Prognostic Assessment of Histopathologic Lesions in Patients with Community-Acquired Acute Kidney Injury with Biopsy-Proven Acute Tubular Necrosis.

BACKGROUND: Community-acquired acute kidney injury (CA-AKI) was more likely to be comorbid with underlying kidney histopathological lesions in addition to acute tubular necrosis (ATN). Thus, we tried to clarify the histological determinants that could influence the prognosis and recovery of CA-AKI patients with biopsy-proven ATN. METHODS: Adult patients with CA-AKI with biopsy-proven ATN who underwent renal biopsy at Shanghai Changzheng Hospital from January 1, 2010, to December 31, 2018, were included and followed up for 5 years. The impacts of histopathological lesions on short-term and long-term renal dysfunction were also analysed. RESULTS: Multivariate analysis revealed that ATNs, crescents, and decrease of arteriole lumens increased short-term dialysis requirements. The severity of ATN was closely associated with renal survival. According to the Kaplan-Meier analysis, the severity of ATN was significantly associated with short-term dialysis needs and long-term development of end-stage kidney disease (ESKD) during follow-up. Crescent and decrease of arteriole lumens are significantly associated with progression to ESKD and exert synergistic effects with ATN. For patients who did not progress to dialysis, tubular atrophic/interstitial fibrosis and endocapillary lesions were more relevant to partial recovery of renal function after CA-AKI at the three-month follow-up and increased the risk of chronic kidney disease (CKD) stage 3-5 at the five-year follow-up. According to our correlation analysis, endocapillary lesions and crescents were positively correlated with ATN. CONCLUSIONS: Histopathologic lesions, apart from tubular necrosis, contributed to the detrimental short-term and long-term renal prognosis of CA-AKI patients with ATN; concomitant histopathologic lesions exerted a combined impact on renal survival together with ATN in CA-AKI patients.

Prognostic analysis of crescentic glomerulonephritis with acute kidney injury: a single-center cohort with 5-year follow-up.

BACKGROUND: Crescentic glomerulonephritis (CrGN) represents a severe form of glomerular injury that results in high rates of renal failure. This study aimed to investigate the influence of potential clinical and pathological factors on renal outcomes of CrGN; and the relationship between 3-month and 5-year follow-up as well. METHODS: The cohort enrolled patients diagnosed of biopsy proven CrGN with acute kidney injury(AKI) from January 1, 2010, to January 1, 2018 in Shanghai Changzheng Hospital and followed up for 5 years. RESULTS: A total of 56 patients were included, among whom 11 patients (19.6%) had type I, 12 (21.4%) had type II, and 33 (58.9%) had type III CrGN. Patients with type II CrGN tended to have a lower crescent score, less renal tubular damage, and lower serum creatinine than the other two types. Three-month cumulative renal survival rates of types I, II, and III CrGN were 45.5%, 66.7%, and 48.5%, respectively. Five-year cumulative renal survival rates of types I, II, and III CrGN were 27.2%, 83.3%, and 36.4%, respectively. The Kappa Consistency Test between 3-month and 5-year outcomes was 0.573(P < 0.001). Cox regression model showed that in-hospital dialysis was an indicative renal survival factor in 3 months (HR 15.670, 95% CI 2.987-82.210, P = 0.001). It also showed that the crescent score had an unfavorable effect for renal survival in 5 years (HR 1.750 95% CI 1.018-3.009, P = 0.043). CONCLUSIONS: Clinical manifestations and outcomes varied by different CrGN types. Three-month outcomes could partially reflect the 5-year outcomes. Severity of crescents was an independent risk factor for renal survival in CrGN.

Comparison of Outcomes between Percutaneous and Surgical Placement of Peritoneal Dialysis Catheters in Uremic Patients: A Meta-Analysis.

BACKGROUND: The optimal technique for inserting peritoneal dialysis catheters in uremic patients remains debated. This meta-analysis aimed to summarize the current evidence evaluating the efficacy and safety of percutaneous insertion methods compared to surgical methods. METHOD: A literature search was performed in the PubMed, EMBASE, Cochrane, and Web of Science databases. The primary outcome was defined as catheter survival. The secondary outcomes were mechanical and infectious complications related to catheter insertion. RESULTS: Twenty studies were finally identified, including 2 randomized controlled trials. The pooled results of catheter survival, overall mechanical complications, and infectious complications were not significant (odds ratio [OR] = 1.10, 95% confidence interval (CI) = 0.76-1.57, p = 0.62; OR = 0.73, 95% CI = 0.48-1.11, p = 0.14; and OR = 0.64, 95% CI = 0.37-1.09, p = 0.14, respectively). Comparison stratified by the blind percutaneous method versus open surgery indicated a lower overall number of mechanical complications (OR = 0.54, 95% CI = 0.31-0.93, I2 = 72%) and malposition rate (OR = 0.56, 95% CI = 0.34-0.90, I2 = 0%). The leakage rate was higher in the blind percutaneous group than in the open surgery group (OR = 2.55, 95% CI = 1.72-3.79, I2 = 0%); the guided percutaneous method achieved a similar leakage risk to the surgical methods. CONCLUSIONS: The blind percutaneous method performed better with fewer overall mechanical complications and less malposition than open surgery. The leakage risk was higher in the blind percutaneous group, while the guided percutaneous placement group showed similar outcomes to the surgical method groups. Percutaneous methods also had a lower infection risk, which needs further evidence to be confirmed.

NS398 as a potential drug for autosomal-dominant polycystic kidney disease: Analysis using bioinformatics, and zebrafish and mouse models.

Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by uncontrolled renal cyst formation, and few treatment options are available. There are many parallels between ADPKD and clear-cell renal cell carcinoma (ccRCC); however, few studies have addressed the mechanisms linking them. In this study, we aimed to investigate their convergences and divergences based on bioinformatics and explore the potential of compounds commonly used in cancer research to be repurposed for ADPKD. We analysed gene expression datasets of ADPKD and ccRCC to identify the common and disease-specific differentially expressed genes (DEGs). We then mapped them to the Connectivity Map database to identify small molecular compounds with therapeutic potential. A total of 117 significant DEGs were identified, and enrichment analyses results revealed that they are mainly enriched in arachidonic acid metabolism, p53 signalling pathway and metabolic pathways. In addition, 127 ccRCC-specific up-regulated genes were identified as related to the survival of patients with cancer. We focused on the compound NS398 as it targeted DEGs and found that it inhibited the proliferation of Pkd1-/- and 786-0 cells. Furthermore, its administration curbed cystogenesis in Pkd2 zebrafish and early-onset Pkd1-deficient mouse models. In conclusion, NS398 is a potential therapeutic agent for ADPKD.

The Role of Renal Pathology in the Prognosis and Recovery of Community-Acquired Acute Kidney Injury.

OBJECTIVES: The determinants leading to different renal outcomes in community-acquired acute kidney injury (CA-AKI) and the influence of renal histological damage on the prognosis and recovery of CA-AKI are scarcely reported. METHODS: Adult patients with CA-AKI admitted to Shanghai Changzheng Hospital with renal biopsy profiles from January 1, 2010, to December 31, 2018, were enrolled in our cohort. After 3 months of follow-up, clinical outcomes, including patient survival, dialysis requirement during hospitalization and at 3 months, CKD stage 3-5, and renal functional recovery at 3 months, were analyzed, and risk factors were identified. RESULTS: A total of 294 patients with CA-AKI with renal pathology were identified for this cohort. Among 282 patients who survived 3 months after AKI, 59.6% completely recovered, 21.3% partially recovered, 21.3% progressed to stage 3-5 CKD without dialysis, and 17.7% maintained dialysis. Moreover, 70.4% of patients in the cohort presented with de novo intrinsic renal disease, except acute tubular necrosis or acute interstitial nephritis, on renal biopsy. In the multivariate analyses, clinical factors were more related to short-term outcomes and severity of CA-AKI, represented by mortality, in-hospital dialysis, and CRRT requirement, while pathological elements were more involved with CKD progression, including dialysis-dependent or stage 3-5 CKD, and renal function recovery at the 3-month follow-up. The detrimental influence of glomerular and arterial lesions on renal prognosis of CA-AKI was as critical as tubular and interstitial lesions. CONCLUSIONS: Clinical and pathological parameters both contribute to patient and renal outcomes after CA-AKI. The value of renal biopsy should be recognized in prognostic prediction.

Inhibition of hepatocyte nuclear factor 1ß contributes to cisplatin nephrotoxicity via regulation of nf-κb pathway.

Cisplatin nephrotoxicity has been considered as serious side effect caused by cisplatin-based chemotherapy. Recent evidence indicates that renal tubular cell apoptosis and inflammation contribute to the progression of cisplatin-induced acute kidney injury (AKI). Hepatocyte nuclear factor 1ß (HNF1ß) has been reported to regulate the development of kidney cystogenesis, diabetic nephrotoxicity, etc However, the regulatory mechanism of HNF1ß in cisplatin nephrotoxicity is largely unknown. In the present study, we examined the effects of HNF1ß deficiency on the development of cisplatin-induced AKI in vitro and in vivo. HNF1ß down-regulation exacerbated cisplatin-induced RPTC apoptosis by indirectly inducing NF-κB p65 phosphorylation and nuclear translocation. HNF1ß knockdown C57BL/6 mice were constructed by injecting intravenously with HNF1ß-interfering shRNA and PEI. The HNF1ß scramble and knockdown mice were treated with 30 mg/kg cisplatin for 3 days to induce acute kidney injury. Cisplatin treatment caused increased caspase 3 cleavage and p65 phosphorylation, elevated serum urea nitrogen and creatinine, and obvious histological damage of kidney such as fractured tubules in control mice, which were enhanced in HNF1ß knockdown mice. These results suggest that HNF1ß may ameliorate cisplatin nephrotoxicity in vitro and in vivo, probably through regulating NF-κB signalling pathway.

Author Correction: PHF14: an innate inhibitor against the progression of renal fibrosis following folic acid-induced kidney injury.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

New-onset glucose disorders in peritoneal dialysis patients: a meta-analysis and systematic review.

BACKGROUND: Peritoneal dialysis (PD) patients are at high risk of developing glucose metabolism disturbance (GMD). The incidence and prevalence of new-onset GMD, including diabetes mellitus (DM), impaired glucose tolerance (IGT) and impaired fast glucose (IFG), after initiation of PD, as well as their correlated influence factors, varies among studies in different areas and of different sample sizes. Also, the difference compared with hemodialysis (HD) remained unclear. Thus we designed this meta-analysis and systematic review to provide a full landscape of the occurrence of glucose disorders in PD patients. METHODS: We searched the MEDLINE, Embase, Web of Science and Cochrane Library databases for relevant studies through September 2018. Meta-analysis was performed on outcomes using random effects models with subgroup analysis and sensitivity analysis. RESULTS: We identified 1124 records and included 9 studies involving 13 879 PD patients. The pooled incidence of new-onset DM (NODM) was 8% [95% confidence interval (CI) 4-12; I2 = 98%] adjusted by sample sizes in PD patients. Pooled incidence rates of new-onset IGT and IFG were 15% (95% CI 3-31; I2 = 97%) and 32% (95% CI 27-37), respectively. There was no significant difference in NODM risk between PD and HD [risk ratio 0.99 (95% CI 0.69-1.40); P = 0.94; I2 = 92%]. PD patients with NODM were associated with an increased risk of mortality [hazard ratio 1.06 (95% CI 1.01-1.44); P < 0.001; I2 = 92.5%] compared with non-DM PD patients. CONCLUSIONS: Around half of PD patients may develop a glucose disorder, which can affect the prognosis by significantly increasing mortality. The incidence did not differ among different ethnicities or between PD and HD. The risk factor analysis did not draw a definitive conclusion. The glucose tolerance test should be routinely performed in PD patients.

Clinical Characteristics and Outcomes of Community-Acquired versus Hospital-Acquired Acute Kidney Injury: A Meta-Analysis.

BACKGROUND: The different clinical characteristics of community-acquired acute kidney injury (CA-AKI) versus hospital-acquired AKI (HA-AKI) have remained inconclusive, and thus, a meta-analysis was conducted to summarize and quantify the clinical significance distinguishing the 2 types of AKI. METHODS: We identified observational studies reporting the clinical characteristics and prognosis of HA-AKI and CA-AKI. ORs and mean differences (MDs) were extracted for each outcome and the results aggregated. The primary outcome was defined as the mortality rate; renal recovery, oliguria incidence, dialysis, intensive care unit (ICU) requirement, and length of hospital stay were secondary outcomes. RESULTS: Fifteen eligible studies involving 46,157 patients (22,791 CA-AKI patients and 23,366 HA-AKI patients) were included. Mortality was significantly lower in CA-AKI than in HA-AKI patients, with an OR of 0.43 (95% CI 0.35-0.53). The incidence of oliguria and need for ICU were also lower in CA-AKI patients (OR 0.58, 95% CI 0.38-0.88; OR 0.24, 95% CI 0.14-0.40, respectively). CA-AKI patients had a shorter hospital stay (MD -9.42, 95% CI -13.73 to -5.12). The renal recovery rate and dialysis need between CA- and HA-AKI were similar (OR 1.27, 95% CI 0.53-3.02; OR 1.05, 95% CI 0.82-1.34, respectively). CONCLUSIONS: CA-AKI showed better clinical manifestations with a lower incidence of oliguria, reduced risk of ICU treatment, and shorter hospital stay. Mortality associated with CA-AKI was lower compared with HA-AKI, indicating a better prognosis. The rate of renal recovery and need for dialysis showed no significant difference between the 2 groups.

Shen-Shuai-Ning granule decreased serum concentrations of indoxyl sulphate in uremic patients undergoing peritoneal dialysis.

Clearance of protein-bound uremic toxins (PBUTs) by dialysis is a challenge in the treatment of uremic patients. Shen-Shuai-Ning (SSN), a traditional Chinese medicine formulation, has been used commonly in China to retard kidney disease progression and decrease uremic toxins in chronic kidney disease (CKD) patients, but the effects of SSN on serum PBUTs in dialysis patients were not investigated. We conducted a randomized controlled trial in patients on peritoneal dialysis (PD) at dialysis center of Changzheng Hospital to evaluate the effects of SSN on serum PBUTs. Participants with SSN intervention took 5 g SSN granule three times daily for 12 weeks, while the baseline medications and dialysis prescriptions remained during the study in all patients. The serum concentrations of indoxyl sulphate (IS) and p-cresol sulphate (PCS) were determined by HPLC/MS/MS and biochemical parameters were assessed during the study. Sixty PD patients were enrolled and randomly allocated into SSN group and control group. Total IS level was significantly lower in SSN group than in control group at week 4, 8, and 12 (27.28 ± 18.19, 29.73 ± 19.10, and 29.41 ± 17.61 mg/l compared with 39.25 ± 20.23, 44.86 ± 23.91, and 45.34 ± 33.52 mg/l, respectively). However, there were no statistical difference of total PCS, free forms of IS and PCS concentrations between SSN group and control group during 12 weeks follow-up. Administration of SSN granule orally decreased serum total IS level effectively in uremic patients on PD with good tolerance. Benefits of PD patients' outcomes from IS reduction by SSN awaits further large size and long duration clinical trials to verify.

PHF14: an innate inhibitor against the progression of renal fibrosis following folic acid-induced kidney injury.

PHF14 is a newly identified regulator of mesenchyme growth in embryonic tissues. Previous studies have shown that phf14-null mutants die just after birth due to interstitial tissue hyperplasia in major organs, including the kidneys. The aim of this study was to investigate PHF14 function in renal fibrosis. By studying the chronic kidney injury mouse model, we found that PHF14 was upregulated in fibrotic kidneys after renal insults induced by folic acid administration. Compared with wild-type mice, PHF14-null mice showed more severe renal fibrosis after pro-fibrotic stimuli. Moreover, PHF14 in rat renal fibroblasts was upregulated by transforming growth factor-ß (TGF-ß) stimulation; while this upregulation was inhibited when smad3 phosphorylation was blocked. A chromatin immunoprecipitation (ChIP) assay further indicated that phospho-smad3 (p-smad3) acted as a transcription factor to enhance PHF14 expression. A lack of PHF14 expression enhanced collagen I and α-smooth muscle actin (α-SMA) synthesis induced by TGF-ß in vitro. PHF14 was involved in inhibition of platelet-derived growth factor (PDGF) signaling overactivation by selectively repressing PDGF receptor-α (PDGFR-α) transcription. In summary, PHF14 expression was upregulated in fibrotic models in vivo and in vitro, and the TGF-ß/smad3/PHF14 pathway acted as a self-limiting mechanism in the TGF-ß-dominated renal pro-fibrotic process by suppressing PDGFR-α expression.