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The International Society of Nephrology (ISN) region of Oceania and South East Asia (OSEA) is a mix of high- and low-income countries, with diversity in population demographics and densities. Three iterations of the ISN-Global Kidney Health Atlas (GKHA) have been conducted, aiming to deliver in-depth assessments of global kidney care across the spectrum from early detection of CKD to treatment of kidney failure. This paper reports the findings of the latest ISN-GKHA in relation to kidney-care capacity in the OSEA region. Among the 30 countries and territories in OSEA, 19 (63%) participated in the ISN-GKHA, representing over 97% of the region’s population. The overall prevalence of treated kidney failure in the OSEA region was 1203 per million population (pmp), 45% higher than the global median of 823 pmp. In contrast, kidney replacement therapy (KRT) in the OSEA region was less available than the global median (chronic hemodialysis, 89% OSEA region vs. 98% globally; peritoneal dialysis, 72% vs. 79%; kidney transplantation, 61% vs. 70%). Only 56% of countries could provide access to dialysis to at least half of people with incident kidney failure, lower than the global median of 74% of countries with available dialysis services. Inequalities in access to KRT were present across the OSEA region, with widespread availability and low out-of-pocket costs in high-income countries and limited availability, often coupled with large out-of-pocket costs, in middle- and low-income countries. Workforce limitations were observed across the OSEA region, especially in lower-middle–income countries. Extensive collaborative work within the OSEA region and globally will help close the noted gaps in kidney-care provision.

IL-33 is an activator of innate lymphoid cells 2 (ILC2s) in innate immunity and allergic inflammation and drives ILC2 expansion. High levels of B cell activating factor (BAFF), which plays a central role in B cell proliferation and differentiation, cause excess antibody production, including IgA. Using an animal model of IgA glomerulonephritis, a transgenic mouse that expresses excessive BAFF, the authors found that IL-33 exacerbates IgA glomerulonephritis, appearing to do so through expansion of ILC2 cells that drive an increase in IgA production and the development of kidney disease. They confirmed the role of ILC2s in exacerbating disease in a mouse model of IgA glomerulonephritis in transfer and depletion experiments. Their findings suggest that evaluation of IL-33 and ILC2s as potential mediators of IgA nephropathy in humans is warranted.

Kidney failure is the permanent impairment of kidney function associated with increased morbidity, hospitalization, and requirement for kidney replacement therapy. A total of 11 countries in the Middle East region (84.6%) responded to the survey. The prevalence of chronic kidney disease in the region ranged from 5.2% to 10.6%, whereas prevalence of treated kidney failure ranged from 152 to 826 per million population. Overall, the incidence of kidney transplantation was highest in Iran (30.9 per million population) and lowest in Oman and the United Arab Emirates (2.2 and 3.0 per million population, respectively). Long-term hemodialysis services were available in all countries, long-term peritoneal dialysis services were available in 9 (69.2%) countries, and transplantation services were available in most countries of the region. Public funding covered the costs of nondialysis chronic kidney disease care in two-thirds of countries, and kidney replacement therapy in nearly all countries. More than half of the countries had dialysis registries; however, national noncommunicable disease strategies were lacking in most countries. The Middle East is a region with high burden of kidney disease and needs cost-effective measures through effective health care funding to be available to improve kidney care in the region. Furthermore, well-designed and sustainable health information systems are needed in the region to address current gaps in kidney care in the region.

The International Society of Nephrology Global Kidney Health Atlas analyzed the current state of kidney care in Newly Independent States and Russia. Our results demonstrated that the Newly Independent States and Russia region was not an exception and showed the same effect of chronic kidney disease on health and its outcomes, facing many difficulties and challenges in terms of improving kidney care across the countries. This work summarized and presented demographics, health information systems, statistics, and national health policy of the region, as well as characteristics of the burden of chronic kidney disease and kidney failure (KF) of participating countries. Besides significant economic advancement in the region, the collected data revealed existing shortage in KF care providers, essential medications, and health product access for KF care. Moreover, there was low reporting of kidney replacement therapy (dialysis and kidney transplantation) quality indicators and low capacity for long-term hemodialysis, peritoneal dialysis, and kidney transplantation. The financial issues and funding structures for KF care across the region needs strategic support for fundamental changes and further advancement. This article emphasizes the urgent need for further effective regional and international collaborations and partnership for establishment of universal health care systems for KF management.

Despite positive economic forecasts, stable democracies, and reduced regional conflicts since the turn of the century, Africa continues to be afflicted by poverty, poor infrastructure, and a massive burden of communicable diseases such as HIV, malaria, tuberculosis, and diarrheal illnesses. With the rising prevalence of chronic kidney disease and kidney failure worldwide, these factors continue to hinder the ability to provide kidney care for millions of people on the continent. The International Society of Nephrology Global Kidney Health Atlas project was established to assess the global burden of kidney disease and measure global capacity for kidney replacement therapy (dialysis and kidney transplantation). The aim of this second iteration of the International Society of Nephrology Global Kidney Health Atlas was to evaluate the availability, accessibility, affordability, and quality of kidney care worldwide. We identified several gaps regarding kidney care in Africa, chief of which are (i) severe workforce limitations, especially in terms of the number of nephrologists; (ii) low government funding for kidney care; (iii) limited availability, accessibility, reporting, and quality of provided kidney replacement therapy; and (iv) weak national strategies and advocacy for kidney disease. We also identified that within Africa, the availability and accessibility to kidney replacement therapy vary significantly, with North African countries faring far better than sub-Sahara African countries. The evidence suggests an urgent need to increase the workforce and government funding for kidney care, collect adequate information on the burden of kidney disease from African countries, and develop and implement strategies to enhance disease prevention and control across the continent.

Information about disease burden and the available infrastructure and workforce to care for patients with kidney disease was collected for the second edition of the International Society of Nephrology Global Kidney Health Atlas. This paper presents findings for the 8 countries in the South Asia region. The World Bank categorizes Afghanistan and Nepal as low-income; Bangladesh, Bhutan, India, and Pakistan as lower-middle-income; and Sri Lanka and the Maldives as upper-middle-income countries. The prevalence of chronic kidney disease (CKD) in South Asia ranged from 5.01% to 13.24%. Long-term hemodialysis and long-term peritoneal dialysis are available in all countries, but Afghanistan lacks peritoneal dialysis services. Kidney transplantation was available in all countries except Bhutan and Maldives. Hemodialysis was the dominant modality of long-term dialysis, peritoneal dialysis was more expensive than hemodialysis, and kidney transplantation overwhelmingly depended on living donors. Bhutan provided public funding for kidney replacement therapy (dialysis and transplantation); Sri Lanka, India, Pakistan, and Bangladesh had variable funding mechanisms; and Afghanistan relied solely on out-of-pocket expenditure. There were shortages of health care personnel across the entire region. Reporting was variable: Afghanistan and Sri Lanka have dialysis registries but publish no reports, whereas Bangladesh has a transplant registry. South Asia has a large, but poorly documented burden of CKD. Diabetes and hypertension are the major causes of CKD throughout the region with a higher prevalence of infectious causes in Afghanistan and a high burden of CKD of an unknown cause in Sri Lanka and parts of India. The extent and quality of care delivery is suboptimal and variable. Sustainable strategies need to be developed to address the growing burden of CKD in the region.

Provision of adequate kidney care for patients with chronic kidney disease or kidney failure (KF) is costly and requires extensive resources. There is an inequality in the global distribution of wealth and resources needed to provide this care. In this second iteration of the International Society of Nephrology Global Kidney Health Atlas, we present data for countries in Eastern and Central Europe. In the region, the median prevalence of chronic kidney disease was 13.15% and treated KF was 764 per million population, respectively, slightly higher than the global median of 759 per million population. In most countries in the region, over 90% of dialysis patients were on hemodialysis and patients with a functioning graft represented less than one-third of total patients with treated KF. The median annual costs for maintenance hemodialysis were close to the global median, and public funding provided nearly universal coverage of the costs of kidney replacement therapy. Nephrologists were primarily responsible for KF care. All countries had the capacity to provide long-term hemodialysis, and 95% had the capacity to provide peritoneal dialysis. Home hemodialysis was generally not available. Kidney transplantation and conservative care were available across most of the region. Almost all countries had official dialysis and transplantation registries. Eastern and Central Europe is a region with a high burden of chronic kidney disease and variable capacity to deal with it. Insufficient funding and workforce shortages coupled with increasing comorbidities among aging patients and underutilization of cost-effective dialysis therapies such as peritoneal dialysis and kidney transplantation may compromise the quality of care for patients with KF. Some workforce shortages could be addressed by improving the organization of nephrological care in some countries of the region.

Populations in the high-income countries of Western Europe are aging due to increased life expectancy. As the prevalence of diabetes and obesity has increased, so has the burden of kidney failure. To determine the global capacity for kidney replacement therapy and conservative kidney management, the International Society of Nephrology conducted multinational, cross-sectional surveys and published the findings in the International Society of Nephrology Global Kidney Health Atlas. In the second iteration of the International Society of Nephrology Global Kidney Health Atlas, we aimed to describe the availability, accessibility, quality, and affordability of kidney failure care in Western Europe. Among the 29 countries in Western Europe, 21 (72.4%) responded, representing 99% of the region’s population. The burden of kidney failure prevalence varied widely, ranging from 760 per million population (pmp) in Iceland to 1612 pmp in Portugal. Coverage of kidney replacement therapy from public funding was nearly universal, with the exceptions of Germany and Liechtenstein where part of the costs was covered by mandatory insurance. Fourteen (67%) of 21 countries charged no fees at the point of care delivery, but in 5 countries (24%), patients do pay some out-of-pocket costs. Long-term dialysis services (both hemodialysis and peritoneal dialysis) were available in all countries in the region, and kidney transplantation services were available in 19 (90%) countries. The incidence of kidney transplantation varied widely between countries from 12 pmp in Luxembourg to 70.45 pmp in Spain. Conservative kidney care was available in 18 (90%) of 21 countries. The median number of nephrologists was 22.9 pmp (range: 9.47–55.75 pmp). These data highlight the uniform capacity of Western Europe to provide kidney failure care, but also the scope for improvement in disease prevention and management, as exemplified by the variability in disease burden and transplantation rates.

Kidney failure (KF) is a public health problem in all regions of the world. We aim to provide comprehensive information regarding the disease burden of KF and capacity for providing optimal care in the International Society of Nephrology North and East Asia region based on data from the International Society of Nephrology Global Kidney Health Atlas project. Seven of eight jurisdictions participated, and wide variation was found in terms of KF burden and care capacity. Prevalence of long-term dialysis ranged from 88.4 per million population in mainland China to 3251 per million population in Taiwan. Hemodialysis was the predominant modality of dialysis in all jurisdictions, except for Hong Kong, where peritoneal dialysis (PD) was much more prevalent than hemodialysis. All jurisdictions provided public funding for kidney replacement therapy (dialysis and transplantation). Although the frequency and duration of hemodialysis followed a standard pattern in all investigated jurisdictions, the density of nephrologists and kidney replacement therapy centers varied according to income level. Conservative care, whether medically advised or chosen by patients, was available in most jurisdictions. All jurisdictions had official registries for KF and recognized KF as a health priority. These comprehensive data provide information about the burden of KF and capacity to provide optimal care in North and East Asia, which varied greatly across jurisdictions in the region.

Latin America is a region with a widely variable socioeconomic landscape, facing a surge in noncommunicable diseases, including chronic kidney disease and kidney failure, exposing significant limitations in the delivery of care. Despite region-wide efforts to explore and address these limitations, much uncertainty remains as to the capacity, accessibility, and quality of kidney failure care in Latin America. Through this second iteration of the International Society of Nephrology Global Kidney Health Atlas, we aimed to report on these indicators to provide a comprehensive map of kidney failure care in the region. Survey responses were received from 18 (64.2%) countries, representing 93.8% of the total population in Latin America. The median prevalence and incidence of treated kidney failure in Latin America were 715 and 157 per million population, respectively, the latter being higher than the global median (142 per million population), with Puerto Rico, Mexico, and El Salvador experiencing much of this growing burden. In most countries, public and private systems collectively funded most aspects of kidney replacement therapy (dialysis and transplantation) care, with patients incurring at least 1% to 25% of out-of-pocket costs. In most countries, >90% of dialysis patients able to access kidney replacement therapy received hemodialysis (n = 11; 5 high income and 6 upper-middle income), and only a small minority began with peritoneal dialysis (1%–10% in 67% of countries; n = 12). Few countries had chronic kidney disease registries or targeted detection programs. There is a large variability in the availability, accessibility, and quality of kidney failure care in Latin America, which appears to be subject to individual countries’ funding structures, underreliance on cheap kidney replacement therapy, such as peritoneal dialysis, and limited chronic kidney disease surveillance and management initiatives.

Oceania and South East Asia (OSEA) is a socioeconomically, culturally, and ethnically diverse region facing a rising epidemic of noncommunicable diseases, including chronic kidney disease (CKD). The second iteration of the International Society of Nephrology Global Kidney Health Atlas aimed to provide a comprehensive evaluation of kidney care in OSEA. Of the 30 countries/territories in OSEA, 15 participated in the survey, representing 98.5% of the region’s population. The median prevalence of treated kidney failure in OSEA was 1352 per million population (interquartile range, 966–1673 per million population), higher than the global median of 787 per million population. Although the general availability, access, and quality of kidney replacement therapy (i.e., dialysis and transplantation) was high in OSEA, inequalities in accessibility and affordability of kidney replacement therapy across the region resulted in variability between countries. According to the survey results, in a third of the participating countries (mostly lower-income countries), less than half the patients with kidney failure were able to access dialysis, whereas it was readily available to all with minimal out-of-pocket costs in high-income countries; similar variability in access to transplantation was also recorded. Limitations in workforce and resources vary across the region and were disproportionately worse in lower-income countries. There was little advocacy for kidney disease, moderate use of registries, restricted CKD detection programs, and limited availability of routine CKD testing in some high-risk groups across the region. International collaborations, as seen in OSEA, are important initiatives to help close the gaps in CKD care provision across the region and should continue receiving support from the global nephrology community.

The International Society of Nephrology established the Global Kidney Health Atlas project to define the global capacity for kidney replacement therapy and conservative kidney care, and this second iteration was to describe the availability, accessibility, quality, and affordability of kidney failure (KF) care worldwide. This report presents results for the International Society of Nephrology North America and the Caribbean region. Relative to other regions, the North America and Caribbean region had better infrastructure and funding for health care and more health care workers relative to the population. Various essential medicines were also more available and accessible. There was substantial variation in the prevalence of treated KF in the region, ranging from 137.4 per million population (pmp) in Jamaica to 2196 pmp in the United States. A mix of public and private funding systems cover costs for nondialysis chronic kidney disease care in 60% of countries and for dialysis in 70% of countries. Although the median number of nephrologists is 18.1 (interquartile range, 15.3–29.5) pmp, which is approximately twice the global median of 9.9 (interquartile range, 1.2–22.7) pmp, some countries reported shortages of other health care workers. Dialysis was available in all countries, but peritoneal dialysis was underutilized and unavailable in Barbados, Cayman Islands, and Turks and Caicos. Kidney transplantation was primarily available in Canada and the United States. Economic factors were the major barriers to optimal KF care in the Caribbean countries, and few countries in the region have chronic kidney disease–specific national health care policies. To address regional gaps in KF care delivery, efforts should be directed toward augmenting the workforce, improving the monitoring and reporting of kidney replacement therapy indicators, and implementing noncommunicable disease and chronic kidney disease–specific policies in all countries.

The coronavirus disease 2019 pandemic presents significant challenges for health systems globally, including substantive ethical dilemmas that may pose specific concerns in the context of care for people with kidney disease. Ethical concerns may arise as changes in policy and practice affect the ability of all health professionals to fulfill their ethical duties toward their patients in providing best practice care. In this article, we briefly describe such concerns and elaborate on issues of particular ethical complexity in kidney care: equitable access to dialysis during pandemic surges; balancing the risks and benefits of different kidney failure treatments, specifically with regard to suspending kidney transplantation programs and prioritizing home dialysis, and barriers to shared decision-making; and ensuring ethical practice when using unproven interventions. We present preliminary advice on how to approach these issues and recommend urgent efforts to develop resources that will support health professionals and patients in managing them.

There is a huge gap between the number of patients worldwide requiring versus those actually receiving safe, sustainable, and equitable care for kidney failure. To address this, the International Society of Nephrology coordinated the development of a Strategic Plan for Integrated Care of Patients with Kidney Failure. Implementation of the plan will require engagement of the whole kidney community over the next 5–10 years.

Kidney failure is an important outcome for patients, clinicians, researchers, healthcare systems, payers, and regulators. However, no harmonized international consensus definitions of kidney failure and key surrogates of progression to kidney failure exist specifically for clinical trials. The International Society of Nephrology convened an international multi-stakeholder meeting to develop consensus on this topic. A core group, experienced in design, conduct, and outcome adjudication of clinical trials, developed a database of 64 randomized trials and the 163 included definitions relevant to kidney failure. Using an iterative process, a set of proposed consensus definitions were developed and subsequently vetted by the larger multi-stakeholder group of 83 participants representing 18 different countries. The consensus of the meeting participants was that clinical trial kidney failure outcomes should be comprised of a composite that includes receipt of a kidney transplant, initiation of maintenance dialysis, and death from kidney failure; it may also include outcomes based solely on laboratory measurements of glomerular filtration rate: a sustained low glomerular filtration rate and a sustained percent decline in glomerular filtration rate. Discussion included important considerations, such as (i) recognition of existing nomenclature for kidney failure; (ii) applicability across resource settings; (iii) ease of understanding for all stakeholders; and (iv) avoidance of inappropriate complexity so that the definitions can be used across ranges of populations and trial methodologies. The final definitions reflect the consensus for use in clinical trials.

The prevalence of chronic kidney disease and its risk factors is increasing worldwide, and the rapid rise in global need for end-stage kidney disease care is a major challenge for health systems, particularly in low- and middle-income countries. Countries are responding to the challenge of end-stage kidney disease in different ways, with variable provision of the components of a kidney care strategy, including effective prevention, detection, conservative care, kidney transplantation, and an appropriate mix of dialysis modalities. This collection of case studies is from 15 countries from around the world and offers valuable learning examples from a variety of contexts. The variability in approaches may be explained by country differences in burden of disease, available human or financial resources, income status, and cost structures. In addition, cultural considerations, political context, and competing interests from other stakeholders must be considered. Although the approaches taken have often varied substantially, a common theme is the potential benefits of multistakeholder engagement aimed at improving the availability and scope of integrated kidney care.

A large gap between the number of people with end-stage kidney disease (ESKD) who received kidney replacement therapy (KRT) and those who needed it has been recently identified, and it is estimated that approximately one-half to three-quarters of all people with ESKD in the world may have died prematurely because they could not receive KRT. This estimate is aligned with a previous report that estimated that >3 million people in the world died each year because they could not access KRT. This review discusses the reasons for the differences in treated and untreated ESKD and KRT modalities and outcomes and presents strategies to close the global KRT gap by establishing robust health information systems to guide resource allocation to areas of need, inform KRT service planning, enable policy development, and monitor KRT health outcomes.

Dialysis provisions and end-stage kidney disease (ESKD) care represents an important challenge, particularly in low-resource settings. The purpose of this project was to survey nephrologists from low- and lower middle-income countries about their experiences in the following domains: (i) Dialysis funding and eligibility; (ii) dialysis-procurement mechanisms; (iii) clinical protocols for dialysis; (iv) monitoring of dialysis outcomes; and (v) barriers to care for ESKD.One hundred and twenty responses from 31 low- and middle-income countries, from 8 ISN regions, were included in the analysis. When stratified by World Bank country income status, responses were received from 7 low-income countries, 12 lower middle-income countries, and 12 upper middle-income countries. Eighty-eight documents from 18 countries were uploaded, including country or institutional guidelines, protocols, and standard operating procedures. The International Society of Nephrology aims to develop a set of guidance documents that put forward a considered approach to dialysis provisions and ESKD care within resource limitations. As an initial step in this project, local practitioners from low-resource settings were surveyed about their experiences with dialysis funding, eligibility, procurement and their use of guidance documents, and how practices and procedures may have been developed with adaptations to the local circumstances. In this manuscript we describe the methodology and the main findings from the survey using an integrated quantitative and qualitative approach.

Secular increases in the burden of kidney failure is a major challenge for health systems worldwide, especially in low- and middle-income countries (LMICs) due to growing demand for expensive kidney replacement therapies. In LMICs with limited resources, the priority of providing kidney replacement therapies must be weighed against the prevention and treatment of chronic kidney disease, other kidney disorders such as acute kidney injury, and other noncommunicable diseases, as well as other urgent public health needs. Kidney failure is potentially preventable—not just through primary prevention of risk factors for kidney disease such as hypertension and diabetes, but also by timely management of established chronic kidney disease. Among people with established or incipient kidney failure, there are 3 key treatment strategies—conservative care, kidney transplantation, and dialysis—each of which has its own benefits. Joining up preventive care for people with or at risk for milder forms of chronic kidney disease with all 3 therapies for kidney failure (and developing synergistic links between the different treatment options) is termed “integrated kidney care” and has potential benefits for patients, families, and providers. In addition, because integrated kidney care implicitly considers resource use, it should facilitate a more sustainable approach to managing kidney failure than providing one or more of its components separately. There is currently no agreed framework that LMIC governments can use to establish and/or scale up programs to prevent and treat kidney failure or join up these programs to provide integrated kidney care. This review presents a suggested framework for establishing integrated kidney care programs, focusing on the anticipated needs of policy makers in LMICs.

Innate lymphoid cells are a recently recognized group of immune cells with critical roles in tissue homeostasis and inflammation. Regulatory innate lymphoid cells are a newly identified subset of innate lymphoid cells, which play a suppressive role in the innate immune response, favoring the resolution of intestinal inflammation. However, the expression and role of regulatory innate lymphoid cells in kidney has not been reported. Here, we show that regulatory innate lymphoid cells are present in both human and mouse kidney, express similar surface markers and form a similar proportion of total kidney innate lymphoid cells. Regulatory innate lymphoid cells from kidney were expanded in vitrowith a combination of IL-2, IL-7 and transforming growth factor-β. These cells exhibited immunosuppressive effects on innate immune cells via secretion of IL-10 and transforming growth factor-β. Moreover, treatment with IL-2/IL-2 antibody complexes (IL-2C) promoted expansion of regulatory innate lymphoid cells in vivo, and prevent renal ischemia/reperfusion injury in Rag–/– mice that lack adaptive immune cells including Tregs. Depletion of regulatory innate lymphoid cells with anti-CD25 antibody abolished the beneficial effects of IL-2C in the Rag–/– mice. Adoptive transfer of ex vivoexpanded regulatory innate lymphoid cells improved renal function and attenuated histologic damage when given before or after induction of ischemia/reperfusion injury in association with reduction of neutrophil infiltration and induction of reparative M2 macrophages in kidney. Thus, our study shows that regulatory innate lymphoid cells suppress innate renal inflammation and ischemia/reperfusion injury.

Globally, the number of patients undergoing maintenance dialysis is increasing, yet throughout the world there is significant variability in the practice of initiating dialysis. Factors such as availability of resources, reasons for starting dialysis, timing of dialysis initiation, patient education and preparedness, dialysis modality and access, as well as varied “country-specific” factors significantly affect patient experiences and outcomes. As the burden of end-stage kidney disease (ESKD) has increased globally, there has also been a growing recognition of the importance of patient involvement in determining the goals of care and decisions regarding treatment. In January 2018, KDIGO (Kidney Disease: Improving Global Outcomes) convened a Controversies Conference focused on dialysis initiation, including modality choice, access, and prescription. Here we present a summary of the conference discussions, including identified knowledge gaps, areas of controversy, and priorities for research. A major novel theme represented during the conference was the need to move away from a “one-size-fits-all” approach to dialysis and provide more individualized care that incorporates patient goals and preferences while still maintaining best practices for quality and safety. Identifying and including patient-centered goals that can be validated as quality indicators in the context of diverse health care systems to achieve equity of outcomes will require alignment of goals and incentives between patients, providers, regulators, and payers that will vary across health care jurisdictions.

The CD40‐CD40L costimulatory pathway is critical for T cell activation in autoimmune disease. We have previously found that blocking the CD40‐CD40L pathway using a dendritic cell‐targeted CD40 DNA (DEC‐CD40) vaccine prevented the development of Heymann nephritis. In this study, we explored the effect of a DEC‐CD40 vaccine in the treatment of experimental autoimmune glomerulonephritis (EAG), an animal model of human Goodpasture's disease induced by antigen α3IV‐NC1. DEC‐CD40 vaccine given at week 3 and week 6 after 3IV‐NC1 injection reduced kidney structural and functional injury significantly in EAG. DEC‐CD40 vaccination suppressed Th17 cell numbers and Th17 immune responses in kidney and spleen, but did not alter Th1 cells number and responses. Serum derived from rats with DEC‐CD40 vaccination suppressed Th17 differentiation, but not Th1 differentiation in vitro. Furthermore, B cell activation, driven by Th17 cytokines, was suppressed by serum from rats vaccinated with DEC‐CD40. A DNA vaccine encoding CD40 and targeting dendritic cell, ameliorates kidney injury in both early and late stages in EAG rats, indicating DEC‐CD40 vaccination has a therapeutic role in EAG. Its effect is associated with the reduction of Th17 differentiation and Th17‐mediated B cell activation. DEC‐CD40 vaccination has a therapeutic role in experimental autoimmune glomerulonephritis, which is associated with the reduction of Th17 differentiation and Th17‐mediated B cell activation.

Tissue macrophages are crucial players in homeostasis, inflammation, and immunity. They are characterized by heterogeneity and plasticity, due to which they display a continuum of phenotypes with M1/M2 presenting 2 extremes of this continuum. M2 macrophages are usually termed in the literature as anti-inflammatory and wound healing. Substantial progress has been made in elucidating the biology of M2 macrophages and their potential for clinical translation. In this review we discuss the current state of knowledge in M2 macrophage research with an emphasis on kidney disease. We explore their therapeutic potential and the challenges in using them as cellular therapies. Some new regulators that shape macrophage polarization and potential areas for future research are also examined.

Regulatory T cells (Tregs) have been shown to be important in maintaining immune homeostasis and preventing autoimmune disease, including autoimmune kidney disease. It is also likely that they play a role in limiting kidney transplant rejection and potentially in promoting transplant tolerance. Although other subsets of Tregs exist, the most potent and well-defined Tregs are the Foxp3 expressing CD4+Tregs derived from the thymus or generated peripherally. These CD4+Foxp3+Tregs limit autoimmune renal disease in animal models, especially chronic kidney disease, and kidney transplantation. Furthermore, other subsets of Tregs, including CD8 Tregs, may play a role in immunosuppression in kidney disease. The development and protective mechanisms of Tregs in kidney disease and kidney transplantation involve multiple mechanisms of suppression. Here we review the development and function of CD4+Foxp3+Tregs. We discuss the specific application of Tregs as a therapeutic strategy to prevent kidney disease and to limit kidney transplant rejection and detail clinical trials in this area of transplantation.

Loss of E-cadherin marks a defect in epithelial integrity and polarity during tissue injury and fibrosis. Whether loss of E-cadherin plays a causal role in fibrosis is uncertain. α3β1 Integrin has been identified to complex with E-cadherin in cell-cell adhesion, but little is known about the details of their cross talk. Herein, E-cadherin gene (Cdh1) was selectively deleted from proximal tubules of murine kidney by Sglt2Cre. Ablation of E-cadherin up-regulated α3β1 integrin at cell-cell adhesion. E-cadherin–deficient proximal tubular epithelial cell displayed enhanced transforming growth factor-β1–induced α-smooth muscle actin (α-SMA) and vimentin expression, which was suppressed by siRNA silencing of α3 integrin, but not β1 integrin. Up-regulation of transforming growth factor-β1–induced α-SMA was mediated by an α3 integrin-dependent increase in integrin-linked kinase (ILK). Src phosphorylation of β-catenin and consequent p-β-catenin-Y654/p-Smad2 transcriptional complex underlies the transcriptional up-regulation of ILK. Kidney fibrosis after unilateral ureteric obstruction or ischemia reperfusion was increased in proximal tubule E-cadherin–deficient mice in comparison to that of E-cadherin intact control mice. The exacerbation of fibrosis was explained by the α3 integrin-dependent increase of ILK, β-catenin nuclear translocation, and α-SMA/proximal tubular–specific Cre double positive staining in proximal tubular epithelial cell. These studies delineate a nonconventional integrin/ILK signaling by α3 integrin–dependent Src/p-β-catenin-Y654/p-Smad2–mediated up-regulation of ILK through which loss of E-cadherin leads to kidney fibrosis.

Abnormalities of cardiac structure and function are common in patients undergoing dialysis, and cardiovascular disease is the major cause of mortality in this group. Heart failure is a common clinical manifestation of cardiovascular disease and is preceded by left ventricular hypertrophy (LVH). There are variable reports about the impact of dialysis on LVH, both deleterious and beneficial. Our study investigated whether the timing of the initiation of dialysis therapy had an impact on cardiac structure and function.

In the past 25 years the International Society of Nephrology has sponsored 545 physicians from 83 developing countries to undertake nephrology training in renal units in the developed world. Data collected biennially from past fellows have demonstrated a very positive impact of the program on individual trainees and their home institutions. Many of the trainees have gone on to leadership positions in their home institutions, countries, and regions. Increasingly, fellowships are undertaken in selected developed centers within the fellow's own region, which increases the relevance and utility of the training to the fellow and the fellow's home institution, and lessens the risk of ‘brain drain’.

As a rich source of pro-fibrogenic growth factors and matrix metalloproteinases (MMPs), macrophages are well-placed to play an important role in renal fibrosis. However, the exact underlying mechanisms and the extent of macrophage involvement are unclear. Tubular cell epithelial−mesenchymal transition (EMT) is an important contributor to renal fibrosis and MMPs to induction of tubular cell EMT. The aim of this study was to investigate the contribution of macrophages and MMPs to induction of tubular cell EMT. The murine C1.1 tubular epithelial cell line and primary tubular epithelial cells were cultured in activated macrophage-conditioned medium (AMCM) derived from lipopolysaccharide-activated J774 macrophages. MMP-9, but not MMP-2 activity was detected in AMCM. AMCM-induced tubular cell EMT in C1.1 cells was inhibited by broad-spectrum MMP inhibitor (GM6001), MMP-2/9 inhibitor, and in AMCM after MMP-9 removal by monoclonal Ab against MMP-9. AMCM-induced EMT in primary tubular epithelial cells was inhibited by MMP-2/9 inhibitor. MMP-9 induced tubular cell EMT in both C1.1 cells and primary tubular epithelial cells. Furthermore, MMP-9 induced tubular cell EMT in C1.1 cells to an extent similar to transforming growth factor-β. Transforming growth factor-β-induced tubular cell EMT in C1.1 cells was inhibited by MMP-2/9 inhibitor. Our in vitrostudy provides evidence that MMPs, specifically MMP-9, secreted by effector macrophages can induce tubular cell EMT and thereby contribute to renal fibrosis.

Epithelial-mesenchymal transition (EMT) plays an important role in organ fibrosis, including that of the kidney. Loss of E-cadherin expression is a hallmark of EMT; however, whether the loss of E-cadherin is a consequence or a cause of EMT remains unknown, especially in the renal system. In this study, we show that transforming growth factor (TGF)-β1-induced EMT in renal tubular epithelial cells is dependent on proteolysis. Matrix metalloproteinase-mediated E-cadherin disruption led directly to tubular epithelial cell EMT via Slug. TGF-β1 induced the proteolytic shedding of E-cadherin, which caused the nuclear translocation of β-catenin, the transcriptional induction of Slug, and the repression of E-cadherin transcription in tubular epithelial cells. These findings reveal a direct role for E-cadherin and for matrix metalloproteinases in causing EMT downstream of TGF-β1 in fibrotic disease. Specific inhibition rather than activation of matrix metalloproteinases may offer a novel approach for treatment of fibrotic disease.

Macrophages are important mediators of injury in most types of human kidney diseases; however, the pathogenic importance of both macrophage number and activation status is unknown. To examine this question, severe-combined immunodeficient mice with adriamycin nephrosis, an experimental model of human focal segmental glomerulosclerosis, were treated intravenously with either resting (1 × 106to 5 × 106) or activated (1 × 103to 1 × 106) macrophages on day 6 postadriamycin administration, and the effects on kidney injury were examined. On day 28, renal injury was worse in the group that received activated macrophages at doses as low as 1 × 104macrophages per mouse compared with control adriamycin nephrotic mice. However, treatment with resting macrophages at doses as high as 5 × 106macrophages per mouse had no significant effect on either renal histology or function. The transferred activated macrophages homed to inflamed kidneys during the middle-to-late stages of the disease, but such homing was not observed for resting macrophages. This study of in vivocell adoptive transfer supports the importance of macrophage activation status over macrophage number in causing renal injury. These data suggest that therapeutic strategies for treating progressive kidney diseases should target activated macrophages.

Background/Aims:Quercetin, a naturally occurring dietary flavonoid, is a potent in vitro inhibitor of the transcription factors, nuclear factor (NF)-ĸB and activator protein (AP)-1. Here we investigated the efficacy of quercetin to suppress renal cortical NF-ĸB/AP-1 activation and tubulointerstitial injury, in vivo, in a nephrotic rat model of chronic glomerular disease. Methods:Adult male Wistar rats with (n = 27) or without (n = 15) Adriamycin nephropathy (AN) were stratified into six groups (according to proteinuria and endogenous creatinine clearance, measured on day 10) and pair-fed a semipurified diet supplemented with or without quercetin (0.5, 2%) from day 14 to 36. Results:Quercetin-fed rats had minimal weight gain during the study (p < 0.05). In AN, proteinuria, the decline in endogenous creatinine clearance, hypercholesterolaemia and cortical tubulointerstitial injury were not reduced by quercetin. Quercetin had no effect on renal cortical NF-ĸB activation, but unexpectedly exacerbated the induction of AP-1 in AN (by 67%, p < 0.05). In normal rats, quercetin increased proteinuria (by 75%, p < 0.05), renal cortical AP-1 activation (by 198%, p = 0.06), and malondialdehyde production (by 110%, p < 0.05). Conclusion:These data suggest that supplementation of the diet with quercetin is not an effective therapeutic strategy alone to reduce NF-ĸB/ AP-1 activation in chronic glomerular diseases, and paradoxically could be associated with adverse renal effects.

Tubulointerstitial damage, in progressive chronic renal disease of all types, arises because of a complex interplay between factors in the tubular lumen, tubular epithelial cells, peritubular capillaries, resident and infiltrating interstitial cells and extracellular matrix. Particularly in proteinuric renal disease, tubular epithelial cells play a central role in orchestrating these events. In response to mediators arising systemically, in the tubular lumen or from other renal cells, tubular epithelial cells undergo a complex series of structural and functional changes and produce a bewildering number of soluble and fixed mediators, which in turn lead to interstitial inflammation and fibrosis. Knowledge of these interactions has increased exponentially over the past decade, and has defined a number of new targets for treatment. Both expansion and consolidation of this knowledge is needed to determine which of these targets holds the most promise for future treatment.

Background/Aim:Inhibition of nuclear factor ĸB with the antioxidant pyrrolidine dithiocarbamate (PDTC) reduced tubulointerstitial injury in Adriamycin nephropathy (AN), whereas N-acetylcysteine (NAC) was ineffective. Here we hypothesize that PDTC reduces the renal cortical expression of nuclear factor ĸB dependent cytokines in AN. Methods:Male Wistar rats received a single intravenous injection of doxorubicin hydrochloride (7.5 mg/kg). NAC (150 mg/kg twice daily i.p.), PDTC (50 mg/kg twice daily i.p.), or vehicle were commenced on day 14 and continued until day 30. Results:On day 30, mRNAs of selected cytokines were increased in AN (TNF-α 3.4-fold, MCP-1 5.1-fold, IL-10 2.7-fold, TGF-β1 3.5-fold, all p < 0.05) as determined by RT-PCR. PDTC reduced IL-10 and TGF-β1 mRNAs (p < 0.05), whereas the upregulation of MCP-1 and TNF-α mRNAs was not affected. In contrast, NAC increased TNF-α and IL-10 mRNAs (p < 0.05). Nuclear protein levels of activator protein-1 were increased in AN (4.4-fold, p < 0.01) and not significantly altered by PDTC (3.0-fold, p = 0.13) or NAC (5.2-fold, p = 0.18). Conclusions:The protective effects of PDTC in AN are not associated with a local reduction in TNF-α and MCP-1 gene expression. The latter may be due to continued transactivation by activator protein-1. These data also suggest that IL-10 and TGF-β1 mRNA expressions are PDTC dependent and have a role in mediating tubulointerstitial injury.

It is well known that innate immune cells, including dendritic cells, macrophages, and natural killer cells, contribute to pathogenesis and protection in various kidney diseases. The understanding of innate immunity has been advanced recently by the discovery of a new group of innate lymphoid cells (ILCs), including ILC1, ILC2, and ILC3. ILCs lack adaptive antigen receptors, yet can be triggered by various pathogens and rapidly provide an abundant source of immunomodulatory cytokines to exert immediate immune reactions and direct subsequent innate and adaptive immune responses. ILCs play critical roles in immunity, tissue homeostasis, and pathological inflammation. In this review, we highlight the biological function of ILC subpopulations in the normal kidney, and their important roles in acute and chronic kidney diseases, thus demonstrating the emerging importance of ILC-regulated immunity in this special organ and providing insights for future research directions and therapeutic interventions.

DNA damage and alterations in DNA Damage Response (DDR) signaling could be one of the molecular mechanisms mediating focal kidney cyst formation in autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to test the hypothesis that markers of DNA damage and DDR signaling are increased in human and experimental ADPKD. In the human ADPKD transcriptome, the number of upregulated DDR-related genes was increased by 16.6-fold compared to normal kidney, and by 2.5-fold in cystic compared to minimally cystic tissue (P<0.0001). In end-stage human ADPKD tissue, gamma (γ)-H2AX, phosphorylated Ataxia Telangiectasia and Rad3-related (p-ATR) and AT Mutated (p-ATM) localized to cystic kidney epithelial cells. In vitro,p-ATR and p-ATM were also constitutively increased in human ADPKD tubular cells (WT 9-7, 9-12) compared to control (HK-2). Additionally, extrinsic oxidative DNA damage by H2O2augmented γ-H2AX and cell survival in human ADPKD cells, and exacerbated cyst growth in the 3D MDCK cyst model. In contrast, DDR-related gene expression was only transiently increased on postnatal day 0 in Pkd1RC/RCmice, and not altered at later timepoints up to 12 months of age. In conclusion, DDR signaling is dysregulated in human ADPKD and during the early phases of murine ADPKD. The constitutive expression of the DDR pathway in ADPKD may promote survival of PKD1-mutated cells and contribute to kidney cyst growth.

Human membranous nephritis is a major cause of end‐stage kidney disease. Active Heymann nephritis (HN) is an auto‐immune model of membranous nephritis induced in Lewis rats by immunization with a crude renal tubular antigen (Fx1A) or megalin (gp330). The pathogenesis of HN is through the binding of anti‐Fx1A autoantibodies to the auto‐antigen expressed on glomerular epithelial cells, resulting in severe glomerular injury and proteinuria. The pathological features of HN include immune deposits in glomeruli and infiltration of glomeruli and the tubulointerstitium by macrophages and T cells. This unit describes the method of the preparation of Fx1A and the induction of HN in Lewis rats by immunization with Fx1A. © 2015 by John Wiley & Sons, Inc.