Assessment of epidemiology and outcomes of adult patients with kidney-limited thrombotic microangiopathies.

Thrombotic microangiopathies (TMA) are usually associated with hematological features (RH-TMA). The epidemiology of TMA limited to kidneys (RL-TMA) is unclear Therefore, patients with TMA and native kidney biopsies were identified during 2009-2022 in 20 French hospitals and results evaluated. RL-TMA was present in 341/757 (45%) patients and associated with lower creatinine levels (median 184 vs 346 µmol/L) than RH-TMA. RL-TMA resulted from virtually all identified causes, more frequently from anti-VEGF treatment and hematological malignancies but less frequently from shigatoxin-associated hemolytic uremic syndrome (HUS), systemic sclerosis, gemcitabine and bacterial infection, and even less frequently when three or more causes/triggers were combined (RL-TMA: 5%; RH-TMA: 12%). RL-TMA was associated with significantly lower major cardiovascular events (10% vs 20%), kidney replacement therapy (23% vs 43%) and death (12% vs 20%) than RH-TMA during follow-up (median 28 months). Atypical HUS (aHUS) was found in 326 patients (RL-TMA: 43%, RH-TMA: 44%). Among the 69 patients with proven complement-mediated aHUS, eculizumab (anti-C5 therapy) was used in 43 (62%) (RL-TMA: 35%; RH-TMA: 71%). Among the 257 other patients with aHUS, including 51% with RL-TMA, eculizumab was used in 29 but with unclear effects of this treatment. Thus, RL-TMA represents a very high proportion of patients with TMA and results from virtually all known causes of TMA and includes 25% of patients with complement-mediated aHUS. Adverse outcomes of RL-TMA are lower compared to RH-TMA but remain significant. Anti-C5 therapy was rarely used in RL-TMA, even in proven complement-mediated aHUS, and its effects remain to be assessed.

Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis.

Disorders of the autosomal dominant polycystic kidney disease (ADPKD) spectrum are characterized by the development of kidney cysts and progressive kidney function decline. PKD1 and PKD2, encoding polycystin (PC)1 and 2, are the two major genes associated with ADPKD; other genes include IFT140, GANAB, DNAJB11, and ALG9. Genetic testing remains inconclusive in ∼7% of the families. We performed whole-exome sequencing in a large multiplex genetically unresolved (GUR) family affected by ADPKD-like symptoms and identified a monoallelic frameshift variant (c.703_704delCA) in ALG5. ALG5 encodes an endoplasmic-reticulum-resident enzyme required for addition of glucose molecules to the assembling N-glycan precursors. To identify additional families, we screened a cohort of 1,213 families with ADPKD-like and/or autosomal-dominant tubulointerstitial kidney diseases (ADTKD), GUR (n = 137) or naive to genetic testing (n = 1,076), by targeted massively parallel sequencing, and we accessed Genomics England 100,000 Genomes Project data. Four additional families with pathogenic variants in ALG5 were identified. Clinical presentation was consistent in the 23 affected members, with non-enlarged cystic kidneys and few or no liver cysts; 8 subjects reached end-stage kidney disease from 62 to 91 years of age. We demonstrate that ALG5 haploinsufficiency is sufficient to alter the synthesis of the N-glycan chain in renal epithelial cells. We also show that ALG5 is required for PC1 maturation and membrane and ciliary localization and that heterozygous loss of ALG5 affects PC1 maturation. Overall, our results indicate that monoallelic variants of ALG5 lead to a disorder of the ADPKD-spectrum characterized by multiple small kidney cysts, progressive interstitial fibrosis, and kidney function decline.

Incremental and Personalized Hemodialysis Start: A New Standard of Care.

Introduction: Incremental hemodialysis (iHD) may attenuate "dialysis shock" and reduce costs, preserving quality of life. It is considered difficult to reconcile with HD wards' routine; fear of underdialysis and increasing mortality are additional concerns. The aim of this study was to evaluate mortality, morbidity, and costs in a large HD ward where iHD is the standard of HD start. Methods: This observational study included all incident HD patients in 2017 to 2021, stratified according to HD start: iHD (1-2 sessions/wk), decremental HD (dHD, 3 sessions/wk at start, later reduced), or standard (3 sessions/wk). Results were compared with data recorded in the same unit before the incremental program (2015-2017) and with a propensity score-matched cohort from the French Renal Epidemiology and Information Network (REIN) registry. Results: A total of 158 patients started HD in 2017 to 2021, 57.6% on iHD, 8.9% dHD, and 33.5% standard HD schedule. Patients on the standard schedule had lower initial estimated glomerular filtration rate (eGFR) (5 vs. 7 ml/min per 1.72 m2, P = 0.003). We found no survival differences according to period of start (same center) and propensity score matching (REIN). Patients intensively followed in the pre-HD period were more likely to start on iHD-dHD. Persistence on iHD-dHD was about 50% at 1 year and 35% at 2 years. Hospitalization rates and time to first hospitalization or death did not differ between the schedules. The iHD-dHD policy allowed a 16% cost saving, even accounting for supplemental biochemical tests. Conclusion: Our study reveals that iHD can be a new standard of care, as it is safe and feasible in up to two-thirds of patients on incident HD.

Diagnosis and risk factors for intracranial aneurysms in autosomal polycystic kidney disease: a cross-sectional study from the Genkyst cohort.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is associated with an increased risk for developing intracranial aneurysms (IAs). We aimed to evaluate the frequency of diagnosis of IAs in the cross-sectional, population-based, Genkyst cohort, to describe ADPKD-associated IAs and to analyse the risk factors associated with the occurrence of IAs in ADPKD patients. METHODS: A cross-sectional study was performed in 26 nephrology centres from the western part of France. All patients underwent genetic testing for PKD1/PKD2 and other cystogenes. RESULTS: Among the 2449 Genkyst participants, 114 (4.65%) had a previous diagnosis of ruptured or unruptured IAs at inclusion, and ∼47% of them had a positive familial history for IAs. Most aneurysms were small and saccular and located in the anterior circulation; 26.3% of the patients had multiple IAs. The cumulative probabilities of a previous diagnosis of IAs were 3.9%, 6.2% and 8.1% at 50, 60 and 70 years, respectively. While this risk appeared to be similar in male and female individuals <50 years, after that age, the risk continued to increase more markedly in female patients, reaching 10.8% versus 5.4% at 70 years. The diagnosis rate of IAs was >2-fold higher in PKD1 compared with PKD2, with no influence of PKD1 mutation type or location. In multivariate analysis, female sex, hypertension <35 years, smoking and PKD1 genotype were associated with an increased risk for diagnosis of IAs. CONCLUSIONS: This study presents epidemiological data reflecting real-life clinical practice. The increased risk for IAs in postmenopausal women suggests a possible protective role of oestrogen.

Sodium Bicarbonate Prescription and Extracellular Volume Increase: Real-world Data Results from the AlcalUN Study.

Oral alkalization with sodium bicarbonate (NaHCO3 ) or citrate is prescribed for conditions ranging from metabolic acidosis to nephrolithiasis. Although most nephrologists/urologists use this method routinely, extracellular volume (ECV) increase is the main feared adverse event reported for NaHCO3 . Thus far, no trial has specifically studied this issue in a real-world setting. AlcalUN (NCT03035812) is a multicentric, prospective, open-label cohort study with nationwide (France) enrollment in 18 (public and private) nephrology/urology units. Participants were adult outpatients requiring chronic (>1 month) oral alkalization by either NaHCO3 -containing or no-NaHCO3 -containing agents. The ECV increase (primary outcome) was judged based on body weight increase (ΔBW), blood pressure increase (ΔBP), and/or new-onset edema at the first follow-up visit (V1). From February 2017 to February 2020, 156 patients were enrolled. After a median 106 days of treatment, 91 (72%) patients reached the primary outcome. They had lower systolic (135 (125, 141) vs. 141 (130, 150), P = 0.02) and diastolic (77 (67, 85) vs. 85 (73, 90), P = 0.03) BP values, a higher plasma chloride (106.0 (105.0, 109.0) vs. 105.0 (102.0, 107.0), P = 0.02) at baseline, and a less frequent history of nephrolithiasis (32 vs. 56%, P = 0.02). Patients experienced mainly slight ΔBP (< 10 mmHg). The primary outcome was not associated (P = 0.79) with the study treatment (129 received NaHCO3 and 27 received citrate). We subsequently developed three different models of propensity score matching; each confirmed our results. Chronic oral alkalization with NaHCO3 is no longer associated with an ECV increase compared to citrate in real-life settings.

Unmet needs for CKD care: from the general population to the CKD clinics-how many patients are we missing?

INTRODUCTION: Prevalence of chronic kidney disease (CKD) varies around the world. Little is known about the discrepancy between the general population's needs and nephrology care offered. We aimed to contribute to filling this gap and propose a means to infer the number of patients needing follow-up. METHODS: All patients undergoing at least one nephrology consultation in 2019 were enrolled. We used the ratio between CKD Stages 3 and 4 reported in the literature, and considered that only 25-50% of CKD Stage 3 patients have progressive CKD, to hypothesize different scenarios to estimate the number of CKD Stage 3 patients still needing nephrology follow-up. RESULTS: The 1992 CKD patients were followed-up in our centre (56.93% males; age 66.71 ± 18.32 years; 16.82% Stage 1; 14.66% Stage 2; 39.46% Stage 3; 19.88% Stage 4; 7.68% Stage 5). The ratio between Stages 3 and 4 in population studies ranged from 7.72 to 51.29, being 1.98 in our centre. Hypothesizing that we followed-up 100, 70 or 50% of CKD Stage 4 patients, 528-2506 CKD Stage 3 patients in our area would need nephrology follow-up [1885-8946 per million population (p.m.p.)]. Three to 17 additional nephrologists p.m.p. would be necessary to fully cover the need for care. CONCLUSIONS: The number of patients with CKD Stage 3 who would benefit from nephrology care is high. Considering that one patient-year of delay of dialysis could cover a nephrologist's annual salary, interventions aimed to improve the care of advanced CKD may be economically sound.

VITADIAL "Does correction of 25 OH-VITAmin D with cholecalciferol supplementation increase muscle strength in hemoDIALysis patients?": study protocol for a randomized controlled trial.

BACKGROUND: Muscle strength decreases as kidney failure progresses. Low muscle strength affects more than 50% of hemodialysis patients and leads to daily life activities impairment. In the general population, numerous studies have linked low 25OH-vitamin D (25OHD) concentrations to the loss of the muscle strength and low physical performances. Data on native vitamin D and muscle function are scarce in the chronic kidney disease (CKD) population, but low 25OHD levels have been associated with poor muscle strength. We present in this article the protocol of an ongoing study named VITADIAL testing if cholecalciferol supplementation in hemodialysis patients with low 25OHD improves their muscle strength. METHODS/DESIGN: VITADIAL is a prospective open randomized French multicenter study. All patients will have 25OHD levels ≤50nmol/L at randomization. One group will receive 100,000 UI cholecalciferol once a month during 6 months; the other group will receive no treatment during 6 months. In order to randomize patients with 25OHD ≤50nmol/L, supplemented patients will undergo a 3 months wash-out period renewable 3 times (maximum of 12 months wash-out) until 25OHD reaches a level ≤50nmol/L. The main objective of this study is to analyze if a 6-month period of oral cholecalciferol (i.e., native vitamin D) supplementation improves muscle strength of hemodialysis patients with low 25OHD vitamin D levels. Muscle strength will be assessed at 0, 3, and 6 months, by handgrip strength measured with a quantitative dynamometer. Secondary objectives are (1) to analyze 25OHD plasma levels after vitamin D wash-out and/or supplementation, as well as factors associated with 25OHD lowering speed during wash-out, and (2) to analyze if this supplementation improves patient's autonomy, reduces frailty risk, and improves quality of life. Fifty-four patients are needed in each group to meet our main objective. DISCUSSION: In the general population, around 30 randomized studies analyzed the effects of vitamin D supplementation on muscle strength. These studies had very different designs, sizes, and studied population. Globally, these studies and the meta-analysis of studies favor a beneficial effect of vitamin D supplementation on muscle strength, but this effect is mainly found in the subgroup of aged patients and those with the lowest 25OHD concentrations at inclusion. We reported a positive independent association between 25OHD and handgrip strength in a population of 130 hemodialysis patients in a dose-dependent manner. In our cohort, a plateau effect was observed above 75 nmol/L. Only two randomized studies analyzed the effect of native vitamin D supplementation on muscle strength in hemodialysis patients, but unfortunately, these two studies were underpowered. VITADIAL is a trial specifically designed to assess whether cholecalciferol might benefit to hemodialysis patient's muscle strength. TRIAL REGISTRATION: ClinicalTrials.gov NCT04262934 . Registered on 10 February 2020 - Retrospectively registered.

Rheopheresis: A new therapeutic approach in severe calciphylaxis.

AIM: Uremic calciphylaxis, also called calcific uraemic arteriolopathy (CUA), is a rare disease with a poor prognosis (mortality between 45% and 80%). Treatment is currently not standardized, and is based mainly on risk factor control, often with administration of sodium thiosulfate. We report the use of rheopheresis, a double filtration apheresis technique, specifically designed to improve blood rheology and tissue perfusion, as adjunctive therapy in eight patients with severe CUA. METHODS: We retrospectively analysed eight cases of severe CUA treated by rheopheresis after failure of conventional measures, including administration of sodium thiosulfate and discontinuation of vitamin K antagonists. RESULTS: Of the patients, there were 5 (63%) women, the median age was 69 (63.9-73) years. Four (50%) patients had biopsy-proven CUA. At diagnosis, the median dialysis vintage was 35 (3.9-42) months; five (63%) patients were anuric. Weekly median dialysis duration and dose were 12 (12-12.75) hours and 1.19 (1.13-1.48) Kt/V per dialysis session, respectively. Median time from CUA onset to first rheopheresis therapy was 26 (3.2-68) days. Patients started with 2-3 weekly sessions, coupled with haemodialysis. Complete remission was obtained in five patients (66%) after 25 (19-39) sessions over a duration of 119 (114-196) days. Three patients died, two of which resulted from an infectious complication related to CUA. CONCLUSION: Rheopheresis is a promising approach, with a good safety profile, for the treatment of CUA. A prospective study with a larger population, would clarify its place in the therapeutic armamentarium.

[e-Health in nephrology: 1st French survey on telenephrology]. / Pratique de la e-santé en néphrologie en France : Résultats de la première enquête sur la télénéphrologie.

The number of new patients with chronic kidney diseases strongly increases while the one of nephrologists does not: this is developing new challenges, in which e-health will take a special part. This field is poorly investigated: so, we developed a dedicated survey. Telenephrology is a new approach that includes all what nephrologists can do in their routine practice: especially, telehealth with teleconsulting, telesurvey, and helpline. We also studied their relationship with m-health. The questionnaire was developed and validated by members from the Club des Jeunes Néphrologues and the Société Francophone de Néphrologie, Dialyse et Transplantation: it was then broadcast to all french nephrologists, thru web media. From June to July, 2017, we collected 175 answers: they represented all kinds of practices of the profession. Results show that French nephrologists are connected: most of them are present on social network(s) and/or uses connected objects, mostly for personal reasons. They communicate a lot, between them and/or with patients, mainly via email. Computerized medical records are mostly used in the follow-up of patients on renal dialysis or with chronic kidney diseases. Most of French nephrologists are satisfied by telenephrology but there are still obstacles to its deployment: mainly, technical, administrative, and/or billing difficulties. All should be taken into account to help telenephrology developing. In conclusion, French nephrologists are yet connected but they really need more help again to face new challenges raised by e-health.

PKD2-Related Autosomal Dominant Polycystic Kidney Disease: Prevalence, Clinical Presentation, Mutation Spectrum, and Prognosis.

BACKGROUND: PKD2-related autosomal dominant polycystic kidney disease (ADPKD) is widely acknowledged to be of milder severity than PKD1-related disease, but population-based studies depicting the exact burden of the disease are lacking. We aimed to revisit PKD2 prevalence, clinical presentation, mutation spectrum, and prognosis through the Genkyst cohort. STUDY DESIGN: Case series, January 2010 to March 2016. SETTINGS & PARTICIPANTS: Genkyst study participants are individuals older than 18 years from 22 nephrology centers from western France with a diagnosis of ADPKD based on Pei criteria or at least 10 bilateral kidney cysts in the absence of a familial history. Publicly available whole-exome sequencing data from the ExAC database were used to provide an estimate of the genetic prevalence of the disease. OUTCOMES: Molecular analysis of PKD1 and PKD2 genes. Renal survival, age- and sex-adjusted estimated glomerular filtration rate. RESULTS: The Genkyst cohort included 293 patients with PKD2 mutations (203 pedigrees). PKD2 patients with a nephrology follow-up corresponded to 0.63 (95% CI, 0.54-0.72)/10,000 in Brittany, while PKD2 genetic prevalence was calculated at 1.64 (95% CI, 1.10-3.51)/10,000 inhabitants in the European population. Median age at diagnosis was 42 years. Flank pain was reported in 38.9%; macroscopic hematuria, in 31.1%; and cyst infections, in 15.3% of patients. At age 60 years, the cumulative probability of end-stage renal disease (ESRD) was 9.8% (95% CI, 5.2%-14.4%), whereas the probability of hypertension was 75.2% (95% CI, 68.5%-81.9%). Although there was no sex influence on renal survival, men had lower kidney function than women. Nontruncating mutations (n=36) were associated with higher age-adjusted estimated glomerular filtration rates. Among the 18 patients with more severe outcomes (ESRD before age 60), 44% had associated conditions or nephropathies likely to account for the early progression to ESRD. LIMITATIONS: Younger patients and patients presenting with milder forms of PKD2-related disease may not be diagnosed or referred to nephrology centers. CONCLUSIONS: Patients with PKD2-related ADPKD typically present with mild disease. In case of accelerated degradation of kidney function, a concomitant nephropathy should be ruled out.

Anti-alpha-actinin antibodies are part of the anti-cell membrane antibody spectrum that characterize patients with lupus nephritis.

Anti-membrane autoantibodies (MbA) have been reported in sera from patients with lupus nephritis (LN) but the targets of the MbA remain to be explored, which is the aim of the current study. Sera were collected from 40 patients with LN determined by renal biopsy, and from 30 systemic lupus erythematosus (SLE) patients without clinical evidence of LN. Thirty autoimmune disease control patients (rheumatoid arthritis, Sjögren's syndrome and systemic sclerosis), and 30 healthy controls were also included. Using flow cytometry, the presence of anti-MbA was explored revealing that IgG anti-MbA positivity was associated with LN (62.5% vs 13.3%) when compared to non-LN SLE patients, autoimmune disease patients (6.7%) and healthy controls (0%). Next, using purified plasma membrane fractions from human embryonic kidney (HEK) cells, the more prominent targets and their occurrence rates were located at 50 kDa, 60/65 kDa, 90 kDa, 110 kDa, 180 kDa and 220 kDa. Alpha-actinin (110 kDa) autoAb was characterized as a major target in LN patients positive for anti-MbA, and anti-MbA binding activity was reduced (36.9 ± 13.7%) in the presence of α-actinin. Laminin (200 kDa) was also characterized as a minor target, which was not the case for annexin A2 (36 kDa). Finally, anti-MbA IgG subclass analysis indicated a predominance of IgG2. In conclusion, IgG anti-MbA were detected at high levels in LN patients supporting a primary pathogenic role for anti-MbA and anti-MbA/α-actinin+ in LN that needs further research.

Homozygous FCGR3A-158F mutation is associated with delayed B-cell depletion following rituximab but with preserved efficacy in a patient with refractory lupus nephritis.

Rituximab (RTX), an anti-CD20 monoclonal antibody, has shown promising results in a small group of systemic lupus erythematosus (SLE) patients treated for lupus nephritis (LN). However, such observations were not confirmed in the double-blind LUNAR study. Accordingly, the factors associated with the clinical response remain to be characterized. We report the case of a young woman with known LN successfully re-treated with RTX and steroids and homozygous for the low-affinity FCG3RA 158F genotype. Although B-cell depletion was delayed, complete remission with anti-DNA antibody negativity and proteinuria normalization were maintained for 5 years. The implications for disease pathogenesis and clinical monitoring are discussed.

Mesangial cell-specific antibodies are central to the pathogenesis of lupus nephritis.

Not only is nephritis a common complaint in systemic lupus erythematosus, but it is also the most life-threatening complication of the disease. Anti-double-stranded DNA antibodies (Abs), which are found in up to 80% of these patients, might be nephritogenic per se. That is, they may cross-react with mesangial cell (MC) surface proteins, such as alpha-actinin and annexin A2, they may cross-react with mesangial matrix protein such as laminine and fibronectin, or they may recognize chromatin material previously deposited in the glomeruli. The consequence of the binding of anti-MC Abs may be their internalization, which results in activation and proliferation of these MCs. In turn, these activated MCs are suspected of promoting immune complex formation by sequestering and thereby protecting chromatin from degradation. The present paper will explain the mechanisms through which such autoAbs may initiate nephritis.