Excretion Patterns of Urinary Sediment and Supernatant Podocyte Biomarkers in Patients with Chronic Kidney Disease

Background: Podocyte depletion causes glomerulosclerosis, and persistent podocyte loss drives progression to end-stage kidney disease. Urinary sediment podocyte (u-sed Pod) mRNA excretion and urinary supernatant podocyte (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 (minor glomerular abnormality with mild proteinuria and/or microscopic hematuria, n = 15; minimal change nephrotic syndrome [MCNS], n = 15; membranous nephropathy [MN], n = 15; IgA nephropathy [IgAN], n = 60; crescentic glomerulonephritis [Cres GN], n = 19; lupus nephritis [LN], n = 10; others, n = 38). 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 glomerulonephritis-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 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 glomerulonephritis indicating podocyte detachment and subepithelial dense deposit-type glomerulonephritis, 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.

Clinicopathological characteristics and prognosis of patients with IgA nephropathy and renal vasculitic lesions

Background We studied patients with IgA nephropathy (IgAN) and compared those with and without renal vasculitic lesions (RVLs). Methods From January 2006 to December 2011, patients with biopsy-proven primary IgAN at our institution were retrospectively examined and assigned to an RVL group or a no-RVL group. RVLs were defined as thromboses in arteries and/or arterioles, necrosis of capillary loops, crescent formation, and fibrinoid necrosis of small blood vessels. The association of RVLs with clinical outcomes was analyzed using multivariate models. The primary composite endpoint was end-stage renal disease or doubling of serum creatinine. Results There were 1570 patients, 50.2% (788) with RVLs and 49.8% (782) without RVLs. The RVL group was younger; had shorter disease course, more severe proteinuria and hematuria, worse renal function; and were prescribed more steroids and/or immunosuppressants. The RVL group had a greater prevalence of global glomerular sclerosis, more crescents, and a higher Oxford classification grade. A total of 501 patients in the RVL group (50.7%) and 487 in the no-RVL group (49.3%) completed follow-up. The RVL group was more likely to reach the composite endpoint after 1, 3, and 5 years (all P < 0.001). Proteinuria, anemia, low eGFR, and global and segmental sclerosis were independent predictors of progression to the composite endpoint in patients with RVLs. Conclusions Almost half of our IgAN patients had RVLs, and these patients were younger and had worse renal function, with more severe proteinuria, hematuria, and severe pathologic lesions. IgAN patients with RVLs had worse renal outcomes than those without RVLs.

Crescentic Glomerulonephritis: Pathogenesis and Therapeutic Potential of Human Amniotic Stem Cells

Chronic kidney disease (CKD) leads to significant morbidity and mortality worldwide. Glomerulonephritis (GN) is the second leading cause of CKD resulting in end stage renal failure. The most severe and rapidly progressive type of GN is characterized by glomerular crescent formation. The current therapies for crescentic GN, which consist of broad immunosuppressive drugs, are partially effective, non-specific, toxic and cause many serious side effects including infections, cancer, and cardiovascular problems. Therefore, new and safer therapies are needed. Human amniotic epithelial cells (hAECs) are a type of stem cell which are isolated from the placenta after birth. They represent an attractive and novel therapeutic option for the treatment of various inflammatory conditions owing to their unique and selective immunosuppressive ability, as well as their excellent safety profile and clinical applicability. In this review, we will discuss the immunopathogenesis of crescentic GN, issues with currently available treatments and how hAECs offer potential to become a new and harmless treatment option for this condition.

Implantation of Dedifferentiated Fat Cells Ameliorated ANCA Glomerulonephritis by Immunosuppression and Increases in TSG-6

We examined the effects of implantation of dedifferentiated fat (DFAT) cells on renal function, proteinuria and glomerulonephritis in SCG mice as a preclinical study of DFAT cell therapy for antineutrophil cytoplasmic antibody (ANCA) glomerulonephritis and investigated mechanisms underlying the immunosuppressive effects of the implantation of DFAT cells. After their intravenous infusion, almost all DFAT cells were trapped in the lung and not delivered into the kidney. Implantation of DFAT cells in SCG mice suppressed glomerular crescent formation, decreased urinary protein excretions, and increased expression of tumor necrosis factor-stimulated gene-6 (TSG-6) mRNA, protein and immunostaining in kidney from these mice. Implantation of DFAT cells increased the expression of microRNA 23b-3p in plasma, kidney and lung in SCG mice and decreased the expression of CD44 mRNA and increased the expression of prostaglandin E2 and interleukin-10 mRNAs in kidney from these mice. Implantation of DFAT cells increased expression of TSG-6 protein and decreased expression of tumor necrosis factor-a protein in kidney from SCG mice. Further, implantation of DFAT cells increased the expression of C-C motif chemokine ligand 17 protein, a chemokine for M2 macrophages, and decreased the expression of MCP-1 protein, a chemokine for M1 macrophages, in kidney from SCG mice. Survival rates were higher in SCG mice with implantation of DFAT cells than in SCG mice without implantation. These results indicate that implantation of DFAT cells suppressed renal injury including glomerular crescent formation in kidney from SCG mice while increasing the expression of TSG-6 without delivery of DFAT cells directly into kidney. Mechanisms underlying the effects of improvement of ANCA glomerulonephritis are associated with immunosuppressive effects by TSG-6 and the transition of M1 to M2 macrophages. These findings suggest that implantation of DFAT cells may become a cell therapy for ANCA glomerulonephritis.

Regulatory role and mechanisms of myeloid TLR4 in anti-GBM glomerulonephritis

Myeloid cells and TLR4 play a critical role in acute kidney injury. This study investigated the regulatory role and mechanisms of myeloid TLR4 in experimental anti-glomerular basement membrane (GBM) glomerulonephritis (GN). Anti-GBM GN was induced in tlr4flox/flox and tlr4flox/flox−lysM−cre mice by intravenous injection of the sheep anti-mouse GBM antibody. Compared to control mice, conditional disruption of tlr4 from myeloid cells, largely macrophages (> 85%), suppressed glomerular crescent formation and attenuated progressive renal injury by lowering serum creatinine and 24-h urine protein excretion while improving creatinine clearance. Mechanistically, deletion of myeloid tlr4 markedly inhibited renal infiltration of macrophages and T cells and resulted in a shift of infiltrating macrophages from F4/80+iNOS+ M1 to F4/80+CD206+ M2 phenotype and inhibited the upregulation of renal proinflammatory cytokines IL-1β and MCP-1. Importantly, deletion of myeloid tlr4 suppressed T cell-mediated immune injury by shifting Th1 (CD4+IFNγ+) and Th17 (CD4+IL-17a+) to Treg (CD4+CD25+FoxP3+) immune responses. Transcriptome analysis also revealed that disrupted myeloid TLR4 largely downregulated genes involving immune and cytokine-related pathways. Thus, myeloid TLR4 plays a pivotal role in anti-GBM GN by immunological switching from M1 to M2 and from Th1/Th17 to Treg and targeting myeloid TLR4 may be a novel therapeutic strategy for immune-mediated kidney diseases.

Drug-Induced Kidney Injury Caused by Osimertinib: Report of a Rare Case

Tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) have shown highly favourable outcomes in patients with advanced-stage non-small-cell lung cancer (NSCLC). The adverse effects of EGFR-TKIs are generally less severe than those of conventional cytotoxic therapies. We report a patient with NSCLC who presented with acute kidney injury associated with biopsy-proven acute tubular injury during osimertinib treatment and whose renal function recovered after reducing the osimertinib dose. A 61-year-old male smoker complained of dyspnoea on exertion for 1 month before his visit to the medical centre. He was diagnosed with lung adenocarcinoma of the left lower lobe (cT4N3M1a, stage IVA) and was positive for an <i>EGFR</i> mutation (exon 19 deletion). Osimertinib was initiated at 80 mg/day. At treatment initiation, the patient’s serum creatinine level was 0.64 mg/dL, with microscopic haematuria; by day 83, this level had increased to 1.33 mg/dL, with proteinuria. On day 83, we reduced the osimertinib dose to 40 mg/day and performed a kidney biopsy on day 98. The histological diagnosis was tubular injury with IgA deposition. Based on the clinical course and histological findings, we speculated that the kidney injury was associated with osimertinib. After dose reduction, the patient’s serum creatinine level decreased to 1.07 mg/dL, and proteinuria disappeared. He maintained a partial response for &#x3e;6 months after osimertinib administration. We report the first case of biopsy-proven mild IgA deposition, crescent formation, and tubular injury probably caused by osimertinib and demonstrate how reducing the osimertinib dose could strike a balance between its anti-cancer efficacy and adverse effects.

A rare case of coexistence of Wegener’s granulomatosis and pulmonary tuberculosis with subsequent development of thrombosis of the cerebral veins

Background Granulomatosis with polyangiitis (GPA), also known as Wegener’s granulomatosis, is an idiopathic systemic disease typically affecting the lungs, although other organs may also be involved. Case presentation A 28-year-old male was admitted to Baqiyatallah university hospital in Teheran (Iran) after a 3-week history of fever and productive cough. The patient gradually developed fatigue, arthralgia, hematuria, nausea, vomiting, dyspnea, hemoptysis, weight loss, oliguria and then anuria. Chest-X-ray (CXR) and computerized tomography scan revealed cavitating nodular opacities in the right lung lobe. Furthermore, plasma creatinine increased from 2.2 to 4 mg/dl in a few days. Histopathological examination of kidney biopsy revealed peri-glomerular and peri-vascular inflammation, degeneration and necrosis of the tubular epithelial lining, red blood cell casts, distorted glomerular structure, fibrin thrombi, segmental breaks of the glomerular basal membrane, disruption of Bowman's capsular membrane and crescent formation of the affected glomeruli. An abnormal CXR, an abnormal urinary sediment and a typical kidney histology were used as criteria to diagnose glomerulonefritis with poliangiitis (GPA). Bronchoalveolar lavage smear and PCR turned out positive for mycobacterium tuberculosis. After 3 months of treatment for (GPA) and tuberculosis the patient developed headache and seizure. Cerebral Magnetic Resonance Venography revealed cerebral venous thrombosis of the sinus transverse and sigmoid. Conclusions Tuberculosis may coexist with GPA, as it occurred in our patient. Since a crescentic glomerulonephritis can progress to renal failure, clinicians should always be aware of potential multiple conditions when considering differential diagnoses.

Complement Activation Is Associated With Crescents in IgA Nephropathy

IntroductionCrescents, especially those found at a percentage greater than 50%, are often associated with rapid progression of kidney disease in IgA nephropathy (IgAN). The mechanism of crescents forming in IgAN is still unclear. In this study, we aimed to evaluate whether excess complement activation participates in the formation of crescents in IgAN.MethodsOne hundred IgAN patients with various proportions of crescents—24 with 1%–24%, 27 with 25%–49%, 21 with 50%–74% 12 with more than 75%, and 16 without crescents—were included. Urinary concentrations of mannose-binding lectin (MBL), Bb, C4d, C3a, C5a, and soluble C5b-9 (sC5b-9) were measured at the time of biopsy. Receiver operating characteristic (ROC) curves were performed to evaluate predictive ability of renal survival for urine complement activation. In addition, historical C4d, C5b-9, and C3d were stained by immunohistochemistry.ResultsIgAN patients with more than 50% crescent formation showed higher complement activation levels than the other patients (urinary C3a/creatinine (C3a/Cr): 6.7295 ng/mg, interquartile range (IQR) 1.4652–62.1086 ng/mg vs. 0.1055 ng/mg, IQR 0–1.4089 ng/mg; urinary C5a/Cr: 15.6202 ng/mg, 4.3127–66.7347 ng/mg vs. 0.3280 ng/mg, IQR 0.0859–2.4439 ng/mg; urinary sC5b-9/Cr: 98.6357 ng/mg, 8.8058–1,087.4578 ng/mg vs. 1.4262 ng/mg, 0.0916–11.0858 ng/mg, all p-values &lt;0.001). The levels of urinary MBL and C4d representing lectin complement pathway showed a linear association with the proportion of crescents (r = 0.457 and 0.562, respectively, both p-values &lt;0.001). Combined urine complement products could increase the predictive ability compared with crescents alone from 0.904 to 0.944 (p = 0.062) with borderline significance. Moreover, the glomerular C4d deposition rate elevated with the increase of proportions of crescents.ConclusionExcess complement activation may be involved in the formation of crescents, especially diffuse crescent formation, in patients with IgAN. Urinary C4d correlated with the proportion of crescents and was a potential biomarker for disease monitoring in crescentic IgAN.