Notable progress in basic, translational and clinical nephrology research has been made over the past five decades. Nonetheless, many challenges remain, including obstacles to the early detection of kidney disease, disparities in access to care and variability in responses to existing and emerging therapies. Innovations in drug development, research technologies, tissue engineering and regenerative medicine have the potential to improve patient outcomes. Exciting prospects include the availability of new drugs to slow or halt the progression of chronic kidney disease, the development of bioartificial kidneys that mimic healthy kidney functions, and tissue engineering techniques that could enable transplantable kidneys to be created from the cells of the recipient, removing the risk of rejection. Cell and gene therapies have the potential to be applied for kidney tissue regeneration and repair. In addition, about 30% of kidney disease cases are monogenic and could potentially be treated using these genetic medicine approaches. Systemic diseases that involve the kidney, such as diabetes mellitus and hypertension, might also be amenable to these treatments. Continued investment, communication, collaboration and translation of innovations are crucial to realize their full potential. In addition, increasing sophistication in exploring large datasets, implementation science, and qualitative methodologies will improve the ability to deliver transformational kidney health strategies. Despite notable progress in basic, clinical and translational nephrology research in the past 50 years, many challenges remain. In this Review, the authors provide an overview of the current status and future directions in nephrology research and patient care. In the past 5 decades, notable progress has been made in basic, translational and clinical nephrology research.Remaining challenges in nephrology include obstacles to the early detection of kidney disease, inconsistency in access to care and variability in responses to established and emerging therapies.A new approach to medical research based on close collaboration between basic and clinical scientists and clinicians is fundamental to ensure patient-centred care and improve clinical outcomes.Deeper understanding and analyses of individual patients, including use of genetic profiles, biomarkers and sophisticated imaging technologies, can aid prediction of disease progression, identify risk factors and enable tailoring of treatment plans.Promising future approaches to the treatment of kidney diseases include cell and gene therapies, xenotransplantation and bioartificial kidneys.In-depth knowledge of the values and preferences of patients, such as their treatment goals, communication preferences, cultural beliefs and financial considerations, is essential to improving kidney care; disadvantaged populations must receive specific attention to avoid widening health inequities.

PDF file - 45K, Toxicological assessment of systemic RNA treatment

<p>PDF file - 702K, RIG-I expression in human pancreatic carcinoma specimens</p>

PDF file - 42K, Effect of RNA treatment on splenic MDSC populations in tumor-bearing mice

<p>PDF file - 702K, RIG-I expression in human pancreatic carcinoma specimens</p>

<p>PDF file - 46K, Bi-functional ppp-siRNA directed against TGF-β1 combines gene silencing with RIG-I signaling in human pancreatic cancer cells</p>

<p>PDF file - 60K, CXCL10 production and lymphocyte activation induced by ppp TGF-β treatment is independent of TRIF or TLR7 signaling</p>

BackgroundThe novel calcineurin inhibitor voclosporin was approved in 2021 for the treatment of adult patients with active lupus nephritis (LN) in combination with background immunotherapy. Voclosporin has a favorable metabolic profile and a consistent dose-concentration relationship, eliminating the need for therapeutic drug monitoring.The Phase 2 AURA-LV and Phase 3 AURORA 1 studies demonstrated that the addition of voclosporin to mycophenolate mofetil (MMF) and low-dose steroids led to significantly higher complete renal response rates in AURA-LV at 24 weeks (32.6% vs 19.3%; odds ratio [OR] 2.03; p=0.046) and in AURORA 1 at 52 weeks (40.8% vs 22.5%; OR 2.65; p<0.0001) of treatment in patients with LN.ObjectivesThe European League Against Rheumatism and European Renal Association (EULAR/ERA) published updated treatment recommendations for LN with targeted reductions in proteinuria over the course of the first year of therapeutic intervention.1 Here we report on a post-hoc analysis of pooled data from the similarly designed 48-week AURA-LV and 52-week AURORA 1 studies based on these updated response criteria.MethodsAURA-LV and AURORA 1 enrolled patients with biopsy-proven active lupus nephritis (Class III, IV, or V ± III/IV) and proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V). Pooled data included 268 patients in the voclosporin (23.7 mg BID) group and 266 patients in the control group, with all patients receiving MMF (target dose 1 g BID) and low-dose steroids (target dose 2.5 mg/day by week 16 according to protocol-defined steroid taper). We assessed the following EULAR/ERA treatment targets: ≥25% reduction in urine protein creatinine ratio (UPCR) by 3 months, ≥50% reduction in UPCR by 6 months, UPCR ≤0.7 mg/mg by 12 months, and steroid dose ≤7.5 mg/day by 3, 6, and 12 months.ResultsWithin the first 3 months of treatment, 78.4% of patients in the voclosporin group and 62.4% of patients in the control group achieved ≥25% reduction in UPCR (odds ratio [OR] 2.25; 95% confidence interval [CI] 1.52, 3.33; p<0.0001). The percentage of patients achieving a reduction of ≥50% in UPCR by 6 months was also significantly greater in the voclosporin group compared to control (66.0% vs 47.0%, respectively; OR 2.24; CI 1.57, 3.21; p<0.0001). After 12 months of treatment, 52.6% and 33.1% of patients receiving voclosporin and control, respectively, had achieved a UPCR ≤0.7 mg/mg (OR 2.52; CI 1.75, 3.63; p<0.0001). Given the protocol-defined steroid taper, at both 3 and 6 months, a similar proportion (>90%) of patients in both groups had achieved the recommended steroid dose, with 89.6% and 82.8% in the voclosporin and control groups, respectively, on the recommended dose at 12 months. The proportion of patients meeting all three UPCR targets during the one-year study period and having a steroid dose ≤7.5 mg/day at 12 months was 37.3% in the voclosporin group and 23.3% in the control group (OR 2.11; CI 1.43, 3.10; p=0.0001).ConclusionThe addition of voclosporin to a background regimen of MMF and low-dose steroids in patients with LN significantly increased the likelihood of achieving the 3-, 6-, and 12-month UPCR targets of therapy recommended by EULAR/ERA.References[1]Fanouriakis, A. et al. 2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis. Ann. Rheum. Dis. 79, 713–723 (2020).Figure 1.Integrated AURA-LV and AURORA 1 Analysis on the Achievement of UPCR Treatment Targets and Use of Low-Dose Steroids per EULAR/ERA Lupus Nephritis RecommendationsDisclosure of InterestsHans-Joachim Anders: None declared, Ray Federico Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc., Simrat Randhawa Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc., Henry Leher Shareholder of: Aurinia Pharmaceutical Inc., Employee of: Aurinia Pharmaceutical Inc.

Acute kidney injury (AKI) is morphologically characterized by a synchronized plasma membrane rupture of cells in a specific section of a nephron, referred to as acute tubular necrosis (ATN). Whereas the involvement of necroptosis is well characterized, genetic evidence supporting the contribution of ferroptosis is lacking. Here, we demonstrate that the loss of ferroptosis suppressor protein 1 (Fsp1) or the targeted manipulation of the active center of the selenoprotein glutathione peroxidase 4 (Gpx4cys/-) sensitize kidneys to tubular ferroptosis, resulting in a unique morphological pattern of tubular necrosis. Given the unmet medical need to clinically inhibit AKI, we generated a combined small molecule inhibitor (Nec-1f) that simultaneously targets receptor interacting protein kinase 1 (RIPK1) and ferroptosis in cell lines, in freshly isolated primary kidney tubules and in mouse models of cardiac transplantation and of AKI and improved survival in models of ischemia-reperfusion injury. Based on genetic and pharmacological evidence, we conclude that GPX4 dysfunction hypersensitizes mice to ATN during AKI. Additionally, we introduce Nec-1f, a solid inhibitor of RIPK1 and weak inhibitor of ferroptosis.

The coronavirus disease 2019 (COVID-19) pandemic has created major challenges for all countries around the globe. Retrospective studies have identified hypertension, cardiovascular disease, diabetes and older age as risk factors for high morbidity and mortality from COVID-19. There is a general concern that patients with immune-mediated kidney diseases, namely those on immunosuppressive therapies and/or those with more advanced kidney failure, could particularly be at risk for adverse outcomes due to a compromised antiviral immunity. Uncertainties exist on how management routines should be reorganized to minimize the risk of severe acute respiratory syndrome coronavirus 2 infection and what measures are necessary for infected patients. The aim of the present review of the Immunonephrology Working Group of the European Renal Association-European Dialysis and Transplant Association is to provide recommendations for the management of patients with immune-mediated kidney diseases based on the available evidence, similar circumstances with other infectious organisms and expert opinions from across Europe. Such recommendations may help to minimize the risk of encountering COVID-19 or developing complications during COVID-19 in patients with immune-mediated kidney disease.

Objective To update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN). Methods Following the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements. Results The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5–0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2–3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3–0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin–angiotensin–aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease. Conclusions We have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.

Background:Up to 40% of systemic lupus erythematosus (SLE) patients develop kidney disease, which represents a major cause of morbidity.Objectives:To update the 2012 EULAR/ERA-EDTA recommendations for the management of lupus nephritis (LN).Methods:We followed the EULAR standardised operating procedures for the publication of treatment recommendations. Delphi-based methodology led to 15 questions for systematic literature review (SLR), which was undertaken by three fellows.Results:The changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNI), and management of end-stage-kidney-disease (ESKD). The target of therapy is complete response (proteinuria <0.5-0.7gr/24h with [near-]normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2-3g/day, or mycophenolic acid at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500mg x6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3-0.5mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1g/24h despite renin-angiotensin-aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations.Conclusion:The updated recommendations intend to inform rheumatologists, nephrologists, patients, national professional societies, hospital officials, social security agencies and regulators about the treatment of LN based on most recent evidence.Disclosure of Interests:Antonis Fanouriakis Paid instructor for: Paid instructor for Enorasis, Amgen, Speakers bureau: Paid speaker for Roche, Genesis Pharma, Mylan, Myrto Kostopoulou: None declared, Kim Cheema: None declared, Hans-Joachim Anders: None declared, Martin Aringer Consultant of: Boehringer Ingelheim, Roche, Speakers bureau: Boehringer Ingelheim, Roche, Ingeborg Bajema Consultant of: GSK, John N. Boletis Grant/research support from: GSK, Pfizer, Paid instructor for: GSK, Abbvie, UCB, Enorasis, Eleni Frangou: None declared, Frederic Houssiau Grant/research support from: UCB, Consultant of: GSK, Jane Hollis: None declared, Alexandre Karras: None declared, Francesca Marchiori: None declared, Stephen Marks: None declared, Gabriela Moroni: None declared, Marta Mosca: None declared, Ioannis Parodis: None declared, Manuel Praga: None declared, Matthias Schneider Grant/research support from: GSK, UCB, Abbvie, Consultant of: Abbvie, Alexion, Astra Zeneca, BMS, Boehringer Ingelheim, Gilead, Lilly, Sanofi, UCB, Speakers bureau: Abbvie, Astra Zeneca, BMS, Chugai, GSK, Lilly, Pfizer, Sanofi, Josef S. Smolen Grant/research support from: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Consultant of: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Vladimir Tesar: None declared, Maria Trachana: None declared, Ronald van Vollenhoven Grant/research support from: AbbVie, Amgen, Arthrogen, Bristol-Myers Squibb, GlaxoSmithKline (GSK), Janssen Research & Development, LLC, Lilly, Pfizer, Roche, and UCB, Consultant of: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo Bioscience, GSK, Janssen, Lilly, Medac, Merck, Novartis, Pfizer, Roche, UCB and Vertex, Speakers bureau: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Celgene, Crescendo Bioscience, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, Vertex, Alexandre Voskuyl: None declared, Y.K. Onno Teng Grant/research support from: GSK, Consultant of: GSK, Aurinia Pharmaceuticals, Novartis, Bernadette van Leeuw: None declared, George Bertsias Grant/research support from: GSK, Consultant of: Novartis, David Jayne Grant/research support from: ChemoCentryx, GSK, Roche/Genentech, Sanofi-Genzyme, Consultant of: Astra-Zeneca, ChemoCentryx, GSK, InflaRx, Takeda, Insmed, Chugai, Boehringer-Ingelheim, Dimitrios Boumpas: None declared

The name of the one of the authors was misspelt. The author's surname is Rodriguez, not Rodriquez as originally published. This has been corrected in both the PDF and HTML versions of the Article.

In April 2016, the International Society of Nephrology held a Nexus meeting in Berlin, Germany, on translational aspects of immune-mediated kidney diseases. It was believed that such a meeting was needed to discuss the hurdles blocking therapeutic advances in the field. During a time when other medical disciplines are expanding treatment options for important diseases rapidly, the kidney field still awaits major breakthroughs in therapy. It was believed that hurdles exist at several levels including inadequate animal models, methods to identify patients by central pathomechanisms rather than by histopathologic lesions, the lack of rare disease collaborative networks, the design of clinical trials, and trial end points that predict meaningful clinical outcomes.

This commentary discusses nephron protection in diabetic kidney disease and describes the way in which renin–angiotensin system inhibitors and the sodium–glucose cotransporter 2 inhibitor empagliflozin have renoprotective effects.

In lupus erythematosus, elevated serum creatinine levels and urinary abnormalities implicate a kidney disorder, which may not always be lupus nephritis as defined by the current classification of the International Society of Nephrology/Renal Pathology Society. The signs of renal dysfunction may be caused by lupus-unrelated renal injury such as drug toxicity or infection or by lupus-associated mechanisms that are not part of the classification, such as minimal change nephrotic syndrome or thrombotic microangiopathy. The latter seems to complicate lupus nephritis more frequently than previously thought. An unbiased assessment of kidney disease in lupus requires a kidney (re-)biopsy to define the appropriate management.

Deregulated TGF-b signaling in pancreatic cancer promotes tumor growth, invasion, metastasis, and a potent immunosuppressive network. A strategy for disrupting this tumor-promoting pathway is silencing TGF-b by siRNA. By introducing a triphosphate group at the 50 end of siRNA (ppp-siRNA), gene silencing can be combined with immune activation via the cytosolic helicase retinoic acid-inducible gene I (RIG-I), a ubiquitously expressed receptor recognizing viral RNA. We validated RIG-I as a therapeutic target by showing that activation of RIG-I in pancreatic carcinoma cells induced IRF-3 phosphorylation, production of type I IFN, the chemokine CXCL10, as well as caspase-9–mediated tumor cell apoptosis. Next, we generated a bifunctional ppp-siRNA that combines RIG-I activation with gene silencing of TGF-b1 (ppp-TGF-b) and studied its therapeutic efficacy in the orthotopic Panc02 mouse model of pancreatic cancer. Intravenous injection of ppp-TGF-b reduced systemic and tumorassociated TGF-b levels. In addition, it induced high levels of type I IFN and CXCL10 in serum and tumor tissue, systemic immune cell activation, and profound tumor cell apoptosis in vivo. Treatment of mice with established tumors with ppp-TGF-b significantly prolonged survival as compared with ppp-RNA or TGF-b siRNA alone. Furthermore, we observed the recruitment of activated CD8þ T cells to the tumor and a reduced frequency of CD11bþ Gr-1þ myeloid cells. Therapeutic efficacy was dependent on CD8þ T cells, whereas natural killer cells were dispensable. In conclusion, combing TGF-b gene silencing with RIG-I signaling confers potent antitumor efficacy against pancreatic cancer by breaking tumor-induced CD8þ T cell suppression. Cancer Res; 73(6); 1709–20. 2013 AACR. Introduction Pancreatic cancer is the fourth leading cause of cancerrelated death and is characterized by early metastasis and resistance to chemotherapy and irradiation. The identification of deregulated molecular pathways in pancreatic cancer and the development of novel targeted therapies had so far little impact on clinical outcome (1). Prognosis of patients with pancreatic cancer has remained extremely poor with a 5-year survival rate of less than 5%. A key event in tumor progression of pancreatic cancer is deregulation of TGF-b signaling (2). Under normal conditions, TGF-bmaintains tissue homeostasis by controlling cellular proliferation, differentiation, survival, and cell adhesion. Deregulated TGF-b signaling allows tumors to usurp homeostatic effects for promoting tumor growth, invasion, metastasis, and tumor angiogenesis (2). Moreover, TGF-b has immunosuppressive effects such as inhibition of cytotoxic T cells and natural killer (NK) cells, induction of FoxP3þ regulatory T cells, and shifting antigen-presenting cell function toward tolerance (3, 4). Both tumor cells and immune cells, such as regulatory T cells and myeloid-derived suppressor cells (MDSC), contribute to enhanced TGF-b production in patients with cancer. Elevated TGF-b levels in serum and tumors correlate with poor prognosis in patients with tumor (5, 6). Thus, TGF-b has generated interest as a target for novel anticancer agents. Anti-TGF-b compounds have shown efficacy in preclinical studies, and some of these have moved into clinical investigation for melanoma, brain tumors, colorectal, renal, and pancreatic cancer (7–11). Tumor infiltration with T cells represents a positive prognostic factor for pancreatic carcinoma, indicating that immune surveillance may occur despite locally active immunosuppressive mechanisms (12). However, tumor-infiltrating T cells frequently lack effector function due to the hostile tumor microenvironment, which is enriched with immunosuppressive Authors' Affiliations: Medizinische Klinik und Poliklinik IV, Klinikum der Universit€ at M€ unchen; Center for Integrated Protein Sciences Munich and Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, Klinikum der Universit€ at M€ unchen; Pathologisches Institut der LMU M€ unchen; MedizinischeKlinik, Universit€ atsklinikumRechts der Isar, Technische Universit€ at, M€ unchen; Institut f€ ur Klinische Chemie und Klinische Pharmakologie, Universit€ atsklinikum, Bonn, Germany; and Medical School of Nanjing University, Nanjing, China. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). J. Ellermeier, J. Wei, and P. Duewell contributed equally to this work. Corresponding Author: Max M. Schnurr, Medizinische Klinik und Poliklinik IV, Klinikum der LMU, Ziemssenstr. 1, M€ unchen 80336, Germany. Phone: 49-89-5160-5300; Fax: 49-89-5160-4568; E-mail: max.schnurr@med.uni-muenchen.de doi: 10.1158/0008-5472.CAN-11-385

TIR8, also known as single Ig IL-1 receptor (IL-R)-related molecule, SIGIRR, is a member of the IL-1R like (ILR) family. Unlike most other members of this family, it has a single extracellular Ig domain, a long cytoplasmic tail and a Toll/IL-1R (TIR) domain with two amino acid substitutions possibly consistent with non-conventional signaling. The TIR8 structure and pattern of expression are conserved in evolution from birds to humans. Current evidence suggests that TIR8 inhibits signaling receptor complexes of IL-1 family members associated with Th1 (IL-18), Th2 (IL-33) and Th17 (IL-1) differentiation. TIR8 also dampens TLR-mediated activation. The ability to dampen signaling from ILR family members and TLRs makes TIR8 a key regulator of inflammation, cancer-related inflammation, and autoimmunity.