Lung-Targeting Perylenediimide Nanocomposites for Efficient Therapy of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis, an idiopathic interstitial lung disease with high mortality, remains challenging to treat due to the lack of clinically approved lung-targeting drugs. Herein, we present PDIC-DPC, a perylenediimide derivative that exhibits superior lung-selective enrichment. PDIC-DPC forms nanocomposites with plasma proteins, including fibrinogen beta chain and vitronectin, which bind to pulmonary endothelial receptors for lung-specific accumulation. Moreover, PDIC-DPC significantly suppresses transforming growth factor beta1 and activates adenosine monophosphate-activated protein kinase. As a result, compared to existing therapeutic drugs, PDIC-DPC achieves superior therapeutic outcomes, evidenced by the lowest Ashcroft score, significantly improved pulmonary function, and an extended survival rate in a bleomycin-induced pulmonary fibrosis model. This study elucidates the lung-selective enrichment of assembled prodrug from biological perspectives and affords a platform enabling therapeutic efficiency on idiopathic pulmonary fibrosis.

Association between preoperative proton pump inhibitor use and postoperative acute kidney injury in patients undergoing major surgery.

BACKGROUND: Acute kidney injury (AKI) is a severe postoperative complication in patients undergoing major surgery. Proton pump inhibitors (PPIs) are used preoperatively as prophylaxis for postoperative gastrointestinal bleeding. Whether preoperative PPI use is associated with an increased risk of postoperative AKI remains uncertain. METHODS: This retrospective cohort study used electronic medical records from the clinical data warehouse of Peking University First Hospital to screen all adult hospitalizations undergoing major surgery between 1 January 2018 and 31 December 2020. Exposure was preoperative PPI use, defined as PPI use within 7 days before major surgery. The primary outcome was postoperative AKI, defined as AKI occurring within 7 days after major surgery; secondary outcomes included in-hospital AKI and in-hospital mortality. RESULTS: A total of 21,533 patients were included in the study (mean [SD] age, 57.8 [15.0] years; 51.2% male), of which 944 (4.4%) were prescribed PPI within 7 days before major surgery (PPI users). Overall, 72 PPI users (7.6%) and 356 non-users (1.7%) developed postoperative AKI. After adjustment, preoperative PPI use was associated with an increased risk of postoperative AKI (adjusted OR, 1.47; 95% CI, 1.04-2.07) and in-hospital AKI (adjusted OR, 1.41; 95% CI, 1.03-1.94). Moreover, subgroup analyses showed that the risk of PPI on postoperative AKI was amplified by the concomitant use of non-steroidal anti-inflammatory drugs or diuretics. No significant difference was observed between preoperative PPI use and in-hospital mortality in the fully adjusted model (adjusted OR 1.63; 95% CI, 0.55-4.85). CONCLUSIONS: Preoperative PPI use was associated with an increased risk of AKI in patients undergoing major surgery. This risk may be enhanced by the concomitant use of other nephrotoxic drugs. Clinicians should weigh the pros and cons before initiating PPI prophylaxis.

The clinical and pathological relevance of waxy casts in urine sediment.

Although casts in urine may imply the underlying pathogenesis and the diagnosis, the waxy cast is poorly understood yet. We aim to investigate the association between waxy casts and clinicopathological indices. Patients undergone renal biopsy and urine sediment examination were enrolled. Waxy casts referred to those presented with a homogeneous melted wax appearance and pre-waxy casts referred to those in which one or more segments demonstrated a waxy-cast appearance. Multivariable logistic regression was used to assess the factors associated with waxy casts. In 1282 patients, the detection rate of waxy casts was 26.3%. If either waxy or pre-waxy cast was considered as a diagnostic marker for renal insufficiency (eGFR < 60 ml/min/1.73 m2), the sensitivity was 0.58 and the specificity was 0.88. If the only waxy cast was considered as the diagnostic marker, the sensitivity was 0.29 and the specificity was 0.97. The patients with waxy or pre-waxy casts had higher blood pressure, more proteinuria, and worse renal function. Waxy or pre-waxy cast was independently associated with eGFR (odds ratio: 0.73 per 10 mL/min/1.73 m2 increase, 95% confidence interval: 0.69-0.77, p < 0.001), proteinuria (odds ratio: 1.07 per 1 g/day increase, 95% confidence interval: 1.03-1.10, p < 0.001) and pathological lesions. Waxy or pre-waxy casts are closely related to impaired renal function. Their presence is a specific indicator of renal insufficiency but is not sensitive enough.

Associations of ABO blood type and galactose-deficient immunoglobulin A1 with adverse outcomes in patients with IgA nephropathy.

BACKGROUND: Both ABO blood group antigens and pathogenic immunoglobulin A1 (IgA1) in patients with IgA nephropathy (IgAN) are influenced by modifications of N-acetylgalactosamine and galactose. The purpose of this study was to assess whether ABO blood type is associated with galactose-deficient IgA1 (Gd-IgA1) in the progression of kidney disease in patients with IgAN. METHODS: We enrolled 1313 IgAN patients with a median of 44 months follow-up and measured the plasma Gd-IgA1 levels. Multivariate Cox regression models were used to estimate the association between all variables and adverse outcomes. Using the propensity score matching method, 718 IgAN patients with blood type either A or B were selected, and their data were used to assess the association of blood type and Gd-IgA1/serum complement 3 (sC3) with outcomes. RESULTS: We found that the risk of adverse outcomes was significantly higher in patients with blood type A than in those with type B (hazard ratio = 1.82, 95% confidence interval 1.23-2.71; P = 0.003) after multivariate adjustment. The Gd-IgA1 levels showed trends similar to the multivariate-adjusted event-free curves for the blood types. However, this higher risk of adverse outcomes in type A than in type B patients was no longer significant after the addition of Gd-IgA1/sC3 to the model. CONCLUSIONS: IgAN patients with blood type A had a higher risk of adverse outcomes than those with type B, and this risk was associated with Gd-IgA1/sC3. Thus, the ABO blood type may provide a reference for the prognostic factors for individuals with IgAN.

A cross-sectional study of chemotherapy-related AKI.

PURPOSE: This study aims to detail the characteristics of chemotherapy-related acute kidney injury (CR-AKI) and investigate its effect on patient outcomes. METHODS: This is a multicenter cross-sectional study of cancer patients with CR-AKI screened from hospital-acquired adult AKI patients based on a nationwide AKI survey in China. RESULTS: Of the 3468 patients with hospital-acquired AKI, 258 cases of CR-AKI were identified. Of the patients, 20.1% (52/258) were ≥ 70 years old. Among the 258 CR-AKI cases, 61 (23.6%) reached AKI stage 3, and 75 (29.1%) reached AKI stage 2. The remaining 122 (47.3%) remained at AKI stage 1. A total of 413 chemotherapeutic agents were related to AKI, of which platinum compounds (24.5%, 101/413) were the most common. In-hospital mortality was 14.7% (38/258), and the rate of AKI non-recovery was 48.3% (100/207). AKI stage 3 (OR 2.930, 95% CI 1.156-7.427) and age ≥ 70 years (OR 3.138, 95% CI 1.309-7.519) were independent risk factors for in-hospital death. Compared to stage 2 or 3 AKI cases, a higher proportion of patients with stage 1 AKI did not recover their renal function (57.1% vs. 41.4% vs. 36.4%, P = 0.032). More AKI episodes were not recognized in patients with stage 1 AKI compared with the other two groups (82.8% vs. 60.0% vs. 36.1%, P < 0.001). CONCLUSIONS: CR-AKI accounted for a noteworthy proportion of hospital-acquired AKI, and severe CR-AKI increased in-hospital mortality. Mild CR-AKI was more likely to be overlooked, and sustained kidney injury was common in this situation. Recognizing CR-AKI at an early stage and personalizing treatment should be emphasized in those undergoing chemotherapy.

Effect of clinical decision support systems on clinical outcome for acute kidney injury: a systematic review and meta-analysis.

BACKGROUND: Clinical decision support systems including both electronic alerts and care bundles have been developed for hospitalized patients with acute kidney injury. METHODS: Electronic databases were searched for randomized, before-after and cohort studies that implemented a clinical decision support system for hospitalized patients with acute kidney injury between 1990 and 2019. The studies must describe their impact on care processes, patient-related outcomes, or hospital length of stay. The clinical decision support system included both electronic alerts and care bundles. RESULTS: We identified seven studies involving 32,846 participants. Clinical decision support system implementation significantly reduced mortality (OR 0.86; 95 % CI, 0.75-0.99; p = 0.040, I2 = 65.3 %; n = 5 studies; N = 30,791 participants) and increased the proportion of acute kidney injury recognition (OR 3.12; 95 % CI, 2.37-4.10; p < 0.001, I2 = 77.1 %; n = 2 studies; N = 25,121 participants), and investigations (OR 3.07; 95 % CI, 2.91-3.24; p < 0.001, I2 = 0.0 %; n = 2 studies; N = 25,121 participants). CONCLUSIONS: Nonrandomized controlled trials of clinical decision support systems for acute kidney injury have yielded evidence of improved patient-centered outcomes and care processes. This review is limited by the low number of randomized trials and the relatively short follow-up period.

Eosinophilic peritonitis and nephrotic syndrome in Kimura's disease: a case report and literature review : Eosinophilic peritonitis in Kimura's disease.

BACKGROUND: Eosinophilic peritonitis is a relatively rare entity. Kimura's disease is a rare chronic inflammatory disorder of unknown etiology, characterized by subcutaneous nodules mainly in the head and neck region, regional lymphadenopathy and occasional involvement of kidney. There is currently no report of eosinophilic peritonitis in Kimura's disease. CASE PRESENTATION: A 44-year-old Chinese man presented with abdominal distention, nausea, vomiting and edema in lower limbs for 1 month. Laboratory data showed elevated eosinophils in peripheral blood and ascites, nephrotic syndrome with progressively renal dysfunction, and elevated IgE. Ultrasonography of lymph nodes showed multiple lymphadenopathy in bilateral inguinal regions. Surgical excision was performed for one of the enlarged lymph nodes and histopathology revealed diagnosis of Kimura's disease. Renal biopsy indicated focal segmental glomerulosclerosis (FSGS) and acute tubulointerstitial nephritis with infiltration of eosinophils in renal interstitium. The patient was prescribed with oral prednisolone therapy (30 mg/day), and underwent continuous ambulatory peritoneal dialysis (CAPD). The peripheral and peritoneal eosinophil count decreased rapidly and normalized within 2 days. Forty-five days after prednisolone therapy, partial remission of nephrotic syndrome and decrease of serum creatinine were achieved while peritoneal dialysis dosage had decreased. Inguinal lymph nodes gradually shrunk in size. The overall conditions remain stable afterwards. CONCLUSIONS: This rare case highlighted the clinical conundrum of a patient presenting with eosinophilic peritonitis, lymphadenopathy, nephrotic syndrome and renal failure associated with Kimura's disease. The remarkable eosinophilia, pathology of lymph node and kidney, as well as significant response to steroids should guide towards the diagnosis.

Elevation of erythrocyte sedimentation rate and C-reactive protein levels reflects renal interstitial inflammation in drug-induced acute tubulointerstitial nephritis.

BACKGROUND: A renal biopsy is needed to define active inflammatory infiltration and guide therapeutic management in drug-induced acute tubulointerstitial nephritis (D-ATIN). However, factors such as various contraindications, refusal of informed consent and limited technical support may stop the biopsy process. It is thus of great importance to explore approaches that could deduce probable pathologic changes. METHODS: A total of 81 biopsy-proven D-ATIN patients were enrolled from a prospective cohort of ATIN patients at Peking University First Hospital. The systemic inflammation score (SIS) was developed based on the CRP and ESR levels at biopsy, and patients were divided into high-SIS, median-SIS, and low-SIS groups. The demographic data, clinicopathologic features, and renal outcomes were compared. RESULTS: The SIS was positively correlated with inflammatory cell infiltration and was inversely correlated with interstitial fibrosis. The number of interstitial inflammatory cells increased significantly with increasing SISs. The proportions of neutrophils and plasma cells were the highest in the high-SIS group compared with the other two groups. Prednisone (30-40 mg/day) was prescribed in all patients. The high-SIS group tended to have more favorable renal restoration than the other two groups. By 12 months postbiopsy, a decreased eGFR (< 60 mL/min/1.73 m2) was observed in 66.7% of medium-SIS patients, 32.4% of high-SIS patients, and 30.4% of low-SIS patients. CONCLUSION: The SIS was positively correlated with active tubulointerstitial inflammation and therefore could help to aid therapeutic decisions in D-ATIN.

Spectrum of chronic kidney disease in China: A national study based on hospitalized patients from 2010 to 2015.

AIM: To investigate the spectrum of chronic kidney disease (CKD) in China. METHODS: We used a large national in-patient database covering 878 class three hospitals and involving 64.7 million adult patients in China from 2010 to 2015. The class 3 hospital in China is ranked as the top tier of medical system in China with at least 500 beds and the accreditation from health authorities. The specific causes of CKD were extracted from the International Classification of Diseases-10 codes of discharge diagnoses. RESULTS: A total of 4.5% of hospitalized patients (1.8 million) were identified as CKD, with an increased percentage from 2010 (3.7%) to 2015 (4.7%). Increasing trends of diabetic kidney disease and hypertensive nephropathy were observed from 2010 to 2015 (19.5% vs 24.3% and 11.5% vs 15.9%, respectively), especially for urban residents from north China. The proportion of obstructive nephropathy also increased gradually (10.3% in 2010 vs 15.6% in 2015) and constituted another important cause of CKD for patients, especially for those from south China and rural residents. CONCLUSION: The spectrum of CKD is changing in China, with variations over time and geographic regions, which has implication regarding developing the prevention strategy of CKD.

Urgent-Start Peritoneal Dialysis Complications: Prevalence and Risk Factors.

BACKGROUND: Mechanical complications are of particular concern in urgent-start peritoneal dialysis (PD) because of the shorter break-in period. However, risk factors have been reported inconsistently and data in urgent-start PD populations are limited. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: All patients treated with urgent-start PD, defined as PD therapy initiated within 1 week after catheter insertion, January 2003 to May 2013. PREDICTORS: Age, sex, abdominal surgery history, body mass index, hemoglobin level, albumin level, C-reactive protein level, break-in period (period between catheter insertion and PD therapy initiation), dialysate exchange volume, and use of overnight dwell. OUTCOMES: The presence of mechanical complications related to abdominal wall or catheter, including hernia, hydrothorax, hydrocele, subcutaneous leak, pericatheter leak, catheter malposition, omental wrap, and obstruction. RESULTS: 922 patients on urgent-start PD therapy were enrolled (mean age, 59.1±15.0 [SD] years). Prevalences of abdominal wall and catheter complications were 4.8% and 9.5%, respectively. The most common abdominal wall complication was hernia (55%), followed by hydrothorax (25%). On adjustment, male sex (HR, 5.41; 95% CI, 2.15-13.59; P<0.001) and history of abdominal surgery (HR, 2.34; 95% CI, 1.04-5.26; P=0.04) were independently associated with higher risk for developing abdominal wall complications. LIMITATIONS: As a cohort study, comparisons could not be established between urgent-start PD and conventional PD. CONCLUSIONS: Urgent-start PD is a safe and practicable approach. Male sex and history of abdominal surgery could contribute to the development of abdominal wall complications.

Association between plasma phosphorus and renal outcome: A prospective cohort of patients majorly with glomerulonephritis.

AIM: Studies investigating the association between blood phosphorus and renal outcomes yielded inconsistent results, and studies from Asian population are extremely limited. We initiated the present cohort study, aiming to prospectively examine the association between blood phosphorus and adverse renal outcomes in a prospective chronic kidney disease (CKD) cohort of Chinese patients majorly with glomerulonephritis. METHODS: A total of 1430 patients were involved in the study. Linear regression analyses were used to assess the relationship between phosphorus and the slope of estimated glomerular filtration rate (eGFR). Cox regression analyses were used to assess the association between phosphorus and composite outcomes, which were defined as the presence of at least one of: eGFR halving, end stage renal disease, or death. RESULTS: During follow-up for an average of 41.4 months, 196 patients developed composite outcomes. The time-average plasma phosphorus was independently associated with the slope of eGFR (ß = -0.18, 95% CI: -4.42 to -2.19, P < 0.001). Each 1 mg/dL increases of baseline and time-average phosphorus were respectively associated with a 1.33 (95% confidence interval (CI): 1.09-1.63; P = 0.005) and 2.79 (95%CI: 2.21-3.52; P < 0.001) fold higher risk of composite outcomes. Compared with participants in the bottom quartile of time-average phosphorus, those in the top quartile were at increased risk of composite outcomes, with a hazard ratio of 6.52 (95% CI: 3.05-13.90; P < 0.001). CONCLUSION: Plasma phosphorus level is an independent risk factor of adverse renal outcomes in Chinese CKD patients majorly with glomerulonephritis. Compared with baseline value, time-average phosphorus has a stronger relationship with renal prognosis.

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy.

Complement activation is common in patients with IgA nephropathy (IgAN) and associated with disease severity. Our recent genome-wide association study of IgAN identified susceptibility loci on 1q32 containing the complement regulatory protein-encoding genes CFH and CFHR1-5, with rs6677604 in CFH as the top single-nucleotide polymorphism and CFHR3-1 deletion (CFHR3-1∆) as the top signal for copy number variation. In this study, to explore the clinical effects of variation in CFH, CFHR3, and CFHR1 on IgAN susceptibility and progression, we enrolled two populations. Group 1 included 1178 subjects with IgAN and available genome-wide association study data. Group 2 included 365 subjects with IgAN and available clinical follow-up data. In group 1, rs6677604 was associated with mesangial C3 deposition by genotype-phenotype correlation analysis. In group 2, we detected a linkage between the rs6677604-A allele and CFHR3-1∆ and found that the rs6677604-A allele was associated with higher serum levels of CFH and lower levels of the complement activation split product C3a. Furthermore, CFH levels were positively associated with circulating C3 levels and negatively associated with mesangial C3 deposition. Moreover, serum levels of the pathogenic galactose-deficient glycoform of IgA1 were also associated with the degree of mesangial C3 deposition in patients with IgAN. Our findings suggest that genetic variants in CFH, CFHR3, and CFHR1 affect complement activation and thereby, predispose patients to develop IgAN.

Evaluation of the Oxford Classification of IgA nephropathy: a systematic review and meta-analysis.

BACKGROUND: The Oxford Classification of the pathology of immunoglobulin A (IgA) nephropathy, developed in 2009, is highly predictive of renal prognosis. It has been validated in different populations, but the results remain inconsistent. STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Patients with biopsy-proven primary IgA nephropathy. SELECTION CRITERIA FOR STUDIES: Studies assessing the Oxford Classification of IgA nephropathy published between January 2009 and December 2012 were included following systematic searching of the MEDLINE and EMBASE databases. PREDICTOR: 4 pathologic lesions of the Oxford Classification: mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T). OUTCOME: Kidney failure defined as doubled serum creatinine level, 50% decline in estimated glomerular filtration rate, or end-stage kidney disease. RESULTS: 16 retrospective cohort studies with 3,893 patients and 570 kidney failure events were included. In a multivariate model, HRs for kidney failure were 0.6 (95% CI, 0.5-0.8; P < 0.001), 1.8 (95% CI, 1.4-2.4; P < 0.001), and 3.2 (95% CI, 1.8-5.6; P < 0.001) for scores of M0 (mesangial hypercellularity score ≤0.5), S1 (presence of segmental glomerulosclerosis), and T1/2 (>25% tubular atrophy/interstitial fibrosis), respectively, without evidence of heterogeneity. Pooled results showed that E lesions were not associated with kidney failure (HR, 1.4; 95% CI, 0.9-2.0; P = 0.1), with evidence of heterogeneity (I(2) = 54.1%; P = 0.01). Crescent (C) lesions were associated with kidney failure (HR, 2.3; 95% CI, 1.6-3.4; P < 0.001), with no evidence of heterogeneity (I(2) = 14.7%; P = 0.3). LIMITATIONS: All studies were retrospective. This was not an individual-patient-data meta-analysis. CONCLUSIONS: This study suggests that M, S, T, and C lesions, but not E lesions, are associated strongly with progression to kidney failure and thus should be included in the Oxford Classification system.

Corticosteroid therapy in IgA nephropathy.

The benefits and risks of steroids for the treatment of IgA nephropathy remain uncertain. We systematically searched MEDLINE, EMBASE, and the Cochrane Library for randomized, controlled trials of corticosteroid therapy for IgA nephropathy published between 1966 and March 2011. We identified nine relevant trials that included 536 patients who had urinary protein excretion >1 g/d and normal renal function. Forty-six (8.6%) of these patients developed a kidney failure event, defined as doubling of the serum creatinine/halving of the GFR or ESRD. Overall, steroid therapy was associated with a lower risk for kidney failure (relative risk, 0.32 [95% confidence interval [CI], 0.15-0.67]; P=0.002) and a reduction in proteinuria (weighted mean difference, -0.46 g/d [95% CI, -0.63 to -0.29 g/d]), with no evidence of heterogeneity in these outcomes. Subgroup analysis suggested that the dose modifies the effect of steroids for renal protection (P for heterogeneity=0.030): Relatively high-dose and short-term therapy (prednisone >30 mg/d or high-dose pulse intravenous methylprednisolone with duration ≤1 year) produced significant renal protection, whereas low-dose, long-term steroid use did not. Steroid therapy was associated with a 55% higher risk for adverse events. The quality of included studies was low, however, limiting the generalizability of the results. In conclusion, steroids appear to provide renal protection in patients with IgA nephropathy but increase the risk for adverse events. Reliably defining the efficacy and safety of steroids in IgA nephropathy requires a high-quality trial with a large sample size.

Long-term renal outcomes of patients with COVID-19: a meta-analysis of observational studies.

BACKGROUND: Kidney involvement is common in hospitalized coronavirus disease 2019 (COVID-19) patients during the acute phase, little is known about the long-term impact of COVID-19 on the kidney. METHODS: This is a systematic review and meta-analysis on long-term renal outcomes among COVID-19 patients. We carried out a systematic literature search in PUBMED, EMBASE, SCOPUS, and Cochrane COVID-19 study register and performed the random-effects meta-analysis of rates. The search was last updated on November 23, 2022. RESULTS: The study included 12 moderate to high-quality cohort studies involving 6976 patients with COVID-19-associated acute kidney injury and 5223 COVID-19 patients without acute kidney injury. The summarized long-term renal non-recovery rate, dialysis-dependent rate, and complete recovery rate among patients with COVID-19-associated AKI was 22% (12-33%), 6% (2-12%), and 63% (44-81%) during a follow-up of 90-326.5 days. Heterogeneity could be explained by differences in the prevalence of chronic kidney disease and proportion of acute kidney injury requiring renal replacement therapy using meta-regression; patients with more comorbidities or higher renal replacement therapy rate had higher non-recovery rates. The summarized long-term kidney function decrease rate among patients without acute kidney injury was 22% (3-51%) in 90-199 days, with heterogeneity partially explained by severity of infection. CONCLUSION: Patients with more comorbidities tend to have a higher renal non recovery rate after COVID-19-associated acute kidney injury; for COVID-19 patients without acute kidney injury, decrease in kidney function may occur during long-term follow-up. Regular evaluation of kidney function during the post-COVID-19 follow-up among high-risk patients may be necessary.

Renal involvement in a large cohort of Chinese patients with Castleman disease.

BACKGROUND: The association of kidney disease with Castleman disease (CD) is uncommon. To date, most studies have been based on single-case reports. Here, we describe renal involvement in CD in a large Chinese cohort. METHODS: Seventy-six CD patients were identified in one clinical center. Clinical and pathological characteristics of patients with renal involvement were described, which were also compared with cases identified through a systematic literature review. RESULTS: Nineteen patients (25%) exhibited renal involvement. Patients with multicentric clinical type (59 versus 0%) or plasma cell (PC)/mixed cellularity histological variant (61.5 versus 6%) were more likely to have renal involvement (P < 0.001). Proteinuria (with 7/19 reaching nephrotic range) and acute renal failure (12/19, 63%) were the main clinical presentations. Kidney biopsy revealed various glomerular diseases (10/11) and interstitial nephritis (1/11), while with 'thrombotic microangiopathy-like' lesions were the most common pathological characteristics (6/11, 55%). This contrasted significantly with the literature in which amyloidosis was the most reported. Renal outcomes responded well to chemotherapy. Nine (9/12, 75%) patients with acute renal failure recovered completely, one recovered partially. Overall, only three (3/19, 16%) patients progressed to end-stage kidney disease. Renal involvement did not influence survival rate (log-rank test, P = 0.73) in the follow-up. CONCLUSIONS: CD with multicentric type and PC or mixed cellularity variant are often associated with renal complications. Thrombotic microangiopathy-like lesions are the most common pathological characteristics. Chemotherapy can reverse kidney damage in most cases.

Human Amnion Epithelial Cells and Their Derived Exosomes Alleviate Sepsis-Associated Acute Kidney Injury via Mitigating Endothelial Dysfunction.

Background: Sepsis is characterized by organ dysfunction resulting from a patient's dysregulated response to infection. Sepsis-associated acute kidney injury (S-AKI) is the most frequent complication contributing to the morbidity and mortality of sepsis. The prevention and treatment of S-AKI remains a significant challenge worldwide. In the recent years, human amnion epithelial cells (hAECs) have drawn much attention in regenerative medicine, yet the therapeutic efficiency of hAECs in S-AKI has not been evaluated. Methods: Septic mice were induced by cecal ligation and puncture (CLP) operation. hAECs and their derived exosomes (EXOs) were injected into the mice via tail vein right after CLP surgery. The 7-day survival rate was observed. Serum creatinine level was measured and H&E staining of tissue sections were performed 16 h after CLP. Transmission electron microscopy was used to examine the renal endothelial integrity in CLP mice. Human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) and EXOs. Zonula occludens-1 (ZO-1) localization was observed by immunofluorescence staining. Expression of phosphor-p65 (p-p65), p65, vascular cell adhesion molecule-1 (VCAM-1), and ZO-1 in the kidney were determined by Western blot. Results: hAECs decreased the mortality of CLP mice, ameliorated septic injury in the kidney, and improved kidney function. More precisely, hAECs suppressed systemic inflammation and maintained the renal endothelial integrity in septic animals. EXOs from hAECs exhibited similar renal protective effects as their parental cells. EXOs maintained endothelial cell adhesion junction in vitro and inhibited endothelial cell hyperactivation in vivo. Mechanistically, EXOs suppressed proinflammatory nuclear factor kappa B (NF-κB) pathway activation in LPS-treated HUVECs and in CLP mice kidneys. Conclusion: Our results indicate that hAECs and their derived EXOs may ameliorate S-AKI via the prevention of endothelial dysfunction in the early stage of sepsis in mice. Stem cell or exosome-based therapy targeting endothelial disorders may be a promising alternative for treatment of S-AKI.

Case Report: A Pathogenic Missense Variant of WT1 Cosegregates With Proteinuria in a Six-Generation Chinese Family With IgA Nephropathy.

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide. In addition to hematuria, proteinuria is observed in a considerable proportion of patients with IgAN and has proven to be a strong risk factor for disease progression. Although the exact pathogenesis of IgAN is still unclear, genetic factors are widely considered to play a role in its occurrence and development. Here, we investigated a large IgAN-associated pedigree of 47 members belonging to six generations. Two members of the family who presented with proteinuria and hematuria were diagnosed with IgAN through renal biopsy. Four other members also exhibited proteinuria or hematuria but without renal biopsy. Using whole-exome sequencing, we identified a likely pathogenic variant in WT1 (c.1397C>T; p.Ser466Phe) that cosegregated with proteinuria in the affected family members. In addition, another pathogenic variant in NPHS1 (c.3478C>T; p.Arg1160Ter) was identified; however, it did not cosegregate with abnormal proteinuria. Compared to individuals in the pedigree with only one heterozygous WT1 variant (c.1397C>T; p.Ser466Phe), the proband and her younger brother carried an additional WT1 variant (c.1433-10G>A) and presented with a more severe phenotype and rapid progression to end-stage kidney disease. Our findings suggest the WT1 missense variant (c.1397C>T; p.Ser466Phe)-induced primary podocyte injury might contribute to the proteinuria phenotype and IgAN progression in this pedigree.

Effectiveness of Chinese herbal medicine combined with Western medicine on deferring dialysis initiation for nondialysis chronic kidney disease stage 5 patients: a multicenter prospective nonrandomized controlled study.

BACKGROUND: In clinical practice, Chinese herbal medicine (CHM) purportedly has beneficial therapeutic effects for chronic kidney disease (CKD), which include delaying disease progression and dialysis initiation. However, there is a lack of high-quality evidence-based results to support this. Therefore, this study aimed to evaluate the efficacy of CHM combined with Western medicine in the treatment of stage 5 CKD. METHODS: This was a prospective nonrandomized controlled study. Stage 5 CKD (nondialysis) patients were recruited form 29 AAA class hospitals across China from July 2014 to April 2019. According to doctors' advice and the patients' wishes, patients were assigned to the CHM group (Western medicine + CHM) and the non-CHM group (Western medicine). Patient demographic data, primary disease, blood pressure, Chinese and Western medical drugs, clinical test results, and time of dialysis initiation were collected during follow-up. RESULTS: A total of 908 patients were recruited in this study, and 814 patients were finally included for further analysis, including 747 patients in the CHM group and 67 patients in the non-CHM group. 482 patients in the CHM group and 52 patients in the non-CHM group initiated dialysis. The median time of initiating dialysis was 9 (7.90, 10.10) and 3 (0.98,5.02) months in the CHM group and non-CHM group, respectively. The multivariate Cox regression analysis showed that patients in the CHM group had a significantly lower risk of dialysis [adjusted hazard ratio (aHR): 0.38; 95% confidence interval (CI): 0.28, 0.53] compared to those in the non-CHM group. After 1:2 matching, the outcomes of 160 patients were analyzed. The multivariate Cox regression analysis showed that patients in the CHM group had a significantly lower risk of dialysis (aHR: 0.32; 95% CI: 0.21, 0.48) compared to patients in the non-CHM group. Also, the Kaplan-Meier analysis demonstrated that the cumulative incidence of dialysis in the CHM group was significantly lower than that in the non-CHM group (log-rank test, P<0.001) before and after matching. CONCLUSIONS: This study suggest that the combination of CHM and Western medicine could effectively reduce the incidence of dialysis and delay the time of dialysis initiation in stage 5 CKD patients.

Acute Kidney Injury in Asia: Disease Burden.

Acute kidney injury (AKI) is a common and critical clinical disorder with non-negligible morbidity and mortality and remains a large public health problem. Asia, as the world's largest and most populous continent, is crucial in eliminating unsatisfactory outcomes of AKI. The diversities in climate, customs, and economic status lead to various clinical features of AKI across Asia. In this review, we focus on the epidemiologic data and clinical features of AKI in different Asian countries and clinical settings, and we show the huge medical and economic burden of AKI in Asian countries. Drugs and sepsis are the most common etiologies for AKI, however, an adequate surveillance system has not been well established. There is significant undertreatment of AKI in many regions, and medical resources for renal replacement therapy are not universally available. Although substantial improvement has been achieved, health care for AKI still needs improvement, especially in developing regions.