Diagnosis and Management of Catastrophic Antiphospholipid Syndrome and the Potential Impact of the 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria.

Catastrophic antiphospholipid syndrome (CAPS) is a rare and life-threatening condition characterized by the persistence of antiphospholipid antibodies and occurrence of multiple vascular occlusive events. CAPS currently remains a diagnostic challenge and requires urgent treatment. The diagnosis of CAPS is made difficult by classification criteria used as diagnostic criteria in clinical practice, knowledge derived from retrospective data and case reports, confounding clinical and biological features, and its rapid onset and mortality. The absence of prospective studies of CAPS limits the strength of evidence for guideline treatment protocols. This comprehensive review summarizes the current understanding of the disease, and discusses how the 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria impact the definition and therapeutic management of CAPS, which is considered the most severe form of APS. The correct integration of 2023 ACR/EULAR APS classification criteria is poised to facilitate CAPS diagnosis, particularly in critical situations, offering a promising avenue for improved outcomes.

Impact of the COVID-19 pandemic on temporal trends of biological indicators of autoimmunity.

Background and objective: Coronavirus Disease 2019 (COVID-19) has been associated with the onset of autoimmune conditions, but whether this relationship is causal remains unknown, partly because robust evidence based on the detection of autoantibodies is lacking. This study explored the potential impact of COVID-19 pandemic on the temporal trends of autoimmunity. Methods: Retrospective analysis of all consecutive autoimmune tests performed at one central laboratory at a University hospital, operating services for 18 other hospitals and clinical laboratories in Belgium, from January 01, 2015 to May 31, 2022. Longitudinal changes in the positivity rates of autoimmunity tests were analyzed, i.e. before and after the onset of the COVID-19 pandemic (March 11, 2020). The tests notably included the detection of autoantibodies associated with type 1 diabetes, thyroid diseases, connective tissue diseases, antiphospholipid syndrome, vasculitis and other organ-specific conditions. Kendall rank correlation test was applied to assess temporal trends. Results: Over a period of 89 months, a total of 301,720 consecutive tests for 24 different autoantibodies among 87,674 unique patients were performed (87% adults, 68% women, mean age 44 ± 20 years). Overall, 52,862 (18%) tests returned positive, with positivity rates for each test ranging between 1% and 46%. No increase in the positivity rate of autoimmunity tests was observed after the start of the pandemic. Conclusion: The onset of the COVID-19 pandemic was not associated with increased positivity rates of a large panel of autoimmune tests. Whether the higher incidence of autoimmune disorders associated with COVID-19 reflects detection bias or reverse causality, or is linked to seronegative autoimmune disorders requires further investigation.

The Peritoneal Membrane and its Role in Peritoneal Dialysis.

A healthy and functional peritoneal membrane is key to achieve sufficient ultrafiltration and to restore fluid balance, a major component of high-quality prescription in patients treated with peritoneal dialysis (PD). Variability in membrane function at the start of PD or changes over time on treatment influence dialysis prescription and outcomes, and dysfunction of the peritoneal membrane contributes to fluid overload and associated complications. In this review, we summarize the current knowledge about the structure, function and pathophysiology of the peritoneal membrane with a focus on clinical implications for patient-centered care. We also discuss the molecular and genetic mechanisms of solute and water transport across the peritoneal membrane, including the role of aquaporin water channels in crystalloid vs. colloid osmosis; why and how to assess membrane function using peritoneal equilibration tests; the etiologies of membrane dysfunction and their specific management; and the impact of genetic variation on membrane function and outcomes in patients treated with PD. This review also identifies the gaps in current knowledge and perspectives for future research to improve our understanding of the peritoneal membrane and, ultimately, to improve the care of patients treated with PD.

ISPD Catheter-related Infection Recommendations: 2023 Update.

Peritoneal dialysis (PD) catheter-related infections are important risk factors for catheter loss and peritonitis. The 2023 updated recommendations have revised and clarified definitions and classifications of exit site infection and tunnel infection. A new target for the overall exit site infection rate should be no more than 0.40 episodes per year at risk. The recommendation about topical antibiotic cream or ointment to catheter exit site has been downgraded. New recommendations include clarified suggestion of exit site dressing cover and updated antibiotic treatment duration with emphasis on early clinical monitoring to ascertain duration of therapy. In addition to catheter removal and reinsertion, other catheter interventions including external cuff removal or shaving, and exit site relocation are suggested.

Epidemiology, Outcomes, and Complement Gene Variants in Secondary Thrombotic Microangiopathies.

BACKGROUND: The identification of complement defects as major drivers of primary atypical hemolytic uremic syndrome (HUS) has transformed the landscape of thrombotic microangiopathies (TMAs), leading to the development of targeted therapies and better patient outcomes. By contrast, little is known about the presentation, genetics, and outcomes of TMA associated with specific diseases or conditions, also referred to as secondary TMA. METHODS: In this study, we assessed the relative incidence, clinical and genetic spectra, and long-term outcomes of secondary TMA versus other TMAs in consecutive patients hospitalized with a first episode of TMA from 2009 to 2019 at two European reference centers. RESULTS: During the study period, 336 patients were hospitalized with a first episode of TMA. Etiologies included atypical HUS in 49 patients (15%), thrombotic thrombocytopenic purpura (TTP) in 29 (9%), shigatoxin-associated HUS in 70 (21%), and secondary TMA in 188 (56%). The main causes of secondary TMA were hematopoietic stem-cell transplantation ( n =56, 30%), solid-organ transplantation ( n =44, 23%), and malignant hypertension ( n =25, 13%). Rare variants in complement genes were identified in 32 of 49 patients (65%) with atypical HUS and eight of 64 patients (13%) with secondary TMA; pathogenic or likely pathogenic variants were found in 24 of 49 (49%) and two of 64 (3%) of them, respectively ( P < 0.001). After a median follow-up of 1157 days, death or kidney failure occurred in 14 (29%), eight (28%), five (7%), and 121 (64%) patients with atypical HUS, TTP, shigatoxin-associated HUS, and secondary TMA, respectively. Unadjusted and adjusted Cox regressions showed that patients with secondary TMA had the highest risk of death or kidney failure (unadjusted hazard ratio [HR], 3.35; 95% confidence interval [CI], 1.85 to 6.07; P < 0.001; adjusted HR, 4.11; 95% CI, 2.00 to 8.46; P < 0.001; considering atypical HUS as reference). CONCLUSIONS: Secondary TMAs represent the main cause of TMA and are independently associated with a high risk of death and progression to kidney failure.

Severe Neurological Involvement in an Adult with Shiga Toxin-Producing Escherichia coli-Hemolytic Uremic Syndrome Treated with Eculizumab.

A 68-year-old man with a medical history of hypertension was admitted to the emergency department for diffuse abdominal pain preceded by bloody diarrhea. Upon admission, neurological examination was normal, but he suddenly developed a left-sided hemiparesis. After a normal brain computed tomography, intravenous thrombolysis was administered for a suspicion of ischemic stroke. In the first laboratory investigations, hemoglobin was 16.9 g/dL, platelets 121 × 109/L (150-450), and serum creatinine 1.17 mg/dL. By the second hospital day, the platelet level dropped to 79 × 109/L, with haptoglobin at 0.12 g/L, 3% schistocytes, and normal ADAMTS13 activity (57%). Serum creatinine increased to 1.84 mg/dL with oliguria. The suspicion of thrombotic microangiopathy was supported by the identification of Shiga toxin genes stx1 and stx2 on a rectal swab and the isolation of an eaeA-negative Shiga toxin-producing E. coli O113:H4. The patient presented a generalized tonic-clonic seizure, and orotracheal intubation was required for decreased consciousness. Plasma exchange therapy was started, and eculizumab was given 6 days after symptoms onset. Brain magnetic resonance imaging (MRI) on day 13 showed symmetric hyperintensities within basal ganglia that disappeared on a second MRI on day 37. At 2-month follow-up, the patient had made a complete neurological and renal recovery and eculizumab therapy was stopped.

Severe parental phenotype associates with hypertension in children with ADPKD.

BACKGROUND: Early detection of hypertension in children with autosomal polycystic kidney disease (ADPKD) may be beneficial, but screening children at risk of ADPKD remains controversial. We investigated determinants of hypertension in children with ADPKD to help identify a subgroup of children at risk of ADPKD for whom screening for the disease and/or its complications would be more relevant. METHODS: In a retrospective study including consecutive children with ADPKD aged 5-18 years and followed at Saint-Luc Hospital Brussels between 2006 and 2020, we investigated the potential association between genotype, clinical characteristics and parental phenotype, and presence of hypertension. Hypertension was defined as blood pressure > P95 during 24-h ambulatory monitoring or anti-hypertensive therapy use. Parental phenotype was considered severe based on age at kidney failure, Mayo Clinic Imaging Classification and rate of eGFR decline. RESULTS: The study enrolled 55 children with ADPKD (mean age 9.9 ± 2.2 years, 45% male), including 44 with a PKD1 mutation and 5 with no mutation identified. Nine (16%) children had hypertension. Hypertension in children was associated with parental phenotype severity (8/27 (30%) children with severe parental phenotype vs. 1/23 (4%) children with non-severe parental phenotype (p = 0.03)) and height-adjusted bilateral nephromegaly (6/9 (67%) children with bilateral nephromegaly vs. 3/44 (7%) children without bilateral nephromegaly (p < 0.001)). CONCLUSIONS: Severe parental phenotype is associated with higher prevalence of hypertension in children with ADPKD. Hence, children of parents with severe ADPKD phenotype may be those who will most benefit from screening of the disease and/or yearly BP measures. A higher resolution version of the Graphical abstract is available as Supplementary information.

Idiopathic nephrotic syndrome relapse following COVID-19 vaccination: a series of 25 cases.

Background: Several cases of idiopathic nephrotic syndrome (INS) relapse following the administration of coronavirus disease 2019 (COVID-19) vaccines have recently been reported, raising questions about the potential relationship between the immune response to COVID-19 vaccination and INS pathogenesis. Methods: We performed a retrospective multicentre survey describing the clinical and biological characteristics of patients presenting a relapse of INS after COVID-19 vaccination, with an assessment of outcome under treatment. Results: We identified 25 patients (16 men and 9 women) presenting a relapse within 1 month of a COVID-19 vaccine injection. The glomerular disease was of childhood onset in half of the patients and most patients (21/25) had received at least one immunosuppressive drug in addition to steroids for frequently relapsing or steroid-dependent nephrotic syndrome (NS). All patients were in a stable condition at the time of injection and 11 had no specific treatment. In five patients, the last relapse was reported >5 years before vaccine injection. The Pfizer-BioNTech (BNT162b2) vaccine was used in 80% of the patients. In 18 cases, INS relapse occurred after the first injection, a mean of 17.5 days after vaccination. A second injection was nevertheless administered in 14 of these patients. Five relapses occurred after administration of the second dose and two relapses after the administration of the third dose. All but one of the patients received steroids as first-line treatment, with an additional immunosuppressive agent in nine cases. During follow-up, complete remission was achieved in 21 patients, within 1 month in 17 cases. Only one patient had not achieved at least partial remission after 3 months of follow-up. Conclusions: This case series suggests that, in rare patients, COVID-19 vaccination may trigger INS relapse that is generally easy to control. These findings should encourage physicians to persuade their patients to complete the COVID-19 vaccination schedule.

Urine metabolomics links dysregulation of the tryptophan-kynurenine pathway to inflammation and severity of COVID-19.

SARS-CoV-2 causes major disturbances in serum metabolite levels, associated with severity of the immune response. Despite the numerous advantages of urine for biomarker discovery, the potential association between urine metabolites and disease severity has not been investigated in coronavirus disease 2019 (COVID-19). In a proof-of-concept study, we performed quantitative urine metabolomics in patients hospitalized with COVID-19 and controls using LC-MS/MS. We assessed whether metabolites alterations were associated with COVID-19, disease severity, and inflammation. The study included 56 patients hospitalized with COVID-19 (26 non-critical and 30 critical disease); 16 healthy controls; and 3 controls with proximal tubule dysfunction unrelated to SARS-CoV-2. Metabolomic profiling revealed a major urinary increase of tryptophan metabolites kynurenine (P < 0.001), 3-hydroxykynurenine (P < 0.001) and 3-hydroxyanthranilate (P < 0.001) in SARS-CoV-2 infected patients. Urine levels of kynurenines were associated with disease severity and systemic inflammation (kynurenine, r 0.43, P = 0.001; 3-hydroxykynurenine, r 0.44, P < 0.001). Increased urinary levels of neutral amino acids and imino acid proline were also common in COVID-19, suggesting specific transport defects. Urine metabolomics identified major alterations in the tryptophan-kynurenine pathway, consistent with changes in host metabolism during SARS-CoV-2 infection. The association between increased urinary levels of kynurenines, inflammation and COVID-19 severity supports further evaluation of these easily available biomarkers.

Characteristics, practices, and outcomes in a Belgian cohort of incident home hemodialysis patients: A 6-year experience.

BACKGROUND: Home hemodialysis (HHD) remains underused in patients with kidney failure. Current literature on HHD mostly originates from non-European countries, making generalization difficult. The present study describes patients' profile and practice patterns from a Belgian HHD center, and assesses patient and technique survival and complications associated with HHD. METHODS: We analyzed data from all our incident patients during a 6-year period. The patient's characteristics were summarized using descriptive statistics. Transition to another therapeutic modality, estimated using a risk model with death and transplantation as competing events, episodes of respite cares and hospitalizations, and access complications were analyzed. RESULTS: Eighty patients (mean age: 47 years; male: 64%) met the inclusion criteria. Fifty-one percent of patients initiated dialysis with a central venous catheter (CVC) and 96% were not assisted. Arterio-venous fistula (AVF) cannulation was performed using buttonhole technique. Standard-frequent HD (47%) and short-frequent low-flow dialysate HD (34%) were mostly used at HHD initiation. Cumulative incidences of technique failure and death were 15%, 24%, and 32% at 1, 2, and 5 years. Incidence rates for respite dialysis and hospitalizations were 2.39 and 0.54 per patient-year of HHD. In comparison with AVF, incidence rate ratios of overall access complications and access-related infections for CVC were 4.3 (95% CI: 3.1-6, p < 0.01) and 4.4 (95% CI: 2.1-10, p < 0.01), respectively. Buttonhole cannulation was complicated by 0.26 (95% CI: 0.15-0.46) infections per 1000 AVF-days. CONCLUSIONS: This present study provides important information about patient's profile and practice patterns and safety in a cohort of 80 incident Belgian HHD patients, with encouraging techniques and patient survival.

Crystalglobulin-Associated Kidney Disease: A Case Report and Literature Review.

The kidney is commonly involved in multiple myeloma and other disorders producing monoclonal immunoglobulins. Crystalglobulinemia is a rare condition characterized by spontaneous crystallization and deposition of monoclonal immunoglobulins within the microvasculature of the kidney and other organs, leading to inflammation, ischemia, and end-organ damage. The present case and literature review highlight the clinical spectrum, diagnostic challenges, management, and outcomes of this underrecognized complication of monoclonal gammopathy. Crystalglobulin-associated kidney disease should be suspected in patients with rapidly progressive kidney disease associated with hematuria, proteinuria, extrarenal lesions (ie, skin and joints), and monoclonal gammopathy. Kidney biopsy is critical to the diagnosis, which relies on the identification by ultrastructural analysis of electron-dense crystalline structures composed of a monoclonal immunoglobulin within the kidney microvasculature. Conventional immunofluorescence on frozen tissue frequently fails to detect monoclonal protein deposits, and pronase-based antigen retrieval on paraffin-embedded material or immunoelectron microscopy is required to unmask antigenic epitopes located within crystalline inclusions. Early intervention combining treatment of clonal cell proliferation and plasma exchanges is warranted to reduce the burden of this rare but dramatic complication of monoclonal gammopathy.

Nephrogenic Diabetes Insipidus following an Off-Label Administration of Sevoflurane for Prolonged Sedation in a COVID-19 Patient and Possible Influence on Aquaporin-2 Renal Expression.

During the recent COVID-19 pandemic, the rapidly progressive shortage of intravenous sedative drugs led numerous intensive care units to look for potential alternatives in patients requiring mechanical ventilation for severe acute respiratory distress syndrome (ARDS). Inhalational sedation using the AnaConDa® device for sevoflurane administration is a possible option. In a 54-year-old COVID-19 patient with severe ARDS requiring extracorporeal membranous oxygenation (ECMO), sevoflurane on AnaConDa® device was administered for 8 days but was complicated by the development of nephrogenic diabetes insipidus (NDI). Other causes of NDI or central diabetes insipidus were reasonably excluded, as in other previously published cases of NDI in ICU patients receiving prolonged sevoflurane-based sedation. In addition, the postmortem examination suggested a lower expression of aquaporin-2 in renal tubules. This observation should prompt further investigations to elucidate the role of aquaporin-2 in sevoflurane-related NDI. Inhaled isoflurane sedation is a possible alternative.

Pathophysiology and Management of Hyperoxaluria and Oxalate Nephropathy: A Review.

Hyperoxaluria results from either inherited disorders of glyoxylate metabolism leading to hepatic oxalate overproduction (primary hyperoxaluria), or increased intestinal oxalate absorption (secondary hyperoxaluria). Hyperoxaluria may lead to urinary supersaturation of calcium oxalate and crystal formation, causing urolithiasis and deposition of calcium oxalate crystals in the kidney parenchyma, a condition termed oxalate nephropathy. Considerable progress has been made in the understanding of pathophysiological mechanisms leading to hyperoxaluria and oxalate nephropathy, whose diagnosis is frequently delayed and prognosis too often poor. Fortunately, novel promising targeted therapeutic approaches are on the horizon in patients with primary hyperoxaluria. Patients with secondary hyperoxaluria frequently have long-standing hyperoxaluria-enabling conditions, a fact suggesting the role of triggers of acute kidney injury such as dehydration. Current standard of care in these patients includes management of the underlying cause, high fluid intake, and use of calcium supplements. Overall, prompt recognition of hyperoxaluria and associated oxalate nephropathy is crucial because optimal management may improve outcomes.

Inhibition of sodium-glucose cotransporter 2 to slow the progression of chronic kidney disease.

Chronic kidney disease (CKD) is a major public health problem, increasing the risk of cardiovascular events and death and potentially leading to kidney failure. Novel drugs that slow the progression of this non-communicable disease are therefore urgently needed. Initially developed as glucose-lowering drugs, inhibitors of the sodium-glucose cotransporter 2 (SGLT2) drastically reduce the overall mortality and cardiovascular events and slow the progression of CKD. Kidney protection conferred by SGLT2 inhibitors is independent from the presence of diabetes, observed on top of renin-angiotensin system inhibition and consistent across a wide range of categories of glomerular filtration rate and albuminuria. The mechanisms through which SGLT2 inhibitors improve kidney outcomes are likely multifactorial. Inhibition of SGLT2 in the kidney proximal tubule results in natriuresis and glucosuria, with beneficial effects on metabolic control, blood pressure and body weight. In addition, SGLT2 inhibitors also improve intraglomerular hemodynamics, podocyte integrity, cell metabolism, and erythropoiesis and reduce hypoxia, oxidative stress, sympathetic nervous activity, inflammation and fibrosis. The major impact of SGLT2 inhibitors on kidney outcomes, along with the excellent safety profile of this new class of drugs, open novel avenues for the treatment of CKD in patients with and without diabetes.

AQP1 Promoter Variant, Water Transport, and Outcomes in Peritoneal Dialysis.

BACKGROUND: Variability in ultrafiltration influences prescriptions and outcomes in patients with kidney failure who are treated with peritoneal dialysis. Variants in AQP1, the gene that encodes the archetypal water channel aquaporin-1, may contribute to that variability. METHODS: We gathered clinical and genetic data from 1851 patients treated with peritoneal dialysis in seven cohorts to determine whether AQP1 variants were associated with peritoneal ultrafiltration and with a risk of the composite of death or technique failure (i.e., transfer to hemodialysis). We performed studies in cells, mouse models, and samples obtained from humans to characterize an AQP1 variant and investigate mitigation strategies. RESULTS: The common AQP1 promoter variant rs2075574 was associated with peritoneal ultrafiltration. Carriers of the TT genotype at rs2075574 (10 to 16% of patients) had a lower mean (±SD) net ultrafiltration level than carriers of the CC genotype (35 to 47% of patients), both in the discovery phase (506±237 ml vs. 626±283 ml, P = 0.007) and in the validation phase (368±603 ml vs. 563±641 ml, P = 0.003). After a mean follow-up of 944 days, 139 of 898 patients (15%) had died and 280 (31%) had been transferred to hemodialysis. TT carriers had a higher risk of the composite of death or technique failure than CC carriers (adjusted hazard ratio, 1.70; 95% confidence interval [CI], 1.24 to 2.33; P = 0.001), as well as a higher risk of death from any cause (24% vs. 15%, P = 0.03). In mechanistic studies, the rs2075574 risk variant was associated with decreases in AQP1 promoter activity, aquaporin-1 expression, and glucose-driven osmotic water transport. The use of a colloid osmotic agent mitigated the effects of the risk variant. CONCLUSIONS: A common variant in AQP1 was associated with decreased ultrafiltration and an increased risk of death or technique failure among patients treated with peritoneal dialysis. (Funded by the Swiss National Science Foundation and others.).