The Lancet series on global kidney disease

Chronic kidney disease (CKD) is now a global epidemic affecting more than 10% of the world's population, say the authors of the first paper in The Lancet Series on Global Kidney Disease, written by Prof Kai-Uwe Eckardt, University of Erlangen-Nürnberg, Germany, and colleagues.

CKD is defined by a reduction in glomerular filtration rate (GFR; the rate at which the kidneys filter blood) and increased excretion of protein in a person's urine. The authors raise concerns that an increasing amount of evidence suggests that the kidneys are not only target organs of many diseases but also can strikingly aggravate or start systemic pathophysiological processes through their complex functions and effects on the body's systems.

As with many other chronic diseases, the prevalence of CKD increases with age, exceeding 20% in individuals older than 60 years and 35% in those older than 70 years. However, 1 in 25 younger adults aged 20-39 years also has this condition. Black people are twice as likely to have CKD as white people. Furthermore patients with diabetes or a history of cardiovascular disease have the highest prevalence of CKD, reaching 50% or higher.

Causes of CKD are complex and include common diseases such as hypertension, metabolic syndrome, and diabetes, and various less common diseases that mainly affect the kidney. Chronic kidney disease also predisposes to acute kidney injury and vice versa. "Even mild forms of kidney disease are associated with various adverse effects on body functions and an increased risk of mortality and cardiovascular morbidity," say the authors. "Genetic causes of specific forms of kidney disease and susceptibility to development of kidney disease in the context of other disorders are also now being increasingly recognised."

The authors conclude: "Collaboration across general and specialised health-care professionals is needed to fully address the challenge of prevention of acute and chronic kidney disease and improve outcomes."

The second paper in The Lancet Series on Global Kidney Disease addresses the growing concern posed by acute kidney injury, which, in tandem with CKD, is increasing worldwide. The distribution of causes differs dependent on the location, say the authors, who include Professor Norbert H Lameire, University Hospital Ghent, Belgium.

Despite technological advances, few preventive and therapeutic options exist to treat acute kidney injury. Even small acute changes in kidney function can result in short-term and long-term complications, including chronic kidney disease, end-stage renal disease, and death. Presence of more than one comorbidity results in high severity of illness scores in all medical settings. Development or progression of chronic kidney disease after one or more episode of acute kidney injury could have striking socioeconomic and public health outcomes for all countries.

In high-income countries, causes of acute kidney injury include kidney ischaemia from hypoperfusion after surgery, bleeding, dehydration, shock, or sepsis, toxic effects from drugs (often polypharmacy, radiocontrast drugs, poison, or trace elements), and pigment injury from myoglobin or haemoglobin that can block the blood vessels in the kidney. In developing countries, including tropical areas (anywhere with poor health¬ system infrastructure) acute kidney injury will usually be a community¬-acquired disease, affecting young and previously healthy individuals, and often attributable to one specific cause, eg, diarrhoeal or tropical infectious diseases, haemolytic uraemic syndrome, or acute post-¬infectious glomerulonephritis. Other causes include postsurgical complications, snake bites, and intake of traditional and nephrotoxic medicines. Patients with HIV/AIDS can develop acute kidney injury in association with infections, decreased blood volume in the body, and use of nephrotoxic antiretroviral drugs.

"A concerted multinational and multidisciplinary effort is needed to enable early recognition and management of this devastating disease," conclude the authors. "We encourage international and national nephrological societies through their educational programmes to collaborate with international institutions (eg, WHO), governments, and non-¬profit organisations to detect and reduce the risk factors for acute kidney injury, especially in low-¬income regions."

They add: "The effect of acute intermittent so¬called kidney attacks (acute kidney injury) on the evolution of chronic kidney disease should be assessed in both children and adults in high¬-income and low-¬income countries."

CKD is moving rapidly up the global cause of death league table, and in fact was one the biggest risers between 1990 (when it was 27th) to 2010 (18th). In the third paper of the Lancet Series on Global Kidney Disease, the authors say that diabetes is the most common cause of chronic kidney disease, but in some regions other causes, such as herbal and environmental toxins, are more common. The paper is by Professor Vivekanand Jha, George Institute for Global Health, New Delhi, India, and colleagues.

Complications of CKD include increased all-cause and cardiovascular mortality, kidney-disease progression, acute kidney injury, cognitive decline, anaemia, mineral and bone disorders, and bone fractures. The poorest populations are at the highest risk of CKD, as are ethnic minorities in rich countries, including black and Asian people in the UK, black, Hispanic, and Native Americans in the USA, and Indigenous Australians, South American Aborigines, Maori, Pacific, and Torres Strait Islanders in New Zealand, and First Nation Canadians.

Screening and intervention can prevent chronic kidney disease, and where management strategies have been implemented the incidence of end-stage kidney disease has been reduced. "Awareness of the disorder, however, remains low in many communities and among many physicians," say the authors, adding that, because of a shortage of trained nephrologists, general practitioners must be involved in caring for patients with chronic kidney disease.

In terms of country-by-country prevalence, the USA, Taiwan, Portugal, Japan and Belgium are among the countries with the highest prevalence. In Taiwan and China, it is thought many cases are linked to aristolochic acid, a compound used to promote slimming. Other herbal preparations in Asia and Africa are also thought to be the cause of many CKD cases. In coming years, CKD burden is likely to grow rapidly in Asia and Africa.

CKD is, according to the authors, viewed as part of the rising worldwide non-communicable disease burden that is consuming healthcare systems in rich and poor nations alike. Hypertension, diabetes mellitus, and obesity are among the growing non-communicable diseases and are important risk factors for CKD.

"CKD is a global public health issue with different features to take into account in different parts of the world. The burden of chronic kidney disease is rising worldwide, as shown by increases in attributable deaths and incidence and prevalence of end-stage kidney disease," conclude the authors. "Chronic kidney disease and its complications, which involve most organ systems, can be prevented, but awareness and use of accurate methods are needed to enable timely diagnosis. Cost-effectiveness of preventive approaches must be assessed in relation to the local levels of economic development and resources. Prevention programmes will function best as part of national non-communicable disease strategies, with the involvement of general practitioners for non-communicable diseases."

The fourth paper in the Series (Dr Valerie Luyckx, University of Alberta, Edmonton, AB, Canada and colleagues) highlights the importance of maternal and fetal health and early childhood nutrition in preventing kidney disease in later life.

"Low birthweight and prematurity are risk factors for hypertension, proteinuria, and chronic kidney disease in later life," say the authors. Low birthweight and prematurity occur in 15% and 9•6% of livebirths, respectively, suggesting a high proportion of the world's children are at risk of hypertension and kidney disease. Low birthweight and prematurity are associated with a congenital reduction in the number of nephrons (the functional units of the kidney) which is associated with an increased risk of higher blood pressure and subsequent kidney disease. High birthweight, especially as a result of maternal diabetes, also increases the risk of kidney disease, as does moving up through the body-mass index centiles (e.g. rapid "catch-up" growth after being born small) in childhood or adolescence. A lower nephron number in itself may not be enough to lead to hypertension and kidney disease, but added (preventable) stresses such as childhood obesity, diet and lifestyle further compound the increasing risk with age.

A whole gamut of factors can be linked with low birthweight and prematurity, including poor maternal nutrition, societal factors such as lack of antenatal care, the age of the mother (with teenage mothers especially prone to premature births/low birthweight children), environmental factors, exposure to wars and conflict, and multiple gestations. Figure 1, p41 of this Series paper outlines the factors involved in maternal and child health that can eventually end in chronic kidney disease.

Optimization of maternal health worldwide is key to prevent low birth weight and prematurity. Subsequently, the authors conclude: "Identification of at-risk pregnancies and offspring of both high and low birthweight should prompt maternal education to optimise childhood nutrition and activity to prevent obesity. Prematurity and low birthweight are among the top ten contributors to the global burden of disease, calculations that might not always have included the long-term costs of programmed adult non-communicable diseases. Acknowledgment of the role of developmental programming in hypertension and renal disease risk, and implementation of locally adapted pre-emptive strategies in individual countries, will have important long-term benefits in terms of future health, productivity, and cost savings worldwide."

In patients with chronic kidney disease, compared with the general population, cardiovascular disease is more frequent and severe, is often not recognised, and is often undertreated, according to paper 5 in the Series by Dr Ron Gansevoort, University Medical Centre Groningen, Netherlands, and colleagues. "The strong causal association between chronic kidney disease and cardiovascular risk implies that to prevent progression of chronic kidney disease is, by definition, to prevent cardiovascular disease," say the authors.

They say that patients with chronic kidney disease should be viewed among the highest-risk groups for cardiovascular events and disease, and require special clinical attention at an individual patient level, in the development of guidelines, and in defining research priorities. They suggest that single preventive treatments could be used to reduce the risk of cardiovascular disease in early-stage CKD. Early CKD is defined as normal kidney function, but increased urinary protein loss. In that respect, screening for urinary protein loss may be cost-effective. For late-stage CKD, evidence shows that a multimodal approach is probably required including strict blood glucose control, antihypertensive medication including angiotensin-converting enzyme inhibitors, and statins and lifestyle interventions (smoking cessation, increased physical activity, and dietary changes such as sodium restriction). The authors call for more trials into both of these suggested strategies.

Although in some parts of the world acute and chronic kidney diseases are preventable or treatable disorders (mainly high-income countries), in many other regions (developing countries) these diseases are left without any medical care. "The nephrology community needs to commit itself to reduction of this divide between high-income and low-income regions," say the authors of paper 6 in the Series, who include Professor Giuseppe Remuzzi, Chairman of the Department of Transplantation at Bergamo Hospital and Research Coordinator of Mario Negri Institute for Pharmacological Research in Bergamo, Italy. They add; "Moreover, new and exciting developments in fields such as pharmacology, genetic, or bioengineering, can give a boost, in the next decade, to a new era of diagnosis and treatment of kidney diseases, which should be made available to more patients."

One of the priorities for the next decade is to reduce the burden of preventable causes of acute kidney injury in low-income countries (so that expensive treatment does not become necessary) and promote affordable renal replacement therapies, so that those with kidney failure can access this life-saving treatment. Commitment to renal replacement therapy and a programme for treatment of all chronic kidney disease and injury in developing countries needs planning and commitment at regional and national level in those countries, plus assistance from the biomedical community. Development of initiatives such as telemedicine centres so that patients in rural areas can be followed up from afar from specialist kidney centres using applications exploiting mobile networks could also be essential.

Globally, interventions are needed to help combat the burden of chronic kidney diseases with selective screening, infant and maternal health care, and prevention and treatment of curable diseases. "We also need to develop new drugs for kidney diseases and create new methods for diagnosis and treatments for inherited kidney disease," say the authors. Using bioengineering to repair damaged tissues and generate new organs is also important, but bioengineered kidneys are still in the infancy and are unlikely to be available for a decade or so.