KTRs without DSAs (n = 28), and 22 subjects with no history of chronic kidney disease (controls). C1q immunocomplexes and CH50 concentration in serum were measured with the enzyme immunoassay (EIA) kit MicroVue CIC-C1q (Quidel, Athens, OH, USA) and EIA kit MicroVue CH50 (Quidel, OH, USA), respectively. Higher concentrations of CIC-C1q was observed in KTRs with DSAs in comparison with controls and with KTRs with no DSAs (6.8 ± 2.7 and 4.8 ± 1.9 vs. 5.0 ± 1.2 µg Eq/mL, respectively, p < 0.01). We found no difference in CIC-C1q between KTRs with no DSAs and controls. CIC-C1q levels were positively correlated with DSA titer. CH50 levels were decreased in KTRs with DSAs in comparison with controls and KTRs with no DSAs (39 ± 15 vs. 68 ± 40 and 71 ± 34 U Eq/mL, respectively, p < 0.01). There was no difference in CH50 between DSA-negative KTRs and controls. Kidney transplant recipients with DSAs had increased serum levels of C1q immunocomplexes and increased classical pathway complement activation.

Keratin Expression in Podocytopathies, ANCA-Associated Vasculitis and IgA Nephropathy.

Keratins are the main components of the cell cytoskeleton of epithelial cells. Epithelial cells under stressful stimuli react by modifying their keratin expression pattern. Glomerular diseases are pathological conditions that may lead to loss of kidney function if not timely diagnosed and treated properly. This study aims to examine glomerular and tubular keratin expression in podocytopathies, ANCA-associated vasculitis, and IgA nephropathy and how this expression correlates to clinical outcomes. We included 45 patients with podocytopathies (minimal change disease and focal segmental glomerulosclerosis), ANCA-associated vasculitis, and IgA nephropathy, with or without crescentic lesions, and healthy controls. All tissues were assessed by photon microscopy and immunohistochemistry. Biopsy sections were examined for keratins 7, 8, 18, and 19 expression in the glomerular and tubulointerstitial areas separately. Moreover, we examined how keratin expression was correlated with long-term kidney function outcomes. All four studied keratins had significantly increased glomerular expression in patients with ANCA vasculitis compared to controls and MCD patients. Tubular expression of keratins 7, 8, and 19 was related to kidney outcome in all groups. Patients with crescents had higher expression of all keratins in both glomeruli and tubulointerstitium. The presence of tubular atrophy, interstitial fibrosis, mesangial hyperplasia, and interstitial inflammation did not affect keratin expression. Keratins, an abundant component of renal epithelial cells, have the potential to be featured as a biomarker for kidney function prognosis in patients with glomerular diseases.

The impact of COVID-19 on paediatric emergency department visits. A one-year retrospective study.

BACKGROUND: The number of paediatric emergency department (ED) visits and hospital admissions was recorded in a tertiary referral centre during the first year of the COVID-19, March 2020-February 2021, and compared with those of the preceding year. METHODS: The number of visits and admissions and the reason of visit and admission were prospectively recorded from 15,087 patients' files. RESULTS: A substantial decline in the total number of visits and increase in the admission rate were documented during the COVID-19 year compared to the preceding year (10691 vs 4396 patients, 22.59% vs 18.15% (OR: 1.316, CI 95%: 1.208-2.242, p < 0.0001), respectively). Fever and/or respiratory symptoms were the commonest reported symptoms in both periods. Possible explanations include: (i) restricted overall infection transmission due to confinement and self-protective measures, (ii) avoidance of unnecessary hospital visits in the absence of severe symptoms and (iii) reduced or delayed access to medical care due to parental fear of children's exposure to COVID-19. CONCLUSION: This study is the first worldwide to investigate the impact of COVID-19 on ED visits and admissions throughout the whole year of the pandemic, and to highlight the need for re-evaluation of future protective strategies to infections, adjustment of health-care systems and parental education so that medical care in a health-care setting is sought in a more appropriate manner. IMPACT: A significant decline in paediatric ED visits and increase in the admission rate was observed during the first year of COVID-19 in a tertiary referral centre, possibly due to reduced overall infection transmission, limited ED overuse, but also ED underuse due to parental fear of children's exposure to SARS-CoV-2. COVID-19 may serve as an opportunity for societies to re-evaluate future strategies to infections, adjust health-care systems accordingly, and reinforce parents to seek medical care more appropriately. Although the incidence of critical illness in children due to COVID-19 and in general is low, special attention should be devoted to identifying children at risk early.

Percutaneous Arteriovenous Fistula Creation with the WavelinQ 4-French EndoAVF System: A Single-Center Retrospective Analysis of 30 Patients.

PURPOSE: To retrospectively assess the safety and efficacy of percutaneous arteriovenous fistula (pAVF) creation with the WavelinQ 4-F EndoAVF System. MATERIALS AND METHODS: From February 2018 to June 2020, 30 pAVFs were created in 30 consecutive patients (men; age, 55.3 years ± 13.6). Of the 30 patients, 21 (70%) were already on hemodialysis using a central venous catheter. The primary outcome measures were technical success, complications, and cannulation rate. The secondary outcome measures included the number of secondary procedures needed for cannulation, maintenance time to cannulation, and pAVF survival. RESULTS: Technical success was 100%. The adverse event rate was 6.7% (2/30), including a pseudoaneurysm of the brachial artery that developed immediately after sheath removal and an aneurysm of the anastomosis 17 days after the procedure, which was treated with a covered stent placed in the arterial side. The mean follow-up was 547 days ± 315.7 (range, 14-1,071 days). The cannulation rate was 86.7% (26/30). The mean time to cannulation was 61.3 days ± 32.5 (range, 15-135 days). The mean follow-up after cannulation was 566.2 days ± 252.7 (range, 35-1,041 days). Four pAVFs were thrombosed after cannulation, with 2 of them successfully declotted. Sixteen interventions were needed to achieve cannulation after the index procedure in 15 patients (overall, 0.53 procedures/patient). Seven maintenance endovascular interventions (following cannulation) were performed during the follow-up period in 6 patients (overall, 0.27 procedures/patient, 0.17 procedures/patient-years). For the pAVFs that were cannulated, patency was 96% at 1 year, and 82% at 2 and 3 years, according to the Kaplan-Meier survival analysis. CONCLUSIONS: This initial experience suggests that pAVF creation is safe and can be successfully performed with high maturation and long-term patency rates. Larger-scale prospective studies are needed to validate the results.

The switch from proteasome to immunoproteasome is increased in circulating cells of patients with fast progressive immunoglobulin A nephropathy and associated with defective CD46 expression.

The proteasome to immunoproteasome (iPS) switch consists of ß1, ß2 and ß5 subunit replacement by low molecular weight protein 2 (LMP2), LMP7 and multicatalytic endopeptidase-like complex-1 (MECL1) subunits, resulting in a more efficient peptide preparation for major histocompatibility complex 1 (MHC-I) presentation. It is activated by toll-like receptor (TLR) agonists and interferons and may also be influenced by genetic variation. In a previous study we found an iPS upregulation in peripheral cells of patients with immunoglobulin A nephropathy (IgAN). We aimed to investigate in 157 IgAN patients enrolled through the multinational Validation Study of the Oxford Classification of IgAN (VALIGA) study the relationships between iPS switch and estimated glomerular filtration rate (eGFR) modifications from renal biopsy to sampling. Patients had a previous long follow-up (6.4 years in median) that allowed an accurate calculation of their slope of renal function decline. We also evaluated the effects of the PSMB8/PSMB9 locus (rs9357155) associated with IgAN in genome-wide association studies and the expression of messenger RNAs (mRNAs) encoding for TLRs and CD46, a C3 convertase inhibitor, acting also on T-regulatory cell promotion, found to have reduced expression in progressive IgAN. We detected an upregulation of LMP7/ß5 and LMP2/ß1 switches. We observed no genetic effect of rs9357155. TLR4 and TLR2 mRNAs were found to be significantly associated with iPS switches, particularly TLR4 and LMP7/ß5 (P < 0.0001). The LMP7/ß5 switch was significantly associated with the rate of eGFR loss (P = 0.026), but not with eGFR at biopsy. Fast progressors (defined as the loss of eGFR >75th centile, i.e. -1.91 mL/min/1.73 m2/year) were characterized by significantly elevated LMP7/ß5 mRNA (P = 0.04) and low CD46 mRNA expression (P < 0.01). A multivariate logistic regression model, categorizing patients by different levels of kidney disease progression, showed a high prediction value for the combination of high LMP7/ß5 and low CD46 expression.

Is there long-term value of pathology scoring in immunoglobulin A nephropathy? A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update.

BACKGROUND: It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up. METHODS: In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1-10.8)]. RESULTS: In this extended analysis, M1, S1 and T1-T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P < 0.01), and there was no effect modification by age for these associations, suggesting that they may be valid in children and in adults as well. Only T lesions were associated with the rate of eGFR loss in the whole cohort, whereas C showed this association only in patients not treated with immunosuppression. In separate prognostic analyses, the whole set of pathology lesions provided a gain in discrimination power over the clinical variables alone, which was similar at 5 years (+2.0%) and for the whole follow-up (+1.8%). A similar benefit was observed for risk reclassification analyses (+2.7% and +2.4%). CONCLUSION: Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy.

Recent developments in endovascular interventions to sustain vascular access patency in haemodialysis patients.

There is amassed evidence regarding the use of endovascular procedures for the treatment of vascular access stenosis and thrombosis. A review was conducted based on available randomized trials, cohort studies and retrospective analyses published after 2000 on endovascular treatment of dysfunctional and thrombosed vascular access, with an aim to illustrate the available device and procedural options. The use of paclitaxel-coated balloons, cutting balloons and covered stents is described in the field of vascular access stenosis. The broad spectrum of available devices and endovascular declotting procedures ranging from thrombolysis to thrombectomy is also discussed. Overall, in this review we demonstrate the increasing role of endovascular procedures in vascular access treatment and the improved patency outcomes provided by the implementation of novel endovascular devices. Moreover, the improvement of post-intervention primary patency rates after endovascular declotting procedures and the shift to more thrombectomy-dependent procedures over time is also highlighted. In conclusion, endovascular treatment of dialysis access stenosis and thrombosis has an established role, owing to the implementation of sophisticated devices, allowing, when needed, the simultaneous treatment of thrombosis and the underlying stenosis.

Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74.

Pathologic proliferation of mesangial and parietal epithelial cells (PECs) is a hallmark of various glomerulonephritides. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that mediates inflammation by engagement of a receptor complex involving the components CD74, CD44, CXCR2, and CXCR4. The proliferative effects of MIF may involve CD74 together with the coreceptor and PEC activation marker CD44. Herein, we analyzed the effects of local glomerular MIF/CD74/CD44 signaling in proliferative glomerulonephritides. MIF, CD74, and CD44 were upregulated in the glomeruli of patients and mice with proliferative glomerulonephritides. During disease, CD74 and CD44 were expressed de novo in PECs and colocalized in both PECs and mesangial cells. Stress stimuli induced MIF secretion from glomerular cells in vitro and in vivo, in particular from podocytes, and MIF stimulation induced proliferation of PECs and mesangial cells via CD74. In murine crescentic GN, Mif-deficient mice were almost completely protected from glomerular injury, the development of cellular crescents, and the activation and proliferation of PECs and mesangial cells, whereas wild-type mice were not. Bone marrow reconstitution studies showed that deficiency of both nonmyeloid and bone marrow-derived Mif reduced glomerular cell proliferation and injury. In contrast to wild-type mice, Cd74-deficient mice also were protected from glomerular injury and ensuing activation and proliferation of PECs and mesangial cells. Our data suggest a novel molecular mechanism and glomerular cell crosstalk by which local upregulation of MIF and its receptor complex CD74/CD44 mediate glomerular injury and pathologic proliferation in GN.

Keratins are novel markers of renal epithelial cell injury.

Keratins, the intermediate filaments of the epithelial cell cytoskeleton, are up-regulated and post-translationally modified in stress situations. Renal tubular epithelial cell stress is a common finding in progressive kidney diseases, but little is known about keratin expression and phosphorylation. Here, we comprehensively describe keratin expression in healthy and diseased kidneys. In healthy mice, the major renal keratins, K7, K8, K18, and K19, were expressed in the collecting ducts and K8, K18 in the glomerular parietal epithelial cells. Tubular expression of all 4 keratins increased by 20- to 40-fold in 5 different models of renal tubular injury as assessed by immunohistochemistry, Western blot, and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The up-regulation became significant early after disease induction, increased with disease progression, was found de novo in distal tubules and was accompanied by altered subcellular localization. Phosphorylation of K8 and K18 increased under stress. In humans, injured tubules also exhibited increased keratin expression. Urinary K18 was only detected in mice and patients with tubular cell injury. Keratins labeled glomerular parietal epithelial cells forming crescents in patients and animals. Thus, all 4 major renal keratins are significantly, early, and progressively up-regulated upon tubular injury regardless of the underlying disease and may be novel sensitive markers of renal tubular cell stress.

Turnover of type III collagen reflects disease severity and is associated with progression and microinflammation in patients with IgA nephropathy.

BACKGROUND: Renal fibrosis is the hallmark of progression to end-stage kidney disease. Non-invasive biomarkers of renal fibrosis could serve as specific end points in clinical trials and improve monitoring and stratification of patients with chronic kidney disease (CKD). To address this, we measured markers of collagen type III turnover in urine and serum of IgA nephropathy (IgAN) patients. METHODS: We measured the collagen type III pro-peptide (Pro-C3), representing production, and a neo-epitope fragment (C3M), representing a specific degradation fragment of collagen type III, in urine and serum samples from two cohorts of IgAN patients using newly developed enzyme-linked immunosorbent assays. RESULTS: With increasing CKD stage, urinary C3M gradually decreased (mean C3M/creatinine: 17.3 ng/mg in CKD stage 1, 3.5 ng/mg in CKD stage 5) whereas urinary Pro-C3 gradually increased (mean Pro-C3/creatinine: 4.1 ng/mg in CKD stage 1, 20.8 ng/mg in CKD stage 5). The urinary Pro-C3/C3M ratio, a measure of collagen type III turnover, significantly increased in advanced CKD stages. Serum C3M was not related to CKD stage but was associated with microinflammation. Urinary C3M was significantly lower in patients whose CKD stage subsequently progressed compared with those who did not progress. CONCLUSIONS: Our results suggest that the combination of urinary markers of collagen type III turnover, in particular the urinary Pro-C3/C3M ratio, is a potential novel, non-invasive diagnostic and prognostic tool to specifically monitor extracellular matrix (ECM) remodelling in kidney fibrosis.

If you lose your nerves, at least you will not get kidney fibrosis!

Kidney fibrosis is one of the most promising treatment targets in nephrology. To design effective treatment approaches, a detailed understanding of the initiating mechanisms is of great importance. Kim and Pandanilam now find that renal nerves are a major trigger for renal fibrosis. Both afferent and efferent nerve fibers are involved via norepinephrine and α2-adrenergic receptors as well as calcitonin gene-related peptide (CGRP) and its receptors.

Serum and urine markers of collagen degradation reflect renal fibrosis in experimental kidney diseases.

BACKGROUND: The extent of renal fibrosis in chronic kidney disease (CKD) is the best predictor for progression of most renal diseases. To date, no established biomarkers of renal fibrosis exist. METHODS: We measured circulating and urinary-specific matrix metalloproteinase (MMP)-generated collagen type I and III degradation fragments (C1M and C3M) and an N-terminal propeptide of collagen III (Pro-C3), as markers of collagen type III production, in three rat models of CKD and fibrosis: renal mass reduction (5/6 nephrectomy), progressive glomerulonephritis (chronic anti-Thy1.1 nephritis) and adenine crystal-induced nephropathy. Healthy rats served as controls. RESULTS: In all three models, the animals developed significant CKD and renal fibrosis. Compared with healthy rats, serum C1M and C3M significantly increased in rats with 5/6 nephrectomy and adenine nephropathy (2- to 3-fold), but not with chronic anti-Thy1.1 nephritis. Urinary C1M and C3M levels increased 9- to 100-fold in all three models compared with controls. Urinary degradation markers correlated closely with renal deposition of collagen type I and type III. Pro-C3 was significantly increased only in the urine of 5/6 nephrectomy rats. CONCLUSIONS: In particular, urinary markers of MMP-driven collagen degradation, rather than collagen production markers, may represent a novel, specific and non-invasive diagnostic approach to assess kidney fibrosis.

Impact of bisphosphonate treatment on bone mineral density after kidney transplant.

BACKGROUND: Mineral bone disease is associated with chronic kidney disease and persists after kidney transplantation. Immunosuppressive treatment contributes to the pathogenesis of this disease. Bisphosphonate treatments have shown positive but indefinite results. AIM: To evaluate the effectiveness and safety of bisphosphonate treatment on post kidney transplantation bone mineral density (BMD). METHODS: We included kidney transplant recipients (KTRs) whose BMD was measured after the operation but before the initiation of treatment and their BMD was measured at least one year later. We also evaluated the BMD of KTRs using two valid measurements after transplantation who received no treatment (control group). RESULTS: Out of 254 KTRs, 62 (39 men) were included in the study. Bisphosphonates were initiated in 35 KTRs in total (20 men), 1.1 ± 2.4 years after operation and for a period of 3.9 ± 2.3 years while 27 (19 men) received no treatment. BMD improved significantly in KTRs who received bisphosphonate treatments (from -2.29 ± 1.07 to -1.66 ± 1.09, P < 0.0001). The control group showed a non-significant decrease in BMD after 4.2 ± 1.4 years of follow-up after surgery. Kidney function was not affected by bisphosphonate treatment. In KTRs with established osteoporosis, active treatment had a similar and significant effect on those with osteopenia or normal bone mass. CONCLUSION: In this retrospective study of KTRs receiving bisphosphonate treatment, we showed that active treatment is effective in preventing bone loss irrespective of baseline BMD.

The effect of different dialysate sodium concentrations on ambulatory blood pressure in hemodialysis patients: a prospective interventional study.

Background: Hypertension is associated with increased morbidity and mortality in hemodialysis patients. Existing recommendations suggest reduction of sodium load, but the effect of dialysate sodium on blood pressure (BP) is not fully elucidated. The aim of the present study is to investigate the effect of different dialysate sodium concentrations on 72-h ambulatory BP in hemodialysis patients. Methods: This prospective study included patients on standard thrice-weekly hemodialysis. All patients initially underwent six sessions with dialysate sodium concentration of 137 meq/L, followed consecutively by another six sessions with dialysate sodium of 139 meq/L and, finally, six sessions with dialysate sodium of 141 meq/L. At the start of the sixth hemodialysis session on each sodium concentration, 72-h ABPM was performed over the long interdialytic interval to evaluate ambulatory systolic and diastolic BP (SBP and DBP) during the overall 72-h, different 24-h, daytime and night-time periods. Results: Twenty-five patients were included in the final analysis. A significant increase in the mean 72-h SBP was observed with higher dialysate sodium concentrations (124.8 ± 16.6 mmHg with 137 meq/L vs 126.3 ± 17.5 mmHg with 139 meq/L vs 132.3 ± 19.31 mmHg with 141 meq/L, P = 0.002). Similar differences were noted for DBP; 72-h DBP was significantly higher with increasing dialysate sodium concentrations (75.1 ± 11.3 mmHg with 137 meq/L vs 76.3 ± 13.7 mmHg with 139 meq/L vs 79.5 ± 13.9 mmHg with 141 meq/L dialysate sodium, P = 0.01). Ambulatory BP during the different 24-h intervals, daytime and night-time periods was also progressively increasing with increasing dialysate sodium concentration. Conclusion: This pilot study showed a progressive increase in ambulatory BP with higher dialysate sodium concentrations. These findings support that lower dialysate sodium concentration may help towards better BP control in hemodialysis patients.

Vacuum-Assisted Thrombo-Aspiration for Paradoxical Embolism in Left Renal Artery: A Case Report and Literature Review.

Paradoxical embolism through the foramen ovale is a rare and devastating event requiring urgent treatment. Herein, we present the case of a 23-year-old male who presented with a pulmonary embolism complicated by a left renal artery paradoxical embolism. Urgent vacuum-assisted thrombo-aspiration restored normal perfusion of the left kidney within 5 hours. The patient had a patent foramen ovale and heterozygous thrombophilia. However, a radioisotopic scan performed 2 years later revealed an unexpected decrease in left renal perfusion. Therefore, despite the angiographic success, functional evaluation using a renal scan should be performed to assess renal function.

Altered Expression of Intestinal Tight Junctions in Patients with Chronic Kidney Disease: A Pathogenetic Mechanism of Intestinal Hyperpermeability.

BACKGROUND: Systemic inflammation in chronic kidney disease (CKD) is associated (as a cause or effect) with intestinal barrier dysfunction and increased gut permeability, with mechanisms not yet fully understood. This study investigated different parameters of the intestinal barrier in CKD patients, especially tight junction (TJ) proteins and their possible association with systemic endotoxemia and inflammation. METHODS: Thirty-three patients with stage I-IV CKD (n = 17) or end-stage kidney disease (ESKD) (n = 16) and 11 healthy controls underwent duodenal biopsy. Samples were examined histologically, the presence of CD3+ T-lymphocytes and the expression of occludin and claudin-1 in the intestinal epithelium was evaluated by means of immunohistochemistry, circulating endotoxin concentrations were determined by means of ELISA and the concentrations of the cytokines IL-1ß, IL-6, IL-8, IL-10 and TNF-α in serum were measured using flow cytometry. RESULTS: Patients with stage I-IV CKD or ESKD had significantly higher serum endotoxin, IL-6, IL-8 and IL-10 levels compared to controls. Intestinal occludin and claudin-1 were significantly decreased, and their expression was inversely correlated with systemic endotoxemia. Regarding occludin, a specific expression pattern was observed, with a gradually increasing loss of its expression from the crypt to the tip of the villi. CONCLUSION: The expression of occludin and claudin-1 in enterocytes is significantly reduced in patients with CKD, contributing to systemic endotoxemia and inflammatory responses in these patients.