Nephropathy Is Aggravated by Fatty Acids in Diabetic Kidney Disease through Tubular Epithelial Cell Necroptosis and Is Alleviated by an RIPK-1 Inhibitor.

Introduction: Diabetic kidney disease (DKD), one of the leading causes of end-stage renal disease, has complex pathogenic mechanisms and few effective clinical therapies. DKD progression is accompanied by the loss of renal resident cells, followed by chronic inflammation and extracellular matrix deposition. Necroptosis is a newly discovered form of regulated cell death and is a major form of intrinsic cell loss in certain diabetic complications such as cardiomyopathy, intestinal disease, and retinal neuropathy; however, its significance in DKD is largely unknown. Methods: In this study, the expression of necroptosis marker phosphorylated MLKL (p-MLKL) in renal biopsy tissues of patients with DKD was detected using immunofluorescence and semiquantified using immunohistochemistry. The effects of different disease-causing factors on necroptosis activation in human HK-2 cells were evaluated using immunofluorescence and Western blotting. db/db diabetic mice were fed a high-fat diet to establish an animal model of DKD with significant renal tubule damage. Mice were treated with the RIPK1 inhibitor RIPA-56 to evaluate its renal protective effects. mRNA transcriptome sequencing was used to explore the changes in signaling pathways after RIPA-56 treatment. Oil red O staining and electron macroscopy were used to observe lipid droplet accumulation in renal biopsy tissues and mouse kidney tissues. Results: Immunostaining of phosphorylated RIPK1/RIPK3/MLKL verified the occurrence of necroptosis in renal tubular epithelial cells of patients with DKD. The level of the necroptosis marker p-MLKL correlated positively with the severity of renal functional, pathological damages, and lipid droplet accumulation in patients with DKD. High glucose and fatty acids were the main factors causing necroptosis in human renal tubular HK-2 cells. Renal function deterioration and renal pathological injury were accelerated, and the necroptosis pathway was activated in db/db mice fed a high-fat diet. Application of RIPA-56 effectively reduced the degree of renal injury, inhibited the necroptosis pathway activation, and reduced necroinflammation and lipid droplet accumulation in the renal tissues of db/db mice fed a high-fat diet. Conclusion: The present study revealed the role of necroptosis in the progression of DKD and might provide a new therapeutic target for the treatment of DKD.

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.

Chromatin accessibility dynamics dictate renal tubular epithelial cell response to injury.

Renal tubular epithelial cells (TECs) can initiate an adaptive response to completely recover from mild acute kidney injury (AKI), whereas severe injury often leads to persistence of maladaptive repair and progression to kidney fibrosis. Through profiling of active DNA regulatory elements by ATAC-seq, we reveal widespread, dynamic changes in the chromatin accessibility of TECs after ischemia-reperfusion injury. We show that injury-specific domains of regulatory chromatin become accessible prior to gene activation, creating poised chromatin states to activate the consequent gene expression program and injury response. We further identify RXRα as a key transcription factor in promoting adaptive repair. Activation of RXRα by bexarotene, an FDA-approved RXRα agonist, restores the chromatin state and gene expression program to protect TECs against severe kidney injury. Together, our findings elucidate a chromatin-mediated mechanism underlying differential responses of TECs to varying injuries and identify RXRα as a therapeutic target of acute kidney injury.

Single Cell RNA Sequencing Identifies a Unique Inflammatory Macrophage Subset as a Druggable Target for Alleviating Acute Kidney Injury.

Acute kidney injury (AKI) is a complex clinical disorder associated with poor outcomes. Targeted regulation of the degree of inflammation has been a potential strategy for AKI management. Macrophages are the main effector cells of kidney inflammation. However, macrophage heterogeneity in ischemia reperfusion injury induced AKI (IRI-AKI) remains unclear. Using single-cell RNA sequencing of the mononuclear phagocytic system in the murine IRI model, the authors demonstrate the complementary roles of kidney resident macrophages (KRMs) and monocyte-derived infiltrated macrophages (IMs) in modulating tissue inflammation and promoting tissue repair. A unique population of S100a9hi Ly6chi IMs is identified as an early responder to AKI, mediating the initiation and amplification of kidney inflammation. Kidney infiltration of S100A8/A9+ macrophages and the relevance of renal S100A8/A9 to tissue injury is confirmed in human AKI. Targeting the S100a8/a9 signaling with small-molecule inhibitors exhibits renal protective effects represented by improved renal function and reduced mortality in bilateral IRI model, and decreased inflammatory response, ameliorated kidney injury, and improved long-term outcome with decreased renal fibrosis in the unilateral IRI model. The findings support S100A8/A9 blockade as a feasible and clinically relevant therapy potentially waiting for translation in human AKI.

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.

Spontaneous perirenal hemorrhage in systemic lupus erythematosus: a rare case report and literature review.

BACKGROUND: Spontaneous perirenal hemorrhage is relatively uncommon but may be life-threatening. There are some challenges in early diagnosis due to the lack of specific presentations. CASE PRESENTATION: We report a case of spontaneous perirenal hemorrhage in a newly diagnosed systemic lupus erythematosus patient who initially presented with non-specific flank pain. Weakness and unstable vital signs were noted on admission. Abdominal ultrasonography and computed tomography revealed a sizable perirenal hematoma over the left retroperitoneal cavity. Renal arteriography identified active extravasation of contrast media from a distant branch of the left renal artery, and selective embolization effectively obliterated the bleeding spot. After cessation of bleeding, the patient received intensive immunosuppressive therapy for acute kidney injury and encephalopathy due to lupus. Her mental status recovered successfully, and she was withdrawn from short-term hemodialysis. CONCLUSIONS: Spontaneous perirenal hemorrhage in the condition of systemic lupus erythematosus was a rare clinical entity with life-threatening potential. Early accurate diagnosis of spontaneous renal hemorrhage requires both detailed clinical examination and radiologic studies. Interventional embolization is essential and effective for both diagnosis and treatment. A high index of suspicion is necessary to avoid missing this potentially fatal syndrome, especially in patients with an increased risk of bleeding.

Acute Kidney Injury Relevant to Tubulointerstitial Nephritis with Late-Onset Uveitis Superimposed by Thrombotic Microangiopathy: A Case Report and Review of the Literature.

BACKGROUND: The syndrome of tubulointerstitial nephritis and uveitis (TINU) is an uncommon and multisystemic autoimmune disorder. This review reports a rare case of TINU being superimposed on thrombotic microangiopathy (TMA) and, by comparing with the available literature, also summarizes the clinical features, associated conditions, treatment, and outcome of patients with TINU. SUMMARY: Herein, we report the case of a 37-year-old male patient with acute kidney injury (AKI) clinicopathologically identified as malignant hypertension-induced TMA superimposed by acute tubulointerstitial nephritis, which was suspected to be related to drug hypersensitivity. After treatment with oral prednisone combined with a renin-angiotensin system inhibitor, the patient achieved partial renal recovery and was withdrawn from hemodialysis. Recurrent AKI concomitant with new-onset asymptomatic uveitis was detected during routine clinical follow-up after cessation of prednisone. TINU was then diagnosed, and prednisone followed by cyclophosphamide was prescribed. The patient achieved better renal recovery than in the first round of treatment and maintained stable renal function afterward. By reviewing the literature, 36 cases were reported as TINU superimposed on other conditions, including thyroiditis, osteoarthropathy, and sarcoid-like noncaseating granulomas. KEY MESSAGES: TINU could be complicated by many other conditions, among which TMA is very rare. When presented as AKI, kidney biopsy is important for differential diagnosis. The case also shows that recurrent AKI with concomitant uveitis after prednisone withdrawal strongly suggested the need for long-term follow-up and elongated prednisone therapy for TINU syndrome.

Acute Kidney Injury in COVID-19: The Chinese Experience.

Coronavirus disease 2019 (COVID-19) is spreading rapidly worldwide. Here, we review recently published studies on COVID-19-associated acute kidney injury (AKI) in China. The pooled incidence of AKI in all reported COVID-19 patients was 6.5%, with a much higher rate in patients from the intensive care unit (32.5%). AKI is associated with the severity of COVID-19 and mortality rates, which is similar to other kidney abnormalities including proteinuria and hematuria. The renal tubule is the main site of injury in COVID-19 patients, and the etiology of renal impairment in COVID-19 patients likely is diverse and multifactorial. Apart from direct viral attack via angiotensin-converting enzyme 2 and transmembrane serine proteases 2, hypoxia and hypercoagulability also may contribute to the occurrence of renal injury. To date, there is only randomized controlled trial evidence to support the use of dexamethasone in patients requiring oxygen therapy and remdesivir for shortening the time to recovery, with no specific treatment for COVID-19-associated AKI. Studies researching kidney pathologies or reporting renal outcome and prognosis are in urgent need. Further studies are urgently warranted to identify risk factors, to predict prognosis and renal outcome, to explore the exact mechanisms of renal injury, and to suggest targeted interventions.

Prevalence of Kidney Injury and Associations with Critical Illness and Death in Patients with COVID-19.

BACKGROUND AND OBJECTIVES: Coronavirus disease 2019 is spreading rapidly across the world. This study aimed to assess the characteristics of kidney injury and its association with disease progression and death of patients with coronavirus disease 2019. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a retrospective study. Two representative cohorts were included. Cohort 1 involved severe and critical patients with coronavirus disease 2019 from Wuhan, China. Cohort 2 was all patients with coronavirus disease 2019 in Shenzhen city (Guangdong province, China). Any kidney injury was defined as the presence of any of the following: hematuria, proteinuria, in-hospital AKI, or prehospital AKI. AKI was defined according to the Kidney Disease Improving Global Outcomes (KDIGO) creatinine criteria. The primary outcome was death at the end of follow-up. The secondary outcome was progression to critical illness during the study period. RESULTS: A total of 555 patients were enrolled; 42% of the cases (229 of 549) were detected with any kidney injury, 33% of the cases (174 of 520) were detected with proteinuria, 22% of the cases (112 of 520) were detected with hematuria, and 6% of the cases (29 of 520) were detected with AKI. Of the 29 patients with AKI, 21 cases were recognized as in-hospital AKI, and eight were recognized as prehospital AKI. Altogether, 27 (5%) patients died at the end of follow-up. The death rate was 11% (20 of 174) in patients with proteinuria, 16% (18 of 112) in patients with hematuria, and 41% (12 of 29) in the AKI settings. Multivariable Cox regression analysis showed that proteinuria (hazard ratio, 4.42; 95% confidence interval, 1.22 to 15.94), hematuria (hazard ratio, 4.71; 95% confidence interval, 1.61 to 13.81), and in-hospital AKI (hazard ratio, 6.84; 95% confidence interval, 2.42 to 19.31) were associated with death. Among the 520 patients with noncritical illness at admission, proteinuria (hazard ratio, 2.61; 95% confidence interval, 1.22 to 5.56) and hematuria (hazard ratio, 2.50; 95% confidence interval, 1.23 to 5.08) were found to be associated with progression to critical illness during the study period. CONCLUSIONS: Kidney injury is common in coronavirus disease 2019, and it is associated with poor clinical outcomes. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_09_18_CJN04780420.mp3.

Sleep Disorders and Cognitive Impairment in Peritoneal Dialysis: A Multicenter Prospective Cohort Study.

BACKGROUND: Patients with chronic kidney disease experience a high burden of sleep disorders, and there are associations between sleep disorders and cognitive impairment. OBJECTIVES: Based on our previous cross-sectional survey on cognitive impairment in peritoneal dialysis, we further explored the relationship between sleep disorders and cognitive impairment, and predictors for declining cognitive function. METHOD: We conducted a multicenter prospective cohort study enrolling 458 clinically stable patients on peritoneal dialysis who were then followed up for 2 years.Demographic data, comorbidities, depression, and biochemistry data were collected at baseline. Sleep disorders including insomnia, restless legs syndrome, sleep apnea syndrome, excessive daytime sleepiness, possible narcolepsy, sleep walking and nightmares, and possible rapid eye movement behavior disorders were assessed using a panel of specific sleep questionnaires at baseline and in a second survey. Global cognitive function was measured at baseline and in a second survey, using the Modified Mini-Mental State Examination. Specific cognitive domains were evaluated using Trail-Making Test Forms A and B for executive function, and subtests of the Battery for the Assessment of Neuropsychological Status were used to asses immediate and delayed memory, visuospatial skills, and language ability. RESULTS: Sleep disorders were common among peritoneal dialysis patients. The prevalence of cognitive impairment evaluated by the Modified Mini-Mental State Examination (3MS) increased from 19.8 to 23.9%. Possible narcolepsy was associated with decreased Modified Mini-Mental State Examination scores at baseline. During follow-up, sleepwalking and nightmares were associated with higher risks of declined delayed memory in the longitudinal study. CONCLUSIONS: Possible narcolepsy was associated with general cognitive dysfunction, and sleep walking and nightmares were risk factors for impaired delayed memory.

Perspectives on acute kidney injury strategy in China.

Acute kidney injury (AKI) has imposed a heavy disease burden in China, with substantial underdiagnosis and undertreatment. The incidence, cause and outcome of patients with AKI vary according to different geographic regions and economic development status; therefore, regional improvement strategies are needed. Defining the etiology of AKI is critical in making the proper therapeutic regimen, and a multidisciplinary cooperative AKI team is essential in order to establish the early diagnosis and proper management of patients with AKI.

Correction to: Tubulointerstitial nephritis-induced hypophosphatemic osteomalacia in Sjögren's syndrome: a case report and review of the literature.

The Funding statement was omitted from the original publication; the authors have requested that this be noted and now presented in this article.

Tubulointerstitial nephritis-induced hypophosphatemic osteomalacia in Sjögren's syndrome: a case report and review of the literature.

Sjögren's syndrome (SS) is a chronic autoimmune inflammatory disease that typically affects the salivary and lacrimal glands. Renal involvement is relatively uncommon and may precede other complaints. Tubulointestitial nephritis (TIN) is the most common renal involvement in SS. Osteomalacia occurring as the first manifestation of renal tubular disorder due to SS is very rare. We report a 39-year-old male who presented with polydipsia, polyuria, and multiple bone pain. Bone density test showed severe osteoporosis, and laboratory findings suggested hypokalemia, hypophosphatemia, and vitamin D deficiency, which supported the diagnosis of hypophosphatemic osteomalacia. He had nephrogenic loss of phosphate and potassium, tubular acidification, and concentration dysfunction. And, the diagnosis of chronic TIN was subsequently confirmed by renal biopsy. The patient reported dry mouth and physical examination showed multiple dental caries. Xerophthalmia, abnormal morphology, and function of the salivary glands by sonography and scintigraphy, together with positive anti-SSA and anti-SSB, confirmed the diagnosis of SS. The TIN indicated SS as the underlying cause of osteomalacia. After taking supplements of potassium, phosphate, vitamin D, and sodium bicarbonate for 1 month, bone pain was alleviated and serological potassium and phosphorus were also back to normal. In conclusion, renal involvement in SS may be latent and precede the typical sicca symptoms. Osteomalacia can be the first manifestation of renal disorder due to SS. Therefore, autoantibody investigations as well as the lacrimal and salivary gland examinations for SS should be considered and performed for suspected patients.