Genetic Analysis of Severe Polycystic Liver Disease in Japan.

BACKGROUND: Polycystic liver disease (PLD) is present in most patients with autosomal dominant polycystic kidney disease (ADPKD). PLD can alternatively be found with few, if any, kidney cysts as a diagnosis of isolated polycystic liver disease (ADPLD). Several genes are identified as causative for this spectrum of phenotypes, however, the relative incidence of genetic etiologies amongst patients with severe PLD is unknown. METHODS: Patients with ADPKD or ADPLD having severe PLD defined as height-adjusted total liver volume (hTLV) over 1,800mL/m were recruited. Subsequent clinical care was followed. Genetic analysis was performed using whole exome sequencing. RESULT: We enrolled and sequenced 49 patients (38 females, 11 males). Pathogenic or suspected pathogenic variants in polycystic disease genes were found in 44 out of 49 patients (90%). The disease gene was PKD1 in 20/44 (45%), PKD2 in 15/44 (34%), PRKCSH in 5/44 (11%), GANAB in 2/44 (5%), SEC63 in 1/44 (2%), and ALG8 in 1/44 (2%). The median hTLV was no different between genetically-defined ADPKD and ADPLD groups (4431 (range 1817-9148) versus 3437 (range 1860-8211) mL, p=0.77), whereas height-adjusted kidney volume (hTKV) was larger as expected in ADPKD than ADPLD (607 (range 190-2842) versus 179 (range 138-234) mL/m, p<0.01). Of the clinically-defined ADPKD cases, 20/38 (53%) were PKD1, 15/38 (39%) were PKD2, and 3 (8%) remain genetically unsolved. Among patients with a pathogenic PKD1 or PKD2 variant, we found three cases with a liver-dominant ADPKD (severe PLD with hTKV <250mL/m). CONCLUSION: ADPLD-related genes represent 20% of severe PLD patients in our cohort. Of those enrolled with ADPKD, we observed a higher frequency of PKD2 carriers than in any previously reported ADPKD cohorts. While there was no significant difference in the hTLV between PKD1 versus PKD2 patients in this cohort, our data suggests that enrollment on the basis of severe PLD may enrich for PKD2 patients.

Early diagnosis of tuberculous peritonitis in peritoneal dialysis patients using the T-SPOT test.

A 49-year-old man was admitted with peritonitis nine months after starting continuous ambulatory peritoneal dialysis (CAPD) for kidney failure. Ceftazidime and cefazolin were started. Peritoneal dialysate culture was negative for bacteria, but antibiotic treatment was continued because peritonitis improved. Twenty days later, the patient was discharged with no signs of peritonitis. However, 40-day culture of the original peritoneal dialysate detected Mycobacterium tuberculosis, and peritonitis recurred, leading to readmission. A T-SPOT test was performed and was positive in 4 days. Anti-tuberculosis therapy was started, which cured the peritonitis. The T-SPOT test may enable early diagnosis of tuberculosis.

De novo posttransplant membranous nephropathy after COVID-19 vaccination 9 years after renal transplantation in a patient with polycystic kidney disease.

A 63-year-old man with polycystic kidney disease underwent kidney transplantation from his wife. Nine years later, after the first and second doses of the COVID-19 vaccination, he developed proteinuria, hematuria, and elevated C-reactive protein. Kidney biopsy 7 months after the initial appearance of proteinuria showed immunoglobulin (Ig)-G granular stain, predominantly IgG1, and spike formation in the glomerular basement membrane. Electron microscopy revealed mainly subepithelial deposits, which corresponds to membranous nephropathy (MN) stage 3 of the Ehrenreich-Churg classification indicating chronic disease, but it also showed electron-dense deposits and endothelial damage. Because a kidney biopsy was performed 1 h after renal transplantation and a biopsy of the patient's native kidney showed intact glomeruli, atypical de novo posttransplant membranous nephropathy (MN) was diagnosed, and a close relationship with COVID-19 vaccination was assumed. Clinicians should consider the involvement of COVID-19 vaccination in de novo posttransplant MN with unclear pathogenesis.

A case of hypertensive emergency with alveolar hemorrhage and thrombotic microangiopathy.

A 28-year-old woman with a 5-year history of untreated hypertension was admitted for respiratory distress, hemoptysis, and retinopathy. Computed tomography showed diffuse plaques in both lung fields. Acute kidney injury, hemolytic anemia, and thrombocytopenia were noted. Kidney biopsy showed thrombosis with fibrinoid necrosis and edematous intimal thickening and luminal narrowing of the small renal artery, indicating thrombotic microangiopathy; the majority of glomeruli were collapsed. After 8 weeks of treatment with antihypertensive drugs, serum creatinine decreased to 1.0 mg/dL, and the patient recovered. In the absence of any other underlying disease, malignant nephrosclerosis associated with a hypertensive emergency was diagnosed.

Is Podocytopathy Associated with Gross Hematuria after COVID-19 Vaccination in Patients with Immunoglobulin A Nephropathy?

We experienced three cases of a fever and subsequent severe, prolonged gross hematuria after COVID-19 vaccination. A kidney biopsy revealed immunoglobulin A (IgA) nephropathy, and electron microscopy showed two types of podocytopathy (podocyte damage): loss of foot processes from the glomerular basement membrane and foot process effacement. Mesangial interposition was also present in cases 1 and 3 but not in case 2. Podocytopathy is known to be a cause of proteinuria; however, the reactions to COVID-19 vaccination described here suggest that it may also be related to hematuria in IgA nephropathy.

Trajectory of GFR Decline and Fluctuation in Albuminuria Leading to End-Stage Kidney Disease in Patients With Biopsy-Confirmed Diabetic Kidney Disease.

Introduction: Data on longitudinal trajectory of kidney function decline and fluctuation in albuminuria leading to end-stage kidney disease (ESKD) is sparse in patients with type 2 diabetes. Methods: Using data from an observational study of patients with type 2 diabetes and biopsy-confirmed diabetic kidney disease (DKD), generalized additive mixed models (GAMMs) were performed to quantify patterns of longitudinal trajectory of estimated glomerular filtration rate (eGFR) decline to ESKD associated with repeated measures of urine albumin-to-creatinine ratio (ACR). Results: Over a median follow-up period of 3.3 years, 155 of 319 patients progressed to ESKD. Among these patients, 91.6% exhibited a curvilinear pattern in their eGFR trajectory. The median coefficient of variation for ACR, representing the variability in ACR measurements, was 48.9 (interquartile range: 36.9, 68.2). The median compound annual growth rate (CAGR) for ACR, reflecting the variation in ACR progression over time, was 43.6% (interquartile range: 0.0, 102.5); and 84.5% of patients developed nephrotic-range albuminuria, with a majority remaining nephrotic and subsequently progressing to ESKD. There was a positive association between the instantaneous speed of eGFR decline and ACR. Conclusion: The observed curvilinear pattern in eGFR trajectory, high variability in ACR progression over time, and positive correlation between the speed of eGFR decline and ACR highlight the complex dynamics of disease progression and emphasize close monitoring of ACR fluctuation over time in patients with DKD.

Gastric Burkitt's monomorphic post-transplant lymphoproliferative disorder after kidney transplantation: A case report.

We report on a 53-year-old Japanese man diagnosed with gastric Burkitt's monomorphic post-transplant lymphoproliferative disorder (B-PTLD) after endoscopy for gastric discomfort 28 months after the patient underwent renal transplantation in Ethiopia. Serum Epstein-Barr virus (EBV) tests were negative before transplantation, but the tumor cells collected from a gastric biopsy showed positive EBV-encoded small RNAs (EBER) at B-PTLD onset. Intensive treatment started with R(rituximab)-CHOP therapy and continued with DA-EPOCH-R therapy has been effective, and relapse has not yet occurred. Burkitt lymphoma has a poor prognosis, but B-PTLD may be effectively treated with high-dose chemotherapy. This is a rare case of gastric B-PTLD in a Japanese patient.

Autopsy of a 45-year-old Man with Liver Failure Due to Polycystic Liver Disease.

A 37-year-old man with autosomal polycystic kidney disease (ADPKD) was admitted to our hospital with a liver volume of 8,000 cm3. Hepatic arterial embolization was performed using a microcoil but was ineffective. Eight years later, the hepatomegaly progressed to liver failure and death. At autopsy, the liver weighed 21.5 kg, and the entire liver had been replaced by cysts; in the few remaining areas of liver parenchyma, microscopic, small cysts of various sizes and fibrosis were evident, with only a few normal hepatocytes observed. Hepatic arterial branches developed; however, the portal vein could not be observed.

Immunoglobulin G4-related Dacryoadenitis Successfully Treated with Baricitinib.

A 48-year-old woman visited our hospital because of bilateral lacrimal gland enlargement. Her serum immunoglobulin G4 (IgG4) level was high, and positron emission tomography-computed tomography showed significant positive findings in the bilateral lacrimal gland. A biopsy revealed a considerable increase in IgG4/CD138, leading to a diagnosis of IgG4-related dacryoadenitis. The disease did not respond to steroid therapy, so treatment was started with baricitinib because of exacerbation of the original atopic dermatitis and dacryoadenitis after the second dose of the coronavirus disease 2019 (COVID-19) vaccine. Baricitinib was effective for resolving both dermatitis and dacryoadenitis, and steroids were able to be discontinued. The IgG4 level also improved.

Diagnostic value of 18F-fluorodeoxyglucose positron emission tomography and computed tomography for differentiating polymyalgia rheumatica and rheumatoid arthritis: Using classification and regression tree analysis.

OBJECTIVES: Determining which sites were important to differentiate polymyalgia rheumatica (PMR) from rheumatoid arthritis (RA) using 18F-fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET-CT) is challenging. METHODS: Patients with PMR or RA who were undergoing PET-CT were recruited at two mutual-aid hospitals in Japan between 2009 and 2018. Classification and regression tree (CART) analyses were performed to identify FDG uptake patterns that differentiated PMR from RA. RESULTS: We enrolled 35 patients with PMR and 46 patients with RA. Univariate CART analysis showed that FDG uptake in the shoulder joints, spinous processes of the lumbar vertebrae, pubic symphysis, sternoclavicular joints, ischial tuberosities, greater trochanters, and hip joints differentiated PMR from RA. Multivariate CART analysis revealed that FDG uptake by at least one of the ischial tuberosities had the highest diagnostic value for distinguishing PMR from RA (sensitivity, 77.1%; specificity, 82.6%). We performed the same CART analysis to patients who had not undergone treatment (PMR, n = 28; RA, n = 9). Similar results were obtained, and sensitivity and specificity were increased (sensitivity, 89.3%; specificity, 88.8%). CONCLUSIONS: In PET-CT, FDG uptake by at least one of the ischial tuberosities best discriminates between PMR and RA.

Histologically Proven Recurrent Synovitis after Nivolumab Treatment.

A 58-year-old woman with rheumatoid arthritis was diagnosed with methotrexate-associated Hodgkin lymphoma. After receiving several chemotherapy regimens, she started nivolumab treatment. Two weeks later, she was hospitalized with worsening finger, wrist, and elbow joint pain. A synovial biopsy of the wrist joint showed villous synovial proliferation and linear infiltration of CD68-/CD3-positive T cells (with more CD8 than CD4 T cells) but no CD20-positive B cells or CD138-positive macrophages. These findings corresponded to synovitis associated with immune-related adverse events, which are induced mainly by T cells and are different from typical rheumatoid arthritis (RA), in which B cells play a central role.

A Case of Autosomal Dominant Polycystic Kidney Disease With Resolution of Massive Pericardial Effusion After Renal Transcatheter Artery Embolization.

A 68-year-old woman being treated with hemodialysis for autosomal dominant polycystic kidney disease was admitted for progressive dyspnea over 6 months. On chest radiography, her cardiothoracic ratio had increased from 52.2% 6 months prior, to 71%, and echocardiography revealed diffuse pericardial effusion and right ventricular diastolic insufficiency. A resultant pericardial tamponade was thought to be the cause of the patient's dyspnea, and therefore a pericardiocentesis was performed, with a total of 2,000mL of fluid removed. However, 21 days later the same amount of pericardial fluid had reaccumulated. The second pericardiocentesis was performed, followed by transcatheter renal artery embolization (TAE). The kidneys, which were hard on palpation before TAE, softened immediately after TAE. After resolution of the pericardial effusion was confirmed, the patient was discharged after 24 days in hospital. Twelve months later, the patient was asymptomatic, the cardiothoracic ratio decreased to 48% on chest radiography and computed tomography revealed no reaccumulation of pericardial effusion. This case illustrates a potential relationship between enlarged kidneys in autosomal dominant polycystic kidney disease and pericardial effusion.

Anti-factor H antibody-positive C3 glomerulonephritis secondary to poststreptococcal acute glomerulonephritis with diabetic nephropathy.

Poststreptococcal acute kidney glomerulonephritis (PSAGN) has been seen in adults in recent years, especially in patients with type 2 diabetes mellitus, and the renal prognosis has not always been good. There have been cases of PSAGN in which complete remission was not achieved and hematuria and proteinuria persisted, leading to end-stage renal disease. Previous reports showed that the patients subjected to PSAGN have an underlying defect in regulating the alternative pathway of complement, and they identified that antibodies to the C3 convertase, C3 nephritic factors (C3NeF), are involved. C3NeF stabilizes C3 convertase, sustains C3 activation, and causes C3 glomerulonephritis (C3GN). On the other hand, factor H is a glycoprotein that suppresses the overactivation of the alternative pathway by decaying the C3 convertase. Anti-factor H (aFH) antibodies interfere with factor H and cause the same activation of the alternative pathway as C3NeF. However, a limited number of reports describe the clinical course of C3GN with aFH antibodies. We encountered a 49-year-old Japanese man with type 2 diabetes mellitus. He was referred to our hospital because of his elevated serum creatinine, proteinuria, hematuria, and developed edema on both legs. He was diagnosed as PSAGN at the first kidney biopsy, and his renal function improved and edema and hematuria disappeared, but proteinuria persisted after 5 months. He was diagnosed as C3GN at the second kidney biopsy. In our case, no C3NeF was detected. However, a high titer of aFH antibodies was detected in stored serum from the initial presentation, providing a unified diagnosis of aFH antibody-positive C3GN secondary to PSAGN. He progressed to end-stage renal disease (ESRD) and hemodialysis was started. The persistence of high levels of aFH autoantibodies may have caused C3GN secondary to PSAGN due to activating the alternative complement pathway, which eventually worsened the nephropathy and led to ESRD.

A case of bullous pemphigoid and renal disease after dipeptidyl peptidase 4 inhibitor administration.

A 62-year-old man with type 2 diabetes was admitted because of a decrease in estimated glomerular filtration rate from 72 to 17.5 mL/min/1.73 m2 in 10 years and development of widespread bullous skin lesions. His hemoglobin A1c level had been maintained at 6.0-7.0% for 10 years with a dipeptidyl peptidase (DPP)-4 inhibitor. Skin biopsy showed typical bullous pemphigoid, and kidney biopsy showed tubulointerstitial nephritis with eosinophilic infiltration and glomerular endothelial cell proliferation. After discontinuing the DPP-4 inhibitor, skin lesions improved, and renal decline slowed. This case indicates that DPP-4 inhibitors can cause not only skin lesions but also renal disease.

Multi-omics Approach in Kidney Transplant: Lessons Learned from COVID-19 Pandemic.

Purpose of Review: Multi-omics approach has advanced our knowledge on transplantation-associated clinical outcomes, such as acute rejection and infection, and emerging omics data are becoming available in kidney transplant and COVID-19. Herein, we discuss updated findings of multi-omics data on kidney transplant outcomes, as well as COVID-19 and kidney transplant. Recent Findings: Transcriptomics, proteomics, and metabolomics revealed various inflammation pathways associated with kidney transplantation-related outcomes and COVID-19. Although multi-omics data on kidney transplant and COVID-19 is limited, activation of innate immune pathways and suppression of adaptive immune pathways were observed in the active phase of COVID-19 in kidney transplant recipients. Summary: Multi-omics analysis has led us to a deeper exploration and a more comprehensive understanding of key biological pathways in complex clinical settings, such as kidney transplantation and COVID-19. Future multi-omics analysis leveraging multi-center biobank collaborative will further advance our knowledge on the precise immunological responses to allograft and emerging pathogens.

Syphilis-related Membranous Nephropathy in a 35-year-old Woman.

A 35-year-old woman was admitted for the examination of lower leg edema and proteinuria. A kidney biopsy showed membranous nephropathy (MN) with fine granular deposits of IgG along the glomerular capillary and poor spike formation, differing from primary MN in the presence of positive IgG3 and C1q. Lupus nephritis was excluded because serum complement and anti-dsDNA antibody, anti-Smith antibody, and anti-cardiolipin antibody tests were negative. The serological test for syphilis was positive, as was the Treponema pallidum hemagglutination test. The patient was diagnosed with syphilis, and the proteinuria disappeared with antibiotic treatment. In MN with positive IgG3 and C1q, syphilis nephropathy may be a differential diagnosis.

Dipeptidyl peptidase-4 inhibitor-related renal disease.

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used to treat type 2 diabetes (T2D). Lowering blood glucose is expected also to reduce the progression of diabetic nephropathy. We experienced a patient with T2D who achieved good glycemic control with a DPP-4 inhibitor but experienced rapid deterioration of renal function. Therefore, we performed a retrospective study of similar patients treated at our hospital. METHODS: Out of 56 patients with biopsy-proven diabetic nephropathy who underwent native kidney biopsy at Toranomon Hospital from January 2018 through December 2022, we selected 22 patients who had been receiving DPP-4 inhibitors for at least 9 months at the time of kidney biopsy. Of these patients, we evaluated 16 diagnosed with class IIa diabetic nephropathy according to Tervaert's pathologic classification. The yearly estimated glomerular filtration rate (eGFR) slope in the 16 patients was arranged from the highest to the lowest slope. Ten patients with a large eGFR slope had thrombotic microangiopathy (TMA)-like lesions characterized by glomerular endothelial cell proliferation and GBM duplication on kidney biopsy (group A), whereas the remaining 6 patients did not have TMA-like lesions (group B). RESULTS: Group A had a median (interquartile range [IQR]) eGFR of 18.2 (16.2, 26.2) and a yearly median (IQR) eGFR slope of -11.2 (-17.6, -9.2) mL/min/1.73 m2 after of DPP-4 administration, whereas group B had a median (IQR) eGFR of 31.5 (21.9, 34.8) mL/min/1.73 m2 and a yearly median (IQR) eGFR slope of -1.6 (-3.1, -0.3). Renal function declined significantly more rapidly in group A than in group B, and proteinuria was higher in group A than in group B (median [IQR], 3.4 [2.6, 4.4] g/day vs 0.8 [0.4, 1.3] g/day, respectively). Five patients in group A progressed to dialysis during follow-up, but none of the patients in group B did. Median (IQR) hemoglobin A1c was 6.2 % (6.0 %, 6.6 %) in group A and 5.8 % (5.7 %, 6.6 %) in group B. CONCLUSION: DPP-4 inhibitors promote vascular endothelial regeneration, but when this effect occurs in the glomerulus, glomerular endothelial cell proliferation leads to TMA-like lesions, which may cause an increase in proteinuria and rapid decline in renal function.

Immunoelectron microscopy findings in a patient with C3 glomerulonephritis.

We performed a kidney biopsy in a 36-year-old man to evaluate microscopic hematuria and proteinuria. Light microscopy showed increased mesangial matrix and partial swelling of the glomerular basement membrane (GBM), and immunofluorescence showed positive staining only for C3. Immunoelectron microscopy showed that gold particle-labeled C3 was localized in the electron-dense and moderately electron-dense deposits shown by electron microscopy in the mesangium, the thickened GBM near the paramesangium, and the thickened distal portion of the GBM but was not localized in the non-thickened GBM. Gold-labeled immunoglobulin G, κ, and λ were not seen. C3 glomerulonephritis was more evident in gold-labeled electron microscopy, which further clarified the localization of C3 deposition.

Can Takayasu Arteritis Cause Hydronephrosis?

A 74-year-old woman was admitted because of malaise and a low-grade fever. Her C-reactive protein level was 0.96 mg/dL. Computed tomography (CT) revealed diffuse uniform thickening of the arterial wall from the abdominal aorta to the common iliac artery and right hydronephrosis. 18F-fluordesoxyglucose positron emission tomography-CT showed an accumulation in the same area. These findings suggested Takayasu arteritis and retroperitoneal fibrosis as differential diagnoses. Takayasu arteritis is characterized by thickening of the arterial walls, and retroperitoneal fibrosis is characterized by membranous lesions covering the outer surface of the arterial walls. Thus, Takayasu arteritis was deemed the most likely diagnosis. Steroid treatment was effective.

Successful peficitinib monotherapy for the new-onset skin manifestations of rheumatoid vasculitis after long-term treatment with tocilizumab for rheumatoid arthritis.

Rheumatoid vasculitis (RV) is a severe extra-articular systemic manifestation of rheumatoid arthritis (RA). Its prevalence has been decreasing for decades because of improved early diagnosis of RA and advances in RA treatment, but it remains a life-threatening disease. The standard treatment for RV has been a glucocorticoid and disease-modifying antirheumatic drugs. Biological agents, including antitumour necrosis factor inhibitors, are also recommended for refractory cases. However, there are no reports of Janus kinase (JAK) inhibitor use in RV. We experienced a case of an 85-year-old woman with a 57-year history of RA who had been treated with tocilizumab for 9 years after receiving three different biological agents over 2 years. Her RA seemed to be in remission in her joints, and her serum C-reactive protein had decreased to 0.0 mg/dL, but she developed multiple cutaneous leg ulcers associated with RV. Because of her advanced age, we changed her RA treatment from tocilizumab to the JAK inhibitor peficitinib in monotherapy, after which the ulcers improved within 6 months. This is the first report to indicate that peficitinib is a potential treatment option for RV that can be used in monotherapy without glucocorticoids or other immunosuppressants.