Predominant CD8+ cell infiltration and low accumulation of regulatory T cells in immune checkpoint inhibitor-induced tubulointerstitial nephritis.

Immune checkpoint inhibitors (ICIs) can provide survival benefits to cancer patients; however, they sometimes result in the development of renal immune-related adverse events (irAEs). Tubulointerstitial nephritis (TIN) is the most representative pathological feature of renal irAEs. However, the clinicopathological entity and underlying pathogenesis of ICI-induced TIN are unclear. Therefore, we compared the clinical and histological features of this condition with those of non-ICI drug-induced TIN. Age and C-reactive protein levels were significantly higher in ICI-induced TIN, but there were no significant differences in renal function. Immunophenotyping of ICI-induced TIN showed massive T cell and macrophage infiltration with fewer B cells, plasma cells, neutrophils, and eosinophils. Compared with those in non-ICI drug-induced TIN, CD4+ cell numbers were significantly lower in ICI-induced TIN but CD8+ cell numbers were not significantly different. However, CD8/CD3 and CD8/CD4 ratios were higher in ICI-induced TIN. Moreover, CD25+ and FOXP3+ cells, namely regulatory T cells, were less abundant in ICI-induced TIN. In conclusion, T cell, B cell, plasma cell, neutrophil, and eosinophil numbers proved useful for differentiating ICI-induced and non-ICI drug-induced TIN. Furthermore, the predominant distribution of CD8+ cells and low accumulation of regulatory T cells might be associated with ICI-induced TIN development.

Changes in Treatment Conditions for Patients Receiving Hemodialysis at Nippon Medical School Hospital During the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic has had an enormous impact on hemodialysis patients. This study investigated changes in hemodialysis treatment at our hospital after the start of the pandemic. METHODS: We analyzed data from the Diagnosis Procedure Combination (DPC) system. Data for inpatients receiving dialysis during collection periods A (before the COVID-19 pandemic) and B (after the start of the COVID-19 pandemic) were extracted and compared. The numbers of inpatients and new patients, the number of patients admitted (by department), duration of stay, mortality, place of residence, surgical procedures, and DPC classification were compared. RESULTS: There were no significant differences between periods in patient age, duration of hospital stay, number of new patients, number of ambulance transports, number of deaths, body mass index, comorbidities, laboratory variables before the first dialysis after hospitalization, or patient area of residence. Although differences were observed among the departments, the numbers of emergency dialysis inpatients and maintenance dialysis inpatients increased. The number of surgeries also increased overall, particularly for maintenance dialysis patients (P = 0.0273). The percentage of DPC III patients was significantly higher in period B (P=0.0368). CONCLUSIONS: The number of surgeries performed on maintenance dialysis patients and the overall DPC III rate significantly increased after the start of the COVID-19 pandemic at our hospital, suggesting that COVID-19 worsened the condition of maintenance dialysis patients and prolonged hospital stays.

The efficacy and safety of ivabradine hydrochloride in hemodialysis patients with chronic heart failure.

INTRODUCTION: There is little evidence for ivabradine hydrochloride in patients undergoing hemodialysis. METHODS: In this open-label prospective interventional trial of hemodialysis patients with chronic heart failure, during 12 weeks of treatment, changes in Heart rate (HR), frequency of dialysis-related hypotension were examined, and we investigated health-related quality of life (HR-QOL) and adverse effects. RESULTS: 18 patients from 6 facilities were enrolled in the study. HR significantly decreased over time, from 87 ± 12.61/min at baseline to 75.85 ± 8.91/min (p = 0.0003), and systolic blood pressure also increased significantly (p < 0.0001). The frequency of dialysis-related hypotension was markedly reduced (p = 0.0001). The HR-QOL survey showed significant improvements in Social Functioning among others (p = 0.0178). No specific adverse events occurred. CONCLUSION: Ivabradine hydrochloride improved dialysis-related hypotension. Furthermore, the HR-QOL improvement effect were suggested. These results demonstrated the safety and effectiveness of ivabradine hydrochloride.

Tissue Sodium Accumulation Induces Organ Inflammation and Injury in Chronic Kidney Disease.

High salt intake is a primary cause of over-hydration in chronic kidney disease (CKD) patients. Inflammatory markers are predictors of CKD mortality; however, the pathogenesis of inflammation remains unclear. Sodium storage in tissues has recently emerged as an issue of concern. The binding of sodium to tissue glycosaminoglycans and its subsequent release regulates local tonicity. Many cell types express tonicity-responsive enhancer-binding protein (TonEBP), which is activated in a tonicity-dependent or tonicity-independent manner. Macrophage infiltration was observed in the heart, peritoneal wall, and para-aortic tissues in salt-loading subtotal nephrectomized mice, whereas macrophages were not prominent in tap water-loaded subtotal nephrectomized mice. TonEBP was increased in the heart and peritoneal wall, leading to the upregulation of inflammatory mediators associated with cardiac fibrosis and peritoneal membrane dysfunction, respectively. Reducing salt loading by a diuretic treatment or changing to tap water attenuated macrophage infiltration, TonEBP expression, and inflammatory marker expression. The role of TonEBP may be crucial during the cardiac fibrosis and peritoneal deterioration processes induced by sodium overload. Anti-interleukin-6 therapy improved cardiac inflammation and fibrosis and peritoneal membrane dysfunction. Further studies are necessary to establish a strategy to regulate organ dysfunction induced by TonEBP activation in CKD patients.

Inhibition of Transglutaminase 2 Reduces Peritoneal Injury in a Chlorhexidine-Induced Peritoneal Fibrosis Model.

Long-term peritoneal dialysis (PD) is often associated with peritoneal dysfunction leading to withdrawal from PD. The characteristic pathologic features of peritoneal dysfunction are widely attributed to peritoneal fibrosis and angiogenesis. The detailed mechanisms remain unclear, and treatment targets in clinical settings have yet to be identified. We investigated transglutaminase 2 (TG2) as a possible novel therapeutic target for peritoneal injury. TG2 and fibrosis, inflammation, and angiogenesis were investigated in a chlorhexidine gluconate (CG)-induced model of peritoneal inflammation and fibrosis, representing a noninfectious model of PD-related peritonitis. Transforming growth factor (TGF)-ß type I receptor (TGFßR-I) inhibitor and TG2-knockout mice were used for TGF-ß and TG2 inhibition studies, respectively. Double immunostaining was performed to identify cells expressing TG2 and endothelial-mesenchymal transition (EndMT). In the rat CG model of peritoneal fibrosis, in situ TG2 activity and protein expression increased during the development of peritoneal fibrosis, as well as increases in peritoneal thickness and numbers of blood vessels and macrophages. TGFßR-I inhibitor suppressed TG2 activity and protein expression, as well as peritoneal fibrosis and angiogenesis. TGF-ß1 expression, peritoneal fibrosis, and angiogenesis were suppressed in TG2-knockout mice. TG2 activity was detected by α-smooth muscle actin-positive myofibroblasts, CD31-positive endothelial cells, and ED-1-positive macrophages. CD31-positive endothelial cells in the CG model were α-smooth muscle actin-positive, vimentin-positive, and vascular endothelial-cadherin-negative, suggesting EndMT. In the CG model, EndMT was suppressed in TG2-knockout mice. TG2 was involved in the interactive regulation of TGF-ß. As inhibition of TG2 reduced peritoneal fibrosis, angiogenesis, and inflammation associated with TGF-ß and vascular endothelial growth factor-A suppression, TG2 may provide a new therapeutic target for ameliorating peritoneal injuries in PD.

A possible role of classical complement pathway activation in the pathogenesis of immunoglobulin G nephropathy: a case report.

Immunoglobulin G (IgG) nephropathy refers to a rare group of diseases characterized by deposits of IgG in the mesangial region. However, IgG nephropathy is controversial as a single disease entity, and its pathogenesis remains to be elucidated. In the present report, we discuss a case of IgG nephropathy in which we observed activation of the classical complement pathway.A 47-year-old woman was admitted to our hospital with nephrotic syndrome. Light-microscopic examination revealed neither proliferative nor sclerotic lesions in the glomeruli. However, unusual and large deposits were observed in the paramesangial area. An immunofluorescence study revealed predominant IgG and C1q and slight C3 deposits in the paramesangial area, suggesting immune-complex-type glomerular disease. An electron microscopic study also revealed different sizes of non-organized electron-dense deposits with a similar pattern of distribution, which were accompanied by foot process effacement. Clinically, there was no evidence of systemic diseases, such as infectious or autoimmune diseases (including systemic lupus erythematosus). Based on these findings, she was diagnosed with IgG nephropathy and treated with prednisolone. Steroid therapy was effective, and complete remission was maintained.Additional immunological examination revealed that IgG deposits were polyclonal and consisted mainly of the IgG1 and IgG3 subclasses. Furthermore, staining was positive for C4d and C5b-9. The present findings indicate that the pathogenesis of IgG nephropathy in our patient may have involved activation of the classical complement pathway.

A Case of Hepatitis E Virus Infection: One of Differential Diagnosis of Liver Injury in Patients Undergoing Peritoneal Dialysis.

Background: There are numerous causes of liver function disorder in patients undergoing peritoneal dialysis (PD). Infection with the Hepatitis E virus (HEV) is a rare cause of liver injury, and the behavior of HEV in patients with PD is unclear. Since patients undergoing dialysis are frequently polypharmatic, liver injury caused by HEV infection may be misdiagnosed as drug-induced liver injury. Case Presentation: A 61-year-old woman with PD developed abrupt elevation of blood transaminase levels on a routine outpatient session. Since the patient has been receiving tolvaptan as the only new medication, we suspected tolvaptan induced liver injury. In further investigating the cause of liver injury, the blood screening test was found to be positive for HEV-IgA. The patient was diagnosed with HEV infection, and had a self-limited course. Conclusion: When encountered with patients developing liver injury during PD, HEV infection should be included in the differential diagnosis.

Interleukin-6 blockade reduces salt-induced cardiac inflammation and fibrosis in subtotal nephrectomized mice.

Cardiovascular disease is the most common comorbidity in patients with chronic kidney disease (CKD), affecting both their prognosis and quality of life. Cardiac fibrosis is common in patients with CKD with left ventricular diastolic dysfunction, and it is associated with increased risk of heart failure and mortality. Recent evidence suggests that high salt intake activates immune responses associated with local accumulation of sodium. We reported that high salt intake promotes cardiac inflammation in subtotal nephrectomized (Nx) mice. We investigated the effects of administration of MR16-1, a rat anti-mouse monoclonal interleukin (IL)-6 receptor antibody, in Nx mice with salt loading (Nx-salt). Expression of monocyte chemoattractant protein-1, tumor necrosis factor-α, IL-1ß, and IL-6 mRNAs and macrophage infiltration was significantly reduced in the heart of Nx-salt mice treated with MR16-1 (Nx-salt-MR16-1) compared with Nx-salt mice treated with control rat rat IgG1 (Nx-salt-rat IgG1). Correspondingly, cardiac fibrosis was significantly attenuated in Nx-salt-MR16-1 mice compared with Nx-salt-rat IgG1 mice. Furthermore, in the heart of Nx-salt-MR16-1 mice, expression of mRNA for nicotinamide adenine dinucleotide phosphate oxidase-2, an oxidative stress marker, was significantly downregulated compared with Nx-salt-rat IgG1 mice. Increases in cardiac metabolites, including histidine and γ-butyrobetaine, were also reversed by IL-6 blockade treatment. In conclusion, IL-6 blockade exerts anti-inflammatory, antifibrotic, and partial antioxidative effects in the heart of Nx-salt mice.NEW & NOTEWORTHY In the present study, IL-6 blockade exerted anti-inflammatory, antifibrotic, and partial antioxidative effects on the hearts of mice with CKD on a high-salt diet. Therefore, IL-6 potentially mediates cardiac fibrosis induced by high salt intake in patients with CKD, a finding with therapeutic implications. Of note, the next therapeutic implication may simply be the reinforcement of low-salt diets or diuretics and further research on the anti-inflammatory effects of these measures rather than IL-6 blockade with high-salt diet.

Analysis of Purine Metabolism to Elucidate the Pathogenesis of Acute Kidney Injury in Renal Hypouricemia.

Renal hypouricemia is a disease caused by the dysfunction of renal urate transporters. This disease is known to cause exercise-induced acute kidney injury, but its mechanism has not yet been established. To analyze the mechanism by which hypouricemia causes renal failure, we conducted a semi-ischemic forearm exercise stress test to mimic exercise conditions in five healthy subjects, six patients with renal hypouricemia, and one patient with xanthinuria and analyzed the changes in purine metabolites. The results showed that the subjects with renal hypouricemia had significantly lower blood hypoxanthine levels and increased urinary hypoxanthine excretion after exercise than healthy subjects. Oxidative stress markers did not differ between healthy subjects and hypouricemic subjects before and after exercise, and no effect of uric acid as a radical scavenger was observed. As hypoxanthine is a precursor for adenosine triphosphate (ATP) production via the salvage pathway, loss of hypoxanthine after exercise in patients with renal hypouricemia may cause ATP loss in the renal tubules and consequent tissue damage.

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.

A case of pathologically confirmed streptococcal infection-related IgA vasculitis with associated glomerulonephritis and leukocytoclastic cutaneous vasculitis.

We report the case of an 80 year-old woman who developed bilateral lower extremity purpura and renal impairment with proteinuria a few days after a transient fever (day 0). High levels of both anti-streptolysin-O antibody (ASO) and anti-streptokinase antibody (ASK), as well as low levels of coagulation factor XIII in serum were noted. Skin biopsy was performed and showed a leukocytoclastic vasculitis with deposition of IgA and C3 in the cutaneous small vessels, indicating IgA vasculitis in the skin. After initiation of oral prednisolone, the skin lesions showed significant improvement. However, renal function and proteinuria gradually worsened from day 12. Kidney biopsy was performed on day 29, which demonstrated a necrotizing and crescentic glomerulonephritis with mesangial deposition of IgA and C3. In addition, the deposition of galactose-deficient IgA1 (Gd-IgA1) was positive on glomeruli and cutaneous small vessels, indicating that the purpura and glomerulonephritis both shared the same Gd-IgA1-related pathogenesis. In addition, the association between the acute streptococcal infection and the IgA vasculitis was confirmed by the deposition of nephritis-associated plasmin receptor (NAPlr) in glomeruli. The patient was treated with steroid pulse and intravenous cyclophosphamide, in addition to the oral prednisolone treatment. Renal function and proteinuria gradually improved, but did not completely recover, as is typically seen with courses of IgA vasculitis in the elderly. In this case, the streptococcal infectionrelated IgA vasculitis was confirmed pathologically by the deposition of both NAPlr and Gd-IgA1 in glomeruli, as well as Gd-IgA1 in the cutaneous small vessels.

A case of proliferative glomerulonephritis with monoclonal IgG3κ deposits accompanied by glomerular capillary microaneurysms.

Glomerular capillary aneurysms are distinctly rare and specific glomerular lesions characterized by aneurysmal dilatation of the glomerular capillaries. This formation is associated with glomerular capillary injuries with focal mesangiolysis. Here, we report a case of proliferative glomerulonephritis with monoclonal immunoglobulin G deposits (PGNMID) presenting with multiple glomerular capillary microaneurysms. A 53-year-old woman presented with persistent proteinuria and microhematuria. She had no underlying diseases, such as hematopoietic or lymphoproliferative disorders. A renal biopsy showed diffuse membranoproliferative lesions with foam cell infiltration and multiple microaneurysms of the glomerular capillary on light microscopy. Immunofluorescence analysis showed granular deposits of monoclonal immunoglobulin G3 kappa (IgG3κ), C1q, C3, and C4 in the glomeruli. Electron microscopy revealed different sizes of non-organized electron-dense deposits in the mesangial, subendothelial, and subepithelial areas. In addition, glomerular endothelial cells showed swelling and loss of fenestra or diffuse formation of fenestrated diaphragms, accompanied by irregular thinning of the glomerular basement membrane. Furthermore, immunostaining for CD31 (a marker for endothelial cell) and low-vacuum scanning electron microscopy study identified loss of endothelial cells in microaneurysm, suggesting severe glomerular endothelial cell injury. After a renal biopsy, only the medication for dyslipidemia was continued because there were no physical symptoms, such as edema, and urinary abnormalities continued with stable renal function. Further studies are needed to elucidate the pathogenesis of glomerular capillary injury in PGNMID and clarify the clinical and pathological characteristics of PGNMID with glomerular capillary microaneurysms.

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.

Risk Factors for Early Peritoneal Dialysis Discontinuation: Importance of Heart Failure.

BACKGROUND: The number of patients on peritoneal dialysis (PD) in our hospital has increased during the past 5 years, but the number discontinuing PD has also increased. The purpose of this study was to identify the risk factors for PD discontinuation by analyzing the association between technical survival period (defined as the duration of PD) and various clinical factors. METHODS: We retrospectively investigated 87 patients who were started on PD at our hospital and attended regularly from April 2015 to March 2020, and we analyzed the association between technical survival period and various clinical factors. We also looked for associations between technical survival period and hospitalizations for heart failure, peritonitis, and exit-site infections among patients undergoing PD. RESULTS: The patients using renin-angiotensin-aldosterone system inhibitors (RASi) (P = 0.0218), those with left ventricular ejection fraction (LVEF) > 50% (P = 0.0194) when they started PD, and those with estimated glomerular filtration rate (eGFR) ≥ 6 (mL/min/1.73 m2) (P = 0.0013) at the initiation of PD showed significantly longer technical survival period, and those who were hospitalized for heart failure had significantly shorter period (P = 0.0008). CONCLUSION: Treatment of RASi, LVEF > 50% and eGFR ≥ 6 mL/ min/1.73 m2 when the initiation of PD and better volume control to prevent ultrafiltration failure and heart failure may improve technical survival period in patients undergoing PD.

Effects of Renal Function on Urinary Excretion and Serum Concentration of Uric Acid in Patients Treated with Febuxostat for Chronic Kidney Disease.

BACKGROUND: Febuxostat is recommended for lowering serum uric acid (sUA) concentration in chronic kidney disease (CKD) patients with hyperuricemia. However, it remains uncertain how febuxostat affects associations between several laboratory variables related to glomerular filtration and renal tubular reabsorption of uric acid. METHODS: We retrospectively analyzed the records of 148 patients with CKD and hyperuricemia: 122 were treated with febuxostat, and 26 were not. Clinical and laboratory variables were used to calculate estimated glomerular filtration rate (eGFR), fractional excretion of uric acid (FEUA), and estimated 24-h urinary excretion of uric acid (eEUA). We examined correlations of those variables and compared patients who did and did not receive febuxostat. RESULTS: eGFR and FEUA were significantly inversely regardless of febuxostat-treatment status. eGFR was significantly inversely correlated with sUA in patients who received febuxostat, but not in those who did not. Similarly, there was a significant positive correlation between FEUA and eEUA only in patients treated with febuxostat. CONCLUSIONS: FEUA increased as eGFR decreased in our patients. Febuxostat changed correlation patterns for clinical and laboratory variables. Additional administration of uricosuric agents might help further lower sUA by increasing FEUA and eEUA in patients treated with febuxostat.

Long-Term Benefits of Treatment with Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Tolvaptan is the first effective drug treatment for autosomal dominant polycystic kidney disease (ADPKD) patients, but few long-term observations of the effects of tolvaptan have been reported. METHODS: In this single center, retrospective cohort study, we investigated nine patients who participated in a phase 3 trial of tolvaptan for ADPKD patients at our hospital between 2008 and 2014. Six of the patients discontinued tolvaptan at the end of the clinical trial and were defined as the discontinuation group, and three continued to take it; these were defined as the continuation group. The observation period was 3 years before and after the end of the tolvaptan trial, and we compared the following data in each group: serum creatinine, estimated glomerular filtration rate (eGFR), total kidney volume, serum sodium concentration, and urine specific gravity. RESULTS: eGFR was significantly improved after the end of the trial in the continuation group (P = 0.0446), but there was no significant change in the regression line before and after the end of the trial in the discontinuation group. The increases in mean total kidney volume rates over the 3 years before and after the trial were 0.01%/year vs. 0.067%/year in the discontinuation group (P = 0.0247). On the other hand, serum sodium concentration and urine specific gravity showed no change during the observation period. CONCLUSION: This study suggested that long-term administration of tolvaptan may improve renal function and inhibit total kidney volume growth.

Imaging Findings in a Case of Bacteremia Caused by Non-Typhoidal Salmonella Associated with a Congenital Venous Malformation.

Non-typhoidal Salmonella infection is a typical food-poisoning disease, which rarely causes bacteremia, except in immunocompromised individuals. We report the case of a healthy adult in whom a varicose vein associated with a lower-leg venous malformation was considered the source of Salmonella bacteremia.

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.