Prognostic value of complement serum C3 level and glomerular C3 deposits in anti-glomerular basement membrane disease.

Background and objectives: Activation of the complement system is involved in the pathogenesis of anti-glomerular basement membrane (anti-GBM) disease. Glomerular deposits of complement 3 (C3) are often detected on kidney biopsies. The primary objective of this study was to analyze the prognostic value of the serum C3 level and the presence of C3 glomerular deposits in patients with anti-GBM disease. Methods: We conducted a retrospective cohort study of 150 single-positive patients with anti-GBM disease diagnosed between 1997 and 2017. Patients were categorized according to the serum C3 level (forming a low C3 (C3<1.23 g/L) and a high C3 (C3≥1.23 g/L) groups) and positivity for C3 glomerular staining (forming the C3+ and C3- groups). The main outcomes were kidney survival and patient survival. Results: Of the 150 patients included, 89 (65%) were men. The median [interquartile range (IQR)] age was 45 [26-64]. At diagnosis, kidney involvement was characterized by a median [IQR] peak serum creatinine (SCr) level of 578 [298-977] µmol/L, and 106 (71%) patients required dialysis. Patients in the low C3 group (72 patients) had more severe kidney disease at presentation, as characterized by higher prevalences of oligoanuria, peak SCr ≥500 µmol/L (69%, vs. 53% in the high C3 group; p=0.03), nephrotic syndrome (42%, vs. 24%, respectively; p=0.02) and fibrous forms on the kidney biopsy (21%, vs. 8%, respectively; p=0.04). Similarly, we observed a negative association between the presence of C3 glomerular deposits (in 52 (41%) patients) and the prevalence of cellular forms (83%, vs. 58% in the C3- group; p=0.003) and acute tubulo-interstitial lesions (60%, vs. 36% in the C3- group; p=0.007). When considering patients not on dialysis at diagnosis, the kidney survival rate at 12 months was poorer in the C3+ group (50% [25-76], vs. 91% [78-100] in the C3- group; p=0.01), with a hazard ratio [95% confidence interval] of 5.71 [1.13-28.85] (p=0.04, after adjusting for SCr). Conclusion: In patients with anti-GBM disease, a low serum C3 level and the presence of C3 glomerular deposits were associated with more severe disease and histological kidney involvement at diagnosis. In patients not on dialysis at diagnosis, the presence of C3 deposits was associated with worse kidney survival.

Early Renal Recovery after the First Flare of Pauci-Immune Glomerulonephritis.

INTRODUCTION: Renal involvement is a severe manifestation of antineutrophil cytoplasmic antibody-associated vasculitis. Patients often progress to end-stage renal disease. The potential for renal recovery after the first flare has seldom been studied. Our objectives were to describe the evolution of the estimated glomerular filtration rate (eGFR) and identify factors associated with the change in the eGFR between diagnosis and the follow-up at 3 months (ΔeGFRM0-M3). METHODS: This was a retrospective study over the period 2003-2018 of incident patients in the Nord-Pas-de-Calais (France). The primary outcome was the ΔeGFRM0-M3. RESULTS: One hundred and seventy-seven patients were included. The eGFR at 3 months was significantly higher than at diagnosis (mean ± standard deviation, 40 ± 24 vs. 28 ± 26 mL/min/1.73 m2, p < 0.001), with a ΔeGFRM0-M3 of 12 ± 19 mL/min/1.73 m2. The eGFR at 12 months was higher than at 3 months (44 ± 13 vs. 40 ± 24 mL/min/1.73 m2, p = 0.003). The factors significantly associated with the ΔeGFRM0-M3 in multivariate analysis were the percentage of cellular crescents and neurological involvement. The mean increase in the eGFR was 2.90 ± 0.06 mL/min/1.73 m2 for every 10-point gain in the percentage of cellular crescents. CONCLUSIONS: Early renal recovery after the first flare of pauci-immune glomerulonephritis occurred mainly in the first 3 months of treatment. The percentage of cellular crescents was the main independent predictor of early renal recovery.

Severe Infection in Anti-Glomerular Basement Membrane Disease: A Retrospective Multicenter French Study.

In patients presenting with anti-glomerular basement membrane (GBM) disease with advanced isolated kidney involvement, the benefit of intensive therapy remains controversial due to adverse events, particularly infection. We aim to describe the burden of severe infections (SI) (requiring hospitalization or intravenous antibiotics) and identify predictive factors of SI in a large cohort of patients with anti-GBM disease. Among the 201 patients (median [IQR] age, 53 [30-71] years) included, 74 had pulmonary involvement and 127 isolated glomerulonephritis. A total of 161 SI occurred in 116 patients during the first year after diagnosis. These infections occurred during the early stage of care (median [IQR] time, 13 [8-19] days after diagnosis) with mainly pulmonary (45%), catheter-associated bacteremia (22%) and urinary tract (21%) infections. In multivariable analysis, positive ANCA (HR [95\% CI] 1.62 [1.07--2.44]; p = 0.02) and age at diagnosis (HR [95% CI] 1.10 [1.00-1.21]; p = 0.047) remained independently associated with SI. Age-adjusted severe infection during the first three months was associated with an increased three-year mortality rate (HR [95% CI] 3.13 [1.24-7.88]; p = 0.01). Thus, SI is a common early complication in anti-GBM disease, particularly in the elderly and those with positive anti-neutrophil cytoplasmic antibodies (ANCA). No significant association was observed between immunosuppressive strategy and occurrence of SI.

[Kidney disease care for the elderly]. / Spécificités des néphropathies du sujet âgé.

In our aging population, kidney disease management needs to take into account the frailty of the elderly. Standardized geriatric assessments can be proposed to help clinicians apprehend this dimension in their daily practice. These tools allow to better identify frail patients and offer them more personalized and harmless treatments. This article aims to focus on the kidney diseases commonly observed in elderly patients and analyze their specific nephrogeriatric care modalities. It should be noticed that all known kidney diseases can be also observed in the elderly, most often with a quite similar clinical presentation. This review is thus focused on the diseases most frequently and most specifically observed in elderly patients (except for monoclonal gammopathy associated nephropathies, out of the scope of this work), as well as the peculiarities of old age nephrological care.

Knockout of receptor for advanced glycation end-products attenuates age-related renal lesions.

Pro-aging effects of endogenous advanced glycation end-products (AGEs) have been reported, and there is increasing interest in the pro-inflammatory and -fibrotic effects of their binding to RAGE (the main AGE receptor). The role of dietary AGEs in aging remains ill-defined, but the predominantly renal accumulation of dietary carboxymethyllysine (CML) suggests the kidneys may be particularly affected. We studied the impact of RAGE invalidation and a CML-enriched diet on renal aging. Two-month-old male, wild-type (WT) and RAGE-/- C57Bl/6 mice were fed a control or a CML-enriched diet (200 µg CML/gfood ) for 18 months. Compared to controls, we observed higher CML levels in the kidneys of both CML WT and CML RAGE-/- mice, with a predominantly tubular localization. The CML-rich diet had no significant impact on the studied renal parameters, whereby only a trend to worsening glomerular sclerosis was detected. Irrespective of diet, RAGE-/- mice were significantly protected against nephrosclerosis lesions (hyalinosis, tubular atrophy, fibrosis and glomerular sclerosis) and renal senile apolipoprotein A-II (ApoA-II) amyloidosis (p < 0.001). A positive linear correlation between sclerosis score and ApoA-II amyloidosis score (r = 0.92) was observed. Compared with old WT mice, old RAGE-/- mice exhibited lower expression of inflammation markers and activation of AKT, and greater expression of Sod2 and SIRT1. Overall, nephrosclerosis lesions and senile amyloidosis were significantly reduced in RAGE-/- mice, indicating a protective effect of RAGE deletion with respect to renal aging. This could be due to reduced inflammation and oxidative stress in RAGE-/- mice, suggesting RAGE is an important receptor in so-called inflamm-aging.

Early predictors of one-year mortality in patients over 65 presenting with ANCA-associated renal vasculitis: a retrospective, multicentre study.

BACKGROUND: The risk of early death is particularly high in patients over the age of 65 presenting with antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis. We hypothesized that by combining disease severity markers, a comorbidity index and serious adverse event reports, we would be able to identify early predictors of one-year mortality in this population. METHODS: We performed a multicentre, retrospective study in the nephrology and internal medicine departments of six tertiary hospitals in northern France. A total of 149 patients (median [interquartile range (IQR)] age: 72.7 [68.5-76.8] years) presenting with ANCA-associated vasculitis and renal involvement were included between January 2002 and June 2015. The primary endpoint was the one-year mortality rate. RESULTS: Renal function was severely impaired at presentation (median [IQR] peak serum creatinine (SCr): 337 [211-522] µmol/l), and 45 patients required dialysis. The Five-Factor Score (FFS, scored as + 1 point for each poor prognostic factor (age > 65 years, cardiac symptoms, gastrointestinal involvement, SCr ≥150 µmol/L, and the absence of ear, nose, and throat involvement)) was ≥3 in 120 cases. The one-year mortality rate was 19.5%. Most of the deaths occurred before month 6, and most of these were related to severe infections. In a univariate analysis, age, a high comorbidity index, a performance status of 3 or 4, a lack of co-trimoxazole prophylaxis, early severe infection, and disease activity parameters (such as the albumin level, haemoglobin level, peak SCr level, dialysis status, and high FFS) were significantly associated with one-year mortality. In a multivariable analysis, the best predictors were a high FFS (relative risk (RR) [95% confidence interval (CI)] = 2.57 [1.30-5.09]; p = 0.006) and the occurrence of a severe infection during the first month (RR [95%CI] = 2.74 [1.27-5.92]; p = 0.01). CONCLUSIONS: When considering various disease severity markers in over-65 patients with ANCA-associated renal vasculitis, we found that an early, severe infection (which occurred in about a quarter of the patients) is a strong predictor of one-year mortality. A reduction in immunosuppression, the early detection of infections, and co-trimoxazole prophylaxis might help to reduce mortality in this population.

Differential Determinants of Tubular Phosphate Reabsorption: Insights on Renal Excretion of Phosphates in Kidney Disease.

We assessed the tubular reabsorption of phosphate (TRP) and maximal renal threshold for phosphate reabsorption to glomerular filtration rate (TmPi/GFR) and their determinants in 64 stages 2-4 chronic kidney disease (CKD) patients in order to define the early changes in phosphate metabolism in CKD. In multivariable analysis, TmPi/GFR correlates were estimated GFR (eGFR), intact parathyroid hormone (iPTH), and hemoglobin (R2 = 0.417), while TRP correlates were eGFR, iPTH, 24-h phosphaturia, and calcitriol (R2 = 0.72). This suggests that TmPi/GFR and TRP, respectively, assess hemoglobin-phosphate and bowel-kidney phosphate regulation axis. Iron supplementation based on TmPi/GFR or earlier phosphate restriction based on TRP should be investigated in view of modifying clinical outcomes in CKD.

[Sucroferric oxyhydroxide, a novel iron-based phosphate binder. Which current use in dialysis patients?] / Oxyhydroxyde sucroferrique, un nouveau chélateur des phosphates à base de fer. Quelle utilisation chez le patient dialysé ?

International guidelines suggest lowering elevated phosphorus level to the normal range in patients on dialysis. Among the phosphate-lowering strategies, phosphate binder is frequently used in addition to dietary phosphate restriction and an adequate dialysis strategy. However, serum phosphate concentration higher than 1.78mmol/L is observed in more than 40% of patients justifying the quest for new drugs. Sucroferric oxyhydroxide is one of the new iron-based agents and is available in France since May 2016. A recent international multicentre study showed this new drug to be as efficacious and non-inferior to sevelamer carbonate in magnitude of serum phosphate control. The serum phosphorus-lowering effect was maintained over 1year. When compared to carbonate sevelamer, the pill-burden was half with sucroferric oxyhydroxide because of its high phosphate binding capacity. As previously shown by experimental studies, no risk of iron accumulation was observed since iron absorption is negligible. Discolored feces and diarrhea were fairly frequent side effects. When diarrhea subsides, the tolerability of this new phosphate binder is excellent on a long-term basis.

Kidney, heart and brain: three organs targeted by ageing and glycation.

Advanced glycation end-product (AGE) is the generic term for a heterogeneous group of derivatives arising from a non-enzymatic reaction between reducing sugars and proteins. In recent years, evidence has accumulated that incriminates AGEs in pathogenic processes associated with both chronic hyperglycaemia and age-related diseases. Regardless of their exogenous or endogenous origin, the accumulation of AGEs and their derivatives could promote accelerated ageing by leading to protein modifications and activating several inflammatory signalling pathways via AGE-specific receptors. However, it remains to be demonstrated whether preventing the accumulation of AGEs and their effects is an important therapeutic option for successful ageing. The present review gives an overview of the current knowledge on the pathogenic role of AGEs by focusing on three AGE target organs: kidney, heart and brain. For each of these organs we concentrate on an age-related disease, each of which is a major public health issue: chronic kidney disease, heart dysfunction and neurodegenerative diseases. Even though strong connections have been highlighted between glycation and age-related pathogenesis, causal links still need to be validated. In each case, we report evidence and uncertainties suggested by animal or epidemiological studies on the possible link between pathogenesis and glycation in a chronic hyperglycaemic state, in the absence of diabetes, and with exogenous AGEs alone. Finally, we present some promising anti-AGE strategies that are currently being studied.

Soluble form of receptor for advanced glycation end-products (sRAGE): do sRAGE ligands or anti-sRAGE auto-antibodies interfere with sRAGE quantification?

BACKGROUND: The soluble form of the receptor for advanced glycation end-products (sRAGE) has been studied in various diseases. It is not clear why sRAGE levels vary between studies, with controversial results. What also remains to be determined is whether receptor for advanced glycation end-products (RAGE) ligands could affect sRAGE assessment by epitope masking. Recently described anti-sRAGE autoantibodies may play an interfering role. The aim of this study was therefore to investigate the influence of RAGE ligands and anti-sRAGE autoantibodies on sRAGE quantification. METHODS: The RAGE ligands carboxymethyllysine (CML; AGEs with a high affinity for RAGE), S100 proteins, high-mobility group protein B1 (HMGB1) and ß-amyloid peptide (aß) were tested by enzyme-linked immunosorbent assay (ELISA) with recombinant sRAGE (rHu-sRAGE) or serum from healthy controls. Using ELISA, anti-sRAGE autoantibodies (IgGs) were identified in haemodialysis (HD) patients, then purified and incubated with rHu-sRAGE or serum to investigate their effects on sRAGE levels. RESULTS: RAGE ligands, either alone at three different concentrations (CML was also tested at different glycation levels) or a mixture of all these ligands, did not affect sRAGE levels when incubated with rHu-sRAGE or control serum. Compared with healthy controls, HD patients had higher levels of sRAGE (P < 0.001) and anti-sRAGE IgGs (P < 0.05). However, incubation of rHu-sRAGE with purified IgGs from HD patients had no effect on sRAGE quantification. CONCLUSIONS: RAGE ligands or anti-sRAGE autoantibodies did not interfere with sRAGE quantification. Further studies are required to elucidate the variability in sRAGE levels reported in the literature and to define the potential of sRAGE for use as a reliable biomarker.

Vitamin D2 versus vitamin D3 supplementation in hemodialysis patients: a comparative pilot study.

BACKGROUND: In patients with chronic kidney disease, vitamin D insufficiency is highly prevalent. It can be corrected by supplementation with either vitamin D(2) or vitamin D3. Recent studies in patients without impaired kidney function suggest that vitamin D(3) is more efficient than vitamin D(2) in correcting vitamin D insufficiency. However, no direct comparison has been made in hemodialysis (HD) patients. METHODS: Thirty-nine HD patients with serum 25-hydroxyvitamin D (25(OH)D) levels =20 ng/mL were enrolled in this comparative, prospective pilot study. They were divided into 3 groups and treated over a 3-month period. Each patient received oral doses of 200,000 international units (IU) vitamin D per month according to the following treatment schedule: (i) vitamin D(2) in small fractionated doses at each HD session, 3 times per week (group D2S); (ii) vitamin D(2) once a month (group D2M); or (iii) vitamin D(3) once a month (group D3M). Changes in serum 25(OH)D levels were measured at the end of the study. RESULTS: Posttreatment serum 25(OH)D levels increased significantly in all groups. The mean ± SD serum 25(OH)D value for group D3M patients (40 ± 13 ng/mL) was significantly higher than that for groups D2M (25 ± 9 ng/mL, p<0.01) and D2S patients (25 ± 9 ng/mL, p<0.01). Serum 25(OH)D increased to levels >30 ng/mL in 84% of group D3M patients, but in only 15% and 27% of group D2M and D2S subjects, respectively. CONCLUSION: Vitamin D(3) is more effective than vitamin D(2) in providing adequate 25(OH)D serum levels in HD patients.

[Cognitive impairment and chronic kidney disease: which links?]. / Troubles cognitifs et insuffisance rénale: quels liens?

Ageing of the population leads to an increase of cognitive disorders and chronic renal failure incidence. Compared to the general population, prevalence of cognitive impairment is more important in renal failure patients, especially in dialyzed patients. No direct link has been established between renal failure and cognitive impairment. The care of older and older patients and the high frequency of vascular risk factors, in particular hypertension and diabetes, partially explain the prevalence of vascular dementia and Alzheimer disease in this population. Other factors as the anemia, phosphocalcic metabolism disorders facilitate the cognitive impairment. The present work reviews the links existing between chronic renal failure and cognitive impairment.

[Renal malakoplakia: an underestimate cause of renal failure]. / Malacoplakie renale: une cause méconnue d'insuffisance rénale.

Malakoplakia is an inflammatory granulomatous disease induced by defective phagocytic activity of macrophage. Malakoplakia is histologically characterized by the presence of Michaelis-Gutmann bodies in macrophages. Although not uncommon in the genito-urinary tract, isolated malakoplakia of the kidney is rarely found. Its main clinical presentation associates acute renal failure and acute pyelonephritis. The clue for diagnosis of renal malakoplakia is based on renal biopsy showing Michaelis-Gutmann bodies. Establishing the diagnosis of renal malakoplakia is essential as it determines the choice of antibiotics and duration of treatment. Prognosis remains poor, leading frequently to chronic renal failure. In this paper, we report four cases of renal malakoplakia and discuss clinical presentation, biological and pathological features, treatment and prognosis of this disease.

Soluble receptor for advanced glycation end products: a new biomarker in diagnosis and prognosis of chronic inflammatory diseases.

The formation of advanced glycation end products (AGEs) is a result of the non-enzymatic reaction between sugars and free amino groups of proteins. AGEs, through interacting with their specific receptor for AGEs (RAGE), result in activation of pro-inflammatory states and are involved in numerous pathologic situations. The soluble form of RAGE (sRAGE) is able to act as a decoy to avoid interaction of RAGE with its pro-inflammatory ligands (AGEs, HMGB1, S100 proteins). sRAGE levels have been found to be decreased in chronic inflammatory diseases including atherosclerosis, diabetes, renal failure and the aging process. The use of measuring circulating sRAGEs may prove to be a valuable vascular biomarker and in this review, we describe the implications of sRAGE in inflammation and propose that this molecule may represent a future therapeutic target in chronic inflammatory diseases.

[Renal aging: risk factors and nephroprotection]. / Vieillissement rénal: facteurs de risque et néphroprotection.

Renal failure in the elderly is currently underestimated and presents a real challenge for the public health system. Kidney function must be routinely assessed by creatinine clearance, estimated with either the Cockcroft and Gault formula or the simplified MDRD formula, which appears especially appropriate for the elderly. Normal kidney aging is related to tissue and functional changes that make older patients very vulnerable to environmental modifications. Numerous factors can accelerate the impairment of rental function during aging. Some of them cannot be modified: sex, genome, and initial kidney disease. Most of them can be managed or treated: hypertension, diabetes mellitus, obesity, smoking, dyslipidemia, proteinuria, and the presence of oxidation and glycation products. Chronic renal failure in the elderly must be managed early with strict treatment targets to avoid the development of end-stage renal disease. Inhibitors of the renin-angiotensin-aldosterone system play an essential role in optimizing nephroprotection: control of hypertension, diabetes complications, and proteinuria. They should be prescribed very carefully in older patients. Age is not a prerequisite for consultations with nephrologists, which should take place early so that nephroprotection can still be useful.