Recent Advances in Senolysis for Age-Related Diseases.

Cellular senescence plays a central role in aging and geriatric diseases. Senolysis is a promising new strategy that selectively kills and eliminates senescent cells to control aging. To date, various senolytic drugs have been discovered and shown efficacy. This review highlights how we can benefit from senolysis.

In vivo dynamics of senescence in rhabdomyolysis-induced acute kidney injury.

Cellular senescence is involved in the pathogenesis of various diseases, including acute kidney injury (AKI). AKI is defined as a sudden loss of kidney function. In severe AKI, irreversible loss of kidney cells can occur. Cellular senescence might contribute to this maladaptive tubular repair, though, its pathophysiological role in vivo is incompletely understood. In this study, we used p16-CreERT2-tdTomato mice in which cells with high p16 expression, a prototypical senescent marker, are labeled with tdTomato fluorescence. Then, we induced AKI by rhabdomyolysis and traced the cells with high p16 expression following AKI. We proved that the induction of senescence was observed predominantly in proximal tubular epithelial cells (PTECs) and occurred in a relatively acute phase within 1-3 days after AKI. These acute senescent PTECs were spontaneously eliminated by day 15. On the contrary, the generation of senescence in PTECs persisted during the chronic recovery phase. We also confirmed that the kidney function did not fully recover on day 15. These results suggest that the chronic generation of senescent PTECs might contribute to maladaptive recovery from AKI and lead to chronic kidney disease progression.

The association between six month intra-dialytic resistance training and muscle strength or physical performance in patients with maintenance hemodialysis: a multicenter retrospective observational study.

BACKGROUND: Reduced muscle strength and physical performance are prevalent in patients of maintenance hemodialysis (MHD), and deleterious changes in these parameters are associated with increased mortality. METHODS: This retrospective observational study included 306 patients, who received a 6-month resistance exercise program during hemodialysis, three times per week on an outpatient basis. The training protocol consisted of two sets of 10 repetitions of knee extension, hip abduction, and hip flexion, using an elastic band in a sitting or supine position. Primary outcome measures included muscle strength, measured by percent knee extension muscle power to dry body weight (pKEMP-dBW), and physical performance, measured by short physical performance battery (SPPB). The adjusted mean differences in these variables during the 6 months were estimated using a multivariate linear regression model. RESULTS: The mean age with standard deviation was 70 ± 11 years. One hundred and sixty patients (52.3%) were men and the dry weight was 55.6 ± 11.3 kg. Sarcopenia, defined as SPPB ≤8, was present in 21.4% patients. Their hemodialysis adequacy was acceptable, with a Kt/V of 1.65 ± 0.29, and their nutritional status was good, with a normalized protein catabolism rate of 0.89 ± 0.18 g/kg/day. During the 6 months, both pKEMP-dBW and SPPB showed a slight but significant increase with an adjusted mean difference of 2.8 (95% confidence interval 1.3-4.3, p <  0.001) and 0.6 (0.4-0.9, p <  0.001), respectively. CONCLUSIONS: Six-month resistance training was associated with improved muscle strength and physical performance in patients with MHD.

A low initial serum sodium level is associated with an increased risk of overcorrection in patients with chronic profound hyponatremia: a retrospective cohort analysis.

BACKGROUND: Even with abundant evidence for osmotic demyelination in patients with hyponatremia, the risk factors for overcorrection have not been fully investigated. Therefore the purpose of this study is to clarify the risks for overcorrection during the treatment of chronic profound hyponatremia. METHODS: This is a single-center retrospective observational study. We enrolled 56 adult patients with a serum sodium (SNa) concentration of ≤125 mEq/L who were treated in an intensive care unit by nephrologists using a locally developed, fixed treatment algorithm between February 2012 and April 2014. The impact of patient parameters on the incidence of overcorrection was estimated using univariable and multivariable logistic regression models. Overcorrection was defined as an increase of SNa by >10 mEq/L and >18 mEq/L during the first 24 and 48 h, respectively. RESULTS: The median age was 78 years, 48.2% were male, and 94.6% of the patients presented with symptoms associated with hyponatremia. The initial median SNa was 115 mEq/L (quartile, 111-119 mEq/L). A total of 11 (19.6%) patients met the criteria for overcorrection with 9 (16.0%) occurring at 24 h, 6 (10.7%) at 48 h, and 4 (7.1%) at both 24 and 48 h. However, none of these patients developed osmotic demyelination. Primary polydipsia, initial SNa, and early urine output were the significant risk factors for overcorrection on univariable analysis. Multivariable analysis revealed that the initial SNa had a statistically significant impact on the incidence of overcorrection with an adjusted odds ratio of 0.84 (95% confidence interval, 0.70-0.98; p = 0.037) for every 1 mEq/L increase. Additionaly, the increase in SNa during the first 4 h and early urine output were significantly higher in patients with overcorrection than in those without (p = 0.001 and 0.005, respectively). CONCLUSIONS: An initial low level of SNa was associated with an increased risk of overcorrection in patients with profound hyponatremia. In this regard, the rapid increase in SNa during the first 4 h may play an important role.

Transcriptomic characterization of Lonrf1 at the single-cell level under pathophysiological conditions.

The LONRF family of proteins consists of three isozymes, LONRF1-3, which harbors RING (really interesting new gene) domain and Lon substrate binding domain. We have recently identified LONRF2 as a protein quality control ubiquitin ligase that acts predominantly in neurons. LONRF2 selectively ubiquitylates misfolded or damaged proteins for degradation. LONRF2-/- mice exhibit late-onset neurological deficits. However, the physiological implications of other LONRF isozymes remain unclear. Here, we analysed Lonrf1 expression and transcriptomics at the single-cell level under normal and pathological conditions. We found that Lonrf1 was ubiquitously expressed in different tissues. Its expression in LSEC and Kupffer cells increased with age in the liver. Lonrf1high Kupffer cells showed activation of regulatory pathways of peptidase activity. In normal and NASH (nonalcoholic steatohepatitis) liver, Lonrf1high LSECs showed activation of NF-kB and p53 pathways and suppression of IFNa, IFNg and proteasome signalling independent of p16 expression. During wound healing, Lonrf1high/p16low fibroblasts showed activation of cell growth and suppression of TGFb and BMP (bone morphogenetic protein) signalling, whereas Lonrf1high/p16high fibroblasts showed activation of WNT (wingless and Int-1) signalling. These results suggest that although Lonrf1 does not seem to be associated with senescence induction and phenotypes, LONRF1 may play a key role in linking oxidative damage responses and tissue remodelling during wound healing in different modes in senescent and nonsenescent cells.

Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis Superimposed on Post-streptococcal Acute Glomerulonephritis.

A 44-year-old woman was admitted due to gross hematuria and progressive renal dysfunction. Poststreptococcal acute glomerulonephritis (PSAGN) was suspected due to her elevated anti-streptolysin O and anti-streptokinase titers and hypocomplementemia. A renal biopsy showed crescent formation and endocapillary hypercellularity with neutrophil infiltrate. An immunofluorescence analysis showed granular immunoglobulin G and C3 deposition, suggesting immune-complex-type glomerulonephritis. However, myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA) was positive, and peritubular capillaritis was observed. Furthermore, citrullinated histone H3-positive neutrophils were detected as markers for neutrophil extracellular trap formation. Therefore, she was diagnosed with ANCA-associated vasculitis superimposed on PSAGN that was the main contributor to her progressive renal injury.

Clinicopathological characteristics of kidney injury in non-small cell lung cancer patients under combination therapy including pembrolizumab.

Combination therapy, consisting of immune checkpoint inhibitors and traditional chemotherapeutic agents, has significantly improved the clinical outcomes of non-small cell lung cancer. Therefore, it will be a promising first-line therapy, whereas, there is a prospect that associated kidney injury may increase during treatment. We presented four patients, diagnosed with advanced non-small cell lung cancer, who received combination therapy, consisting of pembrolizumab, cisplatin, and pemetrexed as first-line treatment. All of them had been referred to nephrologists and had undergone renal biopsy. We observed that three of four patients presented a very rapid time course for acute kidney injury development. Notably, the three patients received only one or two cycles of the combined chemotherapy. In a renal biopsy, one patient showed severe acute tubular injury rather than interstitial nephritis. Another patient presented focal segmental glomerular sclerosis concomitant with tubulointerstitial nephritis. However, it was challenging to distinguish which agent was primarily responsible for kidney injury. Regarding the treatment, all the patients discontinued pembrolizumab and received corticosteroid treatment. We adjusted the dose and duration of corticosteroid according to the pathological results and patient conditions. The current cases provide a further understanding of clinical features and appropriate management in patients treated with combination therapy including pembrolizumab.

Lower Limb Ulcer Associated with Peritonitis in Patients Undergoing Peritoneal Dialysis.

PURPOSE: Peritoneal dialysis (PD)-related peritonitis and lower limb ulcer are the important complications in patients undergoing PD. Although the association between lower limb ulcer and peritonitis in patients undergoing PD is unclear, based on our clinical experience and the clinical importance of the complications in patients undergoing PD, we hypothesized that lower limb ulcer is associated with peritonitis in patients on PD. PATIENTS AND METHODS: In this single center, retrospective cohort study, we studied 87 patients who started undergoing PD at our hospital from April 2015 to March 2020. We compared these 8 patients with lower limb ulcer with the other 79 patients without lower limb ulcer. We compared between the patients in the objection period of this study about peritonitis using Log rank test, and used the unpaired t-test and Fisher's exact test to compare the clinical factors between the two groups. Moreover, we used univariate and multivariate logistic regression analyses to study the association of PD-related peritonitis with the clinical factors. RESULTS: The period developed first peritonitis of the patients on PD with lower limb ulcer was significant shorter than those without lower limb ulcer in Log rank test (P = 0.011). The Fisher's exact test and unpaired t-test showed that the difference in the prevalence of PD-related peritonitis (P = 0.009), peritonitis/patient years (P = 0.036), the BMI (P = 0.007) and icodextrin (P = 0.001) were significant. Lower limb ulcer had significant associations with peritonitis in patients on PD in both univariate [odds ratio (OR) 8.461, 95% confidence interval (CI) 1.854-45.60, P = 0.006] and multivariate [OR 7.169, 95% CI 1.519-39.480, P = 0.013] logistic regression analysis. CONCLUSION: In conclusion, lower limb ulcer may be associated with peritonitis in patients undergoing PD. Further large-scale, prospective studies are required to confirm these results.

Syndrome of Inappropriate Secretion of Antidiuretic Hormone Caused by Very Short-term Use of Proton Pump Inhibitor.

Proton pump inhibitors (PPIs) are widely used medicines worldwide. However, a rare etiology of syndrome of inappropriate secretion of antidiuretic hormone (SIADH) related to PPI was recently reported. Therefore, the putative role of PPIs in SIADH cannot be underestimated. A 78-year-old Japanese woman was admitted to our hospital for treatment of left Bell's palsy. On admission, the patient was oriented with normal laboratory data, including a serum Na level of 135 mEq/L. Oral glucocorticoids and a proton pump inhibitor were initiated in combination with oral valaciclovir. Six days later, the patient's consciousness became impaired. Laboratory data showed a serum Na level of 103 mEq/L, a urine Na level of 64.8 mEq/L, a urine K level of 43.6 mEq/L, and a urine osmolality of 450 mOsm/kg H2O. The patient met the criteria for SIADH. The initial treatment included water restriction and 3% hypertonic saline administration. The cessation of PPI significantly improved the urine diluting capacity and concomitantly increased serum Na, which indicated that the use of PPI had been responsible for the etiology of SIADH. The present case illustrates that physicians need to be aware of the uncommon adverse effects of PPI, such as SIADH.

Tonsillectomy Combined With Steroid Pulse Therapy Prevents the Progression of Chronic Kidney Disease in Patients With Immunoglobulin A (IgA) Nephropathy in a Single Japanese Institution.

Background Despite the abundant experience of tonsillectomy with steroid pulse therapy (TSP) for patients with immunoglobulin A (IgA) nephropathy, the therapeutic efficacy of TSP on renal prognosis remains controversial. The purpose of this study was to evaluate the efficacy of whether TSP effectively prevents chronic kidney disease (CKD) progression. Methods This was a single-center, retrospective observational study. A total of 149 patients were enrolled in the current study who were confirmed with IgA nephropathy by renal biopsy between February 2011 and August 2019. The impact of TSP on CKD progression was compared with conservative treatment during a follow-up period of 3 years. Results In total, 110 patients received TSP and 39 patients received conservative treatment. There were no differences between the two groups in the initial CKD stages: 65.1% of patients had CKD G1-2, 32.2% had CKD G3, and 2.7% had CKD G4-5. The initial urine protein was 0.7 g/gCr, which was not different between the two groups. Kaplan-Meier analysis showed that patients with TSP had a significantly better renal prognosis than those in the conservative treatment group after one and a half years (p = 0.007). Multivariable analysis revealed that TSP had a significant impact on the prevention of CKD progression, with an adjusted odds ratio of 0.07 (95% confidence interval, 0.01-0.87; p=0.039). However, we could not confirm the predictive value of the Oxford Classification on TSP efficacy. Additionally, the initial urinary protein level was a risk factor for CKD progression. Conclusions TSP was associated with a lower risk of CKD progression. In this regard, our study supports that TSP may be a reasonable treatment option for patients with IgA nephropathy. In the featured study, it needs to be elucidated which histopathological classifications benefit from TSP treatment.

Smoking is a Risk Factor for Endogenous Peritonitis in Patients Undergoing Peritoneal Dialysis.

BACKGROUND: Peritonitis is one of the most common complications in patients undergoing peritoneal dialysis, (PD) but it is difficult to predict or prevent. In this study, we analyzed the risk of endogenous peritonitis in patients receiving PD. METHODS: We included all patients who underwent PD at our hospital from April 2015 to March 2020. There were 22 cases of peritonitis, including 18 cases of endogenous peritonitis without evidence of exit-site infection or technical failure. We evaluated older age, female sex, obesity, diabetes, diverticulosis, and constipation as potential important risk factors for endogenous peritonitis and included these as confounding factors, along with a current or previous history of smoking, in univariate logistic regression models. RESULTS: A previous or current history of smoking (p = 0.0065) was the most significant risk factor for endogenous peritonitis in the univariate logistic regression model. In addition, smoking was the most significant independent risk factor for endogenous peritonitis (p = 0.0034) in multivariate logistic regression models. Diabetes was also significant in univariate and multivariate logistic regression analysis. CONCLUSIONS: Smoking is a significant independent risk factor for endogenous peritonitis in patients undergoing PD. Cessation of smoking may lower the risk of endogenous peritonitis in this patient group.

Peritoneal Catheter Removal for Peritoneal Dialysis-Related Peritonitis Caused by Gram-Negative, Rod-Like Pseudomonas aeruginosa Infection During Antibiotic Therapy for Enterococcus faecalis.

Peritonitis is a common complication of peritoneal dialysis (PD) and can result in PD catheter removal, permanent hemodialysis, and, potentially, death. Prediction and prevention of PD-related peritonitis are thus extremely important. In 2016, the International Society for Peritoneal Dialysis published guidelines for patients with peritonitis undergoing PD. The guidelines cover most cases of PD-related peritonitis caused by bacteria and include clear indications for catheter removal. However, difficulties often arise when deciding the timing of catheter removal. When multiple enteric organisms are identified in a culture of dialysis effluent, peritonitis may be caused by intra-abdominal pathology, which is associated with substantial mortality. In such cases, catheter removal is considered. In this report, we describe a case in which, during antibiotic therapy for PD-related peritonitis due to Enterococcus faecalis alone, the patient developed a relapse of peritonitis caused by a newly detected Gram-negative, rod-like Pseudomonas aeruginosa. He required catheter removal because of the possibility of peritonitis recurrence. Although additional study is required, early catheter removal may be effective when a new organism is detected during antibiotic therapy for PD-related peritonitis caused by an organism not meeting the definition of refractory peritonitis.

Primary Tumor Infiltration and Severe Acute Kidney Injury in Patients with Acute Myeloblastic Leukemia.

In patients with hematologic malignancies, acute kidney injury (AKI) is the most common kidney complication requiring nephrologist consultation. Although the causes of AKI are multifactorial, primary tumor infiltration is rare in patients with acute myeloblastic leukemia (AML). This makes it challenging to determine the cause of AKI and the optimal chemotherapy regimen for AML. We describe two cases of AML (French-American-British classification: M2, M4) in patients with AKI requiring hemodialysis. We successfully identified the cause of AKI as primary leukemic infiltration and started induction chemotherapy in the setting of hemodialysis. This treatment significantly improved renal function and resulted in AML remission. In this report, we describe several clinical characteristics of AKI due to primary tumor infiltration. In addition, we emphasize the importance of onconephrology, a new subspecialty concerned with the complex relationship between the kidneys and cancer.

A case of female Fabry disease revealed by renal biopsy.

Fabry disease (FD) is an X-linked inherited glycosphingolipid metabolism disorder, therefore, heterozygous female FD patients display highly variable clinical symptoms, disease severity, and pathological findings. This makes it very challenging to diagnosing female patients with FD. A 69-year-old Japanese female was introduced to the nephrologist for the evaluation of proteinuria. A renal biopsy was performed. Although the light microscopic examinations revealed that most of the glomeruli showed minor glomerular abnormalities, however, vacuolation was apparently found in the tubular epithelial cells. Immunofluorescence staining for globotriaosylceramide was positively detected in some podocytes and distal tubular epithelial cells. In addition, myelin-like structure (zebra body) was detected by electron microscopy. Pathological findings were most consistent with FD. Consequently, biochemical and genetic analysis confirmed the diagnosis of female FD. Enzyme replacement therapy was performed in conjunction with renin-angiotensin aldosterone system inhibitors and beta-blockers. The patient's family members received the analysis, and the same DNA missense mutation was detected in the patient's grandson. The enzyme replacement therapy was introduced to the grandson. The present case showed that renal biopsy can contribute towards a correct diagnosis for FD. Particularly, in female FD patients, careful examination of pathological changes is essential, for example, vacuolation of any type of renal cells may be a clue for the diagnosis.

A case of membranous nephropathy diagnosed with lupus nephritis 11 years after onset.

A 34-year-old female patient presented to our hospital with lower extremity edema and proteinuria during pregnancy. Renal biopsy was performed and the patient was diagnosed with nephrotic syndrome due to lupus-like membranous nephropathy. This diagnosis was reached upon as laboratory findings upon admission, wherein both anti-nuclear and anti-double-stranded DNA antibodies revealed negative, did not fulfill the criteria for systemic lupus erythematosus (SLE) proposed by the American College of Rheumatology (ACR) and the patient did not reveal any typical physical manifestations of SLE. Methylprednisolone pulse therapy was started followed by oral administration of prednisolone. Urinary protein excretion diminished after 1 year of treatment. Eleven years later, the same patient was admitted to our hospital again with relapse of nephrotic syndrome. Laboratory findings upon second admission, wherein both anti-nuclear and anti-double-stranded DNA antibodies revealed positive, fulfilled the ACR criteria. Renal biopsy was performed again, resulting in a diagnosis of lupus nephritis. Steroid therapy combined with administration of mycophenolate mofetil led to an incomplete remission. Immunofluorescence studies confirmed the presence of IgG, IgM, C3, and C1q in renal biopsy specimens both at first and second admissions. Furthermore, immunofluorescence studies confirmed the presence of IgG1-4 in the first biopsy and tubuloreticular inclusions (TRIs) were revealed using electron microscopy. The present case represents the possibility that characteristic pathological findings of lupus nephritis, including TRIs, can reveal themselves before a diagnosis of SLE.

Radiation-induced premature cellular senescence involved in glomerular diseases in rats.

Currently, cellular senescence has emerged as a fundamental contributor to chronic organ diseases. Radiation is one of the stress factors that induce cellular senescence. Although the kidney is known as a radiosensitive organ, whether and how radiation-induced cellular senescence is associated with kidney diseases remains unclear. In this study, we performed experiments on 7-8-week-old male rats that received a single dose of 18-Gy radiation in the unilateral kidney. The irradiated kidneys showed hallmarks of cellular senescence, including increased SA-ß-gal activity, upregulation of cyclin-dependent kinase inhibitor (p53, p21, and p16), and absence of DNA proliferation marker (Ki-67). Furthermore, combined with in-vitro experiments, we demonstrated that radiation-induced senescent glomerular endothelial cells acquired altered gene expression, namely, senescence-associated secretory phenotype (particularly, IL-6), which might be triggered by NF-kB signaling pathway. Pathological analysis suggested severe glomerular endothelial cell injury, as evidenced by thrombotic microangiopathy, collapsing glomeruli, and reduced endothelial cell numbers. We suggested that glomerular endothelial cells were more susceptible to radiation-induced cellular senescence. In conclusion, the current study is the first to identify the important role of radiation-induced cellular senescence, mainly derived from glomerular endothelial cells, for the development of glomerular injury.

Importance of frequency and morphological characteristics of nodular diabetic glomerulosclerosis in diabetic nephropathy.

The Renal Pathology Society proposed a pathological classification for diabetic nephropathy (DN) (RPS 2010). We retrospectively examined the renal structural-functional relationships using the RPS 2010 classification in 49 DN cases. We also evaluated the importance of the percentage of glomeruli with nodular diabetic glomerulosclerosis and their morphological characteristics (cellular, cellular and extracellular matrix [ECM] or ECM types) in the pathology of DN. The classes of DN (RPS 2010) were significantly correlated with the duration of diabetes mellitus (DM), degree of proteinuria, a decreased estimated glomerular filtration rate (eGFR), and the stages of Japanese clinical DM and chronic kidney disease (CKD). When the percentage of glomeruli with nodular glomerulosclerosis (IIIA <25%, IIIB 25-50%, IIIC 50-75%, and IIID >75%) was added to class III in this classification, the classes of DN had a greater correlation with the levels of proteinuria. The morphological characteristics of nodular glomerulosclerosis such as cellular, cellular and ECM, or ECM type were associated with several clinical parameters including the duration of DM, degree of proteinuria, a decreased eGFR, and/or the stages of clinical DM and CKD. Mesangial red blood cell fragments that is indicative of microvascular injury was found in cellular or cellular and ECM types of nodular glomerulosclerosis. The RPS 2010 classification is useful as a DN pathological classification that indicates a good correlation with the clinical characteristics of DN. In addition, the frequency and morphological characteristics of nodular diabetic glomerulosclerosis is important for the evaluation of the pathology in DN.

A Case of Microscopic Polyangiitis with Subarachnoid Hemorrhage and Cardiovascular Complications.

Microscopic polyangiitis (MPA) is a primary systemic vasculitis that predominantly affects small and medium vessels. MPA is rarely complicated with central nervous system or cardiovascular disease. We report a very rare case of MPA complicated with cerebral infarction, cardiovascular disease, and fatal subarachnoid hemorrhage in a 54-year-old man. During the first six days of hospitalization the patient was diagnosed with rapid progressive glomerulonephritis (RPGN), cerebral infarction, and unstable angina. According to patient's symptoms and laboratory findings, were consisted with a diagnosis of severe MPA. Steroid pulse therapy was immediately introduced. However, the patient developed massive subarachnoid hemorrhage on the 8th day of hospitalization. The condition progressively deteriorated, and the patient died on the 33rd hospital day.