Interpretation of GFR slope in untreated and treated adult Fabry patients.

Nephropathy is one of the main features of Fabry disease (FD) that leads, in untreated patients with classical mutations, to end-stage renal disease (ESRD) from the third to the fifth decade of life. The availability of a specific treatment modified the natural history of FD; in particular, it was widely reported that enzyme replacement therapy (ERT) is able to slow the progression of the disease. Regarding Fabry nephropathy, several reports have documented an elevated estimated glomerular filtration rate (eGFR) slope in untreated patients as expression of a rapid disease progression towards ESRD. Otherwise, the prompt start of treatment may be beneficial in stabilizing renal function or slowing its decline. Therefore, based on data in the literature about the effects of ERT on eGFR decline and on the evidence supporting the role of eGFR slope as a surrogate endpoint for chronic kidney disease progression, we suggest, in this 'Expert Opinion', that a treatment should be defined effective when eGFR decline is <1 ml/min/1.73 m2/year and not effective when eGFR loss remains ≥3 ml/min/1.73 m2/year (≥2.5 ml/min/1.73 m2/year in females). Moreover, practical clinical recommendations and guidance for Fabry patients suggests that a change in treatment may be appropriate if individualized therapeutic goals are not achieved. Since a dose-dependent efficacy has been demonstrated for ERT, we suggest considering a switch to a higher dose of ERT in symptomatic adult Fabry patients (ages 18-60 years) with an eGFR of 45-90 ml/min/1.73 m2 and treated with a stable dose of ERT for at least 1 year, in which a linear negative slope of eGFR of 3 ml/min/1.73 m2/year for males (2.5 ml/min/1.73 m2/year for females) was observed.

Association between chronic kidney disease and periodontitis. A systematic review and metanalysis.

OBJECTIVES: Aims of this SR were to assess the association of Periodontitis (PD) with Chronic Kidney Disease (CKD) and with different CKD stages. MATERIALS AND METHODS: MEDLINE, Cochrane Central Register of Trials and EMBASE, up to April 4, 2021 were searched. RCTs, prospective and retrospective cohort studies, case-control studies and cross-sectional studies were considered. JBI's Critical Appraisal Tool for risk of bias assessment was used. The risk of PD was calculated using the Mantel-Haenszel odds ratios (MH-OR); weighted mean difference for clinical attachment level (CAL) and periodontal probing depth (PPD) were also evaluated. RESULTS: Out of 1949 titles screened, 142 full texts were evaluated and 17 studies were included. CKD was associated to higher risk of PD (MH-OR = 2.36, [95% C.I. 1.25, 4.44]; p = 0.008), higher mean CAL (WMD = 0.41 mm [95% C.I. 0.22, 0.60]; p < 0.0001) and mean PPD (WMD = 0.25 mm [95% C.I. 0.03, 0.47]; p = 0.02) compared to healthy individuals. Severe CKD (stages 4-5 vs 2-3) resulted at higher risk of PD (MH-OR = 2.21, [95% C.I. 1.07, 4.54]; p = 0.03). Heterogeneity and risk of bias were high. CONCLUSIONS: An association between PD and CKD was found. It could be appropriate to consider PD a frequent CKD comorbidity.

Multicenter evaluation of use of dried blood spot compared to conventional plasma in measurements of globotriaosylsphingosine (LysoGb3) concentration in 104 Fabry patients.

OBJECTIVES: Fabry disease (FD) is an X-linked lysosomal storage disorder, resulting from a deficiency of the enzyme α-galactosidase A, responsible for breaking down glycolipids such as globotriaosylceramide and its deacylated derivative, globotriaosylsphingosine (LysoGb3). Here, we compare the levels of LysoGb3 in dried blood spots (DBS) and plasma in patients with classic and late-onset phenotypes. METHODS: LysoGb3 measurements were performed in 104 FD patients, 39 males and 65 females. Venous blood was collected. A portion was spotted onto filter paper and another portion separated to obtain plasma. The LysoGb3 concentrations in DBS and plasma were determined by highly sensitive electrospray ionization liquid chromatography tandem mass spectrometry. Agreement between different matrices was assessed using linear regression and Bland Altman analysis. RESULTS: The method on DBS was validated by evaluating its precision, accuracy, matrix effect, recovery, and stability. The analytical performances were verified by comparison of a total of 104 paired DBS and plasma samples from as many FD patients (representing 46 GLA variants). There was a strong correlation between plasma and the corresponding DBS LysoGb3 concentrations, with few exceptions. Discrepancies were observed in anemic patients with typically low hematocrit levels compared to the normal range. CONCLUSIONS: The method proved to be efficient for the rapid analysis of LysoGb3. DBS provides a convenient, sensitive, and reproducible method for measuring LysoGb3 levels for diagnosis, initial phenotypic assignment, and therapeutic monitoring in patients with FD.

Novel Biomarkers for Early Detection of Acute Kidney Injury and Prediction of Long-Term Kidney Function Decline after Partial Nephrectomy.

BACKGROUND: Identifying acute kidney injury (AKI) within few hours of onset is certainly helpful. However, early prediction of a long-term eGFR decline may be an even more important goal. Our aim was to identify and compare serum [creatinine, kineticGFR, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL)] and urinary (NephroCheck, NGAL, proteinuria, albuminuria, acantocytes at urinary sediment) predictors of AKI that might efficiently predict long-term GFR decline after robotic Nephron-Spearing Surgery (rNSS). METHODS: Monocentric prospective observational study. Patients scheduled for rNSS for suspected localized Renal Cell Carcinoma from May 2017 to October 2017 were enrolled. Samples were collected preoperatively and postoperatively (timepoints: 4 h, 10 h, 24 h, 48 h), while kidney function was re-assessed up to 24 months. RESULTS: 38 patients were included; 16 (42%) developed clinical AKI. The eGFR decline at 24 months was more pronounced after postoperative AKI (-20.75 vs. -7.20, p < 0.0001). KineticGFR at 4 h (p = 0.008) and NephroCheck at 10 h (p = 0.001) were, at multivariable linear regression analysis, efficient predictors of post-operative AKI and long-term eGFR decline if compared to creatinine (R2 0.33 vs. 0.04). CONCLUSIONS: NephroCheck and kineticGFR have emerged as promising noninvasive, accurate, and early biomarkers of postoperative AKI and long-term GFR decline after rNSS. Combining NephroCheck and kineticGFR in clinical practice would allow to identify high risk of postoperative AKI and long-term GFR decline as early as 10 h after surgery.

Robotic Versus Open Kidney Transplantation from Deceased Donors: A Prospective Observational Study.

Background: While robot-assisted kidney transplantation (RAKT) from living donors has been shown to achieve favourable outcomes, there is a lack of evidence on the safety and efficacy of RAKT as compared with the gold standard open kidney transplantation (OKT) in the setting of deceased donors, who represent the source of most grafts worldwide. Objective: To compare the intraoperative, perioperative, and midterm outcomes of RAKT versus OKT from donors after brain death (DBDs). Design setting and participants: Data from consecutive patients undergoing RAKT or OKT from DBDs at a single academic centre between October 2017 and December 2020 were prospectively collected. Intervention: RAKT or OKT. Outcome measurements and statistical analysis: The primary outcomes were intraoperative adverse events, postoperative surgical complications, delayed graft function (DGF), and midterm functional outcomes. A multivariable logistic regression analysis assessed the independent predictors of DGF, trifecta, and suboptimal graft function (estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 m2) at the last follow-up. Results and limitations: Overall, 138 patients were included (117 [84.7%] OKTs and 21 [15.3%] RAKTs). The yearly proportion of RAKT ranged between 10% and 18% during the study period. The OKT and RAKT cohorts were comparable regarding all graft-related characteristics, while they differed regarding a few donor- and recipient-related factors. The median second warm ischaemic time, ureterovesical anastomosis time, postoperative complication rate, and eGFR trajectories did not differ significantly between the groups. A higher proportion of patients undergoing OKT experienced DGF; yet, at a median follow-up of 31 mo (interquartile range 19-44), there was no difference between the groups regarding the dialysis-free and overall survival. At the multivariable analysis, donor- and/or recipient-related factors, but not the surgical approach, were independent predictors of DGF, trifecta, and suboptimal graft function at the last follow-up. The study is limited by its nonrandomised nature and the small sample size. Conclusions: Our study provides preliminary evidence supporting the noninferiority of RAKT from DBDs as compared with the gold standard OKT in carefully selected recipients. Patient summary: Kidney transplantation using kidneys from deceased donors is still being performed with an open surgical approach in most transplant centres worldwide. In fact, no study has compared the outcomes of open and minimally invasive (robotic) kidney transplantation from deceased donors. In this study, we evaluated whether robotic kidney transplantation using grafts from deceased donors was not inferior to open kidney transplantation regarding the intraoperative, postoperative, and midterm functional outcomes. We found that, in experienced hands and provided that there was a time-efficient organisation of the transplantation pathway, robotic kidney transplantation from deceased donors was feasible and achieved noninferior outcomes as compared with open kidney transplantation.

Pre-Dialysis B-Line Quantification at Lung Ultrasound Is a Useful Method for Evaluating the Dry Weight and Predicting the Risk of Intradialytic Hypotension.

Intradialytic hypotension (IDH) is a frequent and well-known complication of hemodialysis, occurring in about one third of patients. An integrated approach with different methods is needed to minimize IDH episodes and their complications. In this prospective observational study, recruited patients underwent a multiparametric evaluation of fluid status through a lung ultrasound (LUS) with the quantification of B-lines, a physical examination, blood pressure, NT-proBNP and chest X-rays. The evaluation took place immediately before and at the end of the dialysis session, and the patients were divided into IDH and no-IDH groups. We recruited a total of 107 patients. A pre-dialysis B-line number ≥ 15 showed a high sensitivity in fluid overload diagnosis (94.5%), even higher than a chest X-ray (78%) or physical examination (72%) alone. The identification at the beginning of dialysis of <8 B-lines in the overall cohort or <20 B-lines in patients with NYHA 3−4 class are optimal thresholds for identifying those patients at higher risk of experiencing an IDH episode. In the multivariable analysis, the NYHA class, a low pre-dialysis systolic BP and a low pre-dialysis B-line number were independent risk factors for IDH. At the beginning of dialysis, the B-line quantification at LUS is a valuable and reliable method for evaluating fluid status and predicting IDH episodes. A post-dialysis B-line number <5 may allow for an understanding of whether the IDH episode was caused by dehydration, probably due to due to an overestimation of the dry weight.

Hemolytic uremic syndrome and kidney transplantation in uncontrolled donation after circulatory death (DCD): A two-case report.

BACKGROUND: Hemolytic uremic syndrome (HUS) is a rare disease characterized by microangiopathic hemolysis, thrombocytopenia, and renal involvement. Complement-mediated atypical HUS (aHUS) is a result of genetic defects in the alternative complement pathway components or regulators. The introduction of eculizumab has improved renal and overall survival of aHUS patients. Nowadays, given organ shortage, it is necessary to consider kidney transplantation (KT) even in protocols with a high risk of HUS recurrence, such as from donation after circulatory death (DCD) donors. Here, we describe two patients with HUS who underwent a KT from an uncontrolled DCD (uDCD). CASE SUMMARY: The first patient, affected by aHUS due to a heterozygous deletion in CFHR3-CFHR1 and a novel heterozygous variant in CFHR5 gene, underwent a KT with eculizumab prophylaxis. The patient did not experience a post-transplant aHUS recurrence. The second patient, who experienced an HUS episode characterized by a hypertensive crisis and with no underlying mutations in complement system genes, underwent a KT without eculizumab prophylaxis. At day 5, anti-complement treatment commenced due to hematological signs of thrombotic microangiopathy (TMA). After the introduction of eculizumab, we observed a stabilization of kidney function and hematological remission. CONCLUSION: We present herein two different patients with HUS who both underwent successful KT from uDCD donation under the umbrella of eculizumab therapy. Taking into account the importance of increasing the number of organs available for transplantation, uDCD could represent an additional resource in this subset of HUS patients.

Safety and Efficacy of Eculizumab Therapy in Multiple Sclerosis: A Case Series.

(1) Background: Complement system activation has been proposed as one of the different factors that contribute to Multiple Sclerosis (MS) pathogenesis. In this study, we aimed to describe the potential effects of eculizumab, an anticomplement therapy, on MS disease activity in a cohort of relapsing-remitting (RR) MS patients who discontinued IFN-ß therapy due to IFN-ß-related thrombotic microangiopathy (TMA) onset. (2) Methods: In this retrospective observational multicentric study, we searched for all patients with MS treated by eculizumab with a survey of several nephrological and neurological centers (over 45 centers). (3) Results: Nine patients were included. The mean follow-up time under eculizumab was 3.72 ± 2.58 years. There were no significant differences in disease activity (EDSS, relapses, new T2, and/or Gd-enhancing lesions at MRI) considering the two years before and after eculizumab therapy. No adverse events potentially related to eculizumab therapy were reported during follow-up. (4) Conclusions: In this preliminary study, we described a good safety profile for eculizumab therapy in MS. However, the available data are not sufficient to make firm conclusions about the possible efficacy of eculizumab as a disease-modifying therapy for MS patients.

Preeclampsia in pregnancies complicated by systemic lupus erythematosus (SLE) nephritis: prophylactic treatment with multidisciplinary approach are important keys to prevent adverse obstetric outcomes.

INTRODUCTION: Systemic lupus erythematosus (SLE) commonly affects women of childbearing age. Hypertension, antiphospholipid syndrome, and lupus nephritis are risk factors for adverse maternal/fetal outcome. The aim of this retrospective cohort study is to compare pregnancy outcomes in patients with and without SLE nephritis, using a multidisciplinary approach and a broad prophylaxis protocol. MATERIALS AND METHODS: Data were collected from 86 pregnancies complicated by SLE. Twenty-seven women with nephropathy before pregnancy stated as the study group and 59 formed the control group. Each group received a prophylactic treatment based on their clinical characteristics. Results were expressed as mean ± SD, percentage and χ2-test (significant values when p < .05). RESULTS: The prophylactic treatment (60.4% of the patients) significantly controlled the complications related to some risk factors, such as antiphospholipid antibodies (aPL) and nephritis. Preeclampsia occurred in 14.8% of patients. Patients with pregestational hypertension showed a 2.75 odds ratio of adverse events when compared to the group without chronic hypertension. The presence of proteinuria was associated with a risk of preeclampsia 2.45 times greater, as well as serum creatinine >1.2 mg/dL, which was related to a risk 1.25 times higher than the risk observed in patients with serum creatinine <1.2 mg/dL. A 6-month inactive disease was associated with a better outcome. A value of Estimated Glomerular Filtration Rate (eGFR) < 90 mL/min/1.73 m2 resulted in a 18.73 times greater risk of preeclampsia, intrauterine growth restriction (IUGR), and preterm delivery. DISCUSSION: A multidisciplinary approach in a tertiary care center and a broad prophylactic treatment protocol to patients affected by SLE and complicated by nephritis may definitively foster a successful pregnancy.

Thrombotic microangiopathy induced by interferon beta in patients with multiple sclerosis: three cases treated with eculizumab.

BACKGROUND: Interferon-beta (IFN-beta) is one of the most widely prescribed medications for relapsing-remitting multiple sclerosis (RRMS). IFN-related thrombotic microangiopathy (TMA) is a rare but severe complication, with a fulminant clinical onset and a possibly life-threatening outcome that may occur years after a well-tolerated treatment with IFN. Most patients evolve rapidly to advanced chronic kidney disease and eventually to renal failure. METHODS: We performed a retrospective analysis of TMA cases diagnosed and managed in our Nephrology Department from 2010 to 2015, and performed a literature review of IFN-beta-induced TMA. RESULTS: Three cases of TMA among patients treated with IFN-beta were identified who did not show any renal improvement following conventional therapy: IFN withdrawal and plasma exchange (PE, range 8-18) sessions. All of them responded favourably to eculizumab, with progressive clinical and renal improvement, allowing dialysis discontinuation, without recurrence of TMA during a long-term follow-up (range 1-5 years). CONCLUSIONS: TMA is a recognized severe complication in RRMS patients treated with IFN-beta. Withdrawal of IFN and treatment with PE, steroids or rituximab did not improve the poor renal prognosis in our three patients and in all the previously described cases in the literature. In our experience, eculizumab had a strikingly favourable effect on renal recovery, suggesting a role of IFN-beta as a trigger in complement-mediated TMA. Neurologists and nephrologists should be vigilant to this complication to prevent possibly irreversible renal damage.