Renal hemosiderosis presenting with acute kidney Injury and macroscopic hematuria in Immunoglobulin A nephropathy: a case report.

BACKGROUND: Macroscopic hematuria-associated acute kidney injury (AKI) is a well-known complication of immunoglobulin A (IgA) nephropathy. In such cases, intratubular obstruction by red blood cell (RBC) casts and acute tubular necrosis are mainly observed pathologically. Herein, we report the case of a patient with IgA nephropathy presenting with AKI following an episode of macrohematuria. The patient presented with severe renal tubular hemosiderosis and acute tubular necrosis and without any obvious obstructive RBC casts. CASE PRESENTATION: A 68-year-old woman, who was diagnosed with IgA nephropathy on renal biopsy 6 years ago, was admitted to our hospital after an episode of macroscopic glomerular hematuria and AKI following upper respiratory tract infection. Renal biopsy showed mesangial proliferation of the glomeruli, including crescent formation in 17 % of the glomeruli, and acute tubular necrosis without obvious hemorrhage or obstructive RBC casts. The application of Perls' Prussian blue stain showed hemosiderin deposition in the renal proximal tubular cells. Immunofluorescence showed granular mesangial deposits of IgA and C3. Based on these findings, she was diagnosed with acute tubular necrosis with a concurrent IgA nephropathy flare-up. Moreover, direct tubular injury by heme and iron was considered to be the cause of AKI. She was treated with intravenous pulse methylprednisolone followed by oral prednisolone. Thereafter, the gross hematuria gradually faded, and her serum creatinine levels decreased. CONCLUSIONS: IgA nephropathy presenting with acute kidney injury accompanied by macrohematuria may cause renal hemosiderosis and acute tubular necrosis without obstructive RBC casts. Hemosiderosis may be a useful indicator for determining the pathophysiology of macroscopic hematuria-associated AKI. However, renal hemosiderosis may remain undiagnosed. Thus, Perls' Prussian blue iron staining should be more widely used in patients presenting with hematuria.

Impact of interventions by an antimicrobial stewardship program team on appropriate antimicrobial therapy in patients with bacteremic urinary tract infection.

BACKGROUND: Inappropriate antimicrobial therapy often leads to poor outcomes. This study aimed to evaluate the impact of an antimicrobial stewardship program (ASP) team on appropriate therapy, in patients with bacteremic urinary tract infection (UTI). PATIENTS AND METHODS: We retrospectively reviewed the interventions by the ASP team in 807 patients with bacteremic UTI. Interventions were divided into 3 groups: group A (conventional report), group B (conventional report and written alert on the chart), and group C (conventional report and oral recommendation with/without written alert). The appropriateness of antimicrobial therapy was assessed at 2 time points, based on blood culture results. RESULTS: The ASP team estimated that 166 and 576 patients received inappropriate antimicrobial therapy based on the results of Gram staining, and final report, respectively. Appropriate therapy after intervention was administered to 53.2% of group A, 63.5% of group B, and 89.3% of group C patients, respectively. Mortality was significantly lower in patients of de-escalation than in those with no antimicrobial changes, without prolonged hospital stay. CONCLUSION: This study provides one plausible benchmark for appropriate antimicrobial therapy by ASP, while observer bias and survivor treatment selection bias exist, and further studies including evaluation for severity are needed.

High-molecular-weight adiponectin levels in healthy, community-dwelling, elderly Japanese volunteers: a 5-year prospective observational study.

BACKGROUND: Serum adiponectin levels are associated with frailty and cardiovascular diseases. Longitudinal changes in adiponectin levels might enhance our understanding of age-related conditions and diseases. AIMS: This prospective observational study aimed to: (1) elucidate age-related changes in high-molecular-weight (HMW) adiponectin levels; and (2) identify variables predictive of elevated HMW adiponectin levels and the association with well-known adiponectin single-nucleotide polymorphisms (SNPs) in healthy, elderly Japanese participants. METHODS: Healthy elderly volunteers (n = 196; 55 men and 141 women; median age 72.0 years; range 69.0-75.0 years) underwent anthropometric and physical function measurements, as well as laboratory tests at baseline and the 5-year follow-up. RESULTS: HMW adiponectin levels were significantly higher in women than in men (8.4, 5.3-11.9 vs. 5.7, 3.1-9.0 µg/mL; p < 0.001) at baseline and decreased significantly at follow-up in women (7.7, 4.8-11.2 µg/mL; p < 0.001), but not in men. In the multiple regression analysis, high-density lipoprotein cholesterol levels and body weight were independent predictors of HMW adiponectin levels. The rate of change in HMW adiponectin levels was inversely correlated with the rates of change in body weight, body mass index, and knee leg extension strengths, and positively correlated with rates of change in high-density lipoprotein cholesterol and one-leg standing time. There were no significant differences in HMW adiponectin levels among SNPs. DISCUSSION: Decreasing HMW adiponectin levels might lead to an increased risk of cardiovascular diseases in elderly women. CONCLUSION: HMW adiponectin levels significantly decreased over a 5-year period in community-dwelling elderly Japanese women.

De novo proliferative glomerulonephritis with monoclonal IgG deposits of the IgG1κ subtype in a kidney allograft.

Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) has recently been described in cases with glomerular disease. Only 16 cases of recurrent or de novo PGNMID have been reported in the transplanted kidney. Here we report a case of de novo PGNMID in a renal allograft diagnosed in the early stage by protocol biopsy. A 41-year-old male with end-stage kidney disease caused by focal glomerular sclerosis received a living-related kidney transplant. The post-transplantation course was stable, except for an early episode of acute T cell-mediated rejection. Mesangial C1q deposition was found on the 3-year protocol biopsy. On the 4-year protocol biopsy, mild mesangioproliferative changes and deposition of IgG, C1q, C3, IgG1, and κ light chain were evident, confirming the diagnosis of PGNMID of the IgG1κ subtype. Furthermore, mild proteinuria was detected at that time. Because a subsequent haematological examination revealed high copy number Epstein-Barr virus (EBV) DNA and free κ light chain in blood, the post-transplant lymphoproliferative disorder (PTLD) was suspected. Mycophenolate mofetil (MMF) was discontinued and rituximab was administered for the treatment of PTLD; subsequently, the improvement in proteinuria and serum creatinine was found 2 months after rituximab administration.

[Discussion of Routine Laboratory Data of a Patient Complaining of Back Pain and General Fatigue].

Conventional reversed clinicopathological conference (RCPC) is an educational method to interpret labora- tory data. In this RCPC, physicians and several specialists in laboratory medicine discussed laboratory data of a patient with tuberculous spondylitis who complained of back pain and general fatigue. Then, they and the moderators held a question-and-answer session with an audience in a hall, and they tried to understand the detailed state of the patient. This discussion revealed the usefulness of RCPC to elucidate the clinical state of patient. At the same time, we can understand the limits of laboratory data analysis. [Review].

The Kidney Early Evaluation Program (KEEP) of Japan.

The International Kidney Evaluation Association Japan (IKEAJ) was created to improve public health awareness of chronic kidney disease (CKD) by screening high-risk CKD populations. This study aimed to retrospectively examine data from KEEP Japan and detect the CKD risk factors for the onset and the progression of CKD. A total of 1,947 participants (mean age: 56.9 ± 16.4 years) to KEEP Japan were enrolled. More than 70% of the participants had no CKD. However, 7.5% of the participants were classified as high risk. The participants with a history of hypertension and older than 60 years had significantly higher odds ratio for occurrence of CKD. In addition, the participants with history of diabetes or cardiovascular disease, high blood pressure (BP), anemia, and low HDL-C had high odds ratios. It is therefore suggested that the appropriate control of BP, blood glucose, anemia, and HDL-C is important for populations with CKD risk factors to reduce the likelihood of CKD.

Microvascular inflammation in early protocol biopsies of renal allografts in cases of chronic active antibody-mediated rejection.

AIM: Chronic active antibody-mediated rejection (chronic ABMR) is one important cause of late-stage renal allograft loss. However, few reports have used protocol biopsy to observe changes over time in cases that develop chronic ABMR. The aim of this study was to use protocol biopsy to clarify the histological features of cases that develop chronic ABMR. METHODS: We recruited 379 ABO compatible patients who underwent protocol biopsy at our hospital from 2010 to 2014. Seventeen of these patients were diagnosed with chronic ABMR (chronic ABMR group), and 12 patients were class 2 donor-specific antibody (DSA) positive and were not diagnosed with chronic ABMR (class 2 DSA-positive group). With the addition of a control group consisting of 30 DSA negative patients, these three groups were compared for Banff factors in protocol biopsies taken 3 months, 6 months, 1 year, 3 years, and 5 years after the transplant. RESULTS: Three months post transplant, the chronic ABMR group had a significantly higher number of patients exhibiting g + ptc > 0 than that in the control group (P = 0.01). At 1, 3, and 5 years post transplant, significantly more subjects in the chronic ABMR and class 2 DSA-positive groups compared with the control group exhibited g + ptc > 0 (P < 0.03). Five years post transplant, the chronic ABMR group exhibited a significantly higher mean c4d score than that in the control group (P = 0.02). The only significant difference observed between the chronic ABMR group and the class 2 DSA-positive group was in cg scores at 5 years post transplant, which were significantly higher in the chronic ABMR group (P = 0.03). CONCLUSIONS: These results suggest that cases exhibiting microvascular inflammation in the early post-transplant period may develop chronic ABMR, and it would be highly beneficial to perform focused electron microscope surveillance of these cases.

Sex differences in the prevalence, progression, and improvement of chronic kidney disease.

BACKGROUND/AIMS: We examined sex differences in prevalence, progression, and improvement in early-stage chronic kidney disease (CKD). METHODS: We analyzed data from 533 participants who took 4 consecutive annual CKD detection tests. RESULTS: Urine albumin-creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), and hemoglobin (Hb) at baseline in men with and without CKD and in women with and without CKD were 8.3±6.1, 149.2±310.4, 10.2±5.8, and 96.7±246.8 mg/g Cr; 83.4±14.7, 63.8±18.8, 79.9±13.0, and 69.4±20.0 mL/min/1.73 m2; and 14.8±1.2, 14.3±1.4, 13.0±1.0, and 13.0±1.2 mg/dL, respectively. ACR levels decreased significantly over time in men and women with CKD and they increased significantly over time in men and women without CKD. eGFR levels in men and women with CKD did not significantly change over time, but they decreased significantly over time in men and women without CKD. CKD prevalence and progression rate were not significantly different between sexes. Among the CKD participants, significantly more women had a "cured" status at 3 years (39.1% vs. 19.4%, P<0.01). Most whose eGFR increased to >60 mL/min/1.73 m2 at 3 years had values just below those at baseline. Regression analysis showed that change in eGFR correlated significantly with ACR in men with CKD (change in eGFR = -1.707+0.022×ACR, P<0.001, r2=0.201) and with Hb and ACR in women with CKD (change in eGFR = 48.870-3.803×Hb + 0.018×ACR, P<0.05, r2=0.134). CONCLUSIONS: These results suggest that the slight decrease of Hb within a normal range and mild anemia can be managed in women with early-stage CKD. The key baseline for eGFR is 60 mL/min/1.73 m2.

De novo proteinuria with pathological evidence of glomerulonephritis after everolimus induction.

A 68-year-old man who underwent living-unrelated kidney transplantation from his spousal donor was immunosuppressed with tacrolimus and mycophenolate mofetil. Despite his uneventful clinical course, protocol biopsy at 2 years post transplant showed de novo CNI tubulotoxicity despite low tacrolimus exposure. Everolimus was added in order to discontinue TACER. However, prominent proteinuria impeded continuation of everolimus since biopsy showed diffuse glomerular endocapillary proliferation without C4d deposition. No donor-specific antibody was detected. Pulse steroids were given and proteinuria returned to normal with histological reversal.

Immunohistochemical evidence for the association between attenuated mTOR signaling and diffuse alveolar damage, a fatal lung complication.

Targeted anticancer therapies have been developed to interfere with specific target molecules including those of downstream pathways required for tumor growth and progression. Mammalian target of rapamycin (mTOR) has been considered as one of the target molecules of cancer growth, and its inhibitors have been reported to exert an anticancer effect in various malignant tumors. The pulmonary disorder is one of the major side effects of anticancer drugs including mTOR inhibitor (mTORi), and the diagnosis of lung injury induced by medication is difficult because of non-specific nature of the radiological findings. In this study, we present the detailed autopsy findings of a patient who developed diffuse alveolar damage (DAD) following mTORi treatment for metastatic renal cell carcinoma. We also studied 19 cases of DAD derived from other diseases and 9 cases with non-pathological lung. Of interest, pneumocytes of the patients with DAD, who received other anticancer drugs or contacted bacteria, demonstrated significantly lower mTOR activities than pneumocytes of those with non-pathological lung tissue, as judged by the immunohistochemical analysis. In contrast, both pneumocytes and T cells in DAD tissues of the patient treated with mTORi showed higher mTOR activities than those of patients with DAD of other causes, suggesting that the enhanced mTOR signaling may be involved in the development of DAD after mTORi treatment. This unexpected finding needs to be confirmed in other patients treated with mTORi. In conclusion, the attenuated mTOR signaling in pneumocytes may contribute to the pathogenesis of DAD in patients without mTORi treatment.

[Invasive pneumococcal disease of serotype 6C with skin and soft tissue infections in an immunocompetent adult].

We report herein on a rare case of deep-soft tissue infection due to invasive pneumococcal disease (IPD). A 77-year-old woman was admitted to our hospital with progressive pain in the right upper arm and the distal leg associated with swelling. We diagnosed the condition as multiple instances of cellulitis that were initially treated with ceftriaxone and clindamycin. Penicillin-susceptible Streptococcus pneumoniae (PSSP) was isolated from blood cultures on admission. Although inflammatory marker levels improved following susceptive antibiotic therapy (ampicillin), multiple abscesses, septic arthritis and osteomyelitis were detected with image testing. The antibiotic was then changed to meropenem and arthroscopic surgery was performed for the right shoulder; the patient's clinical symptoms improved. Since pneumococcal infection including skin and soft tissue infection (SSTI) often causes blood stream invasion or metastatic suppurative complications, metastatic lesions or multiple abscesses should be taken care of.

Evaluating Cellularity Estimation Methods: Comparing AI Counting with Pathologists' Visual Estimates.

The development of next-generation sequencing (NGS) has enabled the discovery of cancer-specific driver gene alternations, making precision medicine possible. However, accurate genetic testing requires a sufficient amount of tumor cells in the specimen. The evaluation of tumor content ratio (TCR) from hematoxylin and eosin (H&E)-stained images has been found to vary between pathologists, making it an important challenge to obtain an accurate TCR. In this study, three pathologists exhaustively labeled all cells in 41 regions from 41 lung cancer cases as either tumor, non-tumor or indistinguishable, thus establishing a "gold standard" TCR. We then compared the accuracy of the TCR estimated by 13 pathologists based on visual assessment and the TCR calculated by an AI model that we have developed. It is a compact and fast model that follows a fully convolutional neural network architecture and produces cell detection maps which can be efficiently post-processed to obtain tumor and non-tumor cell counts from which TCR is calculated. Its raw cell detection accuracy is 92% while its classification accuracy is 84%. The results show that the error between the gold standard TCR and the AI calculation was significantly smaller than that between the gold standard TCR and the pathologist's visual assessment (p<0.05). Additionally, the robustness of AI models across institutions is a key issue and we demonstrate that the variation in AI was smaller than that in the average of pathologists when evaluated by institution. These findings suggest that the accuracy of tumor cellularity assessments in clinical workflows is significantly improved by the introduction of robust AI models, leading to more efficient genetic testing and ultimately to better patient outcomes.

Aging and chronic kidney disease.

A recent report has dealt with geriatric nephrology, including epidemiology and pathophysiology of chronic kidney disease (CKD), attempting to get nephrologists to pay more attention to elderly CKD patients. The aims of this article are to summarize the morphological and functional properties of the aging kidney, and to better understand nephrology care for elderly CKD patients. The kidneys are affected by the aging process, which results in numerous effects on the renal system. In addition, the elderly population is hetereogenous - some have a decline in GFR explained by diseases that complicate aging such as arteriosclerosis with hypertension, whereas in the most of healthy adults the decline in GFR is much more modest and not inevitable. The values for normal estimated glomerular filtration rate (eGFR) in aging population have important implications for the diagnosis of CKD in the elderly. However, the MDRD equation underestimates mean eGFR by 25% and the CKD-EPI equation underestimates mean GFR by 16%. This bias may lead to misclassifying healthy older persons as having CKD. It is also still unknown whether and how age influences the predictive role of other risk factors for end-stage renal disease (ESRD) and death in referred as well as unreferred patients. The risk of ESRD was reported to be higher than the risk of death without ESRD for ages <60 years, and independent of eGFR. Proteinuria significantly increased the risk of ESRD with advancing age. In older patients on nephrology care, the risk of ESRD prevailed over mortality even when eGFR was not severely impaired. Proteinuria increases the risk of ESRD, while the predictive role of other modifiable risk factors was unchanged compared with younger patients. The decision to initiate renal replacement therapy in the elderly is complicated by more challenges than in younger patients. Calorie restriction and Klotho deficiency may be a candidate therapeutic target for attenuating kidney aging. © 2014 S. Karger AG, Basel.

Gastric adenocarcinoma of fundic gland type with autoimmune gastritis.

An 87-year-old man with dysphagia presented to our hospital. He was diagnosed with autoimmune gastritis (AIG) with severe atrophy and hypergastrinemia. The patient was positive for parietal cell antibody (PCA) and anti-intrinsic factor antibody (IFA), without evidence of H. pylori infection. A flat elevated tumor was detected in the middle corpus, and therapeutic endoscopic submucosal dissection was performed. Histopathological examination revealed atypical cells mimicking the fundic glands, which were positive for pepsinogen-I and partially positive for MUC6 and H + /K + -ATPase, proliferating to the deep layer. The final diagnosis was gastric adenocarcinoma of the fundic gland type (GAFG). AIG is expected to be difficult to develop GAFG because the basal gastric glands are highly atrophic due to the production of PCA. However, some chief cells may remain and could have the potential to develop into malignancy during AIG progression. Therefore, careful observation is required in patients with AIG when considering the occurrence of GAFG.

Repetitive administration of cultured human CD34+ cells improve adenine-induced kidney injury in mice.

BACKGROUND: There is no established treatment to impede the progression or restore kidney function in human chronic kidney disease (CKD). AIM: To examine the efficacy of cultured human CD34+ cells with enhanced proliferating potential in kidney injury in mice. METHODS: Human umbilical cord blood (UCB)-derived CD34+ cells were incubated for one week in vasculogenic conditioning medium. Vasculogenic culture significantly increased the number of CD34+ cells and their ability to form endothelial progenitor cell colony-forming units. Adenine-induced tubulointerstitial injury of the kidney was induced in immunodeficient non-obese diabetic/severe combined immunodeficiency mice, and cultured human UCB-CD34+ cells were administered at a dose of 1 × 106/mouse on days 7, 14, and 21 after the start of adenine diet. RESULTS: Repetitive administration of cultured UCB-CD34+ cells significantly improved the time-course of kidney dysfunction in the cell therapy group compared with that in the control group. Both interstitial fibrosis and tubular damage were significantly reduced in the cell therapy group compared with those in the control group (P < 0.01). Microvasculature integrity was significantly preserved (P < 0.01) and macrophage infiltration into kidney tissue was dramatically decreased in the cell therapy group compared with those in the control group (P < 0.001). CONCLUSION: Early intervention using human cultured CD34+ cells significantly improved the progression of tubulointerstitial kidney injury. Repetitive administration of cultured human UCB-CD34+ cells significantly improved tubulointerstitial damage in adenine-induced kidney injury in mice via vasculoprotective and anti-inflammatory effects.

Successful endoscopic submucosal dissection of colorectal lipoma with an overlying adenoma.

We report the case of a 65-year-old woman whose colonoscopy revealed a soft submucosal tumor approximately 7 cm in diameter in the ascending colon with an overlying flat lesion. The tumor was diagnosed as a lipoma with an overlying adenoma. Endoscopic submucosal dissection (ESD) was performed. Pathological examination revealed that the epithelium was a low-grade tubulovillous adenoma, while the submucosal yellow tumor was a lipoma. ESD appears to be a safe and effective treatment for colorectal lipomas overlying lipomas with colorectal adenomas.

Unexpectedly high renal pathological scores of two female siblings with Fabry disease presenting with urinary mulberry cells without microalbuminuria.

We describe the cases of 47- and 45-year-old sisters who were diagnosed with Fabry disease by genomic analysis. Although the only abnormal finding was the presence of mulberry cells in their urinary sediment, the renal pathological scores, which were evaluated by light and electron microscopy, were unexpectedly very high due to severe accumulation of globotriaosylceramide in the glomerular podocytes and tubular epithelial cells. Nephrologists and laboratory technicians should recognize the importance of screening for mulberry cells during urinalysis as this is a simple, inexpensive, and non-invasive method for early diagnosis, leading to early treatment of Fabry disease.

MPO-ANCA-associated vasculitis after the Pfizer/BioNTech SARS-CoV-2 vaccination.

Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has demonstrated high efficacy at preventing coronavirus disease 2019 (COVID-19) and a favorable safety profile, however it has also been reported that COVID-19 vaccines may put increase of immune-mediated disease. We herein report a case of MPO-anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis following the mRNA vaccine BNT162b2 (Pfizer/BioNTech) for COVID-19. Although the causal relationship between vaccine and ANCA-associated vasculitis is uncertain, environmental and genetic factors may have set the stage for the development of vasculitis, and the vaccine may have triggered a domino effect.