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Since publication of the first issue of Nature Reviews Nephrology 20 years ago, advances across various subspecialities of nephrology have provided insights into disease processes and led to the development of new therapeutics for people with kidney disease. However, despite this progress, many kidney diseases remain untreatable, the costs of kidney disease care are immense, and vast inequities persist in disease burden and access to care. In this Viewpoint, we ask experts from several key subspecialties of nephrology to reflect on progress made over the past 20 years, remaining challenges and the steps needed to move the field forward.

The enthusiasm for pancreatic β-cell islet transplantation that followed the introduction of the 'Edmonton protocol' in 2000 has been tempered by evidence that the immunosuppressants used in the protocol might be nephrotoxic and that the resultant insulin independence is only short-term in most patients. Cravedi and colleagues analyze the risks and benefits of islet transplantation and argue that it should not be regarded as a general alternative to insulin replacement therapy for patients with type 1 diabetes mellitus.

In this Viewpoint, five members of theNature Reviews Nephrologyadvisory board reflect on the progress and frustrations of the past decade in basic and clinical nephrology research. They comment on areas where effort and money should be invested and the challenges that remain to be overcome, as well as give their predictions for progress in the next decade.

In a meta-analysis of 48 randomized trials of chronic kidney disease progression, reduction in the 6-month urinary albumin:creatinine ratio was associated with lower hazard ratios of established kidney disease endpoints, supporting the use of albuminuria change as a surrogate endpoint in clinical trials for chronic kidney disease.

In this comprehensive review, Giuseppe Remuzzi and colleagues present a hypothesis for the pathophysiology of pre-eclampsia that unifies findings from a recent flurry of research. These new insights should spur the development of novel treatments for the hypertension and proteinuria that are hallmarks of this leading cause of fetal and maternal morbidity.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Standard treatments to reduce cardiovascular risk, including mineralocorticoid receptor antagonists, have not lowered the high cardiovascular mortality and morbidity of patients on long-term haemodialysis. Future research should focus on targeting inflammatory pathways that are activated when blood interacts with dialysis membranes.

Membranous nephropathy is an immune-mediated disease and is the leading cause of nephrotic syndrome in adults. Here, the authors discuss the role of B cell-depleting regimens in the treatment of this disease and the potential use of rescue therapy with agents that target plasma cells, which might prevent antigen–antibody interactions and immune complex-mediated complement activation.

With no specific cures for most acquired chronic kidney diseases, current efforts are focused on preventing disease progression. Here, Remuzzi and colleagues discuss examples of novel drugs and biologics that might be used to target the inflammatory and profibrotic process, and glomerular injury, highlighting results from recent clinical trials.

Two trials recently reported in the New England Journal of Medicine report that use of mammalian target of rapamycin inhibitors does little to halt the progression of autosomal dominant polycystic kidney disease. Do these therapies still have a future in the treatment of this disease?

Studies have shown that rituximab, a chimeric monoclonal antibody that targets the CD20 antigen of B cells, might be a valuable alternative to current therapies for idiopathic membranous nephropathy. In this Viewpoint article, Ruggenenti and colleagues discuss the use of rituximab in idiopathic membranous nephropathy and reason that titrating rituximab therapy to CD20⁺cell counts might be an effective way of limiting patient exposure to rituximab without reducing the efficacy of treatment, and would also substantially reduce treatment costs.

In 1955, the Swiss hematologist Conrad von Gasser coined the term ‘hemolytic uremic syndrome’ to describe the combined symptoms of diarrhea, hemolytic anemia, thrombocytopenia and acute renal failure, which he had observed in five children. Since then, investigators have realized that some forms of hemolytic uremic syndrome can be attributed to genetic abnormalities in circulating and membrane-bound proteins that regulate the complement system. How do these abnormalities influence the course and outcome of the disease, and how should they affect its treatment?

Lymphocyte depletion has recently been adopted to allow immunosuppression minimization or even to achieve donor-specific tolerance in transplant recipients. The long-term aim of such therapy is to minimize toxic effects associated with standard immunosuppression, but this beneficial effect is offset by the potential toxicity of the global depletion of lymphocytes and, in some cases, monocytes and neutrophils. This Viewpoint summarizes current data on depletion strategies in kidney transplantation, typically in the setting of induction treatment.

Several surprising findings indicate that pharmacological blocking of the multifunctional enzyme mTOR fosters distinct differentiation programs in different immunocompetent cells. These data might lead to a striking change in our view of the role that mTOR inhibition should have in immunosuppressive therapy for allogeneic transplant recipients.

A new meta-analysis shows that dual blockade of the renin–angiotensin system is the most effective approach to prevent end-stage renal disease in patients with diabetes and kidney disease. Combination therapy should therefore be reconsidered as the most powerful tool for nephroprotection, provided that treatment is individually tailored by careful dose-titration.

A recent meta-analysis concluded that the risk-to-benefit ratio of dual (versus single-drug) renin–angiotensin system blockade argues against the use of dual therapy. This conclusion, however, seems inconsistent with the actual data and may convey to physicians a misleading message that could misdirect important decisions on treatment.

German health-care providers should be applauded for their heroic efforts in facing the 2011 Escherichia coli O104:H4 outbreak. However, a unique opportunity was missed to compare the efficacy of antibiotics, plasma therapy and eculizumab therapy in a randomized study, and the open questions concerning the optimal treatment of severe Shiga-toxin-associated haemolytic uraemic syndrome remained unanswered.

Candesartan doses in excess of the recommended antihypertensive maxima have been reported to lead to greater reductions of proteinuria than the advised doses. High-dose angiotensin-converting-enzyme inhibitors, however, are at least as effective as high-dose angiotensin blockers and less expensive. Angiotensin-converting-enzyme inhibition is thus the first-line strategy to halt kidney disease progression.

Haemolytic uraemic syndrome (HUS) leads to anaemia, thrombocytopenia and, ultimately, acute renal failure. Some patients are also at risk of cardiovascular complications owing to mutations in the complement pathway, which result in microangiopathic injury of the coronary vasculature. This Perspectives article highlights the cardiovascular complications arising in patients with HUS and the implications for treatment of this rare disease.

The slowly progressing nature of chronic kidney disease makes the design of clinical trials with hard end points extremely challenging. One way of establishing a drug's effectiveness is by demonstrating an effect on a surrogate end point. In this Perspectives article, the authors describe data supporting proteinuria as a valuable predictor of renal survival and argue that it should be used as a surrogate marker of renal disease progression in renal clinical trials.

Atypical haemolytic uraemic syndrome (HUS), Shiga toxin-producingEscherichia coli-associated HUS and thrombotic thrombocytopaenic purpura are diseases characterized by microvascular thrombosis, with subsequent dysfunction of affected organs. In this Review, the authors discuss data indicating that complement dysregulation is a common pathogenetic effector of all three diseases, and describe the emerging evidence indicating that targeting complement may effectively treat these disease entities.

Systematic analysis from the Global Burden of Disease study reported that, despite global improvements from 1990 to 2021, dietary iron deficiency-associated disease burden remains high in women, children and residents in low socio-demographic index countries.

Mesenchymal stromal cells drive renal regeneration following injury. Here, the authors show that human mesenchymal stromal cells, when transplanted into mice with acute kidney injury, stimulate renal tubular cell growth and enhance mitochondrial function via SIRT3.

Fine-scale geospatial mapping of overweight and wasting (two components of the double burden of malnutrition) in 105 LMICs shows that overweight has increased from 5.2% in 2000 to 6.0% in children under 5 in 2017. Although overall wasting decreased over the same period, most countries are not on track to meet the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025.

ONTARGET showed that dual renin–angiotensin system blockade prevents microalbuminuria but facilitates transient renal function impairment in nonproteinuric patients with atherosclerotic vascular disease or diabetes. These findings should not be used as an excuse not to optimize renin–angiotensin system inhibition and target urinary protein in patients with proteinuric nephropathies.

The International Society of Nephrology–Advisory Committee of Clinical Trials and Studies aims to ensure access to timely and unbiased expert advice for all investigators, and to facilitate the development and execution of clinical trials within a highly ethical framework. The initiative will foster high-quality, cost-effective research in a sustainable network.

A meta-analysis of individual-level patient data from 66 clinical studies supports the utility of glomerular filtration rate as a surrogate endpoint in clinical trials for chronic kidney disease, with potential to enable detection of events earlier in the disease course.

Atypical haemolytic uraemic syndrome (aHUS) is associated with genetic or autoimmune defects that affect the complement system; however, the identification of mutations in diacylglycerol kinase ε (DGKE) as the cause of a recessive form of aHUS characterized by proteinuria highlighted podocyte dysfunction as a potential complication of aHUS. Here, Marina Noris et al. discuss the mechanisms by which DGKE deficiency might lead to aHUS and podocyte dysfunction, and the possible links between DGKEand the complement system.

Including proteinuria in the NKF KDOQI staging system for chronic kidney disease will increase the accuracy of risk stratification, but will not improve the precision of glomerular filtration rate (GFR) estimation by prediction formulas. Using markers of glomerular filtration other than serum creatinine will hopefully enable implementation of novel formulas that more precisely estimate true GFR, especially in individuals with near-normal renal function.

A recent meta-analysis concluded that plasma exchange is the most effective intervention for thrombotic thrombocytopenic purpura and that plasma manipulation offers no additional benefit over simple supportive therapy in hemolytic uremic syndrome. These findings must be interpreted with great caution, as response to treatment depends on the underlying disease etiology.

Angiotensin II and other components of the renin–angiotensin–aldosterone system (RAAS) have a central role in the pathogenesis and progression of diabetic renal disease. In this Review, Ruggenenti and colleagues describe the roles of angiotensin II and other effectors of the RAAS—such as aldosterone and renin—in the pathogenesis and progression of diabetic renal disease. In addition, they discuss the renoprotective and cardioprotective effects that inhibition of these effectors may have in individuals with diabetes.

Podocytes have a crucial role in maintaining the glomerular filtration barrier and their loss leads to glomerular disease. This Review discusses the role of podocyte actin dynamics in health and disease as well as the potential for personalized medicine approaches that target podocyte proteins.

Here, the authors describe the determinants of ‘absolute’ and ‘relative’ glomerular hyperfiltration and discuss single-nephron haemodynamic changes as pathophysiological factors that might result in progressive kidney injury. They also explain how interventions that mitigate glomerular hyperfiltration might translate into long-term renoprotection.

The unique immunomodulatory properties of multipotent mesenchymal stromal cells (MSCs) make them a promising candidate for cell therapy in organ transplantation. Here, the authors review preclinical data that support the potential tolerance-inducing effects of MSCs in transplant models and the results of initial clinical studies in kidney transplantation.

Identification of the molecular pathways involved in renal pathophysiology can yield targets for intervention and aid tailored therapy. de Borst and colleagues provide an introduction to the tools that can be used to pinpoint genes involved in renal disease, including gene expression arrays, linkage analysis, association studies and animal models. Examples of genes that have been identified using these techniques are highlighted.

Cellular regeneration—the repair of portions of the existing nephron after tubular damage—is conserved in all animal species. By contrast, nephron neogenesis is present in lower branches of the animal kingdom, but not in adult mammals. Converging evidence suggests that a renal progenitor system is present in the adult kidney across different stages of evolution. Here, the authors look at renal regeneration from an evolutionary perspective and suggest possible explanations for the differences between animals.

Analyses of the proportions of individuals who have completed key levels of schooling across all low- and middle-income countries from 2000 to 2017 reveal inequalities across countries as well as within populations.

High-resolution subnational mapping of child growth failure indicators for 105 low- and middle-income countries between 2000 and 2017 shows that, despite considerable progress, substantial geographical inequalities still exist in some countries.

This Perspectives article describes supporting and contradicting data regarding the role of podocyte B7-1 in the pathogenesis of various podocytopathies and highlights issues that need to be addressed to standardize approaches to the study of this protein.