Dural arteriovenous fistula following cerebral venous sinus thrombosis in a patient with minimal change disease: A case report.

A 78-year-old man presented with nephrotic syndrome and new-onset disorientation. Plasma D-dimer level was increased, and a lower leg deep vein thrombosis was identified on ultrasound. Histopathologic analysis of percutaneous renal biopsy samples confirmed the diagnosis of minimal change disease. Treatment with prednisone (20 mg/day), cyclosporine (50 mg/day), and anticoagulant therapy with edoxaban tosylate hydrate led to the complete resolution of nephrotic syndrome after 4 weeks. Despite this, his disorientation persisted. Head CT and MRI have revealed cerebral venous sinus thrombosis and dural arteriovenous fistula, which was considered a possible complication of nephrotic syndrome. Embolization dramatically improved his disorientation. This paper highlights that cerebral venous sinus thrombosis and dural arteriovenous fistula should always be considered in patients with nephrotic syndrome and new-onset disorientation.

Urinary podocyte mRNA is a potent biomarker of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

BACKGROUND: Anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN) is a critical kidney disease that sometimes results in an unfavorable renal outcome. Cellular crescent formation is a hallmark of ANCA-GN and is associated with renal prognosis, response to treatment, and it was reportedly associated with podocyte detachment. Because there is a need to explore non-invasive biomarkers for the evaluation of ANCA-GN activity, we tested whether urinary podocyte mRNA might be a potent non-invasive biomarker. METHODS: We measured two different types of urinary podocyte mRNA, including podocin mRNA in relation to urine creatinine concentration (U-PodCR) and urinary podocin mRNA in relation to nephrin mRNA (U-PNR), which were reportedly associated with the activity of various glomerular diseases. RESULTS: In ANCA-GN patients (n = 19), we discovered that U-PodCR was positively correlated with the percent of crescent formation until 50% crescent was reached because of podocyte depletion; U-PNR was correlated with the percent of crescent formation in all patients. Furthermore, patients with high levels of urinary podocyte mRNA exhibited a favorable renal outcome compared with the outcomes of patients with low levels of urinary podocyte mRNA. The levels of urinary podocyte mRNA were correlated with the rate of improvement in estimated glomerular filtration rate. CONCLUSIONS: U-PodCR, U-PNR or a combination of these parameters might serve as a non-invasive potential biomarker in patients with ANCA-GN to predict the percent of crescent formation and renal prognosis.

Concurrent minimal change nephrotic syndrome and type 1 diabetes mellitus in an adult Japanese woman: a case report.

BACKGROUND: Concurrent type 1 diabetes mellitus (T1DM) and idiopathic nephrotic syndrome is rare, and most previously reported cases were in children. We report the case of an adult woman who developed T1DM and minimal change nephrotic syndrome (MCNS) nearly simultaneously. CASE PRESENTATION: A 24-year-old woman had first presented to another hospital with nausea, vomiting, and fatigue. She was diagnosed with diabetic ketoacidosis and T1DM on the basis of her hyperglycemia, ketoacidosis, and positive anti-glutamic acid decarboxylase antibody test result. Rapid infusion of normal saline and insulin administration alleviated hyperglycemia and ketoacidosis. Two weeks after admission, however, she developed nephrotic syndrome (NS) with rapidly decreasing urine volume. She was referred to our hospital with a diagnosis of acute kidney injury. Although she temporarily required dialysis and high doses of insulin, within 1 month NS and acute kidney injury had been alleviated by oral prednisolone and low-density lipoprotein apheresis. Renal biopsy showed minor glomerular abnormalities without diabetic nephropathy, so we diagnosed her with MCNS. Seven weeks after the discharge, NS relapsed, and cyclosporine was added to prednisolone. However, NS relapsed twice within the next 4 months, so we started her on rituximab. At 6 months after initiating rituximab therapy, she remained in complete remission. Her mother also had T1DM but not MCNS. The patient had HLA-DRB1*09:01/09:01, DQB1*03:03/03:03, and her mother had HLA-DRB1*04:05/09:01, DQB1*03:03/04:01. CONCLUSIONS: Concurrent T1DM and MCNS is rare and their coexistence might be coincidental. Alternatively, they might have been caused by an underlying, unidentified genetic predisposition. Previous reports and our patient's findings suggest that specific HLA alleles and haplotypes or a Th1/Th2 imbalance might be associated with T1DM and MCNS that occurred nearly simultaneously.

Dasatinib-induced nephrotic syndrome in a patient with chronic myelogenous leukemia: a case report.

BACKGROUND: Dasatinib is a second-generation tyrosine kinase inhibitor that is indicated for the treatment of patients with chronic myeloid leukemia. Here, we report the case of a man with nephrotic syndrome that was caused by dasatinib. CASE PRESENTATION: A 40-year-old man with chronic myeloid leukemia was referred to our hospital because of proteinuria 1 month after dasatinib therapy was introduced. A percutaneous kidney biopsy was performed, diffuse glomerular endothelial injury and effacement of the foot process were noted, and the patient was diagnosed with dasatinib-induced nephrotic syndrome. Additionally, in an electron microscopy study, randomly arranged fibrils were observed in the mesangial and subendothelial regions. Switching from dasatinib to nilotinib led to a decrease in the proteinuria level, from 12 to 0.6 g/g creatinine, within 2 weeks. The patient was discharged from our department on the 25th day after hospitalization, without any drug aftereffects. CONCLUSIONS: Drug-related nephrotic syndrome should be considered when nephrotic syndrome develops during treatment with dasatinib.

Urinary podocyte and TGF-ß1 mRNA as markers for disease activity and progression in anti-glomerular basement membrane nephritis.

BACKGROUND: Podocyte depletion causes glomerulosclerosis, with persistent podocyte loss being a major factor driving disease progression. Urinary podocyte mRNA is potentially useful for monitoring disease progression in both animal models and in humans. To determine whether the same principles apply to crescentic glomerular injury, a rat model of anti-glomerular basement membrane (anti-GBM) nephritis was studied in parallel with a patient with anti-GBM nephritis. METHODS: Podocyte loss was measured by Wilms' Tumor 1-positive podocyte nuclear counting and density, glomerular epithelial protein 1 or synaptopodin-positive podocyte tuft area and urinary podocyte mRNA excretion rate. Glomerulosclerosis was evaluated by Azan staining and urinary transforming growth factor (TGF)-ß1 mRNA excretion rate. RESULTS: In the rat model, sequential kidney biopsies revealed that after a threshold of 30% podocyte loss, the degree of glomerulosclerosis was linearly associated with the degree of podocyte depletion, compatible with podocyte depletion driving the sclerotic process. Urinary podocyte mRNA correlated with the rate of glomerular podocyte loss. In treatment studies, steroids prevented glomerulosclerosis in the anti-GBM model in contrast to angiotensin II inhibition, which lacked a protective effect, and urinary podocyte and TGF-ß1 mRNA markers more accurately reflected both the amount of podocyte depletion and the degree of glomerulosclerosis compared with proteinuria under both scenarios. In a patient successfully treated for anti-GBM nephritis, urinary podocyte and TGB-ß1 mRNA reflected treatment efficacy. CONCLUSION: These results emphasize the role of podocyte depletion in anti-GBM nephritis and suggest that urinary podocyte and TGF-ß1 mRNA could serve as markers of disease progression and treatment efficacy.

An integrated organoid omics map extends modeling potential of kidney disease.

Kidney organoids are a promising model to study kidney disease, but their use is constrained by limited knowledge of their functional protein expression profile. Here, we define the organoid proteome and transcriptome trajectories over culture duration and upon exposure to TNFα, a cytokine stressor. Older organoids increase deposition of extracellular matrix but decrease expression of glomerular proteins. Single cell transcriptome integration reveals that most proteome changes localize to podocytes, tubular and stromal cells. TNFα treatment of organoids results in 322 differentially expressed proteins, including cytokines and complement components. Transcript expression of these 322 proteins is significantly higher in individuals with poorer clinical outcomes in proteinuric kidney disease. Key TNFα-associated protein (C3 and VCAM1) expression is increased in both human tubular and organoid kidney cell populations, highlighting the potential for organoids to advance biomarker development. By integrating kidney organoid omic layers, incorporating a disease-relevant cytokine stressor and comparing with human data, we provide crucial evidence for the functional relevance of the kidney organoid model to human kidney disease.

Excretion Patterns of Urinary Sediment and Supernatant Podocyte Biomarkers in Patients with CKD.

Background: Podocyte depletion causes glomerulosclerosis, and persistent podocyte loss drives progression to ESKD. Urinary sediment podocin (u-sed Pod) mRNA excretion and urinary supernatant podocalyxin (u-sup PCX) protein have been used to monitor disease activity in glomerular diseases. However, the differences in these markers among pathologies have not been investigated. We examined the roles of these markers in kidney diseases. Methods: From January 2013 to March 2016, early morning urine samples were collected from 12 healthy controls and 172 patients with kidney disease (n=15 patients with minor glomerular abnormality with mild proteinuria and/or microscopic hematuria, n=15 with minimal change nephrotic syndrome [MCNS], n=15 with membranous nephropathy [MN], n=60 with IgA nephropathy [IgAN], n=19 with crescentic GN [Cres GN], n=10 with lupus nephritis [LN], and n=38 with other kidney diseases). We examined u-sed Pod mRNA excretion, u-sup PCX protein, and the urinary protein-creatinine ratio (u-PCR). Results: u-sed Pod mRNA excretion was significantly correlated with u-sup PCX protein (r=0.37, P<0.001). Both u-sed Pod mRNA excretion and u-sup PCX protein were significantly correlated with u-PCR (r=0.53, P<0.001 and r=0.35, P<0.001, respectively). Interestingly, u-sed Pod mRNA excretion was significantly increased in proliferative-type GN-including IgAN with extracapillary proliferative lesions, Cres GN, and LN class IV-and significantly correlated with the rate of crescent formation, whereas u-sup PCX protein was significantly increased only in those with MN and subepithelial dense deposit-type LN compared with controls. Conclusions: Higher u-sed Pod mRNA excretion and u-sup PCX protein were associated with proliferative-type GN, indicating podocyte detachment and subepithelial dense deposit-type GN, respectively. The results suggest that u-sed Pod mRNA excretion and u-sup PCX protein have usefulness for the diagnosis and measurement of disease activity with regard to glomerular diseases.

Urinary podocyte mRNAs precede microalbuminuria as a progression risk marker in human type 2 diabetic nephropathy.

Earlier detection of progression risk in diabetic nephropathy will allow earlier intervention to reduce progression. The hypothesis that urinary pellet podocyte mRNA is a more sensitive progression risk marker than microalbuminuria was tested. A cross sectional cohort of 165 type 2 diabetics and 41 age and sex-matched controls were enrolled. Podocyte stress (Urinary pellet podocin:nephrin mRNA ratio), podocyte detachment (Urinary pellet podocin mRNA:creatinine ratio: UPPod:CR) and a tubular marker (Urinary pellet aquaporin 2:creatinine ratio) were measured in macro-albuminuric, micro-albuminuric and norm-albuminuric groups. eGFR was reassessed after 4 years in 124 available diabetic subjects. Urinary pellet podocyte and tubular mRNA markers were increased in all diabetic groups in cross-sectional analysis. After 4 years of follow-up univariable and multivariate model analysis showed that the only urinary markers significantly related to eGFR slope were UPPod:CR (P < 0.01) and albuminuria (P < 0.01). AUC analysis using K-fold cross validation to predict eGFR loss of ≥ 3 ml/min/1.73m2/year showed that UPPod:CR and albuminuria each improved the AUC similarly such that combined with clinical variables they gave an AUC = 0.70. Podocyte markers and albuminuria had overlapping AUC contributions, as expected if podocyte depletion causes albuminuria. In the norm-albuminuria cohort (n = 75) baseline UPPod:CR was associated with development of albuminuria (P = 0.007) and, in the tertile with both normal kidney function (eGFR 84 ± 11.7 ml/min/1.73m2) and norm-albuminuria at baseline, UPPod:CR was associated with eGFR loss rate (P = 0.003). In type 2 diabetics with micro- or macro-albuminuria UPPod:CR and albuminuria were equally good at predicting eGFR loss. For norm-albuminuric type 2 diabetics UPPod:CR predicted both albuminuria and eGFR loss.

A case of lupus vasculopathy presenting favorable renal outcome.

Noninflammatory necrotizing vasculopathy, also referred to as lupus vasculopathy, is not infrequently observed in the pathology of lupus nephritis. It affects vessels causing them to become severely narrowed and occluded by a mechanism involving immune complexes. We experienced a 51-year-old woman with lupus nephritis class IV + V, which was accompanied by lupus vasculopathy. Renal biopsy and light microscopy showed eosinophilic hyaline-like material in the afferent and/or efferent arterioles, which narrowed the lumen, and which were positive for IgG by immunofluorescent analysis. Electron microscopy indicated that amorphous material and endothelial detachment occluded the arterioles. These findings were consistent with those of lupus vasculopathy. We treated the patient with steroids and cyclophosphamide. By the day of discharge, her levels of creatinine and proteinuria had undergone partial remission. Although lupus vasculopathy was implied as a lesion with unfavorable renal prognosis, some recent reports suggest its true renal prognosis is not unfavorable necessarily. Nevertheless, lupus vasculopathy is an important finding in diagnosis in contradiction to other vascular legions in systemic lupus erythematosus. In addition, a standard therapy has also not been established. Therefore, it is important to accumulate cases of lupus vasculopathy to determine its prognosis and develop standard treatments.

Podocyte hypertrophic stress and detachment precedes hyperglycemia or albuminuria in a rat model of obesity and type2 diabetes-associated nephropathy.

Type2 diabetes-associated nephropathy is the commonest cause of renal failure. Mechanisms responsible are controversial. Leptin-deficient hyperphagic Zucker (fa/fa) rats were modeled to test the hypothesis that glomerular enlargement drives podocyte hypertrophic stress leading to accelerated podocyte detachment, podocyte depletion, albuminuria and progression. By 6weeks, prior to development of either hyperglycemia or albuminuria, fa/fa rats were hyperinsulinemic with high urinary IGF1/2 excretion, gaining weight rapidly, and had 1.6-fold greater glomerular volume than controls (P < 0.01). At this time the podocyte number per glomerulus was not yet reduced although podocytes were already hypertrophically stressed as shown by high podocyte phosphor-ribosomal S6 (a marker of mTORC1 activation), high urinary pellet podocin:nephrin mRNA ratio and accelerated podocyte detachment (high urinary pellet podocin:aquaporin2 mRNA ratio). Subsequently, fa/fa rats became both hyperglycemic and albuminuric. 24 hr urine albumin excretion correlated highly with decreasing podocyte density (R2 = 0.86), as a consequence of both increasing glomerular volume (R2 = 0.70) and decreasing podocyte number (R2 = 0.63). Glomerular podocyte loss rate was quantitatively related to podocyte detachment rate measured by urine pellet mRNAs. Glomerulosclerosis occurred when podocyte density reached <50/106um3. Reducing food intake by 40% to slow growth reduced podocyte hypertrophic stress and "froze" all elements of the progression process in place, but had small effect on hyperglycemia. Glomerular enlargement caused by high growth factor milieu starting in pre-diabetic kidneys appears to be a primary driver of albuminuria in fa/fa rats and thereby an under-recognized target for progression prevention. Progression risk could be identified prior to onset of hyperglycemia or albuminuria, and monitored non-invasively by urinary pellet podocyte mRNA markers.

New-onset haematoproteinuria in a 63-year-old man with intraperitoneal lymph node enlargement.

A 63-year-old man was referred to our hospital because of renal dysfunction with haematoproteinuria. Intraperitoneal lymph node enlargement was also noted. M protein was not detected by electrophoresis of his serum and urine; however, an increase in the κ/λ ratio was detected by free light-chain assay. Percutaneous kidney biopsy was performed, and the patient was diagnosed with proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Lymph node biopsy showed follicular lymphoma. Urinalysis findings improved after treatment of the lymphoma. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits is rarely considered to be associated with haematological disease. We report a case of lymphoma-associated proliferative glomerulonephritis with monoclonal immunoglobulin deposits with light-chain abnormality detected by free light-chain assay, but not by electrophoresis.