-
Journal of the American Society of... Mar 2022Understanding nephron loss is a primary strategy for preventing CKD progression. Death of renal tubular cells may occur by apoptosis during developmental and... (Review)
Review
Understanding nephron loss is a primary strategy for preventing CKD progression. Death of renal tubular cells may occur by apoptosis during developmental and regenerative processes. However, during AKI, the transition of AKI to CKD, sepsis-associated AKI, and kidney transplantation ferroptosis and necroptosis, two pathways associated with the loss of plasma membrane integrity, kill renal cells. This necrotic type of cell death is associated with an inflammatory response, which is referred to as necroinflammation. Importantly, the necroinflammatory response to cells that die by necroptosis may be fundamentally different from the tissue response to ferroptosis. Although mechanisms of ferroptosis and necroptosis have recently been investigated in detail, the cell death propagation during tubular necrosis, although described morphologically, remains incompletely understood. Here, we argue that a molecular switch downstream of tubular necrosis determines nephron regeneration versus nephron loss. Unraveling the details of this "switch" must include the inflammatory response to tubular necrosis and regenerative signals potentially controlled by inflammatory cells, including the stimulation of myofibroblasts as the origin of fibrosis. Understanding in detail the molecular switch and the inflammatory responses to tubular necrosis can inform the discussion of therapeutic options.
Topics: Acute Kidney Injury; Apoptosis; Female; Humans; Kidney; Kidney Cortex Necrosis; Male; Necrosis; Nephrons; Renal Insufficiency, Chronic
PubMed: 35022311
DOI: 10.1681/ASN.2021101293 -
The Korean Journal of Internal Medicine May 2022
Topics: Diabetes Mellitus; Humans; Kidney; Necrosis
PubMed: 35417650
DOI: 10.3904/kjim.2021.411 -
Nature Reviews. Nephrology May 2023Disorders of cell number that result from an imbalance between the death of parenchymal cells and the proliferation or recruitment of maladaptive cells contributes to... (Review)
Review
Disorders of cell number that result from an imbalance between the death of parenchymal cells and the proliferation or recruitment of maladaptive cells contributes to the pathogenesis of kidney disease. Acute kidney injury can result from an acute loss of kidney epithelial cells. In chronic kidney disease, loss of kidney epithelial cells leads to glomerulosclerosis and tubular atrophy, whereas interstitial inflammation and fibrosis result from an excess of leukocytes and myofibroblasts. Other conditions, such as acquired cystic disease and kidney cancer, are characterized by excess numbers of cyst wall and malignant cells, respectively. Cell death modalities act to clear unwanted cells, but disproportionate responses can contribute to the detrimental loss of kidney cells. Indeed, pathways of regulated cell death - including apoptosis and necrosis - have emerged as central events in the pathogenesis of various kidney diseases that may be amenable to therapeutic intervention. Modes of regulated necrosis, such as ferroptosis, necroptosis and pyroptosis may cause kidney injury directly or through the recruitment of immune cells and stimulation of inflammatory responses. Importantly, multiple layers of interconnections exist between different modalities of regulated cell death, including shared triggers, molecular components and protective mechanisms.
Topics: Humans; Apoptosis; Kidney; Necrosis; Acute Kidney Injury; Ferroptosis
PubMed: 36959481
DOI: 10.1038/s41581-023-00694-0 -
Nature Reviews. Nephrology Jan 2023Cisplatin is an effective chemotherapeutic agent for various solid tumours, but its use is limited by adverse effects in normal tissues. In particular, cisplatin is... (Review)
Review
Cisplatin is an effective chemotherapeutic agent for various solid tumours, but its use is limited by adverse effects in normal tissues. In particular, cisplatin is nephrotoxic and can cause acute kidney injury and chronic kidney disease. Preclinical studies have provided insights into the cellular and molecular mechanisms of cisplatin nephrotoxicity, which involve intracellular stresses including DNA damage, mitochondrial pathology, oxidative stress and endoplasmic reticulum stress. Stress responses, including autophagy, cell-cycle arrest, senescence, apoptosis, programmed necrosis and inflammation have key roles in the pathogenesis of cisplatin nephrotoxicity. In addition, emerging evidence suggests a contribution of epigenetic changes to cisplatin-induced acute kidney injury and chronic kidney disease. Further research is needed to determine how these pathways are integrated and to identify the cell type-specific roles of critical molecules involved in regulated necrosis, inflammation and epigenetic modifications in cisplatin nephrotoxicity. A number of potential therapeutic targets for cisplatin nephrotoxicity have been identified. However, the effects of renoprotective strategies on the efficacy of cisplatin chemotherapy needs to be thoroughly evaluated. Further research using tumour-bearing animals, multi-omics and genome-wide association studies will enable a comprehensive understanding of the complex cellular and molecular mechanisms of cisplatin nephrotoxicity and potentially lead to the identification of specific targets to protect the kidney without compromising the chemotherapeutic efficacy of cisplatin.
Topics: Animals; Cisplatin; Genome-Wide Association Study; Kidney; Apoptosis; Oxidative Stress; Acute Kidney Injury; Inflammation; Neoplasms; Necrosis; Renal Insufficiency, Chronic; Antineoplastic Agents
PubMed: 36229672
DOI: 10.1038/s41581-022-00631-7 -
Cancer Medicine Feb 2023Dirty necrosis (DN) in renal cell carcinoma (RCC) is morphologically characterized by abundant neutrophil infiltration and has significant potential as an unfavorable...
AIM
Dirty necrosis (DN) in renal cell carcinoma (RCC) is morphologically characterized by abundant neutrophil infiltration and has significant potential as an unfavorable prognostic indicator. This study aimed to analyze the pathological and biological features of DN.
MATERIALS AND METHODS
A total of 81 RCC tumors, including 33 cases of DN and 48 cases of tumor necrosis without DN features (ghost necrosis [GN]), were enrolled in this study. We compared the number of neutrophils; the activation of cell death pathways, including ferroptosis, NETosis, and apoptosis; the rate of epithelial-mesenchymal transition (EMT); and proliferation status using immunohistochemistry. We further assessed the effect of the necrosis type on systemic inflammation.
RESULTS
DN tumors had a significantly higher number of neutrophils in both areas around the necrotic foci and far from the necrotic foci. Ferroptosis status did not differ between DN and GN; however, DN tumors had significantly larger areas exhibiting cell detritus with neutrophil extracellular traps (NETs) detected by citrullinated histone H3 (citH3) than GN tumors. DN tumors also had more apoptotic cells within areas around the necrotic foci. There was no significant difference between the EMT and proliferation status between DN and GN groups. Systemic inflammation markers including C-reactive protein (CRP), CRP-to-albumin ratio (CRP/Alb), platelet-to-lymphocyte ratio (PLR), and hemoglobin were significantly higher in patients with DN. In addition, some of these inflammation markers (CRP/Alb and PLR) significantly decreased after surgery.
CONCLUSIONS
DN in RCC is characterized by NETs production and systemic inflammation.
Topics: Humans; Carcinoma, Renal Cell; Inflammation; Neutrophils; C-Reactive Protein; Kidney Neoplasms; Necrosis
PubMed: 36127822
DOI: 10.1002/cam4.5249 -
American Journal of Clinical Pathology Mar 2022The consensus conference of the International Society of Urological Pathology (ISUP), held in 2012, made recommendations regarding prognostic parameters of renal tumors....
OBJECTIVES
The consensus conference of the International Society of Urological Pathology (ISUP), held in 2012, made recommendations regarding prognostic parameters of renal tumors. There was a strong consensus that tumor morphotype, pathologic tumor stage, and tumor grade are prognostic indicators of poor outcome. It was also agreed upon that prognostic significance of tumor necrosis is in evolution, and both microscopic and macroscopic tumor necrosis should be documented in percentages. The aim of our study was to explore the impact of tumor necrosis on metastasis-free survival in clear cell renal carcinomas (ccRCCs) in Pakistani patients.
METHODS
We retrieved 318 consecutive in-house cases of ccRCC resections from 2014 to 2020 through hospital archives. Histologic slide review was done for assessment of tumor necrosis, tumor stage, and World Health Organization/ISUP grade. The follow-up data to assess metastasis-free survival were available in hospital archives.
RESULTS
In multivariable analysis performed by logistic regression model, tumor necrosis was an independent poor prognostic indicator (P = .0001): group 1 (reference group), 0% necrosis; group 2, 1% to 10% necrosis (adjusted odds ratio [AOR], 8.71; 95% confidence interval [CI], 3.62-20.98); and group 3, more than 10% necrosis (AOR, 9.48; 95% CI, 3.99-22.725).
CONCLUSIONS
Tumor necrosis is an independent predictor of poor outcome in ccRCCs.
Topics: Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Necrosis; Neoplasm Grading; Prognosis
PubMed: 34643216
DOI: 10.1093/ajcp/aqab136 -
Transplant Immunology Apr 2022Renal graft cortical necrosis (GCN) is a catastrophic cause of graft failure. We evaluated the incidence, causes, management, and outcome of GCN across two decades from...
BACKGROUND
Renal graft cortical necrosis (GCN) is a catastrophic cause of graft failure. We evaluated the incidence, causes, management, and outcome of GCN across two decades from our center.
METHODS
This is a retrospective analysis of transplant patients who had biopsy-proven GCN transplanted between 2000 and 2020. The clinical details, immunological workup, induction, maintenance regimen, causes of cortical necrosis, and the outcomes were compared between the first period 2000-2012, and the second period 2013-2020, when Flow cytometric and Luminex based crossmatch were included in the workup plan.
RESULTS
Among 2333 live ABO-compatible renal transplants, 37 (0.015%) patients (36 patients between 2000 and 2012 and 1 between 2013 and 2020) developed GCN (60% had diffuse and 40% patchy GCN) at a median of 8 days after transplantation.Twenty-six (60%) received ATG, 4 received plasmapheresis and ATG (10.8%) as antirejection therapy. The cyclosporine-based regimen was associated with a higher risk of GCN (RR 2.54; 95% CI 1.26 to 5.12, p = 0.009), whereas tacrolimus-based therapy had a lower risk (RR 0.39; 95% CI 0.19 to 0.79, p = 0.009). The introduction of flow cytometry and DSA assay has significantly decreased the incidence of acute rejection and GCN. Only one patient had GCN during the 2013-2020 period because of graft's mucormycosis. Twenty-five (67.56%) patients had no recovery, and 12 (32.43%) had partial recovery of graft function.
CONCLUSION
GCN is mainly associated with rejection, and cyclosporin-based maintenance regimen had a higher incidence. The remarkable decrease in GCN after 2012 onwards could be attributed to the use of Flowcytometry, Luminex-based DSA assays, and tacrolimus-based regimens.
Topics: Allografts; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Necrosis; Retrospective Studies; Tacrolimus
PubMed: 35217167
DOI: 10.1016/j.trim.2022.101558 -
The American Journal of Medicine Jul 1960
Topics: Humans; Kidney Papillary Necrosis; Necrosis
PubMed: 14414546
DOI: 10.1016/0002-9343(60)90012-7 -
BMC Cancer Sep 2018Tumor necrosis (TN) correlates with adverse outcomes in numerous solid tumors. However, its prognostic value in renal cell carcinoma (RCC) remains unclear. In this... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tumor necrosis (TN) correlates with adverse outcomes in numerous solid tumors. However, its prognostic value in renal cell carcinoma (RCC) remains unclear. In this study, we performed a meta-analysis to evaluate associations between TN and cancer-specific survival (CSS), overall survival (OS), recurrence-free survival (RFS) and progression-free-survival (PFS) in RCC.
METHODS
Electronic searches in PubMed, EMBASE and Web of Science were conducted according to the PRISMA statement. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated to evaluate relationships between TN and RCC. A fixed- or random-effects model was used to calculate pooled HRs and 95%CIs according to heterogeneity.
RESULTS
A total of 34 cohort studies met the eligibility criteria of this meta-analysis. The results showed that TN was significantly predictive of poorer CSS (HR = 1.37, 95% CI: 1.23-1.53, p < 0.001), OS (HR = 1.29, 95% CI: 1.20-1.40, p < 0.001), RFS (HR = 1.55, 95% CI: 1.39-1.72, p < 0.001) and PFS (HR = 1.31, 95% CI: 1.17-1.46, p < 0.001) in patients with RCC. All the findings were robust when stratified by geographical region, pathological type, staging system, number of patients, and median follow-up.
CONCLUSIONS
The present study suggests that TN is associated with CSS, OS, RFS and PFS clinical outcomes of RCC patients and may serve as a predictor of poor prognosis in these patients.
Topics: Biomarkers, Tumor; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Male; Necrosis; Prognosis; Treatment Outcome
PubMed: 30176824
DOI: 10.1186/s12885-018-4773-z -
Paediatrics and International Child... Aug 2021Subcutaneous fat necrosis (SFN) in the newborn is a form of panniculitis which presents with erythematous nodules and indurated plaques. Severe life-threatening...
Subcutaneous fat necrosis (SFN) in the newborn is a form of panniculitis which presents with erythematous nodules and indurated plaques. Severe life-threatening hypercalcaemia can occur as a late complication. A 2-month-old girl presented with severe hypercalcaemia and acute renal injury as a complication of SFN. She was admitted to hospital with the chief complaint of failure to thrive. She had a history of therapeutic hypothermia. After successful treatment of the hypercalcaemia with bisphosphonates, the acute renal injury recovered spontaneously. In neonates with SFN, acute renal injury is a rare complication of hypercalcaemia. Timely prevention of the complications of hypercalcaemia in SFN is essential.
Topics: Acute Kidney Injury; Fat Necrosis; Female; Humans; Hypercalcemia; Infant; Infant, Newborn; Necrosis; Subcutaneous Fat
PubMed: 33715600
DOI: 10.1080/20469047.2021.1883960