The Challenging Management of Cancer: An Immunonephrologist's Perspective.

INTRODUCTION: Onconephrology is an emerging medical subspecialization that focuses on the numberless interrelations between cancer and kidney diseases. Tumor cells evade immune surveillance through activation of immune checkpoint pathways that suppress antitumor immune responses. By blocking checkpoints, new anticancer agents disrupt immune homeostasis but potentially induce immune-mediated diseases. Nephrologists and nephroimmunologists should be able to treat the nephrotoxic sequelae of cancer therapy and ensure continuation of the life-saving treatment. METHODS: Thirty-seven renal biopsies have been carried out over 42 months in oncologic patients, that is, 5.2% of the total native renal biopsies were carried out in the same period. The commonest diagnoses (>6 cases) were interstitial tubular nephritis, membranous glomerulopathy, IgA nephropathy, vasculitis, and focal and segmental glomerulosclerosis. CASE PRESENTATION: Three example cases, including focusing on key questions which could involve the nephrologists are reported in detail. They include a cancer-related Goodpasture Syndrome, the peculiar toxic effects of pemetrexed on tubular cells, and the intriguing relationship between bevacizumab and cryoglobulinemic glomerulonephritis. CONCLUSION: As shown by these 3 example cases, nephrologists need to be open-minded with regard to kidney biopsy in order to get a timely diagnosis. Nephrologists also need to improve their knowledge of cancer biology and therapy in order to prevent kidney problems, manage therapy-related immune-mediated disorders, and improve patient life expectancy.

Therapeutic Potential of Extracellular Vesicles in Hypertension-Associated Kidney Disease.

Hypertension-mediated organ damage frequently includes renal function decline in which several mechanisms are involved. The present review outlines the state of the art on extracellular vesicles in hypertension and hypertension-related renal damage. Emerging evidence indicates that extracellular vesicles, small vesicles secreted by most cell types and body fluids, are involved in cell-to-cell communication and are key players mediating biological processes such as inflammation, endothelial dysfunction or fibrosis, mechanisms present the onset and progression of hypertension-associated kidney disease. We address the potential use of extracellular vesicles as markers of hypertension-mediated kidney damage severity and their application as therapeutic agents in hypertension-associated renal damage. The capacity of exosomes to deliver a wide variety of cargos to the target cell efficiently makes them a potential drug delivery system for treatment of renal diseases.

Daily Low-intensity Pulsed Ultrasound Ameliorates Renal Fibrosis and Inflammation in Experimental Hypertensive and Diabetic Nephropathy.

The estimated morbidity rate of chronic kidney disease is 8% to 16% worldwide, and many patients with chronic kidney disease eventually develop renal failure. Thus, the development of new therapeutic strategies for preventing renal failure is crucial. In this study, we assessed the effects of daily low-intensity pulsed ultrasound (LIPUS) therapy on experimental hypertensive nephropathy and diabetic nephropathy. Unilateral nephrectomy and subcutaneous infusion of angiotensin II via osmotic mini-pumps were used to induce hypertensive nephropathy in mice. Immunohistochemistry revealed that daily LIPUS treatment ameliorated renal fibrosis and infiltration of inflammatory cells induced by angiotensin II. A similar therapeutic effect was also observed in mice with angiotensin II-induced hypertensive nephropathy in which splenectomy was performed. In addition, LIPUS treatment significantly decreased systolic blood pressure after 21 days. Subsequently, db/db mice with unilateral nephrectomy developed proteinuria; daily LIPUS treatment significantly reduced proteinuria after 42 days. In addition, immunohistochemistry revealed that renal fibrosis was significantly ameliorated by LIPUS treatment. Finally, LIPUS stimulation suppressed TGF-ß1 (transforming growth factor-ß1)-induced phosphorylation of Smad2 and Smad3 in HK-2 (human proximal tubular cell line) cells. LIPUS treatment may be a useful therapy for preventing the progression of renal fibrosis in patients with chronic kidney disease.

A Kidney Transplant Recipient with Recurrent Henoch-Schönlein Purpura Nephritis Successfully Treated with Steroid Pulse Therapy and Epipharyngeal Abrasive Therapy.

There is no specific treatment for recurrent Henoch-Schönlein purpura nephritis (HSPN) in a transplanted kidney. We herein report a case of a kidney transplant recipient with recurrent HSPN that was successfully treated with steroid pulse therapy and epipharyngeal abrasive therapy (EAT). A 39-year-old Japanese man developed HSPN 4 years ago and had to start hemodialysis after 2 months despite receiving steroid pulse therapy followed by oral prednisolone, plasma exchange therapy, and cyclophosphamide pulse therapy. He had undergone tonsillectomy 3 years earlier in the hopes of achieving a better outcome of a planned kidney transplantation and received a living-donor kidney transplantation from his mother 1 year earlier. Although there were no abnormalities in the renal function or urinalysis 2 months after transplantation, a routine kidney allograft biopsy revealed evidence of mesangial proliferation and cellular crescent formation. Mesangial deposition for IgA and C3 was noted, and he was diagnosed with recurrent HSPN histologically. Since the renal function and urinalysis findings deteriorated 5 months after transplantation, 2 courses of steroid pulse therapy were performed but were ineffective. EAT using 0.5% zinc chloride solution once per day was combined with the third course of steroid pulse therapy, as there were signs of chronic epipharyngitis. His renal function recovered 3 months after daily EAT and has been stable for 1.5 years since transplantation. Daily EAT continued for >3 months might be a suitable strategy for treating recurrent HSPN in cases of kidney transplantation.

Rituximab in severe immunoglobulin-A vasculitis (Henoch-Schönlein) with aggressive nephritis.

OBJECTIVES: Immunoglobulin-A vasculitis (IgAV) is a systemic small-vessel vasculitis in which renal involvement indicates severity of illness, and chronic kidney disease represents the most serious long-term complication. No treatment at present is specifically recommended for IgAV. Recently, rituximab (RTX) has been shown to be effective in case series of adults with IgAV. However, long term results are lacking. Aim of the study is to evaluate the effectiveness of RTX as induction therapy and maintenance of remission in adults with severe IgAV and aggressive glomerulonephritis. METHODS: This study included 12 adult-onset patients, 8 males and 4 females, mean age 45.1 years (range 19-75) with a mean follow-up duration of 33.7 months (range 6-144). All patients had a severe IgAV with biopsy proven crescentic nephritis. RTX was given for the treatment of a refractory disease or because of definite contraindications to standard therapies. RESULTS: Eleven patients (91.7%) achieved a clinical response at 6 months. Ten patients had a complete response (CR) while one had a partial response and was given an additional dose of RTX after 12 months for persistent proteinuria (1gr/24 hrs) despite systemic remission. He achieved a CR 6 months later. One patient was considered unresponsive to RTX and was switched to MMF. Among the 10 patients with CR, 1 needed maintenance doses of RTX every 6 months for iterative relapsing of severe purpura, 1 relapsed after 15 months and received a new induction course showing a CR again. A significant decrease in BVAS (p=0.031) and 24-hour-proteinuria (p=0.043) from RTX initiation through the last follow-up has been detected. One patient, who had a CR with RTX alone died after 6 months for therapy-unrelated cardiovascular cause. CONCLUSIONS: RTX proved to be effective and safe for induction and maintenance of long-lasting remission in severe IgAV with aggresive renal involvement. Data also suggest that RTX can be indicated not only for refractory cases, but can be also proposed as a first line therapy.

Renovascular Hypertension.

Renovascular disease (RVD) is a major cause of secondary hypertension. Atherosclerotic renal artery stenosis is the most common type of RVD followed by fibromuscular dysplasia. It has long been recognized as the prototype of angiotensin-dependent hypertension. However, the mechanisms underlying the physiopathology of hypertensive occlusive vascular renal disease are complex and distinction between the different causes of RVD should be made. Recognition of these distinct types of RVD with different degrees of renal occlusive disease is important for management. The greatest challenge is to individualize and implement the best approach for each patient in the setting of widely different comorbidities.

Clinical and Pathological Characteristics of Elderly Japanese Patients with IgA Vasculitis with Nephritis: A Case Series.

Objective This case series aimed to identify the clinical and pathological characteristics of elderly patients (≥60 years) with biopsy-proven IgA vasculitis with nephritis (IgAVN). Methods The clinical and pathological presentation and treatment outcomes were compared between two groups. Patients Patients with IgAVN who were ≥19 years old at the time of their renal biopsy were divided into elderly (≥60 years) and adult (19-59 years) groups. Results Of the 23 patients in our study, 13 were elderly. In the elderly group, the median age at the diagnosis was 68 years (range, 60-85 years), with a median follow-up period of 15 months (range, 3-80 months). Twelve elderly patients had comorbidities, including hypertension, diabetes mellitus, chronic kidney disease, cardiovascular disease, and malignancies. A decrease in the estimated glomerular filtration rate, as well as massive proteinuria and rapidly progressive nephritic syndrome, were more frequent in the elderly group than in the adult group. Furthermore, renal pathological changes, including cellular or fibrocellular crescents, interstitial fibrosis, tubular atrophy, and arteriosclerosis, were more severe among elderly patients than adult patients. All elderly patients were treated with glucocorticoids and had no incidence of end-stage renal disease at the final follow-up; in addition, nine elderly patients had reduced proteinuria with a preserved renal function. Adverse events, including infection, diabetes mellitus, and vascular disorders, were identified in nine patients. Three elderly patients died from severe infections. Conclusion IgAVN in elderly patients is characterized by severe renal involvement. Elderly patients are at higher risk than adults for treatment-related adverse events.

Targeting kidney inflammation as a new therapy for primary hyperoxaluria?

The primary hyperoxalurias (PHs) are inborn errors of glyoxylate metabolism characterized by endogenous oxalate overproduction in the liver, and thus elevated urinary oxalate excretion. The urinary calcium-oxalate (CaOx) supersaturation and the continuous renal accumulation of insoluble CaOx crystals yield a progressive decline in renal function that often ends with renal failure. In PH Type 1 (AGXT mutated), the most frequent and severe condition, patients typically progress to end-stage renal disease (ESRD); in PH Type 2 (GRHPR mutated), 20% of patients develop ESRD, while only one patient with PH Type 3 (HOGA1 mutated) has been reported with ESRD so far. Patients with ESRD undergo frequent maintenance (haemo)dialysis treatment, and finally must receive a combined liver-kidney transplantation as the only curative treatment option available in PH Type 1. In experimental models using oxalate-enriched chow, CaOx crystals were bound to renal tubular cells, promoting a pro-inflammatory environment that led to fibrogenesis in the renal parenchyma by activation of a NACHT, LRR and PYD domains-containing protein 3 (NALP3)-dependent inflammasome in renal dendritic cells and macrophages. Chronic fibrogenesis progressively impaired renal function. Targeting the inflammatory response has recently been suggested as a therapeutic strategy to treat not only oxalate-induced crystalline nephropathies, but also those characterized by accumulation of cystine and urate in other organs. Herein, we summarize the pathogenesis of PH, revising the current knowledge of the CaOx-mediated inflammatory response in animal models of endogenous oxalate overproduction. Furthermore, we highlight the possibility of modifying the NLRP3-dependent inflammasome as a new and complementary therapeutic strategy to treat this severe and devastating kidney disease.

Bone mesenchymal stem cells pretreated with erythropoietin enhance the effect to ameliorate cyclosporine A-induced nephrotoxicity in rats.

An increasing number of experiments and clinical trials have demonstrated the safety, feasibility, and efficacy of mesenchymal stem cells (MSCs)-based therapies for the treatment of various diseases. The main drawbacks of MSC therapy are the lack of specific homing after systemic infusion and early death of injected cells because of the injury micro-environment. We pretreated bone mesenchymal stem cells (BMSCs) with erythropoietin (EPO) to investigate their positive effect on cyclosporine A (CsA)-induced nephrotoxicity. BMSCs were incubated with different concentrations of EPO (10, 100, 500, and 1000 IU/mL) for 24 and 48 h, and their proliferation rate, cytoskeletal morphology, migration ability, and the expression of CXCR4 were evaluated to determine the optimal pretreatment conditions. To investigate the therapeutic effects of BMSCs pretreated with EPO in CsA-induced nephrotoxicity, we established CsA-induced in vitro and in vivo toxicity models. In our in vitro study, preconditioning of BMSCs with 500 IU/mL EPO for 48 h induced a marked increase in their proliferation rate, cytoskeletal rearrangement, migration in the scrape-healing assay, and migration toward injured HK2 cells. In vivo, EPO-BMSCs showed higher ability to improve renal function than BMSCs, and in CsA-induced rats treated with EPO-BMSCs, interstitial lymphocyte infiltration, tubular swelling, necrosis, and interstitial fibrosis decreased. We demonstrated that pretreatment with 500 IU/mL EPO before infusion markedly increased the homing ability of BMSCs, and obviously ameliorate CsA-induced nephrotoxicity in rats.

Bowman capsulitis predicts poor kidney allograft outcome in T cell-mediated rejection.

Acute T cell-mediated rejection (TCMR) is an important cause of renal allograft loss. The Banff classification for tubulointerstitial (type I) rejection is based on the extent of both interstitial inflammation and tubulitis. Lymphocytes may also be present between parietal epithelial cells and Bowman capsules in this setting, which we have termed "capsulitis." We conducted this study to determine the clinical significance of capsulitis. We identified 42 patients from the pathology archives at The University of Chicago with isolated Banff type I TCMR from 2010 to 2015. Patient demographic data, Banff classification, and graft outcome measurements were compared between capsulitis and noncapsulitis groups using Mann-Whitney U test. Capsulitis was present in 26 (62%) and was more frequently seen in Banff IB than in IA TCMR (88% versus 44%, P = .01). Patients with capsulitis had a higher serum creatinine at biopsy (4.6 versus 2.9 mg/dL, P = .04) and were more likely to progress to dialysis (42% versus 13%, P = .06), with fewer recovering their baseline serum creatinine (12% versus 38%, P = .08). Patients with both Banff IA TCMR and capsulitis have clinical outcomes similar to or possibly worse than Banff IB TCMR compared with those with Banff IA and an absence of capsulitis. Capsulitis is an important pathologic parameter in the evaluation of kidney transplant biopsies with potential diagnostic, prognostic, and therapeutic implications in the setting of TCMR.

Identification of potential biomarkers and therapeutic targets for human IgA nephropathy and hypertensive nephropathy by bioinformatics analysis.

In order to further elucidate the potential correlations and treatments of IgA nephropathy (IgAN) and hypertensive nephropathy (HT), bioinformatics analysis of IgAN and HT was performed. The mRNA expression profiles of human renal biopsy samples from patients with IgAN, patients with HT and pre­transplant healthy living controls (LD) were downloaded from the Gene Expression Omnibus database. Then, the differentially expressed genes (DEGs) were identified and functions of DEGs were analyzed. Finally, the regulatory networks containing DEGs and related­transcription factors (TFs) were constructed using Cytoscape software. When compared with the LD group, 134 and 188 DEGs were obtained in the IgAN and HT groups, respectively. A total of 39 genes were altered in the HT group when compared with the IgAN group. In addition, 66 genes were shared in the IgAN and HT groups when compared with the LD group, 6 of which [early growth response 1, activating transcription factor 3, nuclear receptor subfamily 4 group A member 2 (NR4A2), NR4A1, v­maf avian musculoaponeurotic fibrosarcoma oncogene homolog F and Kruppel like factor 6] were identified as TFs. In addition, DEGs including interleukin (IL) 1 receptor antagonist, collagen type 4 α2 chain, IL8, FBJ murine osteosarcoma viral oncogene homolog and somatostatin were enriched in a number of inflammation­associated biological processes, and DEGs including structural maintenance of chromosomes protein 3, v­crk avian sarcoma virus CT10 oncogene homolog and myosin 6 were enriched in non­inflammation­associated biological processes. Therefore, the differentially expressed TF genes and the genes associated with inflammation may be effective as potential therapeutic targets for IgAN and HT.

[Sarcoidosis : Renal manifestations]. / Sarkoidose : Renale Manifestationen.

Renal involvement in sarcoidosis is much more common than generally assumed from old epidemiological studies and is often only detected when actively searched for. Many patients with renal sarcoidosis present with no or only few symptoms. The diagnostic work-up of sarcoidosis should always include a possible renal involvement. In cases of impaired renal function, proteinuria or a pathological urine sediment, a renal biopsy specimen should be obtained to assess the type, severity and prognosis of the kidney disease. Treatment is primarily based on the use of corticosteroids. Steroid-sparing agents, such as disease-modifying antirheumatic drugs and infliximab can be applied; however, the evidence for efficacy of these therapies is mostly based on case series and expert opinions. Discontinuation of immunosuppression therapy bears a high risk of relapse.

Pre-incubation with hucMSC-exosomes prevents cisplatin-induced nephrotoxicity by activating autophagy.

BACKGROUND: The administration of cisplatin is limited due to its nephrotoxic side effects, and prevention of this nephrotoxicity of cisplatin is difficult. Mesenchymal stem cell (MSC)-derived exosomes have been implicated as a novel therapeutic approach for tissue injury. In this study, we demonstrated that the pretreatment of human umbilical cord MSC-derived exosomes (hucMSC-Ex) can prevent the development of cisplatin-induced renal toxicity by activation of autophagy in vitro and in vivo. METHODS: In vitro, rat renal tubular epithelial (NRK-52E) cells were pre-incubated with exosomes from hucMSC or HFL1 (human lung fibroblast cells; as control) for 30 min, and 3-methyladenine (an autophagic inhibitor) and rapamycin (an autophagic inducer) for 1 h before cisplatin treatment for 8 h, respectively. Cells were harvested for apoptosis assay, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). In vivo, we constructed cisplatin-induced acute kidney injury rat models. Prior to treatment with cisplatin for 0.5 h, hucMSC-Ex or HFL1-Ex were injected into the kidneys via the renal capsule. 3-methyladenine and rapamycin were injected under the kidney capsule before hucMSC-Ex. All animals were sacrificed at 3 days after cisplatin injection. Renal function, Luminex assay, tubular apoptosis and proliferation, and autophagy response were evaluated. RESULTS: hucMSC-Ex inhibited cisplatin-induced mitochondrial apoptosis and secretion of inflammatory cytokines in renal tubular epithelial cells in vitro. hucMSC-Ex increased the expression of the autophagic marker protein LC3B and the autophagy-related genes ATG5 and ATG7 in NRK-52E cells. Rapamycin mimicked the effects of hucMSC-Ex in protecting against cisplatin-induced renal injury, while the effects were abrogated by the autophagy inhibitor 3-methyladenine in the animals. CONCLUSIONS: Our findings indicate that the activation of autophagy induced by hucMSC-Ex can effectively relieve the nephrotoxicity of cisplatin. Therefore, pre-treatment of hucMSC-Ex may be a new method to improve the therapeutic effect of cisplatin.

Therapeutic potentials of mesenchymal stem cells on the renal cortex of experimentally induced hypertensive albino rats: Relevant role of Nrf2.

Bone marrow derived-mesenchymal stem cells (BM-MSCs) have brought great attention in regenerative medicine field, various experimental & clinical trials were held to investigate their therapeutic effects in different disorders. We designed a histological & immunohistochemical study to evaluate effectiveness of MSCs therapy in withhold of end-stage renal disease (ESRD) secondary to hypertension which has become a growing & striking public health problem. 30 adult male albino rats were utilized, 20 of them were exposed to experimental induction of hypertension, then divided equally to MSCs treated group (injected with 1×106 fluorescent labeled cell i.v./rat), while the second one was left without treatment. Renal specimens were subjected to histopathological, ultrastructural and immunohistochemical examination for Nrf2 in addition to biochemical estimation of serum urea & creatinine. Our results documented that BM-derived MSCs exerts considerable reversing effect of histopathologic and ultrastructural hypertensive nephropathy. Moreover, immunohistochemical results clearly pointed to relevant role of Nrf2 pathway in MSCs related renal therapeutic effects.

Acute Focal Bacterial Nephritis Can Lead to Unnecessary Invasive Procedures: A Report of Three Cases.

Acute focal bacterial nephritis (AFBN) is a rarely diagnosed interstitial bacterial infection of the kidney. Due to the non-specific clinical presentation of this entity, correct diagnosis can be challenging. In this work, we present three cases of AFBN aiming to stress the diversity of clinical presentation associated with the disease and the fact that patients with AFBN are at risk of undergoing unnecessary invasive procedures. The employment of invasive diagnostic and therapeutic procedures on the management of AFBN should be limited, as the majority of patients respond well to conservative therapy.

Effect of Roux-en-Y gastric bypass and diet-induced weight loss on diabetic kidney disease in the Zucker diabetic fatty rat.

BACKGROUND: Reductions in urinary protein excretion after Roux-en-Y gastric bypass (RYGB) surgery in patients with diabetic kidney disease have been reported in multiple studies. OBJECTIVES: To determine the weight loss dependence of the effect of RYGB on urinary protein excretion by comparing renal outcomes in Zucker diabetic fatty rats undergoing either gastric bypass surgery or a sham operation with or without weight matching. SETTING: University laboratories. METHODS: Zucker diabetic fatty rats underwent surgery at 18 weeks of age. A subgroup of sham operated rats were weight matched to RYGB operated rats by restricting food intake. Urinary protein excretion was assessed at baseline and at postoperative weeks 4 and 12. Renal histology and macrophage-associated inflammation were assessed at postoperative week 12. RESULTS: Progressive urinary protein excretion was attenuated by both RYGB and diet-induced weight loss, albeit to a lesser extent by the latter. Both weight loss interventions produced equivalent reductions in glomerulomegaly, glomerulosclerosis, and evidence of renal macrophage infiltration. CONCLUSION: Weight loss per se improves renal structure and attenuates renal inflammatory responses in an experimental animal model of diabetic kidney disease. Better glycemic control post-RYGB may in part explain the greater reductions in urinary protein excretion after gastric bypass surgery.

Milk fat globule epidermal growth factor-8 limits tissue damage through inflammasome modulation during renal injury.

Mediators released by apoptotic renal resident cells play a crucial role in modification of the inflammatory microenvironment. We have demonstrated that milk fat globule epidermal growth factor 8 (MFG-E8) is released by apoptotic cells, which results in reduced proinflammatory cytokine production by macrophages. The present study was designed to study the role of MFG-E8 on the modulation of tissue damage and macrophage phenotype in a renal inflammatory model, unilateral ureteral obstruction (UUO). C57BL/6 WT or MFG-E8 KO mice underwent ureteral ligation for 3, 7, and 14 d to evaluate renal injury. MFG-E8 (30 µg/kg) or vehicle was also administered i.p. MFG-E8 administration reduced kidney damage and fibrosis compared with control, whereas its absence in MFG-E8 KO mice was associated with more severe disease. Moreover, MFG-E8 administration was associated with decreased inflammasome activation in the kidney. Furthermore, adoptive transfer of MFG-E8-stimulated macrophages reduced activation of inflammasome and tissue damage. In all cases, both the systemic administration of MFG-E8 and MFG-E8-treated macrophages promoted accumulation of anti-inflammatory CD206+ macrophages. We propose that the protective role of MFG-E8 is mediated through anti-inflammatory macrophage reprogramming which results in decreased inflammasome activation, preventing severe tissue damage. These data provide valuable insight for identification of MFG-E8 as a novel target in modulation of inflammatory diseases.

Acute focal bacterial nephritis, pyonephrosis and renal abscess in children.

BACKGROUND-AIM: Acute focal bacterial nephritis (AFBN), renal abscess and pyonephrosis are uncommon and not fully addressed forms of urinary tract infection (UTI) which may be underdiagnosed without the appropriate imaging studies. Here, we review the characteristics and outcome of these renal entities in children managed at a single medial centre. PATIENTS AND METHODS: The medical files of all children hospitalized for episodes of AFBN, renal abscess and pyonephrosis during a 10-year period (2003-2012) were reviewed. RESULTS: Among the 602 children hospitalized for UTI, 21 presented with AFBN, one with abscess and three with pyonephrosis. All 25 children (13 girls), ranging in age from 0.06 to 13.4 years, were admitted with fever and an impaired clinical condition, and 18 had urological abnormalities. More than one lesion, often of different types, were identified in 11 episodes. Urine cultures from 13 episodes grew non-Escherichia coli pathogens and those from two episodes were negative. Antibiotics were administered for 14-60 days, and emergency surgery was required in three cases. During follow-up, 13 patients underwent corrective surgery. Permanent renal lesions were identified in 16 patients. CONCLUSIONS: AFBN, renal abscess and pyonephrosis should be suspected in children with severe presentation and urological history. Appropriate imaging is crucial for management planning. Prognosis is often guarded despite appropriate treatment. Based on the results of this study we propose a management algorithm.

Systematic implantation of dedifferentiated fat cells ameliorated monoclonal antibody 1-22-3-induced glomerulonephritis by immunosuppression with increases in TNF-stimulated gene 6.

INTRODUCTION: Implantation of mesenchymal stem cells (MSCs) has recently been reported to repair tissue injuries through anti-inflammatory and immunosuppressive effects. We established dedifferentiated fat (DFAT) cells that show identical characteristics to MSCs. METHODS: We examined the effects of 10(6) of DFAT cells infused through renal artery or tail vein on monoclonal antibody (mAb) 1-22-3-induced glomerulonephritis (as an immunological type of renal injury) and adriamycin-induced nephropathy (as a non-immunological type of renal injury) in rats. The mAb 1-22-3-injected rats were also implanted with 10(6) of DFAT cells transfected with TSG-6 siRNA through tail vein. RESULTS: Although DFAT cells transfused into blood circulation through the tail vein were trapped mainly in lungs without reaching the kidneys, implantation of DFAT cells reduced proteinuria and improved glomerulosclerosis and interstitial fibrosis. Implantation of DFAT cells through the tail vein significantly decreased expression of kidney injury molecule-1, collagen IV and fibronectin mRNAs, whereas nephrin mRNA expression was increased. Implantation of DFAT cells did not improve adriamycin-induced nephropathy, but significantly decreased the glomerular influx of macrophages, common leukocytes and pan T cells. However, the glomerular influx of helper T cells, was increased. Implantation of DFAT cells decreased expression of interleukin (IL)-6 and IL-12ß mRNAs and increased expression of TNF-stimulated gene (TSG)-6 mRNA in renal cortex from mAb 1-22-3-injected rats. The basal level of TSG-6 protein was significantly higher in DFAT cells than in fibroblasts. Expression of TSG-6 mRNA in MCs cocultured with DFAT cells was significantly higher than in mesangial cells or DFAT cells alone. Systematic implantation of DFAT cells with TSG-6 siRNA through tail vein did not improve proteinuria, renal dysfunction and renal degeneration in the mAb 1-22-3-injected rats. CONCLUSION: Systematic implantation of DFAT cells effectively ameliorated mAb 1-22-3-induced glomerulonephritis through immunosuppressive effects accompanied by the suppression of macrophage infiltration and expression of IL-6, IL-10 and IL-12ß, and increased production of serum and renal TSG-6 that improved the mAb 1-22-3-induced renal degeneration by the immunosuppressive effects of TSG-6. Thus DFAT cells will be suitable cell source for the treatment of immunological progressive renal diseases.

Renal dysfunction and intragraft proMMP9 activity in renal transplant recipients with interstitial fibrosis and tubular atrophy.

Chronic renal allograft injury is reflected by interstitial fibrosis and tubular atrophy (IF/TA) and by the accumulation of extracellular matrix (ECM). Metalloproteinases (MMPs) are renal physiologic regulators of ECM degradation. Changes in MMPs expression or activity may disturb ECM turnover leading to glomerular scarring and worsening renal function. Our goal was to investigate intragraft MMP2 and MMP9 activities and their correlation with renal dysfunction. Plasma MMP2 and MMP9 activities were analyzed as noninvasive markers of renal allograft deterioration. Transplanted patients were biopsied and histopathologically characterized as IF/TA+ or IF/TA-. Renal function was evaluated by serum creatinine, glomerular filtration rate (GFR) estimated by Modification of Diet in Renal Disease equation and urinary protein/creatinine ratio. Kidney and plasma MMP2 and MMP9 activities were analyzed by zymography. A significant renal dysfunction was observed in IF/TA+ patients. Intragraft proMMP9 showed a significant higher activity in IF/TA+ than in IF/TA- samples and was inversely correlated with the GFR. Intragraft proMMP2 activity tended to increase in IF/TA+ samples, although no statistic significance was reached. Circulating proMMP2 and proMMP9 activities did not show significant differences between groups. Our data provide evidence that correlates intragraft proMMP9 activity with the fibrotic changes and renal dysfunction observed in IF/TA.