Aggressive treatment may be needed for idiopathic membranous nephropathy with focal segmental glomerulosclerosis lesions.

OBJECTIVE: The purpose of this study was to analyze the clinical, pathological, prognostic features and treatment response of the coexistence of focal segmental glomerulosclerosis lesions with idiopathic membranous nephropathy. METHODS: This is a two-center retrospective cohort study. Patients of idiopathic membranous nephropathy were enrolled and divided into two groups with or without focal segmental glomerulosclerosis lesions according to the renal biopsy. Laboratory data and pathological manifestation were compared. Renal phospholipase A2 receptor was detected by immunofluorescence. During the follow-up, the effects of different therapies and renal function were estimated. RESULTS: A total of 236 patients were finally enrolled in this study, of which 60 and 176 idiopathic membranous nephropathy patients were enrolled in the FSGS+ and FSGS- groups, respectively. The FSGS+ group showed a higher percentage of hypertension history (38.3 vs. 20.0%, p=0.004), with a significantly higher level of systolic pressure [137 (120, 160) mmHg vs. 130 (120, 140) mmHg, p=0.009]. Main laboratory findings, including serial albumin (20.4±7.8 g/L vs. 24.5±6.7 g/L, p<0.001), 24-h proteinuria [5.61 (3.10, 7.87) g/day vs. 3.82 (2.31, 5.79) g/day, p=0.002], serial creatinine [80.8 (65.8, 97.9) µmol/L vs. 72.0 (58.7, 84.9) µmol/L, p=0.003], and estimated glomerular filtration rate [86 (66, 101) mL/min/1.73 m2 vs. 95 (81, 108) mL/min/1.73 m2, p=0.007] showed significant differences between the two groups. Pathologically, patients with focal segmental glomerulosclerosis lesions appeared with a higher percentage of crescents, a more severe degree of interstitial fibrosis, and a higher level of membranous nephropathy stage. Renal phospholipase A2 receptor showed a relatively lower positive rate of only 75.0% in the FSGS+ group in comparison with the positive rate of 90.3% in the FSGS- group (p=0.031). The prognosis was generally similar between the two groups. Among patients who were given non-immunosuppression treatment, those with focal segmental glomerulosclerosis lesions took a relatively longer period of time to achieve complete remission (29.3±7.0 m vs. 15.4±8.9 m, p=0.025) and experienced a higher rate of renal function deterioration (37.5 vs. 5.4%, p=0.033) compared with the other ones. While among those receiving immunosuppression treatment, both groups received similar remission rates. CONCLUSION: Compared with FSGS- group, idiopathic membranous nephropathy with focal segmental glomerulosclerosis lesions represented more severe nephrotic syndrome and worse renal function. In view of the renal function decline during the follow-up, more aggressive treatment with the use of immunosuppressants should be considered for idiopathic membranous nephropathy patients with focal segmental glomerulosclerosis lesions.

Risk stratification for infection during immunosuppressive therapy in patients with lupus nephritis: A nested case-control study.

BACKGROUND: The current prediction models for the risk of infection during immunosuppressive treatment for lupus nephritis (LN) lack a prediction time window and have poor pertinence. This study aimed to develop a risk stratification to predict infection during immunosuppressive therapy in patients with LN. METHODS: This retrospective nested case-control study collected patients with LN treated with immunosuppressive therapy between 2014 and 2022 in the Nephrology ward in Huashan Hospital affiliated to Fudan University and Huashan Hospital Baoshan Branch. Cases were defined as patients who experienced infection during the follow-up period; patients were eligible as controls if they did not have infection during the follow-up period. RESULTS: There were 53 patients with infection by CTCAE V5.0 grade ≥2. According to the 1:3 nested matching, the 53 patients with infection were matched with 159 controls. In the multivariable logistic regression model, the change rate of fibrinogen (OR = 0.97, 95% CI: 0.94-0.99, p = 0.008), leukopenia (OR = 8.68, 95% CI: 1.16-301.72, p = 0.039), and reduced albumin (OR = 6.25, 95% CI: 1.38-28.24, p = 0.017) were independently associated with infection. The AUC of the ROC curve in the validation set of the multivariable logistic regression model in the internal random sampling was 0.864. The scores range from -2 to 10. The infection risk stratification ranges from 2.8% at score -2 to 97.5% at score 10. CONCLUSION: A risk stratification was built to predict the risk of infection in patients with LN undergoing immunosuppressive therapy.

Collecting duct NCOR1 controls blood pressure by regulating mineralocorticoid receptor.

INTRODUCTION: Nuclear receptor corepressor 1(NCOR1) is reported to play crucial roles in cardiovascular diseases, but its function in the kidney has remained obscure. OBJECTIVE: We aim to elucidate the role of collecting duct NCOR1 in blood pressure (BP) regulation. METHODS AND RESULTS: Collecting duct NCOR1 knockout (KO) mice manifested increased BP and aggravated vascular and renal injury in an angiotensin II (Ang II)-induced hypertensive model. KO mice also showed significantly higher BP than littermate control (LC) mice in deoxycorticosterone acetate (DOCA)-salt model. Further study showed that collecting duct NCOR1 deficiency aggravated volume and sodium retention after saline challenge. Among the sodium transporter in the collecting duct, the expression of the three epithelial sodium channel (ENaC) subunits was markedly increased in the renal medulla of KO mice. Consistently, BP in Ang II-infused KO mice decreased significantly to the similar level as those in LC mice after amiloride treatment. ChIP analysis revealed that NCOR1 deficiency increased the enrichment of mineralocorticoid receptor (MR) on the promoters of the three ENaC genes in primary inner medulla collecting duct (IMCD) cells. Co-IP results showed interaction between NCOR1 and MR, and luciferase reporter results demonstrated that NCOR1 inhibited the transcriptional activity of MR. Knockdown of MR eliminated the increased ENaC expression in primary IMCD cells isolated from KO mice. Finally, BP was significantly decreased in Ang II-infused KO mice after treatment of MR antagonist spironolactone and the difference between LC and KO mice was abolished. CONCLUSIONS: NCOR1 interacts with MR to control ENaC activity in the collecting duct and to regulate sodium reabsorption and ultimately BP. Targeting NCOR1 might be a promising tactic to interrupt the volume and sodium retention of the collecting duct in hypertension.

Prostacyclin Mitigates Renal Fibrosis by Activating Fibroblast Prostaglandin I 2 Receptor.

SIGNIFICANCE STATEMENT: Renal fibrosis is a common pathologic process of progressive CKD. We have provided strong evidence that PGI 2 is an important component in the kidney injury/repairing process by reducing fibrosis and protecting renal function from declining. In our study, administration of a PGI 2 analog or selective PTGIR agonist after the acute injury ameliorated renal fibrosis. Our findings provide new insights into the role of PGI 2 in kidney biology and suggest that targeting PGI 2 /PTGIR may be a potential therapeutic strategy for CKD. BACKGROUND: Prostanoids have been demonstrated to be important modulators to maintain tissue homeostasis in response to physiologic or pathophysiologic stress. Prostacyclin (PGI 2 ) is a member of prostanoids. While limited studies have shown that PGI 2 is involved in the tissue injury/repairing process, its role in renal fibrosis and CKD progression requires further investigation. METHODS: Prostacyclin synthase ( Ptgis )-deficient mice, prostaglandin I 2 receptor ( Ptgir )-deficient mice, and an oral PGI 2 analog and selective PTGIR agonist were used to examine the role of PGI 2 in renal fibrosis in mouse models. We also analyzed the single-cell RNA-Seq data to examine the PTGIR -expressing cells in the kidneys of patients with CKD. RESULTS: Increased PTGIS expression has been observed in fibrotic kidneys in both humans and mice. Deletion of the PTGIS gene aggravated renal fibrosis and decline of renal function in murine models. A PGI 2 analog or PTGIR agonist that was administered after the acute injury ameliorated renal fibrosis. PTGIR, the PGI 2 receptor, deficiency blunted the protective effect of the PGI 2 analog. Fibroblasts and myofibroblasts were the major cell types expressing PTGIR in the kidneys of patients with CKD. Deletion of PTGIR in collagen-producing fibroblastic cells aggravated renal fibrosis. The protective effect of PGI 2 was associated with the inhibition of fibroblast activation through PTGIR-mediated signaling. CONCLUSIONS: PGI 2 is an important component in the kidney injury/repairing process by preventing the overactivation of fibroblasts during the repairing process and protecting the kidney from fibrosis and decline of renal function. Our findings suggest that PGI 2 /PTGIR is a potential therapeutic target for CKD.

Renal outcomes in IgA nephropathy following inactivated SARS-CoV-2 vaccination.

INTRODUCTION: There are increasing case reports on de novo or relapsing IgA nephropathy (IgAN) following SARS-CoV-2 vaccines, although the follow-up information on renal outcomes in IgAN patients post-SARS-CoV-2 vaccination is limited. In this study, we evaluated the renal outcomes of IgAN patients following inactivated vaccines. METHODS: We investigated the change in eGFR, proteinuria and hematuria in 113 primary IgAN patients post-vaccination. Worsening proteinuria was defined as an increase in proteinuria by more than 0.5 times and proteinuria > 1 g/d. Univariate and multivariable logistic regression analysis were used to evaluate possible predictors of worsening proteinuria. We then compared the renal outcomes of vaccinated patients after 6 months with 101 unvaccinated patients who were followed during the same period. RESULTS: A 2.54% (0.64, 8.61) decrease in renal function was observed in post-vaccination patients. Subgroup analysis revealed a significant decrease in eGFR in patients with 30 ≤ eGFR < 60 (mL/min/1.73 m2) post second SARS-CoV-2 dose (n = 18, p = 0.01). In addition, 10 individuals displayed worsening proteinuria post-vaccination, with the proteinuria subsequently ameliorating significantly after 6-month. Multivariate analysis showed that higher eGFR levels was an independent protective factor for worsening proteinuria. The renal outcome tended towards a decrease in eGFR in vaccinated patients after 6 months follow-up, although the difference was not significant (p = 0.06). CONCLUSION: Kidney function in IgAN patients tended to worsen after SARS-CoV-2 vaccination, particularly those with initial poor kidney function. This pattern of disease flare appears to be clinically mild, and further research is needed to determine whether the impact on kidney function is long-term.

Widening the Prostacyclin Paradigm: Tissue Fibroblasts Are a Critical Site of Production and Antithrombotic Protection.

BACKGROUND: Prostacyclin is a fundamental signaling pathway traditionally associated with the cardiovascular system and protection against thrombosis but which also has regulatory functions in fibrosis, proliferation, and immunity. Prevailing dogma states that prostacyclin is principally derived from vascular endothelium, although it is known that other cells can also synthesize it. However, the role of nonendothelial sources in prostacyclin production has not been systematically evaluated resulting in an underappreciation of their importance relative to better characterized endothelial sources. METHODS: To address this, we have used novel endothelial cell-specific and fibroblast-specific COX (cyclo-oxygenase) and prostacyclin synthase knockout mice and cells freshly isolated from mouse and human lung tissue. We have assessed prostacyclin release by immunoassay and thrombosis in vivo using an FeCl3-induced carotid artery injury model. RESULTS: We found that in arteries, endothelial cells are the main source of prostacyclin but that in the lung, and other tissues, prostacyclin production occurs largely independently of endothelial and vascular smooth muscle cells. Instead, in mouse and human lung, prostacyclin production was strongly associated with fibroblasts. By comparison, microvascular endothelial cells from the lung showed weak prostacyclin synthetic capacity compared with those isolated from large arteries. Prostacyclin derived from fibroblasts and other nonendothelial sources was seen to contribute to antithrombotic protection. CONCLUSIONS: These observations define a new paradigm in prostacyclin biology in which fibroblast/nonendothelial-derived prostacyclin works in parallel with endothelium-derived prostanoids to control thrombotic risk and potentially a broad range of other biology. Although generation of prostacyclin by fibroblasts has been shown previously, the scale and systemic activity was unappreciated. As such, this represents a basic change in our understanding and may provide new insight into how diseases of the lung result in cardiovascular risk.

Finerenone in Patients with Chronic Kidney Disease and Type 2 Diabetes: The FIDELIO-DKD Subgroup from China.

Background: This prespecified subgroup analysis of the FIDELIO-DKD trial aimed to evaluate the efficacy and safety of finerenone in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) in China. Methods: 372 participants were recruited from 67 centers in China and randomized 1:1 to oral finerenone or placebo with standard therapy for T2DM. The primary composite outcome included kidney failure, sustained decrease of estimated glomerular filtration rate ≥40% from baseline over at least 4 weeks, or renal death. The key secondary composite outcome included death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Results: After a median follow-up of 30 months, the finerenone group showed a relative risk reduction (RRR) of 41% (hazard ratio [HR] = 0.59, 95% confidence interval [CI], 0.39-0.88; p = 0.009) for the primary composite outcome compared with placebo, consistent across its components with treatment benefits with finerenone. Based on an absolute between-group difference of 12.2% after 30 months, the number of patients who needed to be treated with finerenone to prevent one primary outcome event was eight (95% CI: 4-84). For the key secondary composite outcome, the finerenone group showed a RRR of 25% (HR = 0.75, 95% CI, 0.38-1.48; p = 0.408). Adverse events were similar between the two groups. The effects of finerenone on blood pressure were modest. No gynecomastia events were reported in the study. Hyperkalemia leading to discontinuation occurred in eight (4.3%) and two (1.1%) participants in the finerenone and control groups, respectively. The incidence of acute kidney injury was comparable between the two groups (1.6% vs. 1.6%). Conclusions: Finerenone resulted in lower risks of CKD progression than placebo and a balanced safety profile in Chinese patients with CKD and T2DM.

Activation of GPER1 in macrophages ameliorates UUO-induced renal fibrosis.

Numerous studies have proven the critical role of macrophages in the renal fibrosis process. Notably, G Protein-coupled Estrogen Receptor 1 (GPER1), a novel estrogen receptor, has been shown to play a ubiquitous role in regulating macrophage activities and proinflammatory pathways. However, the precise role of GPER1 in macrophage-mediated renal fibrosis is unknown. In this study, we aimed to investigate the function of macrophage GPER1 in the UUO-induced renal fibrosis model. Compared to vehicle-treated ovariectomized (OVX) female and male unilateral ureteral obstruction (UUO) models, we observed that G-1 (GPER1 agonist)-treated OVX female and male UUO mice had fewer renal fibrotic lesions and less M1 and M2 macrophage infiltration in the kidney tissues. Conversely, Gper1 deletion in male UUO mice accelerated renal fibrosis and increased inflammation. In vitro studies also revealed that GPER1 activation reduced M0 macrophage polarization towards M1 or M2 phenotypes. The RNA-sequencing analysis and immunoblotting indicated that GPER1 activation was primarily involved in downregulating immune pathways activation and inactivating MAPK pathways. Tubular epithelial cells co-cultured with G-1-pretreated M1 macrophages exhibited fewer injuries and immune activation. In addition, fibroblasts co-cultured with G-1-pretreated M2 macrophages showed downregulated extracellular matrix expression. Overall, this is the first study to demonstrate the effect of GPER1 on macrophage-mediated renal fibrosis via inhibition of M1 and M2 macrophage activation. These findings indicate that GPER1 may be a promising therapeutic target for treating renal fibrosis.

Functional iron deficiency anemia was associated with higher mortality in chronic kidney disease patients: the NHANES III follow-up study.

Anemia, a common complication of chronic kidney disease (CKD), is associated with poor prognosis. However, it is not completely clear whether this association is caused by anemia per se or other comorbidities. Whether different types of iron deficiency anemia can predict the outcomes of CKD remains unclear. The dataset from NHANES III was analyzed and Cox multivariate regression models and propensity score matching (PSM) method were used to evaluate the effect of anemia on mortality. Of 4103 patients with CKD, 14.6% had anemia. Among those with anemia, 38.8% had absolute iron deficiency (AID), and 19.8% had functional iron deficiency (FID). During the median follow-up time of 13.8 years, 2964 deaths and 804 cardiovascular deaths were observed. Anemia was robustly associated with a high risk of all-cause mortality in CKD patients after adjusting covariates by two multivariate regression models (Model 1: HR = 1.485, 95%CI:1.340-1.647, p < 0.001; Model 2: HR = 1.391, 95%CI:1.250-1.546, p < 0.001). In the PSM cohort, anemia was still an independent risk factor for all-cause mortality (Model 1: HR = 1.443, 95%CI: 1.256-1.656, p < 0.001; Model 2: HR = 1.357, 95%CI:1.177-1.564, p < 0.001). In the CKD population, anemia patients with FID had the highest risk of mortality than the other anemia groups (p < 0.05), while AID had a mortality rate similar to those without anemia (p > 0.05). In conclusion, anemia was associated with a worse prognosis in patients with CKD, which may be attributed to the higher mortality risk of FID rather than AID. AID wasn't associated with a higher mortality rate compared with CKD patients without anemia.

Recurrent exercise-induced acute kidney injury associated with hypouricemia: a case report and literature review.

BACKGROUND: Hereditary renal hypouricemia (RHUC) is a heterogenous disorder characterized by defective uric acid (UA) reabsorption resulting in hypouricemia and increased fractional excretion of UA. RHUC is an important cause of exercise-induced acute kidney injury (EIAKI), nephrolithiasis and posterior reversible encephalopathy syndrome (PRES). We present here an unusual case of a patient with RHUC who presented with recurrent EIAKI and had two heterozygous mutations in the SLC2A9 gene. CASE PRESENTATION: A 43-year old man was admitted to our clinic because of bilateral loin pain, nausea and sleeplessness for 3 days after strenuous exercise. The laboratory results revealed increased levels of blood urea nitrogen (BUN) (15 mmol/l) and serum creatinine (Scr) (450 µmol/l), while the UA level was extremely low at 0.54 mg/dl, and his fractional excretion of urate (FE-UA) was 108%. The patient had an episode of acute kidney injury after playing soccer approximately 20 years ago, and on routine physical examination, his UA was less than 0.50 mg/dl. In view of the marked hypouricemia and high FE-UA, a diagnosis of RHUC was suspected, which led us to perform mutational screening of the SLC22A12 and SLC2A9 genes. DNA sequencing revealed no mutation in SLC22A12 gene, but two heterozygous mutations in the SLC2A9 gene. CONCLUSIONS: This is a rare report of a patient with RHUC2 due to the mutation of SLC2A9. And this unique symptom of EIAKI and decreased or normal serum concentrations of UA warrant more attention as an early cue of RHUC.

A case of NCAM1 positive lupus nephritis with NCAM1 antibody titers responsive to rituximab.

NCAM1 is a recently identified new antigen of membranous nephropathy (MN) mostly secondary to systemic lupus erythematosus (SLE) with a low positive rate of 6.6%, and its corresponding antibody was detected in patients' sera. Here, we reported a case of NCAM1-positive lupus nephritis (class Ⅴ+Ⅲ) developed from MN. The patient was refractory to multiple immunosuppressive regimens, but achieved remission after the application of rituximab as an add-on therapy and showed a reduction of anti-NCAM1 antibody and proteinuria.

Knockout of the C3a receptor protects against renal ischemia reperfusion injury by reduction of NETs formation.

Renal ischemia/reperfusion (I/R) injury is a local sterile inflammatory response driven by innate immunity. Emerging data have revealed that complement and neutrophils contribute to hyperinflammation and oxidative stress in I/R induced acute kidney injury (AKI). However, the interplay between the C3a/C3aR axis and neutrophil extracellular traps (NETs) is imcompletelyunderstood. Here, we utilize genetically engineered mouse models and pharmacological inhibitors to investigate this association. The C3a/C3aR axis is found to promote neutrophil recruitment and NETs formation, thereby accelerating renal damage and dysfunction. Knockout of C3aR restores NETs release and improves renal function after I/R injury. Antibody-mediated blockade of NETs can also significantly ameliorate renal tubular injury and inflammation. Consistently, under stimulation by C3a, neutrophils are activated to promote NETs formation and subsequent renal tubular epithelial cell damage, and blocking C3aR rescued the injury. Interfering with reactive oxygen species (ROS) accumulation in neutrophils by antioxidant treatment significantly attenuates NETs formation. Our findings demonstrate that the C3a/C3aR-ROS-NETs axis constitutes a promising target for prevention or treatment of renal I/R injury.

Progression of Vascular Calcification and Clinical Outcomes in Patients Receiving Maintenance Dialysis.

Importance: Baseline findings from the China Dialysis Calcification Study (CDCS) revealed a high prevalence of vascular calcification (VC) among patients with end-stage kidney disease; however, data on VC progression were limited. Objectives: To understand the progression of VC at different anatomical sites, identify risk factors for VC progression, and assess the association of VC progression with the risk of cardiovascular events and death among patients receiving maintenance dialysis. Design, Setting, and Participants: This cohort study was a 4-year follow-up assessment of participants in the CDCS, a nationwide multicenter prospective cohort study involving patients aged 18 to 74 years who were undergoing hemodialysis or peritoneal dialysis. Participants were recruited from 24 centers across China between May 1, 2014, and April 30, 2015, and followed up for 4 years. A total of 1489 patients receiving maintenance dialysis were included in the current analysis. Data were analyzed from September 1 to December 31, 2021. Exposures: Patient demographic characteristics and medical history; high-sensitivity C-reactive protein laboratory values; serum calcium, phosphorus, and intact parathyroid hormone (iPTH) values; and previous or concomitant use of medications. Main Outcomes and Measures: The primary outcome was progression of VC at 3 different anatomical sites (coronary artery, abdominal aorta, and cardiac valves) and identification of risk factors for VC progression. Participants received assessments of coronary artery calcification (CAC), abdominal aortic calcification (AAC), and cardiac valve calcification (CVC) at baseline, 24 months, 36 months, and 48 months. Secondary outcomes included (1) the association between VC progression and the risk of all-cause death, cardiovascular (CV)-related death, and a composite of all-cause death and nonfatal CV events and (2) the association between achievement of serum calcium, phosphorus, and iPTH target levels and the risk of VC progression. Results: Among 1489 patients, the median (IQR) age was 51.0 (41.0-60.0) years; 59.5% of patients were male. By the end of 4-year follow-up, progression of total VC was observed in 86.5% of patients; 69.6% of patients had CAC progression, 72.4% had AAC progression, and 33.4% had CVC progression. Common risk factors for VC progression at the 3 different anatomical sites were older age and higher fibroblast growth factor 23 levels. Progression of CAC was associated with a higher risk of all-cause death (model 1 [adjusted for age, sex, and body mass index]: hazard ratio [HR], 1.97 [95% CI, 1.16-3.33]; model 2 [adjusted for all factors in model 1 plus smoking status, history of diabetes, and mean arterial pressure]: HR, 1.89 [95% CI, 1.11-3.21]; model 3 [adjusted for all factors in model 2 plus calcium, phosphorus, intact parathyroid hormone, and fibroblast growth factor 23 levels and calcium-based phosphate binder use]: HR, 1.92 [95% CI, 1.11-3.31]) and the composite of all-cause death and nonfatal CV events (model 1: HR, 1.98 [95% CI, 1.19-3.31]; model 2: HR, 1.91 [95% CI, 1.14-3.21]; model 3: HR, 1.95 [95% CI, 1.14-3.33]) after adjusting for all confounding factors except the presence of baseline calcification. Among the 3 targets of calcium, phosphorus, and iPTH, patients who achieved no target levels (model 1: odds ratio [OR], 4.75 [95% CI, 2.65-8.52]; model 2: OR, 4.81 [95% CI, 2.67-8.66]; model 3 [for this analysis, adjusted for all factors in model 2 plus fibroblast growth factor 23 level and calcium-based phosphate binder use]: OR, 2.76 [95% CI, 1.48-5.16]), 1 target level (model 1: OR, 3.71 [95% CI, 2.35-5.88]; model 2: OR, 3.62 [95% CI, 2.26-5.78]; model 3: OR, 2.19 [95% CI, 1.33-3.61]), or 2 target levels (model 1: OR, 2.73 [95% CI, 1.74-4.26]; model 2: OR, 2.69 [95% CI, 1.71-4.25]; model 3: OR, 1.72 [95% CI, 1.06-2.79]) had higher odds of CAC progression compared with patients who achieved all 3 target levels. Conclusions and Relevance: In this study, VC progressed rapidly in patients undergoing dialysis, with different VC types associated with different rates of prevalence and progression. Consistent achievement of serum calcium, phosphorus, and iPTH target levels was associated with a lower risk of CAC progression. These results may be useful for increasing patient awareness and developing appropriate strategies to improve the management of chronic kidney disease-mineral and bone disorder among patients undergoing dialysis.

[Regulation of kidney on potassium balance and its clinical significance].

Virtually all of the dietary potassium intake is absorbed in the intestine, over 90% of which is excreted by the kidneys regarded as the most important organ of potassium excretion in the body. The renal excretion of potassium results primarily from the secretion of potassium by the principal cells in the aldosterone-sensitive distal nephron (ASDN), which is coupled to the reabsorption of Na+ by the epithelial Na+ channel (ENaC) located at the apical membrane of principal cells. When Na+ is transferred from the lumen into the cell by ENaC, the negativity in the lumen is relatively increased. K+ efflux, H+ efflux, and Cl- influx are the 3 pathways that respond to Na+ influx, that is, all these 3 pathways are coupled to Na+ influx. In general, Na+ influx is equal to the sum of K+ efflux, H+ efflux, and Cl- influx. Therefore, any alteration in Na+ influx, H+ efflux, or Cl- influx can affect K+ efflux, thereby affecting the renal K+ excretion. Firstly, Na+ influx is affected by the expression level of ENaC, which is mainly regulated by the aldosterone-mineralocorticoid receptor (MR) pathway. ENaC gain-of-function mutations (Liddle syndrome, also known as pseudohyperaldosteronism), MR gain-of-function mutations (Geller syndrome), increased aldosterone levels (primary/secondary hyperaldosteronism), and increased cortisol (Cushing syndrome) or deoxycorticosterone (hypercortisolism) which also activate MR, can lead to up-regulation of ENaC expression, and increased Na+ reabsorption, K+ excretion, as well as H+ excretion, clinically manifested as hypertension, hypokalemia and alkalosis. Conversely, ENaC inactivating mutations (pseudohypoaldosteronism type 1b), MR inactivating mutations (pseudohypoaldosteronism type 1a), or decreased aldosterone levels (hypoaldosteronism) can cause decreased reabsorption of Na+ and decreased excretion of both K+ and H+, clinically manifested as hypotension, hyperkalemia, and acidosis. The ENaC inhibitors amiloride and Triamterene can cause manifestations resembling pseudohypoaldosteronism type 1b; MR antagonist spironolactone causes manifestations similar to pseudohypoaldosteronism type 1a. Secondly, Na+ influx is regulated by the distal delivery of water and sodium. Therefore, when loss-of-function mutations in Na+-K+-2Cl- cotransporter (NKCC) expressed in the thick ascending limb of the loop and in Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule (Bartter syndrome and Gitelman syndrome, respectively) occur, the distal delivery of water and sodium increases, followed by an increase in the reabsorption of Na+ by ENaC at the collecting duct, as well as increased excretion of K+ and H+, clinically manifested as hypokalemia and alkalosis. Loop diuretics acting as NKCC inhibitors and thiazide diuretics acting as NCC inhibitors can cause manifestations resembling Bartter syndrome and Gitelman syndrome, respectively. Conversely, when the distal delivery of water and sodium is reduced (e.g., Gordon syndrome, also known as pseudohypoaldosteronism type 2), it is manifested as hypertension, hyperkalemia, and acidosis. Finally, when the distal delivery of non-chloride anions increases (e.g., proximal renal tubular acidosis and congenital chloride-losing diarrhea), the influx of Cl- in the collecting duct decreases; or when the excretion of hydrogen ions by collecting duct intercalated cells is impaired (e.g., distal renal tubular acidosis), the efflux of H+ decreases. Both above conditions can lead to increased K+ secretion and hypokalemia. In this review, we focus on the regulatory mechanisms of renal potassium excretion and the corresponding diseases arising from dysregulation.

The metabolites of de novo NAD+ synthesis are a valuable predictor of acute kidney injury.

Background: Acute kidney injury (AKI) is often iatrogenic and potentially preventable. Reduced renal nicotinamide adenine dinucleotide (NAD+) is reported to increase the susceptibility of AKI. The present study explored the predictive value of urinary de novo NAD+ synthetic metabolites for AKI using two independent cohorts. Methods: The expression of de novo NAD+ synthetic enzymes in human kidney was examined by immunohistochemistry and single-cell transcriptomes. Urine samples were collected from two independent cohorts: the methotrexate (MTX) cohort with high-dose MTX treatment for lymphoma (n = 189) and the liver transplantation cohort with orthotopic liver transplantation (n = 49). Urinary metabolomics study of NAD+ de novo synthesis was performed by liquid chromatography with mass spectrometry, screening for AKI predictive biomarkers. Nephroseq database and immunohistochemistry were used to analyze kidney de novo NAD+ synthetic enzymes expression in AKI-susceptible conditions. Results: Human proximal tubule was the main structure in the kidney that expressed the necessary enzymes for NAD+ de novo synthesis. In the MTX cohort, the urinary quinolinic acid (QA)/3-hydroxyanthranilic acid (3-OH AA) ratio before chemotherapy was significantly lower in those who developed AKI after chemotherapy compared with those who did not. This finding was consistent in the liver transplantation cohort. The area under the receiver-operating characteristic curve (AUC) of urinary QA/3-OH AA for AKI prediction was 0.749 and 0.729 in two cohorts, respectively. 3-Hydroxyanthranilic acid dioxygenase (HAAO), the enzyme catalyzing QA synthesis from 3-OH AA, decreased in AKI-susceptible diabetic kidneys. Conclusions: The human proximal tubules were important source of NAD+ from the de novo pathway. Reduced urinary QA/3-OH AA ratio, which possibly suggested decreased HAAO activity, could be a potential AKI predictive biomarker.

Randomized Phase 2 Trial of Telitacicept in Patients With IgA Nephropathy With Persistent Proteinuria.

Introduction: To date, no specific therapies have been approved for immunoglobulin A nephropathy (IgAN) treatment. Telitacicept is a fusion protein composed of transmembrane activator and calcium-modulating cyclophilin ligand interactor and fragment crystallizable portion of immunoglobulin G (IgG), which neutralizes the B lymphocyte stimulator and a proliferation-inducing ligand. Methods: This phase 2 randomized placebo-controlled trial aimed to evaluate the efficacy and safety of telitacicept in patients with IgAN. Participants with an estimated glomerular filtration rate (eGFR) >35 ml/min per 1.73 m2 and proteinuria ≥0.75 g/d despite optimal supportive therapy, were randomized 1:1:1 to receive subcutaneous telitacicept 160 mg, telitacicept 240 mg, or placebo weekly for 24 weeks. The primary end point was the change in 24-hour proteinuria at week 24 from baseline. Results: Forty-four participants were randomized into placebo (n = 14), telitacicept 160 mg (n = 16), and telitacicept 240 mg (n = 14) groups. Continuous reductions in serum IgA, IgG, and IgM levels were observed in the telitacicept group. Telitacicept 240 mg therapy reduced mean proteinuria by 49% from baseline (change in proteinuria vs. placebo, 0.88; 95% confidence interval, -1.57 to -0.20; P = 0.013), whereas telitacicept 160 mg reduced it by 25% (-0.29; 95% confidence interval, -0.95 to 0.37; P = 0.389). The eGFR remained stable over time. Adverse events (AEs) were similar in all groups. Treatment-emergent AEs were mild or moderate, and no severe AEs were reported. Conclusion: Telitacicept treatment led to a clinically meaningful reduction in proteinuria in patients with IgAN in the present phase 2 clinical trial. This effect is indicative of a reduced risk for future kidney disease progression.

Updates on Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors in the Treatment of Renal Anemia.

Background: Anemia is a common complication of chronic kidney disease. The hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) is a new class of oral drugs for the treatment of renal anemia. Summary: Clinical trials have consistently shown that HIF-PHIs can effectively increase hemoglobin in both the dialysis population and the nondialysis population. The effects of HIF-PHIs in treating renal anemia include promoting endogenous erythropoietin production and facilitating iron mobilization. Several studies suggest that the erythropoiesis effect of roxadustat is less affected by inflammation. Careful monitoring of thromboembolic events and tumor before and during HIF-PHI treatment is necessary. Key Messages: HIF-PHIs are effective in correcting renal anemia. The long-term safety of HIF-PHIs needs to be further studied.

Genome-Wide Association Study in Acute Tubulointerstitial Nephritis.

SIGNIFICANCE STATEMENT: Polymorphisms of HLA genes may confer susceptibility to acute tubulointerstitial nephritis (ATIN), but small sample sizes and candidate gene design have hindered their investigation. The first genome-wide association study of ATIN identified two significant loci, risk haplotype DRB1*14-DQA1*0101-DQB1*0503 (DR14 serotype) and protective haplotype DRB1*1501-DQA1*0102-DQB1*0602 (DR15 serotype), with amino acid position 60 in the peptide-binding groove P10 of HLA-DR ß 1 key. Risk alleles were shared among different causes of ATIN and HLA genotypes associated with kidney injury and immune therapy response. HLA alleles showed the strongest association. The findings suggest that a genetically conferred risk of immune dysregulation is part of the pathogenesis of ATIN. BACKGROUND: Acute tubulointerstitial nephritis (ATIN) is a rare immune-related disease, accounting for approximately 10% of patients with unexplained AKI. Previous elucidation of the relationship between genetic factors that contribute to its pathogenesis was hampered because of small sample sizes and candidate gene design. METHODS: We undertook the first two-stage genome-wide association study and meta-analysis involving 544 kidney biopsy-defined patients with ATIN and 2346 controls of Chinese ancestry. We conducted statistical fine-mapping analysis, provided functional annotations of significant variants, estimated single nucleotide polymorphism (SNP)-based heritability, and checked genotype and subphenotype correlations. RESULTS: Two genome-wide significant loci, rs35087390 of HLA-DQA1 ( P =3.01×10 -39 ) on 6p21.32 and rs2417771 of PLEKHA5 on 12p12.3 ( P =2.14×10 -8 ), emerged from the analysis. HLA imputation using two reference panels suggested that HLA-DRB1*14 mainly drives the HLA risk association . HLA-DRB1 residue 60 belonging to pocket P10 was the key amino acid position. The SNP-based heritability estimates with and without the HLA locus were 20.43% and 10.35%, respectively. Different clinical subphenotypes (drug-related or tubulointerstitial nephritis and uveitis syndrome) seemed to share the same risk alleles. However, the HLA risk genotype was associated with disease severity and response rate to immunosuppressive therapy. CONCLUSIONS: We identified two candidate genome regions associated with susceptibility to ATIN. The findings suggest that a genetically conferred risk of immune dysregulation is involved in the pathogenesis of ATIN.

Alpha 2-Heremans-Schmid glycoprotein gene polymorphism (rs4918) is associated with coronary artery calcification in incident peritoneal dialysis patients.

AIM: Coronary artery calcification (CAC) is a common and severe complication in peritoneal dialysis (PD) patients, and it progresses in a majority of patients. Fetuin-A, encoded by the alpha 2-Heremans-Schmid glycoprotein (AHSG) gene, is a serum calcification inhibitor. The study aimed to examine the role of AHSG gene polymorphism rs4918 in CAC and CAC progression of PD patients. METHODS: Incident PD patients at Huashan Hospital Fudan University in China from August 2007 to July 2018 were recruited in this prospective study and followed up for 2 years. Patients underwent CAC measurements at recruitment and 2 years later. AHSG gene polymorphism rs4918 and serum fetuin-A were determined at baseline. The demographic characteristics, clinical data, and laboratory data were collected during the follow-up period. Binary logistic regression was performed to explore the association between rs4918 with CAC and CAC progression. RESULTS: A total of 202 PD patients (112 men, 55.4%) were recruited, with a mean age of 54 ± 16 years. The multivariate logistic regression identified genotype GG as an independent risk factor that correlates to CAC (odds ratio [OR] = 2.153; 95% CI: 1.182-3.925; p = .012) and CAC progression (OR = 2.482; 95% CI: 1.422-4.330; p = .001). The serum fetuin-A level was influenced by the rs4918 variants of AHSG, with a dose-dependent effect depending on the number of the G allele. CONCLUSION: AHSG gene polymorphism rs4918 affects serum fetuin-A levels and is significantly associated with both CAC and CAC progression in a cohort of patients receiving PD.