Use of Fever Duration to Guide Management of Urinary Tract Infection.

BACKGROUND: The appropriate duration of antimicrobial therapy for febrile urinary tract infection (fUTI) in children has not been established. This study examined the optimal duration of treatment for fUTI in children. METHODS: We created a protocol that used fever duration to determine the duration of antibiotic administration. Transvenous antibiotics were administered until 3 days after resolution of fever, followed by oral antibiotics for 1 week. Diagnosis of fUTI was based on a fever of 37.5°C or higher and a quantitative culture of catheterized urine yielded a bacteria count of ≥5 × 104. Acute focal bacterial nephritis (AFBN) and pyelonephritis (PN) were diagnosed on the basis of contrast-enhanced computed tomography (eCT) findings. We retrospectively reviewed treatment outcomes. RESULTS: Of the 78 patients treated according to our protocol, data from 58 were analyzed-49 children (30 boys) had PN and nine (three boys) had AFBN. Blood test results showed that patients with AFBN had significantly higher white blood cell counts and C-reactive protein levels than did those with PN; however, urinary findings and causative bacteria did not differ between groups. Time to resolution of fever and duration of intravenous antibiotic administration were significantly longer in patients with AFBN than in those with PN. However, average duration of AFBN treatment was 14.2 days, which was shorter than the previously reported administration period of 3 weeks. No recurrence was observed in AFBN patients. CONCLUSIONS: A protocol that used fever duration to determine the duration of antimicrobial treatment was useful. Invasive examinations, such as eCT, were not required.

Targeting endogenous kidney regeneration using anti-IL11 therapy in acute and chronic models of kidney disease.

The kidney has large regenerative capacity, but this is compromised when kidney damage is excessive and renal tubular epithelial cells (TECs) undergo SNAI1-driven growth arrest. Here we investigate the role of IL11 in TECs, kidney injury and renal repair. IL11 stimulation of TECs induces ERK- and p90RSK-mediated GSK3ß inactivation, SNAI1 upregulation and pro-inflammatory gene expression. Mice with acute kidney injury upregulate IL11 in TECs leading to SNAI1 expression and kidney dysfunction, which is not seen in Il11 deleted mice or in mice administered a neutralizing IL11 antibody in either preemptive or treatment modes. In acute kidney injury, anti-TGFß reduces renal fibrosis but exacerbates inflammation and tubule damage whereas anti-IL11 reduces all pathologies. Mice with TEC-specific deletion of Il11ra1 have reduced pathogenic signaling and are protected from renal injury-induced inflammation, fibrosis, and failure. In a model of chronic kidney disease, anti-IL11 therapy promotes TEC proliferation and parenchymal regeneration, reverses fibroinflammation and restores renal mass and function. These data highlight IL11-induced mesenchymal transition of injured TECs as an important renal pathology and suggest IL11 as a therapeutic target for restoring stalled endogenous regeneration in the diseased kidney.

Lectin and alternative complement pathway activation in cutaneous manifestations of IgA-vasculitis: A new target for therapy?

IgA-vasculitis is a systemic small-vessel leucocytoclastic vasculitis and is associated with a high morbidity. The disease can progress to IgA-vasculitis with nephritis (IgAVN) which can result in chronic renal failure. Complement activation is involved in the pathogenesis of IgA-vasculitis. A recent study has shown that cutaneous C3c deposition in IgA-vasculitis is associated with a higher risk to develop IgAVN. In the current study we investigated the different complement pathways that are activated in cutaneous IgA-vasculitis in order to reveal potential targets for intervention. In addition, we analyzed the association of complement factors with IgAVN and the clinical course of the disease. In this retrospective study, the clinicopathological features of 17 patients with IgA-vasculitis were compared with 25 non-IgA-vasculitis cases. Deposition of immunoglobulins and complement was analyzed by direct immunofluorescence for IgA, IgG, IgM, C1q, C4d, properdin, mannan-binding lectin (MBL), ficolin-2 (FCN2), MBL-associated serine protease 1/3 (MASP1/3), MASP2 and C3c. The vascular intensity and positive area was scored on a nominal scale and cumulative score was calculated by multiplying the intensity x area. Properdin was positive in 82% of IgA-vasculitis cases, reflecting alternative pathway activation. C4d was positive in 88% of IgA-vasculitis cases reflecting classical and/or lectin pathway activation, although only 12% of cases were positive for C1q. Lectin pathway activation was demonstrated by deposition of MBL (47%), MASP1/3 (53%) and MASP2 (6%) while FCN2 was found negative. Significantly more deposition of MASP1/3 was found in IgA-vasculitis versus non-IgA-vasculitis. This study demonstrates for the first time activation of lectin and alternative pathways in cutaneous manifestations of IgA-vasculitis. Hence, drugs that intervene in these complement pathways may be an interesting more targeted alternative to the current drugs, in reducing local cutaneous symptoms of the disease, with potentially less side-effects. No association was found between complement activation and IgAVN and/or response to therapy. Therefore, it is unlikely that intervention in complement activation will lead to a better clinical course of the disease.

Efficacy of acupuncture combined with Chinese herbal medicine for the treatment of chronic nephritis: A protocol for systematic review and meta-analysis.

BACKGROUND: Chronic nephritis is a common kidney disease that afflicts people worldwide. The disease has main manifestations of proteinuria, hematuria, edema, and hypertension that are associated with kidney-damaging processes that eventually lead to kidney failure. Traditional Chinese medicine involving combination treatment with herbal remedies and acupuncture has been shown clinically to alleviate chronic nephritis, although to date no systematic review of the efficacy of this combination treatment for this purpose has been reported, prompting this study. Here we conducted a systematic review and meta-analysis of published randomized clinical trials to scientific evidence and credible medical references supporting the clinical efficacy of this combination treatment when used to treat chronic nephritis. METHODS: We will search the following 8 electronic Chinese and English databases: Web of Science, PubMed, Cochrane Library, Embase, China Biomedical Literature Database, China National Knowledge Infrastructure, China Scientific Journal Database, and the Wanfang database. All electronic databases will be searched from inception to October 10, 2021. All statistical analyses will be performed using Review Manager Version 5.4 provided by the Cochrane Collaboration Network. RESULTS: The protocol for systematic review and meta-analysis will be applied to evaluate the efficacy of acupuncture combined with Chinese herbal medicine for the treatment of chronic nephritis. CONCLUSION: We plan to submit the results of this research to a peer-reviewed journal. INPLASY REGISTRATION NUMBER: INPLASY2021100051.

Resistance exercise shifts the balance of renin-angiotensin system toward ACE2/Ang 1-7 axis and reduces inflammation in the kidney of diabetic rats.

AIMS: We aimed to determine whether resistance training (RT) regulates renal renin-angiotensin system (RAS) components and inflammatory mediators in diabetic rats. MAIN METHODS: Male Wistar rats (3 months old) were randomly assigned into four groups: non-trained (NT), trained (T), non-trained + diabetes (NTD) and trained +diabetes (TD). Diabetes was induced by streptozotocin (50 mg/kg, Sigma Chemical Co., St. Louis, MO, USA), before RT protocol. Trained rats performed RT protocol on a 110-cm ladder (8 ladder climbs, once/day, 5 days/week, 8 weeks), carrying a load corresponding to 50-80% of maximum carrying capacity. Blood glucose, albuminuria and urinary volume were measured. Renal levels of angiotensin peptides (angiotensin I, II and 1-7), inflammatory markers, and also the activities of angiotensin-converting enzyme (ACE) and ACE2 were determined. KEY FINDINGS: Blood glucose and urinary volume were elevated in diabetic animals, and RT decreased albuminuria, renal Ang I and Ang II levels in diabetic rats. RT shifted the balance of renal RAS toward ACE2/Ang 1-7 axis in TD group, and mitigated the high levels of interleukin (IL)-10, IL-1ß and cytokine-induced neutrophil chemoattractant 1 (CINC) in the context of diabetes. Strong positive correlations were found between albuminuria and Ang II, IL-10 and IL-1ß. On the other hand, intrarenal Ang 1-7 levels were negatively correlated with IL-10 and IL-1ß levels. SIGNIFICANCE: RT improved kidney function by modulating intrarenal RAS toward ACE2/Ang 1-7 axis and inflammatory cytokines. RT represents a reasonable strategy to improve the renal complications induced by diabetes, counteracting nephropathy-associated maladaptive responses.

Administration of Lactobacillus reuteri Combined with Clostridium butyricum Attenuates Cisplatin-Induced Renal Damage by Gut Microbiota Reconstitution, Increasing Butyric Acid Production, and Suppressing Renal Inflammation.

Cisplatin-induced nephrotoxicity is associated with gut microbiota disturbance. The present study aimed to investigate whether supplementation of Lactobacillus reuteri and Clostridium butyricum (LCs) had a protective effect on cisplatin-induced nephrotoxicity through reconstruction of gut microbiota. Wistar rats were given different treatments: control, cisplatin (Cis), cisplatin + C. butyricum and L. reuteri (Cis+LCs), and C. butyricum and L. reuteri (LCs). We observed that cisplatin-treated rats supplemented with LCs exhibited significantly decreased renal inflammation (KIM-1, F4/80, and MPO), oxidative stress, fibrosis (collagen IV, fibronectin, and a-SMA), apoptosis, concentration of blood endotoxin and indoxyl sulfate, and increased fecal butyric acid production compared with those without supplementation. In addition, LCs improved the cisplatin-induced microbiome dysbiosis by maintaining a healthy gut microbiota structure and diversity; depleting Escherichia-Shigella and the Enterobacteriaceae family; and enriching probiotic Bifidobacterium, Ruminococcaceae, Ruminiclostridium_9, and Oscillibacter. Moreover, the LCs intervention alleviated the cisplatin-induced intestinal epithelial barrier impairment. This study indicated LCs probiotic serves as a mediator of the gut-kidney axis in cisplatin-induced nephrotoxicity to restore the intestinal microbiota composition, thereby suppressing uremic toxin production and enhancing butyrate production. Furthermore, the renoprotective effect of LCs is partially mediated by increasing the anti-inflammatory effects and maintaining the integrity of the intestinal barrier.

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.

Evaluación de las tendencias y presentación clínica de pacientes con cólico nefrítico que acuden al servicio de urgencias durante la era pandémica del COVID-19 / Assessment of trends and clinical presentation in the emergency department of patients with renal colic during the COVID-19 pandemic era

INTRODUCCIÓN: Nuestra hipótesis es que la pandemia por COVID-19, y el estado de alarma impuesto por los gobiernos, pueden haber retrasado las visitas a urgencias por cólicos nefríticos, debido al miedo a contagiarse en los centros sanitarios. Este atraso en acudir a los servicios de urgencias puede llevar a un empeoramiento clínico y aumentar las complicaciones relacionadas con la enfermedad o el tratamiento recibido. MATERIAL Y MÉTODOS: Realizamos una revisión retrospectiva de 3 centros hospitalarios en España e Italia. Fueron incluidos pacientes atendidos en el servicio de urgencias por cólico renal (unilateral o bilateral) secundario a litiasis confirmadas en pruebas de imagen durante los 45 días previos y posteriores a la declaración del estado de alarma de cada país. Se recolectaron datos demográficos, síntomas y signos de presentación, análisis de sangre y orina, pruebas de imagen, y manejo terapéutico. El análisis estadístico se realizó entre dos grupos, Grupo A: pacientes que acudieron antes de la declaración del estado de alarma y Grupo B: pacientes que acudieron tras la declaración del estado de alarma. RESULTADOS: Un total de 397 pacientes que acudieron a urgencias por cólicos nefríticos secundarios a litiasis fueron incluidos en el estudio, 285 (71,8%) en el Grupo A y 112 (28,2%) en el Grupo B (p < 0,001). Un total de 135 (47,4%) en el Grupo A y 63 (56,3%) en el Grupo B (p = 0,11) admitieron haber pospuesto su búsqueda de atención médica urgente. En el momento de la valoración inicial, no se encontraron diferencias entre ambos grupos en los niveles de creatinina sérica, leucocitosis, fiebre, oliguria, dolor, o hidronefrosis. Además, no se observaron diferencias en relación con la estancia media, ingreso en el servicio de urología, o necesidad de tratamientos invasivos. CONCLUSIÓN: Nuestros resultados muestran una disminución significativa de atenciones en urgencias por cólicos nefríticos tras la declaración del estado de alarma en España e Italia. A diferencia de otros estudios publicados recientemente, no encontramos diferencias en la estancia media, ingreso al servicio de urología, o necesidad de tratamientos invasivos en pacientes que se presentaron antes y después del estado de alarma

INTRODUCTION: We hypothesized that the recent COVID-19 pandemic may lead to a delay in renal colic patients presenting to the Emergency Department due to the fear of getting infected. This delay may lead to a more severe clinical condition at presentation with possible complications for the patients. MATERIAL AND METHODS: Retrospective review of data collected from three institutions from Spain and Italy. Patients who presented to Emergency Department with unilateral or bilateral renal colic caused by imaging confirmed urolithiasis during the 45 days before and after each national lockdown were included. Data collected included patients’ demographics, biochemical urine and blood tests, radiological tests, signs, symptoms and the therapeutic management. Analysis was performed between two groups, Group A: patients presenting prior to the national lockdown date; and Group B: patients presenting after the national lockdown date. RESULTS: A total of 397 patients presented to Emergency Department with radiology confirmed urolithiasis and were included in the study. The number of patients presenting to Emergency Department with renal/ureteric colic was 285 (71.8%) patients in Group A and 112 (28.2%) patients in Group B (p < 0.001). The number of patients reporting a delay in presentation was 135 (47.4%) in Group A and 63 (56.3%) in Group B (p = 0.11). At presentation, there were no statistical differences between Group A and Group B regarding the serum creatinine level, C reactive protein, white blood cell count, fever, oliguria, flank pain and hydronephrosis. In addition, no significant differences were observed with the length of stay, Urology department admission requirement and type of therapy. CONCLUSION: Data from our study showed a significant reduction in presentations to Emergency Department for renal colic after the lockdown in Spain and Italy. However, we did not find any significant difference with the length of stay, Urology department admission requirement and type of therapy

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.

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.

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.

Kidney Diseases Associated With Parvovirus B19, Hanta, Ebola, and Dengue Virus Infection: A Brief Review.

Viral infection-associated kidney diseases are an emerging public health issue in both developing and developed countries. Many new viruses have emerged with new paradigms of kidney injury, either directly through their cytopathic effect or indirectly through immune-mediated glomerulopathy, tubulointerstitial disease, and acute kidney injury as part of multiorgan failure. Herein, we will discuss Parvovirus, which causes glomerulopathy, and Hanta, Ebola, and Dengue viruses, which cause viral hemorrhagic fever and acute kidney injury. Clinical manifestations also depend on extrarenal organ systems involved. Diagnosis of these viral infections is mainly based on a high index of suspicion, serologic testing, and isolation of viral DNA/RNA. Management is largely conservative, as specific antiviral agents are unavailable.

Novel therapeutic strategies for renovascular disease.

PURPOSE OF REVIEW: Renovascular disease (RVD) remains an important cause of hypertension and renal dysfunction. Given the failure of renal revascularization to provide consistent clinical benefit in the Cardiovascular Outcomes for Renal Artery Lesions trial among others, further research has underscored the need for mechanistically targeted interventions to improve renal outcomes in patients in RVD. This review discusses novel therapeutic approaches for RVD in the post-Cardiovascular Outcomes for Renal Artery Lesions era. RECENT FINDINGS: Emerging evidence indicates that renal inflammation, microvascular remodeling, and mitochondrial damage accelerate progression of renal injury and are important determinants of the response to revascularization. Experimental studies have identified interventions capable of ameliorating renal inflammation (e.g., cytokine inhibitors, mesenchymal stem cells), microvascular remodeling (proangiogenic interventions), and mitochondrial injury (mito-protective drugs), alone or combined with renal revascularization, to preserve the structure and function of the poststenotic kidney. Recent prospective pilot studies in patients with atherosclerotic RVD demonstrate the safety and feasibility of some of such interventions to protect the kidney. SUMMARY: Experimental studies and pilot clinical trials suggest that therapies targeting renal inflammation, microvascular remodeling, and mitochondrial damage have the potential to preserve the structure and function of the stenotic kidney. Further studies in larger cohorts are needed to confirm their renoprotective effects and clinical role in human RVD.

Complement-mediated microangiopathy in IgA nephropathy and IgA vasculitis with nephritis.

Complement factor C4d was recently observed in renal biopsies from patients who had IgA nephropathy and a poor prognosis. We previously reported that C4d is a common denominator in microangiopathies. In this retrospective cohort study, we investigated whether C4d is a marker of microangiopathy in both IgA nephropathy and IgA vasculitis with nephritis, and whether patients with C4d and microangiopathy have poor renal outcome. We examined 128 renal biopsies from adult and pediatric patients, including normotensive and hypertensive patients, who presented with IgA nephropathy or IgA vasculitis with nephritis. Biopsies were re-evaluated in accordance with the Oxford classification, scored for additional lesions, and stained for complement proteins using immunohistochemistry, including C4d and C5b-9. Clinical data were collected with a mean (±SD) follow-up period of 51 ± 39 months. Changes in estimated glomerular filtration rate over time were compared using linear mixed-effects models. Renal survival was analyzed using multivariable Cox regression. Microangiopathic lesions were present in 20% of all biopsies (23% and 9% of patients with IgA nephropathy and IgA vasculitis with nephritis, respectively). Microangiopathy was associated with C4d and C5b-9 deposits, a higher number of chronic lesions, and hypertension (all p < 0.05). Patients with C4d and microangiopathic lesions had significantly poorer renal survival than patients without these findings, corrected for hypertension (p < 0.01). In conclusion, patients with IgA nephropathy or IgA vasculitis with nephritis with a combination of C4d positivity and microangiopathy comprise a clinical subgroup with an increased number of chronic lesions, lower estimated glomerular filtration rate, and poorer renal survival, even when corrected for hypertension. These data suggest that complement activation is involved in the development of microangiopathy in patients with IgA nephropathy and IgA vasculitis with nephritis, and that complement-mediated microangiopathy contributes to disease progression.

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.