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Background In human glomerular diseases, visualizing podocyte injury is desirable since podocytes do not regenerate and podocyte injury leads to podocyte loss. Herein, we investigated the utility of immunostaining for early growth response 1 (EGR1), which is expressed in injured podocytes from the early stages of injury in animal experiments, as a podocyte injury marker in human glomerular diseases. Methods This study included 102 patients with biopsy-proven glomerular diseases between 2018 and 2021. The proportion of EGR1 expression in podocytes (%EGR1pod) was analyzed in relation to clinical and histopathological features, including glomerular and urinary podocyte-specific markers. Results %EGR1pod correlated significantly with the urinary protein:creatinine ratio, urinary nephrin and podocin mRNA levels, and glomerular podocin staining (rho = 0.361, 0.514, 0.487 and –0.417, respectively; adjusted P  = .002, <.001, <.001 and <.001, respectively). Additionally, %EGR1pod correlated with cellular/fibrocellular crescents (rho = 0.479, adjusted P  <.001). %EGR1pod was high in patients with glomerulonephritis, such as immunoglobulin A nephropathy (IgAN), lupus nephritis and antineutrophil cytoplasmic antibody–associated glomerulonephritis, and in those with podocytopathies, such as membranous nephropathy and primary focal segmental glomerulosclerosis, while %EGR1pod was low in patients with minimal change disease. In a subgroup analysis of IgAN, %EGR1pod was higher in Oxford C1 patients than in C0 patients. However, unexpectedly, patients with higher %EGR1pod were more prone to attain proteinuria remission, suggesting that EGR1 in the context of IgAN reflects reversible early injury. Conclusions Our findings indicate that EGR1 is a promising potential marker for identifying active early podocyte injury in human glomerular diseases. [ABSTRACT FROM AUTHOR]

Background Sodium–glucose cotransporter-2 inhibitors (SGLT2is) have cardioprotective and renoprotective effects. However, experience with SGLT2is in diabetic kidney transplant recipients (DKTRs) is limited. Methods This observational multicentre study was designed to examine the efficacy and safety of SGLT2is in DKTRs. The primary outcome was adverse effects within 6 months of SGLT2i treatment. Results Among 339 treated DKTRs, adverse effects were recorded in 26%, the most frequent (14%) being urinary tract infection (UTI). In 10%, SGLT2is were suspended mostly because of UTI. Risk factors for developing a UTI were a prior episode of UTI in the 6 months leading up to SGLT2i use {odds ratio [OR] 7.90 [confidence interval (CI) 3.63–17.21]} and female sex [OR 2.46 (CI 1.19–5.03)]. In a post hoc subgroup analysis, the incidence of UTI emerged as similar in DKTRs treated with SGLT2i for 12 months versus non-DKTRs (17.9% versus 16.7%). Between baseline and 6 months, significant reductions were observed in body weight [−2.22 kg (95% CI −2.79 to −1.65)], blood pressure, fasting glycaemia, haemoglobin A1c [−0.36% (95% CI −0.51 to −0.21)], serum uric acid [−0.44 mg/dl (95% CI −0.60 to −0.28)] and urinary protein:creatinine ratio, while serum magnesium [+0.15 mg/dl (95% CI 0.11–0.18)] and haemoglobin levels rose [+0.44 g/dl (95% CI 0.28–0.58]. These outcomes persisted in participants followed over 12 months of treatment. Conclusions SGLT2is in kidney transplant offer benefits in terms of controlling glycaemia, weight, blood pressure, anaemia, proteinuria and serum uric acid and magnesium. UTI was the most frequent adverse effect. According to our findings, these agents should be prescribed with caution in female DKTRs and those with a history of UTI. [ABSTRACT FROM AUTHOR]

Background Correct identification of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) patients is crucial to implement therapeutic interventions that may prevent disease progression. Methods We compared the real prevalence of DKD in T2DM patients according to actual serum and urine laboratory data with the presence of the diagnostic terms DKD and/or CKD on the electronic medical records (EMRs) using a natural language processing tool (SAVANA Manager). All patients ˃18 years of age and diagnosed with T2DM were selected. DKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or a urinary albumin:creatinine ratio (UACR) >30 mg/g or a urinary protein:creatinine ratio (UPCR) >0.3 g/g after excluding acute kidney injury. Results A total of 15 304 T2DM patients identified on EMRs were eligible to enter the study. A total of 4526 (29.6%) T2DM patients had DKD according to lab criteria. However, the terms CKD or DKD were only present in 33.1% and 7.5%, representing a hidden prevalence of CKD and DKD of 66.9% and 92.5%, respectively. Less severe kidney disease (lower UACR or UPCR, higher eGFR values), female sex and lack of insulin prescription were associated with the absence of DKD or CKD terms in the EMRs (P < .001) Conclusions The prevalence of DKD among T2DM patients defined by lab data is significantly higher than that reported on hospital EMRs. This could imply underdiagnosis of DKD, especially in patients with the least severe disease who may benefit the most from optimized therapy. [ABSTRACT FROM AUTHOR]

Background Hereditary transthyretin amyloidosis (ATTRv) is a disabling and life-threatening disease that primarily affects the nervous system and heart. Its kidney involvement has not been systematically studied, particularly in non-V30M mutations, and is not well known to nephrologists. Methods We conducted a retrospective study describing the kidney phenotype of all prevalent patients with ATTR mutations, with neurological or cardiac involvement or presymptomatic carriers, followed up in two university hospitals from the South of France between June 2011 and June 2021. Results A total of 103 patients were included, among whom 79 were symptomatic and 24 were presymptomatic carriers. Patients carried 21 different ATTR mutations and 54% carried the V30M mutation. After a mean follow-up of 7.9 ± 25.7 years, 30.4% of the symptomatic patients had developed chronic kidney disease (CKD) and 20.3% had a urinary protein:creatinine ratio ≥0.5 g/g. None of the presymptomatic carriers had CKD or proteinuria. In a multivariate analysis, late onset of symptoms (after 60 years), the V122I mutation and proteinuria were significantly associated with CKD. The median CKD-free survival in symptomatic patients was estimated at 81.0 years (interquartile range 77.1–84.9). It did not differ between V30M and non-V30M patients, but was lower in patients with the V122I mutation. The average age of the onset of CKD was 69.3 ± 13.0 years. In one 38-year-old V30M female who presented a kidney-predominant phenotype, treatment with patisiran resulted in remission of the nephrotic syndrome. Conclusion CKD affects almost one-third of patients with symptomatic ATTRv. The role of ATTRv per se in the development of CKD in this population remains to be determined, but some patients may benefit from specific therapies. [ABSTRACT FROM AUTHOR]

Background Improvement of proteinuria as a marker for disease activity is associated with a better renal outcome in immunoglobulin A nephropathy (IgAN). Complement is an effector pathway in IgA-mediated kidney injury. Avacopan, a selective C5a receptor inhibitor, has previously shown efficacy in anti-neutrophil cytoplasmic antibody–associated vasculitis. The aim of this study was to evaluate the safety and efficacy of avacopan in patients with IgAN with persistent proteinuria despite a maximally tolerated dose of renin–angiotensin–aldosterone system blockade. The efficacy evaluation was based on the change in proteinuria. Methods This open-label pilot trial enrolled adult patients with biopsy-proven IgAN, urinary protein:creatinine ratio (UPCR) >1 g/g creatinine and an estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2 or >45 mL/min/1.73 m2 if eGFR has not declined >10 mL/min/1.73 m2 over the previous 24 weeks. If the UPCR remained at >1 g/g creatinine after an 8-week run-in period, patients started avacopan 30 mg twice daily. The primary efficacy endpoint was the change in the slope of the UPCR from the 8-week run-in period to the slope in the 12-week avacopan dosing period. Results A total of 10 of 15 screened patients entered the run-in period. Seven patients with a UPCR >1 g/g creatinine received avacopan. Six of seven patients had numerical improvement in the UPCR during the avacopan treatment period, three of whom had a numerical improvement of ∼50% at week 12. At week 24, five of seven patients still showed numerical improvement in the UPCR compared with baseline. The urinary monocyte chemoattractant protein-1:creatinine ratio decreased numerically 30% by week 8, possibly reflecting the anti-inflammatory activity of avacopan. Avacopan was well tolerated. There was one serious adverse event of unstable angina, which was deemed to be unrelated to avacopan. Conclusions This short-term pilot study showed an improvement in the slope of the UPCR, with ∼50% improvement in three of seven patients with IgAN. Longer avacopan treatment duration may be indicated for maximal benefit. [ABSTRACT FROM AUTHOR]

Background Little is known about clinical characteristics and kidney outcomes in patients with biopsy-proven immunoglobulin A nephropathy (IgAN) in a context of inflammatory bowel disease (IBD). Methods We conducted a retrospective multicentre study with a centralized histological review to analyse the presentation, therapeutic management and outcome of 24 patients suffering from IBD-associated IgAN relative to a cohort of 134 patients with primary IgAN without IBD. Results Crohn's disease and ulcerative colitis accounted for 75 and 25% of IBD-associated IgAN cases, respectively. IBD was diagnosed before IgAN in 23 cases (a mean of 9 years previously) and was considered active at IgAN onset in 23.6% of patients. Hypertension was present in 41.7% of patients. The urinary protein:creatinine ratio exceeded 100 mg/mmol in 70.8% of patients (mean 254 mg/mmol). Estimated glomerular filtration rate (eGFR) was >60 mL/min/1.73   m2 in 13/24 patients and only 1 patient required dialysis. In the Oxford mesangial hypercellularity, endocapillary cellularity, segmental sclerosis and interstitial fibrosis/tubular atrophy with crescents classification of renal biopsies, 57% were M1, 48% E1, 76% S1, 57% T1–2 and 38% C1–2. Steroids were administered in 50% of cases. After a mean follow-up of 7.2 years, 4 patients (16.7%) had a poor kidney outcome: end-stage renal disease (n  =   3) or a >50% decrease in eGFR from initial values (n  =   1). A similar evolution was observed in patients with primitive IgAN. Conclusions This first case series suggests that IBD-associated IgAN has frequent inflammatory lesions at onset and variable long-term outcomes. [ABSTRACT FROM AUTHOR]

Background Contemporaneous data are required for women with chronic kidney disease (CKD) Stages 3–5 to inform pre-pregnancy counselling and institute appropriate antenatal surveillance. Methods A retrospective cohort study in women with CKD Stages 3–5 after 20 weeks' gestation was undertaken in six UK tertiary renal centres in the UK between 2003 and 2017. Factors predicting adverse outcomes and the impact of pregnancy in accelerating the need for renal replacement therapy (RRT) were assessed. Results There were 178 pregnancies in 159 women, including 43 women with renal transplants. The live birth rate was 98%, but 56% of babies were born preterm (before 37 weeks' gestation). Chronic hypertension was the strongest predictor of delivery before 34 weeks' gestation. Of 121 women with known pre-pregnancy hypertension status, the incidence of delivery before 34 weeks was 32% (31/96) in women with confirmed chronic hypertension compared with 0% (0/25) in normotensive women. The risk of delivery before 34 weeks doubled in women with chronic hypertension from 20% [95% confidence interval (CI) 9–36%] to 40% (95% CI 26–56%) if the gestational fall in serum creatinine was <10% of pre-pregnancy concentrations. Women with a urinary protein:creatinine ratio >100 mg/mmol prior to pregnancy or before 20 weeks' gestation had an increased risk for birthweight below the 10th centile (odds ratio 2.57, 95% CI 1.20–5.53). There was a measurable drop in estimated glomerular filtration rate (eGFR) between pre-pregnancy and post-partum values (4.5 mL/min/1.73 m2), which was greater than the annual decline in eGFR prior to pregnancy (1.8 mL/min/1.73 m2/year). The effect of pregnancy was, therefore, equivalent to 1.7, 2.1 and 4.9 years of pre-pregnancy renal disease in CKD Stages 3a, 3b and 4–5, respectively. The pregnancy-associated decline in renal function was greater in women with chronic hypertension and in those with a gestational fall in serum creatinine of <10% of pre-pregnancy concentrations. At 1 year post-partum, 46% (58/126) of women had lost ≥25% of their pre-pregnancy eGFR or required RRT. Most women with renal transplants had CKD Stage 3 and more stable renal function prior to pregnancy. Renal transplantation was not independently associated with adverse obstetric or renal outcomes. Conclusions Contemporary pregnancies in women with CKD Stages 3–5 are complicated by preterm delivery, low birthweight and loss of maternal renal function. Chronic hypertension, pre- or early pregnancy proteinuria and a gestational fall in serum creatinine of <10% of pre-pregnancy values are more important predictors of adverse obstetric and renal outcome than CKD Stages 3–5. Pregnancy in women with CKD Stages 3–5 advances the need for dialysis or transplantation by 2.5 years. [ABSTRACT FROM AUTHOR]

Background Membranous nephropathy (MN) can be associated with hepatitis infection and less commonly with human immunodeficiency virus (HIV) infection. The significance of anti-phospholipase A2 receptor (PLA2R) and anti-thrombospondin type 1 domain-containing 7A (THSD7A) antibodies in this setting is unclear. Methods We describe the clinical, histopathological and outcome data of 19 patients with MN and hepatitis B virus (HBV), hepatitis C virus (HCV) or HIV infection identified through our renal biopsy database and the association with anti-PLA2R antibodies and anti-THSD7A antibodies. Results The cohort consisted of 19 patients, 8 male and 11 female, with a median age of 42 years (range 23–74). HBV infection was found in six cases, HCV in four and HIV in nine (two HIV patients had HBV co-infection and one HCV co-infection). PLA2R staining on biopsy was positive in 10/19 patients: 4 with HBV-MN, 3 with HCV-MN and 3 with HIV-MN and circulating anti-PLA2R antibodies were detected in 7/10 cases. THSD7A staining on biopsy was positive in three PLA2R-negative cases, one with HBV-MN and two with HIV-MN. Mean proteinuria was higher in the PLA2R-positive group and the median urinary protein:creatinine ratio (uPCR) was 963 mg/mmol (range 22–2406) compared with the PLA2R-negative group [median uPCR 548 mg/mmol (range 65–1898); P = 0.18 Mann–Whitney]. Spontaneous remission occurred in 6/19 patients and after-treatment remission occurred in 7/11 patients. Renal function was preserved in all but two patients who required haemodialysis 2 and 11 years from diagnosis. Conclusions We describe a cohort of patients with MN associated with viral infection, including rare cases of HIV-MN with PLA2R and THSD7A positivity. The mechanism of coincidental or viral-related MN needs to be investigated further. [ABSTRACT FROM AUTHOR]

Background Interstitial fibrosis and tubular atrophy (IFTA) is a well-recognized risk factor for poor renal outcome in patients with diabetic kidney disease (DKD). However, a noninvasive biomarker for IFTA is currently lacking. The purpose of this study was to identify urinary markers of IFTA and to determine their clinical relevance as predictors of renal prognosis. Methods Seventy patients with biopsy-proven isolated DKD were enrolled in this study. We measured multiple urinary inflammatory cytokines and chemokines by multiplex enzyme-linked immunosorbent assay in these patients and evaluated their association with various pathologic features and renal outcomes. Results Patients enrolled in this study exhibited advanced DKD at the time of renal biopsy, characterized by moderate to severe renal dysfunction [mean estimated glomerular filtration rate (eGFR) 36.1 mL/min/1.73 m2] and heavy proteinuria (mean urinary protein:creatinine ratio 7.8 g/g creatinine). Clinicopathologic analysis revealed that higher IFTA scores were associated with worse baseline eGFR (P   <   0.001) and poor renal outcome (P   =   0.002), whereas glomerular injury scores were not. Among measured urinary inflammatory markers, C-X-C motif ligand 16 (CXCL16) and endostatin showed strong correlations with IFTA scores (P   =   0.001 and P   <   0.001, respectively), and patients with higher levels of urinary CXCL16 and/or endostatin experienced significantly rapid renal progression compared with other patients (P   <   0.001). Finally, increased urinary CXCL16 and endostatin were independent risk factors for poor renal outcome after multivariate adjustments (95% confidence interval 1.070–3.455, P   =   0.029). Conclusions Urinary CXCL16 and endostatin could reflect the degree of IFTA and serve as biomarkers of renal outcome in patients with advanced DKD. [ABSTRACT FROM AUTHOR]

Objectives. To evaluate the use of urinary free light chains (FLCs) as a biomarker for proliferative LN and the potential association between the intensity of plasma cell infiltration of the kidney and urinary FLC levels in LN.Methods. Forty-three SLE patients were consecutively enrolled in the study. These patients were divided into an International Society of Nephrology and Renal Pathology Society (ISN/RPS) class III/IV LN subset (n = 18) and an ISN/RPS class I/II/V (class non-III/IV) LN subset (n = 25). The expression of κ-LCs, λ-LCs, CD19 and CD138 in kidney specimens was also evaluated with immunohistochemical staining. To measure FLC levels before and after treatment, an additional six patients with class III/IV LN were consecutively enrolled.Results. Urinary FLCs were significantly higher in the class III/IV LN subset than in the class non-III/IV LN subset. Urinary λ-FLC levels were significantly correlated with the urinary protein–creatinine ratio in the class III/IV LN subset (rs = 0.67, P < 0.01). Moreover, the LC-secreting CD19−/CD138+ cell counts in the kidney specimens were higher in the class III/IV LN subset than in the class non-III/IV LN subset. Total urinary FLC levels were correlated with the numbers of CD138+ cells in the kidney (r = 0.71, P = 0.03). Following treatment, urinary λ-FLCs could not be detected in any of the patients.Conclusion. The intensity of plasma cell infiltration of the kidney is associated with urinary FLC levels. Urinary FLCs are potentially useful biomarkers in ISN/RPS class III/IV LN or proliferative LN. [ABSTRACT FROM PUBLISHER]

Background Immunosuppressant drugs reduce proteinuria and anti-phospholipase A2 receptor autoantibodies (PLA2R-Ab) in primary membranous nephropathy (PMN) with varying success and associated toxicities. This study aimed to evaluate the effect of belimumab on proteinuria and PLA2R-Ab in participants with PMN. Methods In this prospective, open-label, experimental medicine study, 14 participants with PMN and persistent nephrotic-range proteinuria received up to 2 years belimumab monotherapy (10 mg/kg, every 4 weeks). Changes in proteinuria (urinary protein:creatinine ratio), PLA2R-Ab, albumin, cholesterol, B-cell subsets and pharmacokinetics were analysed during treatment and up to 6 months after treatment. Results Eleven participants completed to the primary endpoint (Week 28) and nine participants completed the study. In the intention-to-treat population population, baseline proteinuria of 724 mg/mmol [95% confidence interval (CI) 579–906] decreased to 498 mg/mmol (95% CI 383–649) and 130 mg/mmol (95% CI 54–312) at Weeks 28 and 104, respectively, with changes statistically significant from Week 36 (n  =   11, P = 0.047). PLA2R-Ab decreased from 174 RU/mL (95% CI 79–384) at baseline to 46 RU/mL (95% CI 16–132) and 4 RU/mL (95% CI 2–6) at Weeks 28 and 104, respectively, becoming statistically significant by Week 12 (n  =   13, P = 0.02). Nine participants achieved partial (n  =   8) or complete (n  =   1) remission. Participants with abnormal albumin and/or cholesterol at baseline gained normal/near normal levels by the last follow-up. Adverse events were consistent with those expected in this population. Conclusions Belimumab treatment in participants with PMN can reduce PLA2R-Ab and subsequently proteinuria, important preludes to remission induction. [ABSTRACT FROM AUTHOR]

Background Prior nonrandomized studies have suggested nephroprotective effects of arteriovenous fistula (AVF) formation, but these are plausibly susceptible to immortal time and selection biases. Methods We studied patients attending nephrology clinics in the West of Scotland during 2010–22 with an estimated glomerular filtration rate (eGFR) ≤15 mL/min/1.73 m2 and no prior AVF. Using target trial emulation and a sequential trial design, we simulated a hypothetical trial that would randomize patients to either undergo AVF formation immediately or not to undergo AVF formation. The primary outcome was the difference in eGFR slope for the first 6 months of follow-up, estimated using a mixed-effects model. The secondary outcomes were 5-year absolute risks of dialysis and death, estimated using the Aalen–Johansen and Kaplan–Meier estimators respectively. Results A total of 1364 unique patients (mean age 51.1 years, 55.7% male) contributed 3125 person-trials, with 561 in the AVF and 2564 in the no AVF group. Mean eGFR was 12.6 mL/min/1.73 m2 and the median number of eGFR measurements per person-trial was 7 (interquartile range 4–12). Slope of eGFR decline did not differ significantly between the AVF and no AVF groups (between-group difference –0.67 mL/min/1.73 m2/year, 95% CI –1.43, 0.10). The 5-year absolute risk of dialysis was 87% (95% CI 84, 91) in the AVF group and 75% (95% CI 73, 77) in the no AVF group, and the 5-year survival probability was 77% (95% CI 70, 83) in the AVF group and 67% (95% CI 64, 69) in the no AVF group. Conclusions In this study of patients with advanced chronic kidney disease, there was no evidence of a nephroprotective effect of AVF formation. [ABSTRACT FROM AUTHOR]

Background Patients with frequently relapsing (FR), steroid-dependent (SD) and steroid-resistant (SR) nephrotic syndrome are a therapeutic challenge with limited treatment options. Here, we retrospectively analyze the efficacy and safety of rituximab-induced continuous B-cell depletion in these populations. Methods Patients were included if they were at least 18 years of age and had FR, SD or SR minimal change disease (MCD) or primary focal segmental glomerulosclerosis (FSGS) and were treated with a strategy of continuous B-cell depletion. Partial remission (PR) was defined as a urinary protein:creatinine ratio (UPCR) of ≤3.5 g/g and a 50% reduction in the UPCR from baseline. Complete remission (CR) was defined as a UPCR ≤0.3 g/g. Results We identified 20 patients with MCD (n  = 13) or FSGS (n  = 7) who fulfilled the inclusion criteria. All patients had either SD (n  = 12), SR (n  = 7) or FR (n  = 1) disease. Patients received a median of nine rituximab doses [interquartile range (IQR) 7.5, 11] and were treated for a median time of 28 months (IQR 23, 41). Prednisone was weaned from a median of 60 mg daily (IQR 40, 60) at rituximab initiation to 4.5 mg daily (IQR 0, 5.5) by 12 months. All patients achieved PR. CR occurred in 11 of 13 patients with FR or SD disease, but only 1 of 7 patients with SR disease (logrank P = 0.01). Four relapses occurred, all in patients with SR disease. Three serious infections occurred over 70.3 patient-years. Conclusion Continuous B-cell depletion is a therapeutic option in the management of complicated nephrotic syndrome. Additional studies are needed to clarify the utility of this strategy. [ABSTRACT FROM AUTHOR]

Background In Fabry nephropathy, podocyturia is an early event that may lead to glomerulosclerosis and chronic kidney disease. The glycocalyx is a potential podocyte damaged compartment in glomerulopathies. We investigated glycocalyx podocalyxin in urinary detached podocytes compared with cytoplasmic synaptopodin. Methods This was a cross-sectional study including 68 individuals: Controls (n  = 20) and Fabry patients (n  = 48), 15 untreated and 33 treated. Variables included age, gender, urinary protein/creatinine ratio (UPCR), estimated glomerular filtration rate (eGFR), lyso-triasocylsphingosine (lyso-Gb3) levels and enzyme replacement therapy (ERT). Podocyturia was assessed by immunofluorescence and podocyte subpopulations were analyzed. Results Fabry patients displayed higher podocyturia than controls. Fabry treated subjects (n  = 33) presented significantly higher UPCR compared with untreated ones (n  = 15); podocyturia, eGFR and lyso-Gb3 levels were not different. All control podocytes colocalized synaptopodin and podocalyxin; 13 Fabry patients (27%) colocalized these proteins, while 35 (73%) were only synaptopodin positive. No podocalyxin-positive/synaptopodin-negative cells were encountered. In Fabry patients, podocyturia was significantly higher and proteinuria lower in those that colocalized. Conclusion Fabry patients present higher podocyturia and a presumably more damaged glycocalyx assessed by podocalyxin. Treated patients had significant higher proteinuria suggesting ERT is initiated late, at advanced stages. The degree of podocalyxin-negative podocytes was similar in both groups, but colocalization was associated with lower proteinuria. Podocyturia assessed by podocalyxin alone may be underestimated. The implications of podocyte glycocalyx damage deserve further investigations. [ABSTRACT FROM AUTHOR]

BACKGROUND Obstructive sleep apnea (OSA) is associated with hypertension and the progression of chronic kidney disease (CKD). Renal sympathetic innervation contributes to either condition. METHODS We investigated the effect of renal sympathetic denervation (RDN) on blood pressure (BP), renal perfusion, and neurohumoral responses during and after repetitive obstructive apneas in a pig model for OSA. BP, femoral artery, and renal artery flow were measured in 29 spontaneously breathing urethane-chloralose–anesthetized pigs. The effect of RDN (n = 14) and irbesartan (n = 3) was investigated. Repetitive tracheal occlusions for 2 minutes with applied negative tracheal pressure at −80 mbar were performed over 4 hours. RESULTS Spontaneous breathing attempts during tracheal occlusion caused an intra-apneic breathing synchronous oscillating pattern of renal flow. Renal flow oscillations were >2-fold higher compared with femoral flow that almost showed changes proportional to the BP alterations (2.9%/mm Hg vs. 1.3%/mm Hg; P < 0.0001). A marked postapneic BP rise from 102±3 to 172±8 mm Hg (P < 0.00001) was associated with renal hypoperfusion (from 190±24 to 70±20ml/min; P < 0.00001) occurring after application of obstructive respiratory events. RDN, but not irbesartan, inhibited postapneic BP rises and renal hypoperfusion and attenuated increased plasma renin activity and aldosterone concentration induced by repetitive tracheal occlusions. Additionally, increased urinary protein/creatinine ratio was significantly reduced by RDN, whereas intra-apneic hemodynamic changes or blood gases were not modified by RDN. CONCLUSIONS Repetitive obstructive respiratory events result in postapneic BP rises and renal hypoperfusion, as well as neurohumoral responses and increased protein/creatinine ratio. These changes are mainly sympathetically driven because they could be attenuated by RDN. [ABSTRACT FROM AUTHOR]

Background Due to the high correlation of chronic kidney disease (CKD) with other comorbidities, the sole effect of CKD on deprived people is not clear. In addition, there is a paucity of evidence in the literature linking isolated domains of deprivation to outcomes. This study aimed to examine whether deprivation was associated with adverse outcomes in patients with CKD, independent of cardiometabolic morbidities. Individual domains of deprivation were also evaluated. Methods A retrospective study of patients with non-dialysis-dependent CKD (ND-CKD) in the Salford Kidney Study to investigate the association of deprivation with outcomes. The English Indices of Deprivation was used for the comparative analysis of the five quintiles of deprivation. Two propensity score methods were used to attenuate the confounding effect of cardiometabolic morbidities between the least and the most deprived groups. Results People living in the least deprived areas (n  = 319) had a lower risk of combined outcomes (all-cause mortality and renal replacement therapy) when compared with the most deprived group (n  = 813) [hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.71–0.98]. The negative association of deprivation remained after matching but with mixed statistical significance when using different propensity methods (HR 0.85; 95% CI 0.70–1.03 for propensity score matching and HR 0.77; 95% CI 0.61–0.98 for inverse probability weighting). The association of combined outcomes varied across component index of multiple deprivation domains with wide CIs. However, areas with lower scores for education, income and employment were significantly associated with a higher risk. Conclusions This study has identified that in people with ND-CKD, unemployment, poor educational attainment and lower household income were associated with poor outcomes. The association of deprivation with adverse outcomes persists despite adjustment for cardiometabolic morbidities. [ABSTRACT FROM AUTHOR]

Background Phospholipase A2 receptor (PLA2R) is a major target antigen in idiopathic membranous nephropathy (MN). Anti-PLA2R antibodies are mainly of the immunoglobulin G (IgG) subclass IgG4, although other IgG subclass depositions in glomeruli may also be detected. However, the importance of the subclass of the IgG deposit has not been proven. Thus we investigated clinical findings from patients with idiopathic MN in relation to glomerular PLA2R deposition and IgG subclass. Methods We enrolled 132 Japanese patients with biopsy-proven idiopathic MN in a multicentre retrospective observational study. We investigated the complete remission rate as the primary outcome and the development of end-stage kidney disease (ESKD) as the secondary outcome in relation to glomerular PLA2R deposition. Moreover, we evaluated prognostic factors, including glomerular IgG subclass, in the PLA2R-positive group. Results The percentage of cases with glomerular PLA2R deposition was 76.5% (n  = 101). The first complete remission rate of the PLA2R-positive group was worse than that of the PLA2R-negative group (logrank test P  < .001). ESKD incidence did not significantly differ between the glomerular PLA2R-negative and PLA2R-positive MN groups (logrank test P  = .608). In the PLA2R-positive group, higher PLA2R intensities and IgG2 staining were associated with a poorer first complete remission rate (logrank test P  < .001 and P  = .032, respectively). Cox proportional hazards analysis also showed that strong PLA2R deposition and positive IgG2 staining were significantly associated with a failure to reach complete remission [hazard ratio 2.09 (P  = .004) and 1.78 (P  = .030), respectively]. Conclusions Our results suggest that intense glomerular PLA2R and IgG2 positivity predict a poor proteinuria remission rate in idiopathic MN. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is one of the major causes of morbidity and mortality, affecting >800 million persons globally. While we still lack efficient, targeted therapies addressing the major underlying pathophysiologic processes in CKD, findings of several recent trials have brought about a shifting landscape of promising therapies. The endothelin system has been implicated in the pathophysiology of CKD and endothelin receptor antagonists are one class of drugs for which we have increasing evidence of efficacy in these patients. In this review we summarize the most recent findings on the safety and efficacy of endothelin receptor antagonists in diabetic and non-diabetic CKD, future directions of research and upcoming treatments. [ABSTRACT FROM AUTHOR]

Background Disruptions in gene expression associated with the glomerular basement membrane (GBM) could precipitate glomerular dysfunction. Nevertheless, a comprehensive understanding of the characterization of GBM components within pediatric glomerular diseases and their potential association with glomerular function necessitates further systematic investigation. Methods We conducted a systematic analysis focusing on the pathological transformations and molecular attributes of key constituents within the GBM, specifically Collagen IV α3α4α5, Laminin α5β2γ1, and Integrin α3β1, across prevalent pediatric glomerular diseases. Results We observed upregulation of linear expression levels of COL4A3/4/5 and Laminin 5α proteins, along with a partial reduction in the linear structural expression of Podocin in idiopathic nephrotic syndrome (INS), encompassing minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), but showing a reduction in IgA nephropathy (IgAN), IgA vasculitis nephritis (IgAVN) and lupus nephritis (LN). Furthermore, our study revealed reductions in Laminin β2γ1 and Integrin α3β1 in both primary and secondary childhood glomerular diseases. Conclusion In INS, notably MCD and FSGS, there is a notable increase in the linear expression levels of COL4A3/4/5 and Laminin 5α proteins. In contrast, in IgAN, IgAVN, and LN, there is a consistent reduction in the expression of these markers. Furthermore, the persistent reduction of Laminin β2γ1 and Integrin α3β1 in both primary and secondary childhood glomerular diseases suggests a shared characteristic of structural alterations within the GBM across these conditions. [ABSTRACT FROM AUTHOR]

Background Proteinuria is a major predictor for progression of renal disease, including diabetic nephropathy. In a post hoc analysis of the ORIENT, a double-blinded randomized trial of 566 type 2 diabetic patients with nephropathy, we examined the risk association of composite renal outcome [end-stage renal disease, ESRD, doubling of serum creatinine (SCr) and death] with baseline, change and residual urinary protein/creatinine ratio (UPCR). Methods We estimated the hazard ratios (HRs) with 95% confidence interval (CI) of composite renal outcome with baseline UPCR (low <1.0 g/gCr; moderate ≥1.0 g/gCr, <3.0 g/gCr and high ≥3.0 g/gCr) as well as percentage reduction of UPCR (Δ) (worsening: <0%; moderate: ≥0%, <30% and high ≥30%) and residual UPCR at 24 weeks (remission <1.0 g/gCr; moderate ≥1.0 g/gCr, <3.0 g/gCr and heavy ≥3.0 g/gCr). Results Compared with the low group with baseline UPCR < 1.0g/gCr, the respective HRs with 95% CI in the moderate and high UPCR groups were 3.02 (1.76–5.19) and 9.24 (5.43–15.73). Compared with patients with a worsening UPCR (<0%) at 24 weeks, the HR was 0.54 (0.39–0.74) in those with ≥0%, <30% ΔUPCR and 0.43 (0.31–0.61) in those with ≥30% ΔUPCR. Compared with the remission at 24 weeks, the HR was 2.12 (1.28–3.49) in moderate residual proteinuria and 4.59 (2.74–7.69) in heavy residual proteinuria. Compared with patients with residual UPCR ≥1.0 g/gCr and ΔUPCR <30%, the HR in those with ΔUPCR≥30% and residual UPCR<1.0 g/gCr was 0.38 (0.22–0.64). Conclusions In patients with type 2 diabetes and overt nephropathy, over 30% reduction of UPCR compared with baseline and/or residual UPCR<1.0 g/gCr at 24 weeks predicted renoprotection. These values may be used as targets to guide anti-proteinuric and renoprotective therapy in diabetic nephropathy. Trial registration ClinicalTrials.gov NCT00141453. [ABSTRACT FROM PUBLISHER]

Background: Renal ischaemia-reperfusion injury (IRI) is a major cause of acute renal failure and renal transplant dysfunction. The aim of this study was to investigate the efficacy of the endogenous gaseous signalling molecule hydrogen sulphide in protecting against renal IRI. Methods: Large White female pigs underwent laparotomy and cross-clamping of the left renal pedicle for 60 min. Animals were allocated randomly to treatment with either intravenous hydrogen sulphide ( n = 6) or saline control ( n = 6) 10 min before clamp release, and then underwent a right nephrectomy. Staff were blinded to treatment allocation and animals were recovered for 7 days. Results: Hydrogen sulphide therapy resulted in a marked reduction in kidney injury with reduced serum creatinine levels on days 1-5, in a reduced area under the creatinine-time curve, and a halving of the time to achieve a creatinine level of less than 250 µmol/l, compared with the control. Hydrogen sulphide also preserved glomerular function, as shown by the urinary protein/creatinine ratio, which, compared with baseline, increased on days 1 and 3 in the control group (mean(s.e.m.) 3·22(1·43), P = 0·016 and 2·59(1·27), P = 0·031), but not in the treatment group (0·99(0·23), P = 0·190 and 1·06(0·44), P = 0·110, respectively). Mean(s.e.m.) tumour necrosis factor α levels at 6 h postreperfusion increased in the control animals (56(6) versus 115(21) pg/ml; P = 0·026), but not in the hydrogen sulphide-treated animals (61(7) versus 74(11) pg/ml; P = 0·460). Renal neutrophil infiltration at 30 min (myeloperoxidase staining) was also significantly reduced by treatment with hydrogen sulphide ( P = 0·016). Conclusion: Hydrogen sulphide offers a promising new approach to ameliorating renal IRI with potential translation into a number of clinical settings, including renal transplantation. Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

…in several European countries children often perform urine analysis before entering intensive sport programs or by chance as routine analysis before minor surgery or for other health problems. In these cases the detection of isolated proteinuria and/or hematuria leads the Pediatricians and sometimes also the Nephrologists into the dilemma on whether to perform or not a renal biopsy.Background The criterion of a renal biopsy in children with asymptomatic persistent isolated proteinuria is controversial. Methods To determine an adequate renal biopsy criterion in children with asymptomatic constant isolated proteinuria, the optimal cutoff maximum urinary protein/creatinine ratio (uP/Cr) to separate minor glomerular abnormalities (MGA) and other significant glomerular changes was obtained by receiver operating characteristic analysis in 44 children with asymptomatic constant isolated proteinuria (uP/Cr ≥0.2 g/g) screened from 1167 patients who underwent a renal biopsy between September 2000 and April 2010. Patients were divided into two groups according to the cutoff value to verify its validity. Results The optimal uP/Cr was 0.5 g/g. In Group 1 (uP/Cr <0.5 g/g, n = 15), only one patient (6.7%) showed focal segmental glomerulosclerosis (FSGS) and the other 14 patients (93.3%) had MGA. In Group 2 (uP/Cr ≥0.5 g/g at least once before biopsy, n = 29), 5 patients showed FSGS and 7 patients had nephritis such as IgA nephropathy (41.4%, n = 12) and the other 17 patients (58.6%) showed MGA. These findings indicated that the ratio of non-MGA/MGA was significantly higher in Group 2 than that in Group 1 (P = 0.016) and that if renal biopsies were performed with a criterion of a maximum uP/Cr ≥0.5 g/g (criterion for Group 2), renal biopsies could be avoided in 45.2% of patients with MGA. One patient with FSGS in Group 1 showed proteinuria with uP/Cr ≥0.5 g/g in the clinical course. Conclusions An adequate renal biopsy criterion in children with asymptomatic constant isolated proteinuria is uP/Cr ≥0.5 g/g. [ABSTRACT FROM AUTHOR]

Objectives Many chronic kidney disease (CKD) patients have persistent overt proteinuria despite angiotensin receptor blocker (ARB) treatment. This study investigated whether the initial difference in intrarenal renineangiotensin system activity measured with urinary angiotensinogen would affect the antiproteinuric effects of ARB. Methods Between September 2005 and September 2008, in 50 non-diabetic proteinuric CKD patients not taking renineangiotensin system inhibitors, the urinary protein/creatinine ratio (P/Cr), angiotensinogen/creatinine ratio (AGT/Cr), plasma renin and aldosterone were measured before starting valsartan, and were followed for 18 months. Results Patients were divided into three groups according to their initial urinary AGT/Cr. The urinary P/Cr was lower in the low angiotensinogen group, but similar in the high and extremely high angiotensinogen groups (1.3±0.38 vs 2.0±0.92 vs 2.2±0.78). In all groups, the urinary P/Cr was decreased most for the first 6 months. The urinary P/Cr reduction at 6 months was greatest in the high angiotensinogen group (-24.2% vs -46.2% vs -16.4%). The urinary AGT/Cr was decreased most in the high angiotensinogen group. Renal functional deterioration was attenuated in the high angiotensinogen group compared with the extremely high angiotensinogen group. Conclusions The antiproteinuric effects of ARB were different according to the initial urinary angiotensinogen levels. These results suggest the potential value of the initial urinary AGT/Cr for predicting the therapeutic effect of ARB in proteinuric non-diabetic CKD patients. [ABSTRACT FROM AUTHOR]

Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Results. Men within the first quartile had a mean eGFR slope of –0.1 mL/min/1.73m2/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of –6.7 mL/min/1.73m2/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4–3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2–184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope –4.4 mL/min/1.73m2/year). Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes. [ABSTRACT FROM PUBLISHER]

Background. Renal AA amyloidosis presents as a life-threatening disease in patients with rheumatoid arthritis (RA). Although several newly developed immunosuppressive drugs have been tried, patients often progress to end-stage renal failure with unsatisfactory survival rate. Methods. A total of nine consecutive cases of severe nephrotic renal AA amyloidosis presented to us. Complete remission of proteinuria was observed in four cases (responders), and the remaining five reached the end point of haemodialysis or death (non-responders); these groups were retrospectively compared. The patients were treated with immunosuppressants, biological drugs and anti-hypertensive drugs. Levels of serum creatinine (S-Cr), urinary protein–creatinine ratio (UP/UCr), blood pressure (BP) and C-reactive protein (CRP) were measured. Histological characteristics of renal amyloid deposition and extent of kidney injury were also scored. Results. Prior to treatment, clinical data (S-Cr, UP/UCr, BP and CRP) and histological severity (glomerular sclerosis, tubulointerstitial injury and extent of amyloid deposition) observed in the renal biopsy specimen were not significantly different between the groups. Following therapeutic intervention, proteinuria disappeared (UP/UCr <0.3) in responders within 12 ± 5.4 months but persisted in non-responders. Consequently, renal function stabilized in responders, but it deteriorated in all non-responders. Strict inflammatory control along with optimal control of hypertension was achieved in responders during the treatment. Conclusion. Regardless of histological severity, intensive therapeutic intervention that includes strict inflammatory control and optimal control of hypertension may change the histology-predicted prognosis of RA-associated renal AA amyloidosis. [ABSTRACT FROM AUTHOR]

Background. No prospective, randomized, double-blind trials of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have previously been reported in adults or children with proteinuria secondary to Alport syndrome.Methods. This 12-week, double-blind multinational study investigated the effects of losartan 0.7–1.4 mg/kg/day compared with placebo (normotensive patients) or amlodipine 0.1–0.2 mg/kg/day up to 5 mg/day (hypertensive patients) on proteinuria [early morning-void urinary protein/creatinine ratio (UPr/Cr), baseline ≥34 mg/mmol] in 30 children of up to 17 years of age with Alport syndrome.Results. Twelve weeks of treatment with losartan significantly reduced proteinuria compared with placebo/amlodipine: losartan −14.7 mg/mmol (interquartile range −49.7 to −5.7 mg/mmol) or 31.6% reduction using a mixed model approach versus placebo/amlodipine 2.3 mg/mmol (−26.0 to 18.1 mg/mmol), P = 0.01 or 2.3% increase using a mixed model approach. Adverse event incidence was low and comparable between losartan and placebo/amlodipine groups.Conclusions. Losartan significantly lowered proteinuria and was well tolerated after 12 weeks of treatment in children aged 1–17 years with proteinuria secondary to Alport syndrome with or without hypertension, a population that has not previously been rigorously studied. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is diagnosed when glomerular filtration rate (GFR) falls below 60 ml/min/1.73 m2 or urinary albumin:creatinine ratio (UACR) reaches ≥30 mg/g, as these two thresholds indicate a higher risk of adverse health outcomes, including cardiovascular mortality. CKD is classified as mild, moderate or severe, based on GFR and UACR values, and the latter two classifications convey a high or very high cardiovascular risk, respectively. Additionally, CKD can be diagnosed based on abnormalities detected by histology or imaging. Lupus nephritis (LN) is a cause of CKD. Despite the high cardiovascular mortality of patients with LN, neither albuminuria nor CKD are discussed in the 2019 European League Against Rheumatism (EULAR)/European Renal Association–European Dialysis and Transplant Association recommendations for the management of LN or the more recent 2022 EULAR recommendations for cardiovascular risk management in rheumatic and musculoskeletal diseases. Indeed, the proteinuria target values discussed in the recommendations may be present in patients with severe CKD and a very high cardiovascular risk who may benefit from guidance detailed in the 2021 European Society of Cardiology guidelines on cardiovascular disease prevention in clinical practice. We propose that the recommendations should move from a conceptual framework of LN as an entity separate from CKD to a framework in which LN is considered a cause of CKD and evidence generated from large CKD trials applies unless demonstrated otherwise. [ABSTRACT FROM AUTHOR]

Background Data on belimumab efficacy in patients with lupus nephritis (LN) according to diagnosis duration or induction therapy are limited. Post hoc analyses of the phase 3, randomized, double-blind BLISS-LN study (GSK BEL114054; NCT01639339) were performed to assess belimumab efficacy on kidney-related outcomes in newly diagnosed and relapsed LN subgroups and according to the use of glucocorticoid (GC) pulses at induction. Methods BLISS-LN randomized 448 patients with active LN to monthly intravenous belimumab 10 mg/kg or placebo plus standard therapy. Post hoc analyses assessed primary efficacy renal response (PERR) and complete renal response (CRR) at week 104, time to kidney-related event or death and time to first LN flare from week 24 in newly diagnosed and relapsed patients and patients with/without GC pulses at induction. Results A greater proportion of patients achieved a PERR with belimumab versus placebo in the newly diagnosed {69/148 [46.6%] versus 55/148 [37.2%]; odds ratio [OR] 1.36 [95% confidence interval (CI) 0.85–2.20]} and relapsed [27/75 (36.0%) versus 17/75 (22.7%); OR 2.31 (95% CI 1.07–5.01)] subgroups. Similarly for CRR [newly diagnosed: 50/148 (33.8%) versus 36/148 (24.3%); OR 1.49 (95% CI 0.88–2.51) and relapsed: 17/75 (22.7%) versus 8/75 (10.7%); OR 3.11 (95% CI 1.16–8.31)]. The probability of kidney-related event or death, or LN flare was lower with belimumab versus placebo in both subgroups. Belimumab was associated with improved kidney outcomes versus placebo with or without GC pulses at induction. Conclusion Data suggest consistent benefits of belimumab on kidney outcomes for newly diagnosed and relapsed patients, and irrespective of GC pulses at induction. [ABSTRACT FROM AUTHOR]

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Recent years have witnessed significant improvements in the understanding of the pathogenesis of IgAN and particularly, the pathogenic role of complement activation. The alternative complement pathway is the major complement cascade activator in IgAN, and glomerular C3 deposition has been shown to correlate with disease progression. In addition, several studies have provided insight into the pathogenic role of factor H–related proteins -1 and -5 in IgAN, as independent players in complement dysregulation. The lectin pathway has also been shown to be associated with the severity of IgAN. Glomerular deposition of C4d has been associated with increased histologic disease activity, faster decline in estimated glomerular filtration rate and higher risk of kidney failure. On the other hand, although overlooked in the Oxford classification, numerous studies have shown that the coexistence of thrombotic microangiopathy in IgAN is a significant indicator of a poorer prognosis. All the breakthroughs in the understanding of the contributing role of complement in IgAN have paved the way for the development of new complement-targeted therapies in this disease. Several ongoing trials are evaluating the efficacy of new agents against factor B (iptacopan, Ionis-FB-LRX), C3 (pegcetacoplan), factor D (vemircopan, pelecopan), C5 (ravulizumab, cemdisiran) and C5a receptor 1 (avacopan). In this study, we provide a comprehensive review of the role of complement in IgAN, including the emerging mechanisms of complement activation and the promising potential of complement inhibitors as a viable treatment option for IgAN. [ABSTRACT FROM AUTHOR]

This article discusses the 2023 Annual Meeting of the American Society for Bone and Mineral Research (ASBMR). The article presents a list of award recipients as well as all abstracts of all research presented at the meeting. Research topics include bone mineral density, osteoporosis and osteoclasts. [Extracted from the article]

A refined understanding of the role of complement in the pathogenesis of glomerular and other kidney diseases has, over the past two decades, been matched by the development of novel, complement-targeting therapies. As we increasingly recognize the important role that complement activation across all three pathways—classical, lectin and alternative—plays in glomerular lesions both rare (e.g. C3 glomerulopathy) and common (e.g. immunoglobulin A nephropathy), we can identify avenues for precise, targeted approaches to modifying the natural history of these kidney diseases. In this review, we survey the evidence on using complement inhibition from the earliest, small-scale studies focusing on C5-targeting agents to more recent, large, multicenter, randomized trials utilizing complement blockade higher up in the complement pathway at the level of C3. We conclude by examining where the field of complement targeting therapy may be headed in light of these studies. [ABSTRACT FROM AUTHOR]

Immunoglobulin A nephropathy (IgAN) is the most common primary form of glomerular disease worldwide and carries a high lifetime risk of kidney failure. The underlying pathogenesis of IgAN has been characterized to a sub-molecular level; immune complexes containing specific O -glycoforms of IgA1 are central. Kidney biopsy remains the gold-standard diagnostic test for IgAN and histological features (i.e. MEST-C score) have also been shown to independently predict outcome. Proteinuria and blood pressure are the main modifiable risk factors for disease progression. No IgAN-specific biomarker has yet been validated for diagnosis, prognosis or tracking response to therapy. There has been a recent resurgence of investigation into IgAN treatments. Optimized supportive care with lifestyle interventions and non-immunomodulatory drugs remains the backbone of IgAN management. The menu of available reno-protective medications is rapidly expanding beyond blockade of the renin–angiotensin–aldosterone system to include sodium-glucose cotransporter 2 and endothelin type A receptor antagonism. Systemic immunosuppression can further improve kidney outcomes, although recent randomized controlled trials have raised concerns regarding infectious and metabolic toxicity from systemic corticosteroids. Studies evaluating more refined approaches to immunomodulation in IgAN are ongoing: drugs targeting the mucosal immune compartment, B-cell promoting cytokines and the complement cascade are particularly promising. We review the current standards of treatment and discuss novel developments in pathophysiology, diagnosis, outcome prediction and management of IgAN. [ABSTRACT FROM AUTHOR]

Chest computed tomography (CT) showed bilateral pleural effusions and pericardial fluid and abdominal CT showed several simple cysts in both kidneys without atrophy. Although the details concerning the mechanism underlying the glomerular deposition of type VI collagen are unclear, the diagnosis in the present case was type VI collagen-related nephropathy. Glomerular diseases with organized deposits are classified as amyloidosis, diabetic fibrillosis, fibrillary glomerulopathy, immunotactoid glomerulopathy, fibronectin glomerulopathy, collagenofibrotic glomerulopathy, cryoglobulinemic glomerulonephritis and various advanced kidney diseases [[1]]. [Extracted from the article]

Lupus nephritis (LN) is the most frequent serious manifestation of patients with systemic lupus erythematosus (SLE). Up to 60% of SLE patients develop LN, which has a significant impact on their quality of life and prognosis. Recent advances have improved the diagnostic approach to LN, and new drugs that block specific pathways and kidney damage progression have been developed. Several randomized and well-powered clinical trials have confirmed the efficacy of these agents in terms of proteinuria remission and preservation of kidney function in the medium and long term, with an acceptable safety profile and good tolerance. The combination of different therapies allows for reduction of the dose and duration of corticosteroids and other potentially toxic therapies and leads to an increase in the number of patients achieving complete remission of the disease. This consensus document carried out by the Spanish Group for the Study of Glomerular Diseases (GLOSEN) provides practical and updated recommendations, based on the best available evidence and clinical expertise of participating nephrologists. [ABSTRACT FROM AUTHOR]

Background Vascular endothelial growth factor inhibitors (VEGFis) have transformed the treatment of many retinal diseases, including diabetic maculopathy. Increasing evidence supports systemic absorption of intravitreal VEGFi and development of significant cardiorenal side effects. Methods We conducted a systematic review and meta-analysis (PROSPERO: CRD42020189037) of randomised controlled trials of intravitreal VEGFi treatments (bevacizumab, ranibizumab and aflibercept) for any eye disease. Outcomes of interest were cardiorenal side effects (hypertension, proteinuria, kidney function decline and heart failure). Fixed effects meta-analyses were conducted where possible. Results There were 78 trials (81 comparisons; 13 175 participants) that met the criteria for inclusion: 47% were trials in diabetic eye disease. Hypertension (29 trials; 8570 participants) was equally common in VEGFi and control groups {7.3 versus 5.4%; relative risk [RR] 1.08 [95% confidence interval (CI) 0.91–1.28]}. New or worsening heart failure (10 trials; 3384 participants) had a similar incidence in VEGFi and control groups [RR 1.03 (95% CI 0.70–1.51)]. Proteinuria (5 trials; 1902 participants) was detectable in some VEGFi-treated participants (0.2%) but not controls [0.0%; RR 4.43 (95% CI 0.49–40.0)]. Kidney function decline (9 trials; 3471 participants) was similar in VEGFi and control groups. In participants with diabetic eye disease, the risk of all-cause mortality was higher in VEGFi-treated participants [RR 1.62 (95% CI 1.04–2.46)]. Conclusion In trials of intravitreal VEGFi, we did not identify an increased risk of cardiorenal outcomes, although these outcomes were reported in only a minority of cases. There was an increased risk of death in VEGFi-treated participants with diabetic eye disease. Additional scrutiny of post-licensing observational data may improve the recognition of safety concerns in VEGFi-treated patients. [ABSTRACT FROM AUTHOR]

Sodium–glucose cotransporter-2 inhibitors (SGLT2is) improve cardiovascular and renal outcomes in chronic kidney disease patients with and without diabetes. Kidney transplant recipients have been excluded from landmark trials using SGLT2is and literature on safety and efficacy are scarce. Recent studies suggest that the SGLT2i use in kidney transplant recipients with diabetes is safe, paving the way to investigate whether SGLT2is could also reduce cardiovascular events and kidney function deterioration in kidney allograft recipients. [ABSTRACT FROM AUTHOR]

A group of experts from the International Pediatric Nephrology Association (IPNA) has recently updated recommendations for steroid-resistant and steroid-sensitive nephrotic syndrome (SRNS and SSNS) in children [[1]]. Anti-CD20 monoclonal antibodies (rituximab) [[11]]: indicated in children >7-9 years of age with FRNS or SDNS who are not controlled on therapy after a course of treatment with at least one other steroid-sparing agent at an adequate dose, especially in case of non-adherence. Sequential rituximab therapy sustains remission of nephrotic syndrome but carries high risk of adverse effects. [Extracted from the article]

Background Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD), but currently available treatments do not improve kidney function or prevent the initiation of dialysis/kidney replacement therapy. A previous study demonstrated that bardoxolone methyl improves the estimated glomerular filtration rate (eGFR), but the study was prematurely terminated because of an imbalance in heart failure between treatment groups. The subsequent phase 2 TSUBAKI study demonstrated no incidence of heart failure and an improved eGFR and GFR as determined by inulin clearance in DKD patients. Methods This randomized, double-blind, placebo-controlled multicentre phase 3 study was designed to assess the efficacy and safety of bardoxolone methyl in DKD patients with an eGFR ≥15.0–<60.0 ml/min/1.73 m2 and a urinary albumin:creatinine ratio (UACR) ≤3500 mg/g but without risk factors for heart failure. The primary endpoint is the time to onset of a ≥30% decrease in the eGFR or ESKD. Randomized patients (1:1) have been under treatment with once-daily oral bardoxolone methyl (5, 10 or 15 mg by intrapatient dose adjustment) or placebo for at least 3 years. Results The mean age of the 1013 patients is 65.9 years, 21.5% are female, the mean eGFR is 37.84 ml/min/1.73 m2 and the median UACR is 351.80 mg/g. Conclusions Appropriate patients are enrolled in this study. This study will investigate the long-term efficacy and safety of bardoxolone methyl in DKD patients covering a wider range of eGFR (≥15.0–<60.0 ml/min/1.73 m2) and albuminuria (≤3500 mg/g) compared with previous studies. [ABSTRACT FROM AUTHOR]

For a long time, kidney biopsy was the only diagnostic means for membranous nephropathy (MN) and proteinuria and serum creatinine were the only markers of disease activity. The discovery of the phospholipase A2 receptor (PLA2R) antibody in 2009 has induced a paradigm shift in both the diagnosis and monitoring of patients. Two serological tests are routinely used: the enzyme-linked immunosorbent assay (ELISA), which is quantitative, and the immunofluorescence assay (IFA), which is more sensitive. In centres where the two assays are available, the recommendation is to use IFA for screening and diagnosis of immunological remission and ELISA for monitoring the effectiveness of therapy. In patients with positive PLA2R antibody serology, normal kidney function and no evidence of an underlying disease, a kidney biopsy is not mandatory given the almost 100% specificity of the assays. Because MN has different phases, one cannot base a clinical or therapeutic decision on a single measurement of PLA2R antibody at baseline. Risk evaluation of disease progression is a dynamic process that should be performed repeatedly to capture the trajectory of the disease based on both the traditional biomarkers (proteinuria and serum creatinine) and PLA2R antibody levels. The effectiveness of therapy is also evaluated on the PLA2R antibody trajectory, particularly during the first 6 months. Finally, PLA2R antibody monitoring has transformed the management of patients with kidney allografts. Future studies are needed to develop more subtle immunological tests, including monitoring of antigen-specific memory B cells. [ABSTRACT FROM AUTHOR]

In 2019 and 2021, the European League for Rheumatism (EULAR) jointly with the European Renal Association (ERA) and the Kidney Disease: Improving Global Outcomes (KDIGO), respectively, released updated guidelines on the management of lupus nephritis (LN). The Immunology Working Group of the ERA reviewed and compared both updates. Recommendations were either consistent or differences were of negligible clinical relevance for: indication for kidney biopsy, kidney biopsy interpretation, treatment targets, hydroxychloroquine dosing, first-line initial immunosuppressive therapy for active class III, IV (±V) LN, pregnancy in LN, LN in paediatric patients and LN patients with kidney failure. Relevant differences in the recommended management relate to the recognition of lupus podocytopathies, uncertainties in steroid dosing, drug preferences in specific populations and maintenance therapy, treatment of pure class V LN, therapy of recurrent LN, evolving alternative drug options and diagnostic work-up of thrombotic microangiopathy. Altogether, both documents provide an excellent guidance to the growing complexity of LN management. This article endeavours to prevent confusion by identifying differences and clarifying discrepancies. [ABSTRACT FROM AUTHOR]

Background Coarctation of the aorta (CoA) is one of the more common congenital heart defects affecting up to 5% of patients with congenital heart disease. Pregnant patients with unrepaired or severe re-coarctation are considered to be modified World Health Organisation (mWHO) IV, have the highest risk of maternal mortality and morbidity. The management of unrepaired CoA during pregnancy is influenced by a variety of factors which include the extent of the coarctation and coarctation characteristics, but due to paucity of data, it largely relies on expert opinion. Case summary A 27 year old multi-gravid woman underwent successful percutaneous stent implantation for severe native CoA due to maternal resistant hypertension and foetal cardiac compromise on echocardiography. After intervention, the remainder of her pregnancy was uneventful with improved arterial hypertension control. The foetal cardiac structures, namely left ventricular size, improved after intervention. This case demonstrates the importance of CoA intervention during pregnancy to optimise both maternal and foetal outcome. Conclusion Coarctation of the aorta should be considered in pregnant women with poorly controlled hypertension. This case also highlights that, despite associated risks, percutaneous intervention can lead to improved maternal haemodynamics and fetal growth. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to evaluate the utility of urine CD163 for detecting disease activity in childhood-onset SLE (cSLE) patients. Methods Sixty consecutive pediatric patients fulfilling four or more ACR criteria for SLE and 20 healthy controls were recruited for testing of urinary CD163 using ELISA. SLE disease activity was assessed using the SLEDAI-2K. Results Urine CD163 was significantly higher in patients with active LN than inactive SLE patients and healthy controls, with receiver operating characteristics area under the curve values ranging from 0.93 to 0.96. LN was ascertained by kidney biopsy. Levels of CD163 significantly correlated with the SLEDAI, renal SLEDAI, urinary protein excretion and C3 complement levels. Urine CD163 was also associated with high renal pathology activity index and chronicity index, correlating strongly with interstitial inflammation and interstitial fibrosis based on the examination of concurrent kidney biopsies. Conclusion Urine CD163 emerges as a promising marker for identifying cSLE patients with active kidney disease. Longitudinal studies are warranted to validate the clinical utility of urine CD163 in tracking kidney disease activity in children with lupus. [ABSTRACT FROM AUTHOR]

A 34-year-old woman of African ancestry had a diagnosis of systemic lupus erythematosus that was antinuclear antibodies (> 1 : 640, speckled), anti-U1-ribonucleoprotein, anti-Smith and anti-C1q positive. She presented to hospital with severely painful annular and polycyclic erosions, some with a targetoid-like appearance. After 6 weeks she developed slowly evolving dusky papules/plaques and flaccid bullae, suggestive of toxic epidermal necrolysis-like lupus, and was successfully treated with intravenous rituximab and intravenous immunoglobulin (2 g kg–1 over 3 days). [ABSTRACT FROM AUTHOR]