論文

The Oxford (split) and Japanese Histological Grade (JHG [lumped]) classifications of immunoglobulin A nephropathy (IgAN) are widely used in Japan. We compared their prognostic ability and explored the benefits of combining them. Data were from a prospective IgAN cohort (2005–2015). The primary endpoint was a ≥ 50% decline in estimated glomerular filtration rate (eGFR) or end-stage renal disease. Cox regression with Uno C assessed prognostic discrimination. The integrated discrimination improvement index evaluated the added value of histologic to clinical variables (eGFR, urinary protein, and mean arterial pressure) at 1, 5, and 10 years. Kaplan–Meier analysis stratified patients into JHG 1 and 2–4 to assess the prognostic value of mesangial hypercellularity (M) and interstitial fibrosis/tubular atrophy (T). Among 938 patients (median follow-up: 66 months), 58 (6.2%) reached the endpoint. M and T (Oxford) and JHG were significantly associated with outcomes. Both systems showed good discrimination (Uno C: 0.83 and 0.86). Adding Oxford to clinical variables improved prediction at 5 and 10 years; adding JHG improved prediction at 1, 5, and 10 years. M and T were predictive in JHG 2–4 but not in JHG 1. Both classifications demonstrated comparable discrimination. Their combined use can help enhance predictive precision.

Malignant hypertension is traditionally defined as severe systemic blood pressure elevation accompanied by end-organ damage. In kidney transplant recipients, however, kidney allografts may be particularly vulnerable to hypertensive injury even at lower blood pressure levels, owing to impaired autoregulation associated with denervation and calcineurin inhibitor exposure. We report a 52-year-old kidney transplant recipient presenting with severe kidney injury (serum creatinine, 4.90 mg/dL) 16 months after transplantation. Although systemic blood pressure remained within the range of 140–170/90–105 mmHg—below the classical threshold of malignant hypertension—an allograft biopsy revealed the lesions suggestive of thrombotic microangiopathy (TMA), including mesangiolysis and edematous intimal thickening of the arteries. After exclusion of antibody-mediated rejection, calcineurin inhibitor toxicity, and primary TMAs, the patient was diagnosed with kidney-limited TMA attributable to relative hypertension producing a malignant hypertension-like phenotype in the setting of graft-specific vulnerability. Given the presumed contribution of the renin-angiotensin system (RAS)-mediated vascular injury, an angiotensin II receptor blocker was initiated despite severe kidney dysfunction, resulting in marked improvement in kidney function and proteinuria. This case illustrates that kidney allografts may develop a malignant hypertension-like pathophysiology with kidney-limited TMA at blood pressure levels below the classical malignant range. Awareness of this discrepancy may help clinicians recognize atypical hypertensive injury in transplant recipients, and early RAS blockade may be considered as a potential strategy to preserve allograft function, even in the setting of severe kidney injury.

COL4A1 variants cause a spectrum of systemic disorders encompassed by Gould syndrome. While kidney involvement is recognized, its long-term progression and detailed kidney pathology remain uncharacterized. We present a 39-year-old man with a heterozygous p.G1239R COL4A1 variant, persistent microscopic hematuria, and a progressive estimated glomerular filtration rate decline of −1.2 mL/min/1.73 m2 per year over a 10-year follow-up. Light microscopy showed only focal global glomerulosclerosis and mild tubular dilatation. Immunofluorescence for the α1 chain of type IV collagen (α1[IV]) revealed reduced signal intensity in the tubular basement membrane (TBM). Electron microscopy demonstrated focal thinning of the glomerular basement membrane (GBM) and heterogeneous abnormalities, including thinning, focal thickening, reticulation, and lamellation, of the TBM. Immunoelectron microscopy using FluoroNanogold showed decreased density of gold particles in the TBM, correlating with the fluorescence intensity. This report analyzes COL4A1 expression using correlative light and electron microscopy (CLEM), and describes the long-term kidney function decline. In patients with hematuria and a thin GBM, in addition to Alport syndrome, COL4A1 -associated nephropathy should also be considered. Recognizing this entity is essential for accurate systemic risk assessment and genetic counseling. Semi-quantitative assessment of COL4A1 expression in biopsy specimens using CLEM may be a key diagnostic tool for patients with heterozygous COL4A1 variants.

Drug-induced thrombotic microangiopathy (TMA) is an important cause of kidney injury in patients receiving anticancer therapy, although kidney-limited forms without systemic manifestations are often difficult to recognize. Pegylated liposomal doxorubicin (PLD)-associated TMA remains under-recognized, particularly in patients receiving concomitant vascular endothelial growth factor (VEGF) inhibitors. We report a case of biopsy-proven kidney-limited TMA associated with bevacizumab and PLD in a 52-year-old woman with metastatic ovarian serous adenocarcinoma, characterized by a biphasic clinical course. She developed progressive kidney dysfunction and proteinuria during treatment with bevacizumab followed by PLD. Despite discontinuation of bevacizumab, kidney dysfunction persisted. Kidney biopsy demonstrated findings consistent with TMA, including mesangiolysis, glomerular basement membrane duplication, and focal PAS-positive pseudothrombi suggestive of VEGF inhibitor–associated endothelial injury. Electron microscopy further revealed endothelial detachment, accompanied by a substance containing liposome-like particles, suggestive of the characteristic ultrastructural findings previously reported in PLD-associated TMA. The patient had no evidence of microangiopathic hemolytic anemia or thrombocytopenia, and no alternative cause of TMA was identified. Following discontinuation of PLD, kidney function improved markedly with complete resolution of proteinuria. This case highlights the importance of kidney biopsy and careful clinicopathological correlation in diagnosing drug-induced kidney-limited TMA.

BACKGROUND: – Cardiovascular diseases increase with aging and are closely linked to metabolic dysfunction and kidney disease through the cardiovascular-kidney-metabolic axis, but the underlying molecular mechanisms remain unclear. Accumulating evidence suggests that vascular endothelial cells (ECs) are particularly vulnerable to aging stressors, such as DNA damage. We investigated whether EC DNA damage drives cardiovascular-kidney-metabolic dysfunction. METHODS: – We generated mice with EC-specific DNA double-strand breaks using an endonuclease I-PpoI and subjected them to a high-fat diet (HFD). This approach allowed us to investigate the impact of EC-specific DNA damage on cardiovascular, metabolic, and renal systems. Furthermore, we analyzed the correlation between EC DNA damage markers (γH2AX [phosphorylated histone H2AX]) and clinical parameters in human kidney biopsy samples. RESULTS: – High-fat diet-fed endonuclease I-PpoI mice rapidly developed hypertension, dyslipidemia (low high-density lipoprotein cholesterol), hepatic steatosis, and visceral fat accumulation. Mechanistically, high-fat diet feeding compromised DNA repair capacity by suppressing ATM (ataxia-telangiectasia mutated) expression in the aorta. Consequently, DNA damage in aortic ECs triggered ET-1 (endothelin-1) secretion. This induced hepatic hypoxia and ETAR (endothelin type A receptor) activation, which promoted lipid metabolic reprogramming via ACSS2 (acetyl-CoA synthetase 2) upregulation. In addition, renal aging was accelerated. The selective ETAR antagonist atrasentan normalized blood pressure, reversed hepatic steatosis, restored high-density lipoprotein cholesterol, reduced visceral fat, and attenuated renal aging. In humans, EC DNA damage correlated negatively with estimated glomerular filtration rate and high-density lipoprotein cholesterol and positively with hepatic steatosis indices and renal cortical ETAR expression. CONCLUSIONS: – Endothelial DNA damage is a pivotal driver of cardiovascular-kidney-metabolic dysfunction through the ET-1-ETAR-ACSS2 signaling cascade. ETAR blockade offers a mechanism-based therapeutic strategy for age-related cardiovascular, renal, and metabolic diseases.

IgA nephropathy (IgAN) is the most common chronic glomerulonephritis worldwide, exhibiting substantial clinical and pathological heterogeneity. However, patient stratification and the low reproducibility of scoring by pathologists remain challenges. We propose an explainable deep learning model combining the large-scale pathology foundation model UNI with Multiple Instance Learning and an attention mechanism to analyze glomerular regions in Whole Slide Image of renal biopsy specimens of IgAN patients. Attention weight visualization highlights the specific glomerular regions most influential in prediction, and quantitative feature representation provides explainability. Risk stratification derived from predicted clinical data was compared with the Oxford classification using Kaplan–Meier analysis, demonstrating comparable or superior prognostic performance. Our findings show that deep learning–based pathology analysis can deliver accurate, interpretable predictions, facilitating transparent and clinically meaningful decision support in IgAN.

Background: Nephrotic syndrome (NS) carries a high risk of severe complications and kidney failure, necessitating reliable prognostic markers. Given the link between tubular injury and poor remission of proteinuria, markers of tubular function may be informative in NS. The urine-to-blood urea nitrogen ratio (UBUR) reflects tubular urea handling, yet its prognostic value in NS is unclear. We evaluated whether baseline UBUR predicts proteinuria remission in adult NS. Methods: This multicenter retrospective study included patients with NS who underwent kidney biopsy between January 2012 and June 2022. Patients were followed from kidney biopsy until complete remission, dialysis initiation, death, or the end of the observation period (12 months after kidney biopsy). Results: A total of 237 patients (median age, 63 years; 47% female) were included, and divided into two groups based on a UBUR cutoff of 25.4 determined by the receiver operating characteristic curve. Patients with high UBUR had a significantly higher cumulative incidence of complete remission compared to those with low UBUR (P < 0.001, log-rank test). In multivariable Cox regression analysis, high UBUR independently predicted a greater likelihood of complete remission (hazard ratio 2.30 [95% confidence interval 1.47–3.61]). This association persisted in the subgroup analyses for podocytopathies, defined as minimal change disease and focal segmental glomerulosclerosis. Conclusions: High UBUR independently predicts proteinuria remission in adults with NS. UBUR could have potential as a simple, valuable biomarker to help guide the management of NS.

症例は55歳、女性。骨髄増殖性疾患に対する治療経過中に腎不全に至り、54歳時に血液透析導入となった。透析導入10ヵ月時に小脳失調症状が出現し、当院に入院となり、頭部MRIにて小脳にT2強調画像で異常信号を認めた。病変部位は小脳のみであり非特異的であったが、脳脊髄液検査にてJCウイルスPCR陽性であったことから、進行性多巣性白質脳症が第一に疑われた。病巣が急速に拡大するにつれて症状は進行し、不随意運動・構音障害・嚥下障害が出現、誤嚥性肺炎を繰り返すようになり、発症後10ヵ月(透析導入後20ヵ月)に死亡された。剖検にて小脳・脳幹部に脱髄を認め、同部位にJCウイルスの存在を確認し、小脳型進行性多巣性白質脳症の確定診断に至った。また本症例の透析導入前の腎生検を再度検討したところ萎縮・変性した尿細管上皮細胞内に一致して免疫組織化学ならびに電子顕微鏡的に多量のJCウイルス蛋白が確認された。一般に進行性多巣性白質脳症の中で小脳・脳幹を侵す病型は稀であるが、本邦の透析患者における進行性多巣性白質脳症では、小脳型の報告が散見されており、透析患者では小脳型が稀でない可能性がある。また、本症例において透析導入に至った腎不全の原因として、JCウイルス腎症が関与した可能性が高いことが示唆された。JCウイルス感染の腎障害における病的意義については不明な点が多く、今後、症例の蓄積による病態の解明が必要である。(著者抄録)