On the relationship between proteinuria and plasma phosphate.

Albuminuria is strongly associated with renal and cardiovascular outcomes independently of renal function level. However, the pathophysiology of these associations is debated. In chronic kidney disease (CKD), phosphate retention participates in cardiovascular events and increased cardiovascular mortality. We hypothesised that albuminuria may modulate tubular phosphate handling by the kidney. To verify this hypothesis, we first studied the association between phosphataemia and albuminuria in children with nephrotic syndrome and in adults with CKD. In both cases, higher albuminuria was associated with higher phosphate level, independently of glomerular filtration rate. We further tried to decipher the molecular mechanisms of these observations. Using animal models of nephrotic proteinuria, we could show that albuminuric rats and mice had abnormally elevated sodium-phosphate apical co-transporter expression, despite elevated fibroblast growth factor 23 (FGF23). The FGF23 downstream pathway was inhibited despite elevated FGF23 levels. Klotho protein expression was also lower in proteinuric animals compared to controls. Finally, albumin had no direct effects on phosphate transport in cells. Altogether, we show that albuminuria induces alteration of phosphate tubular handling, independently of glomerular filtration rate. The mechanisms involved appear to include Klotho down-regulation and resistance to FGF23. This observation may link albuminuria to increased cardiovascular disease via altered phosphate handling. Finally, this observation opens up further opportunities to better understand the link between albuminuria, Klotho, FGF23 and phosphate handling

Association of Clonal Hematopoiesis of Indeterminate Potential with Inflammatory Gene Expression in Patients with COPD

Chronic obstructive pulmonary disease (COPD) is a disease with an inflammatory pheno type with increasing prevalence in the elderly. Expanded population of mutant blood cells carrying somatic mutations is termed clonal hematopoiesis of indeterminate potential (CHIP). The associ ation between CHIP and COPD and its relevant effects on DNA methylation in aging are mainly unknown. Analyzing the deep-targeted amplicon sequencing from 125 COPD patients, we found enhanced incidence of CHIP mutations (~20%) with a predominance of DNMT3A CHIP-mediated hypomethylation of Phospholipase D Family Member 5 (PLD5), which in turn is positively correlated with increased levels of glycerol phosphocholine, pro-inflammatory cytokines, and deteriorating lung function

Purpura de Henoch-Schönlein: une prise en charge entre pédiatre et néphrologue pédiatre [Henoch-Schönlein Purpura a dual follow up between pediatrician and pediatric nephrologist].

Henoch-Schönlein purpura is a well known paediatric disease characterized by the classic triad: purpura, arthritis and abdominal pain. Short term prognosis is excellent and is mostly dependant on abdominal complications. Long term morbidity depends essentially on the severity of renal involvement which occurs in 35% of cases. Microhematuria and light proteinuria are the only signs in 80% of cases. The remaining 20% presents with nephrotic or nephritic syndrome and acute renal insufficiency. Among patients with Henoch-Schönlein nephritis the risk of developing renal insufficiency varies between 11-30% of cases. Currently, the follow up guidelines are multiple and the optimal treatment of nephritis is controversial; this is what this article proposes to discuss

Immaturité rénale et oligonéphronie du prématuré: conséquences à long terme [Premature kidneys and oligonephronia: long term repercussion]

The premature has a reduced number of nephrons. This condition, added to an immature renal function at birth, increases the vulnerability to hemodynamic changes, drug toxicity, and nephrocalcinosis. The oligonephronia worsens the risk to present in adulthood, hypertension and renal insufficiency. Nephrocalcinosis appears in the postnatal period, secondary to renal calcifications. This condition increases the risk of further renal endowment. The nephrocalcinosis is closely related to rickets in the premature. Indeed, an excess of vitamin D and calcium, increases the risk of nephrocalcinosis. The early recognition of markers, such as microalbuminuria, hypertension and hypercalciuria, allow targeting prevention measures

Variables of interest to predict glomerular filtration rate in preterm newborns in the first days of life.

Measurement of neonatal renal function is challenging, and accurate, easy-to-use markers to estimate glomerular filtration rate (eGFR) are lacking. This study aimed to evaluate principal determinants of GFR in neonates and develop a predictive equation. GFR was measured, using single injection inulin clearance, at median day 3 of life in 48 newborns. Associations of clearance with height, gestational age, weight, creatinine, and cystatin C were explored and a multivariable model to estimate GFR developed. We also evaluated preexisting GFR equations (Schwartz, Zappitelli, combined Zappitelli). Forty-four clearances were measured, 36 very preterm neonates (28-32 weeks); 5 extremely preterm (< 28 weeks), and 3 term newborns. No patient presented acute renal insufficiency. Median inulin clearance in preterm infants was 18.83 ml/min/1.73 m <sup>2</sup> (IQ 15.29; 24.99). Inulin clearance correlated with weight (ρ 0.74), gestational age (ρ 0.72), height (ρ 0.49), and creatinine (ρ - 0.42), but not cystatin C. In the multivariable model, predicted GFR equation was 2.32* (weight (g)) <sup>0.64</sup> /(creatinine (mcmol/l)) <sup>0.62</sup> . Mean error in predicting clearance was - 0.8 ml/min/1.73 m <sup>2</sup> (- 3.0-1.4) ranging from - 14.9 to 13.3 ml/min/1.73 m <sup>2</sup> . Mean prediction error with Zappitelli and combined Zappitelli equations were 28.5 ml/min/1.73 m <sup>2</sup> (95% CI 24.6-32.3) and 28.3 ml/min/1.73 m <sup>2</sup> (95% CI 24.9-31.7), respectively, and 2 ml/min/1.73 m <sup>2</sup> (95% CI - 0.6-4.6) for Schwartz equation. Weight and gestational age are crucial determinants of GFR in neonates. The Zappitelli models were not validated in our population. Our predictive model and Schwartz models performed better. Our model should be evaluated in another preterm population, particularly in those presenting renal insufficiency

Optimizing seroprotection against pneumococcus in children with nephrotic syndrome using the 13-valent pneumococcal conjugate vaccine.

BACKGROUND: Infections are among the main life-threatening complications in patients with nephrotic syndrome (NS), in particular with Streptococcus pneumoniae, the first cause of bacterial peritonitis and sepsis in these patients. This study aims to evaluate the baseline seroprotection of NS patients against S. pneumoniae, and immunize them with the 13-valent pneumococcal conjugate vaccine (PCV13) regardless of disease activity and previous immunization history, in order to evaluate the immunogenicity, safety profile, and effect of NS treatment on vaccine responses. METHODS: This multicentre prospective interventional study enrolled 42 children with NS at disease onset or during a regular follow-up appointment. PCV13 was administered at inclusion. Serotype-specific S. pneumoniae IgG titer were assessed at baseline, after immunization, and at 1year follow-up. Vaccine safety was evaluated clinically and by urinary tests. RESULTS: PCV13 induced high serotype-specific IgG titers that were maintained at high levels one year after vaccination, even in children previously immunized. No serious adverse event occurred and relapse frequency was unchanged. CONCLUSION: Given that high IgG titers were achieved and maintained after PCV13 vaccination, and considering the high morbidity related to S. pneumoniae, we propose PCV13 (re-)vaccination for all NS patients, irrespective of their previous immunization history, treatment and disease activity

Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling.

Proteinuria and hyperphosphatemia are cardiovascular risk factors independent of GFR. We hypothesized that proteinuria induces relative phosphate retention via increased proximal tubule phosphate reabsorption. To test the clinical relevance of this hypothesis, we studied phosphate handling in nephrotic children and patients with CKD. Plasma fibroblast growth factor 23 (FGF-23) concentration, plasma phosphate concentration, and tubular reabsorption of phosphate increased during the proteinuric phase compared with the remission phase in nephrotic children. Cross-sectional analysis of a cohort of 1738 patients with CKD showed that albuminuria≥300 mg/24 hours is predictive of higher phosphate levels, independent of GFR and other confounding factors. Albuminuric patients also displayed higher plasma FGF-23 and parathyroid hormone levels. To understand the molecular mechanisms underlying these observations, we induced glomerular proteinuria in two animal models. Rats with puromycin-aminonucleoside-induced nephrotic proteinuria displayed higher renal protein expression of the sodium-phosphate co-transporter NaPi-IIa, lower renal Klotho protein expression, and decreased phosphorylation of FGF receptor substrate 2α, a major FGF-23 receptor substrate. These findings were confirmed in transgenic mice that develop nephrotic-range proteinuria resulting from podocyte depletion. In vitro, albumin did not directly alter phosphate uptake in cultured proximal tubule OK cells. In conclusion, we show that proteinuria increases plasma phosphate concentration independent of GFR. This effect relies on increased proximal tubule NaPi-IIa expression secondary to decreased FGF-23 biologic activity. Proteinuria induces elevation of both plasma phosphate and FGF-23 concentrations, potentially contributing to cardiovascular disease

Association of Clonal Hematopoiesis of Indeterminate Potential with Inflammatory Gene Expression in Patients with COPD

Chronic obstructive pulmonary disease (COPD) is a disease with an inflammatory phenotype with increasing prevalence in the elderly. Expanded population of mutant blood cells carrying somatic mutations is termed clonal hematopoiesis of indeterminate potential (CHIP). The association between CHIP and COPD and its relevant effects on DNA methylation in aging are mainly unknown. Analyzing the deep-targeted amplicon sequencing from 125 COPD patients, we found enhanced incidence of CHIP mutations (similar to 20%) with a predominance of DNMT3A CHIP-mediated hypomethylation of Phospholipase D Family Member 5 (PLD5), which in turn is positively correlated with increased levels of glycerol phosphocholine, pro-inflammatory cytokines, and deteriorating lung function