Histological grading in primary membranous nephropathy is essential for clinical management and predicts outcome of patients.

AIMS: Diagnosis of primary membranous nephropathy (PMN) is mainly based on immunofluorescence/immunohistochemistry findings. However, assessment of specific features on optical microscopy can help to estimate the severity of the disease, guide treatment and predict the response. The aim of this study was to identify, classify and grade the precise histological findings in PMN to predict renal function outcome and guide treatment. METHODS AND RESULTS: Histological parameters, including focal segmental sclerosis (FSGS), tubular atrophy (TA), interstitial fibrosis (IF) and vascular hyalinosis (VH), were re-evaluated in 752 patients with PMN. Their predictive value was estimated separately, and also in a combination score (FSTIV) graded from 0 to 4. Finally, the impact of histology was assessed in the response to immunosuppressive treatment. Mean age of patients was 53.3 (15-85) years and most presented with nephrotic syndrome. FSGS was present in 32% and VH in 51% of the patients, while TA and IF were graded as stage ≥1 in 52% and 51.4%, respectively. The follow-up period was 122.3 (112-376) months. FSGS, TA and IF and VH were associated with impaired renal function at diagnosis (P = 0.02, P < 0.0001, P = 0.001 and P = 0.02, respectively) and at the end of follow-up (P = 0.004, P < 0.0001, P < 0.0001 and P = 0.04, respectively). In multiple regression and binary logistic analysis, the presence of FSGS and degree of TA were the most significant parameters predicting renal function outcome, defined either by eGFR (end), FSGS (r = 0.6, P < 0.0001) and TA (r = 0.6, P < 0.0001), or by the endpoint of >50% eGFR reduction, FSGS (P = 0.001) and TA (P = 0.02). Also, patients presented with FSGS, IF, VH and/or with FSTIV > 1 could benefit from immunosuppression, regardless of clinical presentation. CONCLUSIONS: The presence and degree of four histological indices, FSGS, VH, TA and IF, assessed separately or in combination, and FSTIV score not only predict renal function outcome after long-term follow-up, but can also help in the choice of appropriate treatment. Decisions concerning immunosuppressive treatment can be guided by pathology regardless of clinical findings.

Soluble Klotho is associated with mortality and cardiovascular events in hemodialysis.

BACKGROUND: Klotho is a transmembrane protein acting as a co-receptor for FGF-23 and thus exerts clinical actions on mineral metabolism. The association of secreted Klotho with outcomes in CKD patients is unclear. This study examined the relation between plasma Klotho and cardiovascular events in dialysis patients, accounting for common and CKD-MBD related risk factors, arterial stiffness and atherosclerotic burden. METHODS: Seventy-nine chronic hemodialysis patients were observed for a median follow-up of 5.5 years. Klotho levels as well as carotid-femoral pulse wave velocity (cfPWV) and common carotid intima-media thickness (ccIMT) measurements were performed at baseline. The primary end-point was first occurrence of all-cause death, non-fatal myocardial infarction or non-fatal stroke. Secondary end-points were: (i) all-cause mortality; (ii) cardiovascular mortality; (iii) a combination of cardiovascular death, non-fatal MI, non-fatal stroke, resuscitation after cardiac arrest, coronary revascularization, heart failure hospitalization and atrial fibrillation. RESULTS: Cumulative freedom from the primary endpoint was 31% for the low-Klotho group (≤745 pg/ml) and 53% for the high-Klotho group (logrank p = 0.017); HR: 2.137, 95%CI 1.124-4.065. Cumulative survival was insignificantly lower (44% vs 56%, p = 0.107), but cumulative cardiovascular survival (63% vs 88%, p = 0.029) and cumulative freedom from the cardiovascular composite outcome (18% vs 45%, p = 0.009) were significantly lower in the low-Klotho group. In modelled Cox-regression analysis the association of low Klotho with the primary endpoint remained significant after stepwise adjustment for cFGF3, PTH, Ca x P product, established risk factors (age, dialysis vintage, diabetes, hypertension, smoking, history of cardiovascular disease) as well as cfPWV and ccIMT [Model 6: HR:2.759, 95%CI 1.223-6.224, p = 0.014]. CONCLUSIONS: Low Klotho is associated with cardiovascular events in hemodialysis patients, independently from factors associated with mineral-bone disease, common risk factors and intermediate outcomes, such as cfPWV and ccIMT.

To intervene or not? A man with multidrug-resistant hypertension, endovascular abdominal aneurysm repair, bilateral renal artery stenosis and end-stage renal disease salvaged with renal artery stenting.

We report the case of a 69-year-old man with uncontrolled multidrug-resistant secondary hypertension following a 10 year history of endovascular abdominal aortic aneurysm repair, with suprarenal fixation and concurrent angioplasty with stenting of the left renal artery for atherosclerotic renal disease, and progressive chronic kidney disease. Renal scintigraphy revealed complete loss of the right kidney's and severe reduction of the left kidney's perfusion and function. Following recent evidence and consultation with vascular surgeons regarding the technical difficulties of any procedure, escalation of antihypertensive treatment was initially chosen. Careful drug adjustments significantly improved but did not fully control blood pressure (BP); further, the patient experienced an acute ischaemic stroke and renal function deterioration towards end-stage renal disease within a few months. At this point, revascularization of the left renal artery coupled with three haemodialysis sessions to remove contrast media was justified as rescue therapy against permanent renal replacement therapy. Successful intervention achieved an immediate BP reduction, with BP fully controlled, despite a > 70% decrease in antihypertensive treatment, while renal function improved at 6 months from 11.5 to 22 ml/min/1.73 m(2). Renal angioplasty confers undisputed benefits in BP control and nephroprotection, and should be offered without delay to patients with renovascular hypertension and/or ischaemic nephropathy.

Diagnosing and Treating IgAN: Steroids, Budesonide, or Maybe Both?

IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, is characterized by a mesangial IgA deposit and a variety of histological lesions, as described by the Oxford classification system. Despite the well-described "four-hit hypothesis", there are still plenty of less or undescribed mechanisms that participate in the disease pathogenesis, such as B-cell priming, which seems to be initiated by different antigens in the intestinal microbiota. Diagnosis of the disease is currently based on kidney biopsy findings, as the sensitivity and specificity of the many serum and urinary biomarkers described so far do not seem to have diagnostic accuracy. Therapeutic strategies consist of the initial step of non-immune medication, aiming to reduce both the intraglomerular pressure and proteinuria to below 0.5 g/day, followed by systemic corticosteroid administration in patients who remain at high risk for progressive chronic kidney disease despite the maximum non-immune treatment. The 6-month systemic corticosteroid treatment reduces proteinuria levels; however, the increased possibility of adverse events and increased relapse rate after treatment raises the need for a new therapeutic approach. Targeted-release budesonide is a therapeutic modality that aims to inhibit disease pathogenetic pathways at early stages; it has minor systemic absorption and proven beneficial effects on renal function and proteinuria. In the present systemic review, the benefits and adverse events of steroids and budesonide are described, and the possibility of combined treatment is questioned in selected cases with active histologic lesions.

A nephrology trainee can define the fluid status through lung ultrasonography and inferior vena cava measurements in hemodialysis patients: an observational study in a single center.

AIMS: The determination of ideal weight in hemodialysis patients remains a common problem. The use of Lung Ultrasound (LUS) is an emerging method of assessing the hydric status of hemodialysis patients. LUS combined with Inferior Vena Cava (IVC) ultrasonography can define the fluid status in hemodialysis patients. METHODS: This study included 68 hemodialysis patients from the Dialysis Unit of Papageorgiou General Hospital in Thessaloniki. The patients underwent lung and IVC ultrasound 30 min before and after the end of the dialysis session by a nephrology trainee. Patients' ideal weight was modified based on daily clinical practice rather than ultrasound findings. The presence of B lines and ultrasound findings of the IVC were evaluated. RESULTS: The average B line score was 11.53 ± 5.02 before dialysis and became 5.57 ± 3.14 after the session. The average diameter of the IVC was 14.266 ± 0.846 mm before dialysis and 12.328 ± 0.879 mm after the session. The patients were categorized based on the magnitude of overhydration and the findings were evaluated. In addition, findings after the session showed a statistically significant correlation between the b line score and the diameter of the IVC adjusted for the body surface area. (p = 0.009 < 0.05). CONCLUSIONS: A high rate of hyperhydration was detected before the dialysis session (25%). While it is the first study conducted by a nephrology trainee highlighting that it is a feasible technique. Intervention studies should be carried out in the future to draw more precise conclusions.

The Incidence of Clostridioides difficile Infection in the Post-COVID-19 Era in a Hospital in Northern Greece.

Clostridioides difficile infection (CDI) has evolved to be the most significant cause of healthcare-associated diarrhoea and one of the leading representatives of healthcare-associated infections, with a high associated mortality. The aim of this retrospective study was to record the incidence rates and the epidemiological and clinical features of CDI in a large tertiary hospital of northern Greece in the years 2022-2023. All patients with CDI-compatible symptomatology and a positive CDI diagnostic test (GDH-glutamate dehydrogenase and toxin-positive FIA-Fluorescent Immuno-chromatography-SD Biosensor, and/or film array) were included (104 from a total of 4560 admitted patients). Their demographic, laboratory, and clinical data were recorded and analysed. The incidence of CDI in admitted patients was found to be higher than previous reports in the geographical area, reaching 54.6/10,000 patient days and following a rising trend over the course of the study. Thirty-day mortality was high (39.4%), potentially related to new emerging hypervirulent C. difficile strains. In view of the high prevalence of multidrug-resistant organisms in the region, and the significant mortality associated with this infection, these findings particularly point to the need for the implementation of organized surveillance and infection prevention protocols.

Associations of fetuin-A and osteoprotegerin with arterial stiffness and early atherosclerosis in chronic hemodialysis patients.

BACKGROUND: Cardiovascular morbidity and mortality remains excessive in patients with chronic kidney disease. The association of vascular changes with regulators of extraosseous calcification in this patient population is still under investigation. The aim of the present study was to investigate the associations of the calcification inhibitor fetuin-A, and the anti-osteoclastic factor osteoprotegerin (OPG) with vascular pathology in chronic hemodialysis patients. METHODS: In this cross-sectional study including 81 stable chronic hemodialysis patients, we measured carotid-to-femoral pulse wave velocity (cfPWV) with applanation tonometry, reflecting arterial stiffness, and common carotid intima-media thickness (ccIMT), a surrogate of early atherosclerosis, as well as serum levels of fetuin-A and OPG. Co-morbidities, traditional cardiovascular risk factors, inflammatory markers and mineral-bone disease serology parameters were also recorded. RESULTS: cfPWV correlated inversely with fetuin-A (r=-0.355, p=0.001) and positively with OPG (r=0.584, p<0.001). In multilinear regression analysis including age, gender, diabetes, cardiovascular disease, hypertension, pulse pressure, LDL, logCRP, both fetuin-A and OPG were independently associated with cfPWV (p=0.024 and p=0.041 respectively). ccIMT was negatively associated with fetuin-A (r=-0.312, p=0.005) and positively with OPG (r=0.521, p<0.0001); however these associations lost statistical significance after adjustment for age. CONCLUSION: In chronic hemodialysis patients both fetuin-A and OPG levels are independently associated with arterial stiffness but not with early atherosclerotic vascular changes.

Targeting the B-cell pathway in lupus nephritis: current evidence and future perspectives.

Nephritis represents a frequent, severe complication of systemic lupus erythematosus. Autoantibodies appear to be fundamental in the pathogenesis of lupus nephritis. Several hypotheses are currently experimentally tested to further elucidate the direct induction of inflammation through interaction of the pathological autoantibodies with intrinsic glomerular components and the triggering of a complement-driven autoinflammatory cascade. B-cells have, in the last decade, emerged as a promising new therapeutic target, as biological treatments successfully attempting B-cell depletion, inhibition of B-cell proliferation and differentiation, or modulation of B-cell function have become bioengineered. Clinical trials have so far proved controversial regarding the efficacy of these new agents. Thus, despite the short and long-term side effects associated with immunosuppressive treatment alternative emerging treatments are still regarded "rescue" regimens in refractory patients. In an effort to accurately evaluate the potential of these therapies in lupus nephritis, several issues have been raised mainly in terms of patient selection criteria and trial duration. This review aims to expand on the proposed pathophysiologic mechanisms implicating the B-cell pathway in the pathogenesis of lupus nephritis and summarize current knowledge obtained from clinical trials introducing these biologics in its treatment. Finally, it will elaborate on potential applications of currently available biologic agents and forthcoming treatment options.

Heart rate variability at rest and in response to stress: Comparative study between hemodialysis and peritoneal dialysis patients.

Cardiac arrhythmias and sudden death are the leading causes of mortality in end-stage kidney disease (ESKD). Autonomic nervous system (ANS) dysfunction contributes to this arrhythmogenic background. This study compared heart rate variability (HRV) indices between hemodialysis (HD) and peritoneal dialysis (PD) patients, both at rest and in response to mental and physical stimulation maneuvers. Thirty-four HD and 34 PD patients matched for age, sex, and dialysis vintage, and 17 age- and sex-matched controls were studied. ANS function was examined by linear and non-linear HRV indices. Heart rate was recorded continuously (Finometer-PRO) at rest and during ANS maneuvers (orthostatic, mental-arithmetic, sit-to-stand, handgrip exercise tests). At rest, no significant differences between HD and PD were observed in HRV (root mean square of successive differences [RMSSD]: HD = 57.1 ± 81.1 vs PD = 69.6 ± 113.4 ms; P = 0.792), except for detrended fluctuation analysis (DFA-α1) (HD = 0.87 ± 0.40 vs PD = 0.70 ± 0.20; P = 0.047). DFA-α1 was significantly lower in PD than controls (1.00 ± 0.33; P < 0.05). All HRV indices during the mental-arithmetic test (RMSSD: HD = 128.2 ± 346.0 vs PD = 87.5 ± 150.0 ms; P = 0.893) and the physical stress tests were similar between HD and PD. The standard deviation along the line-of-identity (SD2)/the standard deviation perpendicular to the line-of-identity (SD1) ratio during mental-arithmetic was marginally lower in HD and significantly lower in PD than controls (PD = 1.31 ± 0.47 vs controls = 1.79 ± 0.64; P < 0.05). Both dialysis groups presented similar patterns in HRV responses during orthostatic and handgrip exercise tests. After the sit-to-stand, RMSSD, SD1, SD2, and DFA-α2 were higher compared to rest only in HD (RMSSD = 57.1 ± 81.1 vs 126.7 ± 185.7 ms; P = 0.028), suggesting a greater difficulty of HD patients in recovering normal ANS function in response to physical stress. In conclusion, HRV indices at rest and after mental and physical stimulation did not differ between HD and PD; however, the ANS responses following the sit-to-stand test were more impaired in HD. These findings suggest that ANS dysfunction is not largely affected by dialysis modality, but small differences in normal ANS recovery may exist.

Impact of long-term cinacalcet, ibandronate or teriparatide therapy on bone mineral density of hemodialysis patients: a pilot study.

BACKGROUND: Insufficient evidenced-based information is available for the treatment of osteoporosis in hemodialysis (HD) patients. METHODS: In 102 HD patients, bone mineral density (BMD) was measured twice 16 ± 3 months apart. In the second BMD measurement 66 of them had a femoral neck (FN) T-score <-2.5. Of these 66 patients, 38 consented to a bone biopsy. Depending on both the bone biopsy findings and parathyroid hormone levels, patients were assigned to treatment groups. Eleven patients with osteitis fibrosa and iPTH >300 pg/ml received cinacalcet, 11 with osteitis fibrosa and iPTH <300 pg/ml received ibandronate, 9 with adynamic bone disease received teriparatide, and 7 with mild abnormalities received no treatment. A third BMD measurement was done after an average treatment period of 13-16 months. We compared the annual percent change of FN and lumbar spine (LS) BMD before and during treatment. RESULTS: FN and LS BMD decreased significantly in the cinacalcet group, with an annual change of 3.6 and 3.4% before treatment to -4.2% (p = 0.04) and -7.7% (p = 0.02) during treatment, respectively. In the teriparatide group, FN and LS BMD increased, although not significantly, with an annual change of -5.4 and -2.6% before treatment to 2.7 and 4.9% during treatment, respectively. In both the ibandronate and the no treatment groups, BMD change rate remained negative during the whole study. CONCLUSIONS: Teriparatide administration improved BMD in HD patients with adynamic bone disease, although these results did not reach statistical significance. In HD patients with osteitis fibrosa, ibandronate did not improve BMD while cinacalcet reduced BMD.

Cardiac geometry, function, and remodeling patterns in patients under maintenance hemodialysis and peritoneal dialysis treatment.

Cardiovascular disease is the leading cause of mortality in patients with end-stage-kidney disease. Evidence on the possible echocardiographic differences between hemodialysis and peritoneal dialysis (PD) is scarce. This study aimed to evaluate differences in left (LA) and right atrial (RA), left (LV) and right ventricular (RV) geometry, systolic and diastolic function in hemodialysis, and PD patients. Thirty-eight hemodialysis and 38 PD patients were matched for age, sex, and dialysis vintage. Two-dimensional and tissue-Doppler echocardiography, and lung ultrasound were performed during an interdialytic day in hemodialysis and before a programmed follow-up visit in PD patients. Vena cava diameter (11.09 ± 4.53 vs. 14.91 ± 4.30 mm; p < 0.001) was significantly lower in hemodialysis patients. Indices of LA, RA, LV, and RV dimensions were similar between the two groups. LVMi (116.91 [38.56] vs. 122.83 [52.33] g/m2 ; p = 0.767) was similar, but relative wall thickness was marginally (0.40 [0.14] vs. 0.45 [0.15] cm; p = 0.055) lower in hemodialysis patients. LV hypertrophy prevalence was similar between groups (73.7% vs. 71.1%; p = 0.798), but hemodialysis patients presented eccentric and PD patients concentric LVH. Regarding ventricular systolic function, stroke volume (p = 0.030) and cardiac output (p = 0.036) were higher in hemodialysis, while RV systolic pressure (RVSP) (20.37 [22.54] vs. 27.68 [14.32] mm Hg; p = 0.009) was higher in PD. No significant differences were evidenced in diastolic function indices and lung water excess between the two groups. A moderate association was noted between ultrasound B-lines score and LA volume index (r = 0.465, p < 0.001), RVSP (r = 0.431, p < 0.001), and E/e' ratio (r = 0.304, p = 0.009). Hemodialysis and PD patients present largely similar echocardiographic indices reflecting cardiac geometry, systolic, and diastolic function, but different patterns of abnormal LV remodeling.

Angiotensin II triggers release of neutrophil extracellular traps, linking thromboinflammation with essential hypertension.

Innate immunity and chronic inflammation are involved in atherosclerosis and atherothrombosis, leading to target organ damage in essential hypertension (EH). However, the role of neutrophils in EH is still elusive. We investigated the association between angiotensin II (Ang II) and neutrophil extracellular traps (NETs) in pathogenesis of EH. Plasma samples, kidney biopsies, and surgical specimens of abdominal aortic aneurysms (AAAs) from patients with EH were used. Cell-based assays, NETs/human aortic endothelial cell cocultures, and in situ studies were performed. Increased plasma levels of NETs and tissue factor (TF) activity were detected in untreated, newly diagnosed patients with EH. Stimulation of control neutrophils with plasma from patients with untreated EH generated TF-enriched NETs promoting endothelial collagen production. Ang II induced NETosis in vitro via an ROS/peptidylarginine deiminase type 4 and autophagy-dependent pathway. Circulating NETs and thrombin generation levels were reduced substantially in patients with EH starting treatment with Ang II receptor blockers, whereas their plasma was unable to trigger procoagulant NETs. Moreover, TF-bearing NETotic neutrophils/remnants accumulated in sites of interstitial renal fibrosis and in the subendothelial layer of AAAs. These data reveal the important pathogenic role of an Ang II/ROS/NET/TF axis in EH, linking thromboinflammation with endothelial dysfunction and fibrosis.

A comparative study of ambulatory central hemodynamics and arterial stiffness parameters in peritoneal dialysis and hemodialysis patients.

BACKGROUND: Ambulatory pulse-wave velocity (PWV), augmentation pressure, and augmentation index (AIx) are associated with increased cardiovascular events and death in hemodialysis. The intermittent nature of hemodialysis generates a distinct ambulatory pattern, with a progressive increase of augmentation pressure and AIx during the interdialytic interval. No study so far has compared the ambulatory course of central hemodynamics and PWV between peritoneal dialysis and hemodialysis patients. METHODS: Thirty-eight patients under peritoneal dialysis and 76 patients under hemodialysis matched in a 1 : 2 ratio for age, sex and dialysis vintage underwent 48-h ambulatory blood pressure (BP) monitoring with the oscillometric Mobil-O-Graph device. Parameters of central hemodynamics [central SBP, DBP and pulse pressure (PP)], wave reflection [AIx, heart rate-adjusted AIx; AIx(75) and augmentation pressure] and PWV were estimated from the 48-h recordings. RESULTS: Over the total 48-h period, no significant differences were observed between peritoneal dialysis and hemodialysis patients in mean levels of central SBP, DBP, PP, augmentation pressure, AIx, AIx(75) and PWV. However, patients under peritoneal dialysis and hemodialysis displayed different trajectories in all the above parameters over the course of the recording: in peritoneal dialysis patients no differences were noted in central SBP (125.0 ±â€Š19.2 vs. 126.0 ±â€Š17.8 mmHg, P = 0.25), DBP, PP, augmentation pressure (13.0 ±â€Š6.8 vs. 13.7 ±â€Š7. mmHg, P = 0.15), AIx(75) (25.9 ±â€Š6.9 vs. 26.3 ±â€Š7.8%, P = 0.54) and PWV (9.5 ±â€Š2.1 vs. 9.6 ±â€Š2.1 m/s, P = 0.27) from the first to the second 24-h period of the recording. In contrast, hemodialysis patients showed significant increases in all these parameters from the first to second 24 h (SBP: 119.5 ±â€Š14.4 vs. 124.6 ±â€Š15.0 mmHg, P < 0.001; augmentation pressure: 10.9 ±â€Š5.3 vs. 13.1 ±â€Š6.3 mmHg, P < 0.001; AIx(75): 24.7 ±â€Š7.6 vs. 27.4 ±â€Š7.9%, P < 0.001; PWV: 9.1 ±â€Š1.8 vs. 9.3 ±â€Š1.8 m/s, P < 0.001). Peritoneal dialysis patients had numerically higher levels than hemodialysis patients in all the above parameters during all periods studied and especially during the first 24-h. CONCLUSION: Central BP, wave reflection indices and PWV during a 48-h recording are steady in peritoneal dialysis but gradually increase in hemodialysis patients. During all studied periods, peritoneal dialysis patients have numerically higher levels of all studied parameters, a fact that could relate to higher cardiovascular risk.

Efficacy and safety of a low monthly dose of intravenous iron sucrose in peritoneal dialysis patients.

PURPOSE: Scientific data regarding intravenous iron supplementation in peritoneal dialysis (PD) patients are scarce. In attempting to administer the minimum monthly IV iron dose that could improve erythropoiesis, we wanted to assess the safety and efficacy of monthly maintenance intravenous administration of 100 mg iron sucrose in PD patients. METHODS: In a 9-month prospective study, all clinically stable PD patients received intravenously 200 mg of iron sucrose as a loading dose, followed by monthly doses of 100 mg for five consecutive months. Levels of hemoglobin (Hb), ferritin, transferrin saturation (TSAT), reticulocyte hemoglobin content (CHr) and C-reactive protein (CRP) were measured before each administration and 3 months after the last iron infusion. Also, doses of concurrent erythropoietin administration were recorded. RESULTS: Eighteen patients were eligible for the study. Mean levels of Hb and ferritin increased significantly (from 10.0 to 10.9 mg/dL, p = 0.01 and from 143 to 260 ng/mL, p = 0.005), as well as the increase in TSAT levels approached borderline significance (from 26.2 to 33.1%, p = 0.07). During the 6 months of iron administration, the erythropoietin dose was reduced in five patients and discontinued in one. During the 3 months following the last iron infusion, three of them again raised the erythropoietin dose to previous levels. None of the patients experienced any side effects related to IV iron administration. CONCLUSIONS: A monthly maintenance intravenous dose of 100 mg iron sucrose may be a practical, effective, and safe in the short term, treatment of anemia in PD patients resulting in improved hemoglobin levels, iron indices, and erythropoietin response.

Normal white blood cell counts predict long-term mortality of hemodialysis patients.

PURPOSE: It is unclear whether normal white blood cell (WBC) counts are predictive of subsequent mortality in hemodialysis patients. METHODS: All patients aged 17 years or more, who initiated hemodialysis at a tertiary Hospital from January 2000 to August 2017 with a dialysis vintage of greater than 90 days and normal median WBC count of their first dialysis year were included in the study. They were followed until they died, transferred to other dialysis facilities, switched to peritoneal dialysis, received a renal transplant or reached the end of the study (August 31, 2018). Cox regression was used to estimate hazard ratios for mortality of tertiles of WBC counts, adjusting for baseline demographic, clinical and laboratory variables. RESULTS: 611 patients [median (interquartile range) age 65.2 (53.3-72.6) years, 62.4% male] were studied. During a median follow-up of 3.9 (1.6-7.2) years, 270 participants died. Patients in the mid- (6.25-7.73 × 103/µL, n = 203) and top-tertile (7.73-10.50 × 103/µL, n = 203) of normal WBC counts had significantly higher mortality than patients in the bottom-tertile (3.50-6.25 × 103/µL, n = 205). The adjusted hazard ratio for mortality relative to the bottom-tertile was 1.54, 95% confidence interval (CI) 1.05-2.25 and 2.20, 95% CI 1.46-3.32, for the mid- and top-tertiles, respectively. CONCLUSIONS: In hemodialysis patients, higher WBC count within the normal range is associated with increased long-term mortality. This finding is described for the first time and provides further insight into the clinical significance of a "normal" WBC count result in dialysis patients.

Fabry disease due to D313Y and novel GLA mutations.

OBJECTIVES: Our aim is to report four novel α-gal A gene (GLA) mutations resulting in Fabry disease (FD) and provide evidence of pathogenicity of the D313Y mutation regarding which contradictory data have been presented in the literature. SETTING AND PARTICIPANTS: Twenty-five family members of nine unrelated patients with definite FD diagnosis, 10 clinically suspected cases and 18 members of their families were included in this polycentric cohort study. PRIMARY AND SECONDARY OUTCOME MEASURES: Genotyping and measurement of lyso-Gb3 was performed in all individuals. The α-Gal A activity was measured in all men as well as plasma and urine Gb3 concentration in selected cases. Optical and electron microscopy was performed in kidney biopsies of selected patients. All the above were evaluated in parallel with the clinical data of the patients. RESULTS: Fourteen new cases of FD were recognised, four of which were carrying already described GLA mutations. Four novel GLA mutations, namely c.835C>T, c.280T>A, c.924A>C and c.511G>A, resulting in a classic FD phenotype were identified. Moreover, FD was definitely diagnosed in five patients carrying the D313Y mutation. Eight D313Y carriers were presenting signs of FD despite not fulfilling the criteria of the disease, two had no FD signs and two others were apparently healthy. CONCLUSIONS: Four novel GLA pathogenic mutations are reported and evidence of pathogenicity of the D313Y mutation is provided. It seems that the D313Y mutation is related to a later-onset milder phenotype than the typical phenotype with normal lysoGb3 concentration. Our study underlines the significance of family member genotyping and newborn screening to avoid misdiagnoses and crucial delays in diagnosis and treatment of the disease.

Experience with a thin-layer, liquid-based cervical cytologic screening method.

OBJECTIVE: To assess the utility of a thin-layer cytology system for cervicovaginal screening in clinical practice. STUDY DESIGN: Twenty-five hundred cervicovaginal split samples were processed with the traditional direct smearing method and with the ThinPrep Pap Test (Cytyc Corp., Boxborough, Massachusetts, U.S.A.) method and evaluated according to the Bethesda system, focusing mainly on the cytomorphologic features. RESULTS: The ThinPrep Pap Test yielded improved specimen adequacy and an increased detection rate of squamous abnormalities, which resulted in a decrease in the ASCUS/SIL ratio. Moreover, the thin-layer system provided adequate material for concomitant HPV testing, mainly in the LSIL and the ASCUS favor SIL cases, with satisfactory results, as well as for cell block preparations in a few selected cases that presented diagnostic difficulties. Furthermore, the morphologic features of the LSIL cases were virtually identical on both preparations, while in the HSIL cases, distinct features were noted on ThinPrep. CONCLUSION: The ThinPrep Pap Test is significantly more effective than the conventional smear in clinical practice. However, training and experience are necessary to take full advantage of this promising new technology.

CD20+ B cell depletion in systemic autoimmune diseases: common mechanism of inhibition or disease-specific effect on humoral immunity?

Autoimmunity remains a complex physiologic deviation, enabled and perpetuated by a variety of interplayers and pathways. Simplistic approaches, targeting either isolated end-effectors of more centrally placed interactors of these mechanisms, are continuously tried in an effort to comprehend and halt cascades with potential disabling and deleterious effects in the affected individuals. This review focuses on theoretical and clinically proved effects of rituximab-induced CD20+ B cell depletion on different systemic autoimmune diseases and extrapolates on pathogenetic mechanisms that may account for different interindividual or interdisease responses.

Cardiorenal syndrome type 4-cardiovascular disease in patients with chronic kidney disease: epidemiology, pathogenesis, and management.

The term cardiorenal syndrome refers to the interaction between the heart and the kidney in disease and encompasses five distinct types according to the initial site affected and the acute or chronic nature of the injury. Type 4, or chronic renocardiac syndrome, involves the features of chronic renal disease (CKD) leading to cardiovascular injury. There is sufficient epidemiologic evidence linking CKD with increased cardiovascular morbidity and mortality. The underlying pathophysiology goes beyond the highly prevalent traditional cardiovascular risk burden affecting renal patients. It involves CKD-related factors, which lead to cardiac and vascular pathology, mainly left ventricular hypertrophy, myocardial fibrosis, and vascular calcification. Risk management should consider both traditional and CKD-related factors, while therapeutic interventions, apart from appearing underutilized, still await further confirmation from large trials.

FGF-23 Levels before and after Renal Transplantation.

Phosphatonin fibroblast growth factor-23 (FGF-23) is involved in phosphate (P) excretion and vitamin D metabolism. Recently, FGF-23 has been suggested to be responsible for the hypophosphatemia and inappropriately low calcitriol levels observed after renal transplantation. We performed a prospective study to investigate FGF-23 levels in patients with end-stage renal disease before and after renal transplantation and their probable association with markers of bone and mineral metabolism. Intact FGF-23 levels were determined before and at 3, 6, and 12 months posttransplantation in 18 renal transplant recipients. Intact parathyroid hormone (iPTH), calcium (Ca), P, 25(OH)VitD, and 1,25(OH)(2)VitD levels were measured at the same time periods. Renal threshold phosphate concentration (TmPO(4)/GFR) was also calculated at 3, 6, and 12 months posttransplantation. The results showed that FGF-23 levels decreased by 89% 3 months posttransplantation (346 +/- 146 versus 37 +/- 9 pg/mL, P < .01) and remained stable throughout the study period. iPTH and P levels also decreased significantly after renal transplantation, while Ca and 1,25(OH)(2)VitD increased. Pretransplantation FGF-23 was significantly correlated with P levels at 3 months posttransplantation (P < .005). In conclusion, FGF-23 levels decrease dramatically after successful renal transplantation. Pre-transplantation FGF-23 correlate with P levels 3 months posttransplantation.