Elsevier

The Lancet

Volume 382, Issue 9887, 13–19 July 2013, Pages 158-169
The Lancet

Series
Evolving importance of kidney disease: from subspecialty to global health burden

https://doi.org/10.1016/S0140-6736(13)60439-0Get rights and content

Summary

In the past decade, kidney disease diagnosed with objective measures of kidney damage and function has been recognised as a major public health burden. The population prevalence of chronic kidney disease exceeds 10%, and is more than 50% in high-risk subpopulations. Independent of age, sex, ethnic group, and comorbidity, strong, graded, and consistent associations exist between clinical prognosis and two hallmarks of chronic kidney disease: reduced glomerular filtration rate and increased urinary albumin excretion. Furthermore, an acute reduction in glomerular filtration rate is a risk factor for adverse clinical outcomes and the development and progression of chronic kidney disease. 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 body homoeostasis. Risk of kidney disease has a notable genetic component, and identified genes have provided new insights into relevant abnormalities in renal structure and function and essential homoeostatic processes. 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.

Introduction

More than 50 years ago, nephrology emerged as a medical subspecialty dealing with the effects of severely impaired kidney function on body homoeostasis. At that time, the understanding of renal physiology and the complex and diverse involvement of kidney function on various body functions was ahead of its clinical application. Few options to treat renal disorders of mineral and electrolyte handling existed, hormonal deficiencies resulting from kidney disease could not be corrected, and almost no techniques were available to prolong the life of individuals with kidney failure.

Nephrology progressed gradually with the establishment of renal pathology and a better understanding of disease entities, but the first major change occurred when dialysis and transplantation became widely available in the 1960s. The ability to provide life-sustaining renal replacement therapy was an outstanding achievement in medicine. Unsurprisingly, nephrologists have since strived to optimise renal replacement therapy and the prevention and treatment of comorbidities in patients with renal failure. However, the costs associated with these achievements are high. In countries that can afford to offer renal replacement therapy to all patients with renal failure, the proportion of health-care expenditure for this group of patients is far out of proportion to its size.1, 2 In most countries, economic constrains allow only restricted access to this expensive chronic treatment, which creates striking social inequalities and pressure on constrained health-care resources.3

By contrast with the importance and obvious relevance of chronic kidney failure requiring replacement therapy, the effect of less severe chronic kidney disease, which affects far more patients, had for a long time been largely ignored by the medical community, policy makers, and the public. Reduced kidney function was thought to be of little importance until the glomerular filtration rate reached less than 15%. This viewpoint resulted in two sets of terms to distinguish between patients with so-called end-stage renal disease and others with a lesser degree of renal impairment, who were often collectively summarised as pre-end-stage renal disease or pre-dialysis patients. Moreover, numerous vague and poorly defined terms were commonly used (eg, renal insufficiency or pre-uraemia) in parallel to nomenclature describing the cause of kidney disease (eg, glomerulonephritis, polycystic kidney disease, or diabetic nephropathy). However a uniform and unequivocal definition of chronic kidney disease was unavailable.

Key messages

  • Chronic kidney disease is chiefly defined by a reduction in glomerular filtration rate and increased urinary albumin excretion

  • Chronic kidney disease affects more than 10% of the population in many countries worldwide

  • Causes of chronic kidney disease 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 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

  • Genetic causes of specific forms of kidney disease and susceptibility to development of kidney disease in the context of other disorders are increasingly recognised

  • A multilevel interdisciplinary approach will be needed to address the public health burden of kidney disease

Only in 2002 did the medical community first agree on a uniform definition and staging system for chronic kidney disease, based on measures of kidney function and independent of the cause of impaired kidney function.4, 5 Application of this uniform concept to large databases showed that chronic kidney disease is far more frequent than was appreciated previously.6 More than 10% of people have chronic kidney disease and the overall prevalence at least equals that of diabetes.7 As with many other chronic diseases, the prevalence of chronic kidney disease increases with age, exceeding 20% in individuals older than 60 years and 35% in those older than 70 years.8 The importance of chronic kidney disease became apparent when large analyses showed that even early-stage disease is associated with increased prevalence and severity of numerous disorders and adverse outcomes. In particular, chronic kidney disease is now recognised as a very relevant and independent cardiovascular risk factor (see paper 5 in this Series).9, 10

Similar considerations hold true for acute changes in kidney function. Acute renal failure was well known to be associated with poor prognosis, but was regarded as harmless and reversible for a long time, provided patients survived the critical condition during which it occurred. However, even small, transient changes in serum creatinine (suggesting temporary decreases in glomerular filtration rate) have been associated with significantly worsened prognosis, including a strikingly increased risk of mortality and development and progression of chronic kidney disease.11, 12 After several initiatives were undertaken, a uniform definition and staging of what is now known as acute kidney injury was developed, which could potentially further advance the specialty.13

These developments, which were not based on technical, surgical, or immunological progress, but rather on a consensus for a uniform terminology and its application with rigorous epidemiological methods, has greatly expanded the focus on kidney disease beyond nephrology. Standardised terminology has stimulated research, affected patient care, and influenced public policies. And, as for any major advancement, it has also raised new questions. The seemingly most straightforward, but most pressing, of these questions are why is kidney disease so frequent and why is it associated with such a poor prognosis? To answer these two questions, researchers might need to return to the physiology of the organ to better understand why the kidney is a frequent target of many chronic disturbances and why, conversely, disorders of kidney function affect extrarenal tissues so strikingly, in particular the cardiovascular system. Aspects of renal function generally accepted to be understood need to be revisited. Additionally, linkage of the new definitions and staging of acute and chronic kidney disease with genomic, proteomic, and metabolomic information offers new opportunities to understand underlying mechanisms of disease.

Here, we aim to review the central role of the kidney for body homoeostasis and its fate as a target organ of disease. We will also describe the current definitions and staging systems for chronic kidney disease and acute kidney injury, and advances in understanding of the genetic predisposition to kidney disease. Subsequent articles in this series will focus on the global effects, clinical consequences, and management of chronic kidney disease14 and acute kidney injury;15 the link between kidney disease and cardiovascular disease;16 the effects of maternal, neonatal, and child health on kidney health;17 and future perspectives of the specialty.18

Section snippets

The kidney and body function

Each kidney contains about 1 million functional units, nephrons, consisting of numerous specialised cell types originating from distinct embryological lineages (figure 1). Each nephron contains a filtrating body, the glomerulus, and a long tubule made of a dozen differentiated segments. The final parts of these tubules are interconnected to form the collecting ducts, which open into the renal pelvis.

The basic principles of kidney physiology dictate the central role played by this organ in

Kidney disease

The present definition and staging of chronic kidney disease and acute kidney injury were proposed by independent guideline development workgroups.13, 34 The criteria were based on, or were partly validated by, major research efforts that have revolutionised the understanding of outcomes of kidney disease. The foundation for the definition and staging systems is the strong, graded, and consistent association of measures of abnormalities in kidney structure and function with clinical prognosis,

Chronic kidney disease

The impetus for the first guidelines defining chronic kidney disease in 2002 stemmed from the rising incidence and prevalence of chronic kidney failure, with associated high cost and poor outcomes, and concerns about late referral to nephrologists.4 The recommendations focused on estimation of glomerular filtration rate from serum creatinine and ascertainment of markers of kidney damage (primarily albuminuria). Methodological issues about which measurements to use were a key discussion point.

Acute kidney injury

KDIGO also developed an acute kidney injury guideline,13 recognising that the prognosis of acute kidney failure had not improved in decades, despite substantial improvements in intensive care and methods of dialysis, and that small declines in glomerular filtration rate, which are not severe enough to be classified as acute kidney failure, are associated with adverse outcomes. The acute kidney injury guideline is based on earlier efforts to define the disorder56, 57 and concentrates on changes

Kidney as a cause and target organ of disease

Diseases affecting the kidney are usually categorised into primary and secondary diseases (table 2). However, with increased understanding of the underlying causes of disease, this classification becomes indistinct, because most diseases that mainly manifest in the kidney are associated with extrarenal pathogenesis and systemic manifestations. In view of its notable role in the circulation, the kidney is frequently a target organ of systemic vascular, haemodynamic, metabolic, and inflammatory

Obesity, metabolic syndrome, and diabetes

Prevalence of obesity has increased substantially in the past century. In the USA, obesity (body-mass index >30 kg/m2) has increased in men aged 60 years from 3.4% in 1890 to more than 30% in 2000.59 Obesity also presents a serious health threat in developing countries.60 The increase in obesity has been accompanied by notable increases in hypertension, diabetes, cardiovascular disease, and chronic kidney disease.8, 61 The association of chronic kidney disease with an increased frequency of

Arterial hypertension

The pathogenesis of hypertension shows that the kidney can have an important role in health and disease even when renal function, defined by glomerular filtration rate, is normal. Primary hypertension, defined as a blood pressure of more than 140/90 mm Hg, was once present in only 5–10% of the adult population in the early 1900s, but has meanwhile increased to a prevalence of 20–40% in most developed countries, and has been projected to affect more than 1·5 billion people worldwide by 2025.66

Genetic predisposition to kidney disease

Clustering of kidney disease in families is well established, but underappreciated. From the 1980s, linkage analysis and subsequently positional cloning emerged as a technique that allowed for the detection of disease-causing mutations in one gene (termed monogenic or Mendelian diseases). In 2010, more than 110 genes underlying monogenic diseases with a renal phenotype had been described.74 The most prominent example is autosomal-dominant polycystic kidney disease (table 3). Although this

Complications of kidney disease

In general, all acute and chronic diseases have a worse prognosis in the presence of kidney disease. This association is of particular relevance for the various types of cardiovascular disease,9 including acute myocardial infarction,99 stroke,100 and heart failure.101 Chronic kidney disease also worsens the prognosis of patients with metabolic disease and diabetes, chronic pulmonary disease, pneumonia,102, 103 and other acute infections. An increased incidence of cancer in patients with chronic

Implications for general practice

In view of the importance of kidney function on body homoeostasis and the high prevalence of kidney disease, its recognition is important to all providers of health care. Serum creatinine concentrations and urinary excretion of albumin related to creatinine in spot urine samples are straightforward and robust techniques to exclude or diagnose and stage chronic kidney disease.4, 34 Although the quantitative association between serum creatinine concentrations and glomerular filtration rate is

Future challenges

Despite the compelling evidence for strong associations of kidney disease with adverse outcomes and increasing insight into possible mechanisms, the ultimate proof for a causal association between impaired kidney function and poor health will rely on proof of benefit after improvements in kidney function. Unfortunately, therapeutic strategies that would enable such a hypothesis to be addressed, are very limited. The number of randomised clinical trials in nephrology continues to lag behind most

Search strategy and selection criteria

References included in this Series were identified by the authors, based on their respective areas of expertise and supplemented by unsystematic database searches.

References (121)

  • SA Teteris et al.

    Homeostatic and pathogenic role of renal dendritic cells

    Kidney Int

    (2011)
  • LS Chawla et al.

    Acute kidney injury and chronic kidney disease: an integrated clinical syndrome

    Kidney Int

    (2012)
  • MT James et al.

    Glomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: a cohort study

    Lancet

    (2010)
  • TJ Hoerger et al.

    A health policy model of CKD: 1. Model construction, assumptions, and validation of health consequences

    Am J Kidney Dis

    (2010)
  • KU Eckardt et al.

    Definition and classification of CKD: the debate should be about patient prognosis—a position statement from KDOQI and KDIGO

    Am J Kidney Dis

    (2009)
  • AS Levey et al.

    The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report

    Kidney Int

    (2011)
  • PM Kearney et al.

    Global burden of hypertension: analysis of worldwide data

    Lancet

    (2005)
  • AC Guyton et al.

    Arterial pressure regulation. Overriding dominance of the kidneys in long-term regulation and in hypertension

    Am J Med

    (1972)
  • F Hildebrandt

    Genetic kidney diseases

    Lancet

    (2010)
  • M Chaki et al.

    Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling

    Cell

    (2012)
  • MS Lipkowitz et al.

    Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans

    Kidney Int

    (2013)
  • L Rampoldi et al.

    The rediscovery of uromodulin (Tamm-Horsfall protein): from tubulointerstitial nephropathy to chronic kidney disease

    Kidney Int

    (2011)
  • M Noris et al.

    Genetics and genetic testing in hemolytic uremic syndrome/thrombotic thrombocytopenic purpura

    Semin Nephrol

    (2010)
  • CM O'Seaghdha et al.

    Performance of a genetic risk score for CKD stage 3 in the general population

    Am J Kidney Dis

    (2012)
  • M Kerr et al.

    Estimating the financial cost of chronic kidney disease to the NHS in England

    Nephrol Dial Transplant

    (2012)
  • R Vanholder et al.

    Reimbursement of dialysis: a comparison of seven countries

    J Am Soc Nephrol

    (2012)
  • K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification

    Am J Kidney Dis

    (2002)
  • J Coresh et al.

    Prevalence of chronic kidney disease in the United States

    JAMA

    (2007)
  • MJ Sarnak et al.

    Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention

    Circulation

    (2003)
  • KDIGO clinical practice guideline for acute kidney injury

    Kidney Int Suppl

    (2012)
  • V Jha et al.

    Chronic kidney disease: global dimension and perspectives

    Lancet

    (2013)
  • NH Lameire et al.

    Acute kidney injury: an increasing global concern

    Lancet

    (2013)
  • RT Gansevoort et al.

    Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention

    Lancet

    (2013)
  • VA Luyckx et al.

    Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease

    Lancet

    (2013)
  • G Remuzzi et al.

    Kidney failure: aims for the next 10 years and barriers to success

    Lancet

    (2013)
  • B Haraldsson et al.

    Properties of the glomerular barrier and mechanisms of proteinuria

    Physiol Rev

    (2008)
  • D Brown et al.

    New insights into the dynamic regulation of water and acid-base balance by renal epithelial cells

    Am J Physiol Cell Physiol

    (2012)
  • EI Christensen et al.

    Receptor-mediated endocytosis in renal proximal tubule

    Pflugers Arch

    (2009)
  • P Singh et al.

    Renal homeostasis and tubuloglomerular feedback

    Curr Opin Nephrol Hypertens

    (2010)
  • RF Reilly et al.

    Mammalian distal tubule: physiology, pathophysiology, and molecular anatomy

    Physiol Rev

    (2000)
  • NK Shah et al.

    Dapagliflozin: a novel sodium-glucose cotransporter type 2 inhibitor for the treatment of type 2 diabetes mellitus

    Pharmacotherapy

    (2012)
  • CW Bourque

    Central mechanisms of osmosensation and systemic osmoregulation

    Nat Rev Neurosci

    (2008)
  • M Kuro-O

    Klotho in health and disease

    Curr Opin Nephrol Hypertens

    (2012)
  • A Martin et al.

    Regulation and function of the FGF23/klotho endocrine pathways

    Physiol Rev

    (2012)
  • JM Gleadle

    Review article: how cells sense oxygen: lessons from and for the kidney

    Nephrology (Carlton)

    (2009)
  • KD Smith

    Toll-like receptors in kidney disease

    Curr Opin Nephrol Hypertens

    (2009)
  • KDIGO clinical practice guideline for chronic kidney disease

    Kidney Int Suppl

    (2013)
  • K Matsushita et al.

    Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis

    Lancet

    (2010)
  • K Matsushita et al.

    Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate

    JAMA

    (2012)
  • SI Hallan et al.

    Age and association of kidney measures with mortality and end-stage renal disease

    JAMA

    (2012)
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