Epidemiology and Pathophysiology of Chronic Kidney Disease

C H A P T E R

75

 

Epidemiology and Pathophysiology of Chronic Kidney Disease Aminu Bello, Bisher Kawar, Mohsen El Kossi, Meguid El Nahas

DEFINITION Chronic kidney disease (CKD) is defined as kidney damage or glomerular filtration rate (GFR) below 60 ml/min per 1.73 m2 for 3 months or more irrespective of the cause. The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines have classified CKD into five stages.1 This classification, although useful in simplifying the categorization of CKD, has its limitations, which include classifying people with isolated microalbuminuria as suffering from CKD, labeling mild and stable kidney damage as CKD, and not differentiating between age-related impaired kidney function and progressive disease-induced CKD.2 In 2005, the Kidney Disease: Improving Global Outcomes (KDIGO) group suggested clarifications including the addition of the suffix T for patients with renal allografts and D to identify CKD stage 5 patients on dialysis.3 The U.K. National Institute of Health and Clinical Excellence (NICE) has modified, in 2008, the KDOQI CKD classification by subdividing CKD stage 3 into 3A and 3B, estimated GFR of 45 to 59 ml/min per 1.73 m2 and 30 to 44 ml/min per 1.73 m2, respectively.4 The NICE CKD guidelines also stipulated that the suffix p be added to the stages in proteinuric patients (Fig. 75.1). This refinement of the initial CKD classification by NICE assumes that there is a distinction between patients with GFR below 60 ml/min per 1.73 m2 and those with GFR below 45 ml/min per 1.73 m2 in terms of prognosis and that the presence of significant proteinuria has to be acknowledged in the classification.4

EPIDEMIOLOGY OF CHRONIC KIDNEY DISEASE The true incidence and prevalence of CKD within a community are difficult to ascertain as early to moderate CKD is usually asymptomatic. However, various epidemiologic studies attempted to clarify that issue and have made relatively similar observations suggesting a prevalence of CKD of around 10%, albuminuria (mostly microalbuminuria) of around 7%, and GFR below 60 ml/min per 1.73 m2 of around 3% (Fig. 75.2). Of note, most of these studies are limited by the fact that individuals were tested only once, thus precluding a clear assumption of chronicity. The high prevalence of CKD is confounded by a number of facts: 1. Microalbuminuria is considered a marker of CKD when it may merely reflect underlying vascular disease, endothelial dysfunction, or atherosclerosis or chronic inflammatory conditions such as hepatitis, dermatitis, and colitis. Also, microalbuminuria is associated with aging, obesity, and smoking. Finally, it is often transient and reversible.

2. The majority of those screened within the community and found to have reduced GFR are elderly individuals. Age is known to be associated with a decline in kidney function that some consider physiologic, whereas others attribute it to underlying vascular aging and pathologic processes, mostly atherosclerosis and progressive renal ischemia. 3. Formulae such as the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault are used to estimate GFR in spite of their known limitations and underestimation of normal kidney function (bias and imprecision) (see Chapter 3). All these limitations of current CKD screening strategies may tend to overinflate the overall prevalence of significant CKD.

EPIDEMIOLOGY OF END-STAGE RENAL DISEASE Incidence of end-stage renal disease (ESRD) refers to the number of patients with ESRD beginning renal replacement therapy (RRT) during a given time (usually a year) in relation to the general population; it is usually expressed as number of patients per million population per year. Of note, the incidence of ESRD according to most national registries does not take into account patients not treated by RRT; therefore, it underestimates the overall true incidence of ESRD (CKD stage 5). The prevalence of ESRD is the proportion in a specific population who have ESRD at a given time; it encompasses both new and continuing patients on RRT; it is expressed as patients per million population. Prevalence is a function of the incidence (new cases) and outcomes (transplantation or death) rates of ESRD in a given population. The global epidemiology of ESRD is heterogeneous and influenced by several factors. Consequently, the incidence and prevalence of ESRD vary widely from country to country (Fig. 75.3). Disparities in the incidence and prevalence of ESRD within and between developed countries reflect racial and ethnic diversities as well as their impact on the prevalence of diabetes and hypertension in respective countries and communities. Recently, different progression rates of CKD in the population, referral patterns, and quality of pre-ESRD care have been linked to the heterogeneity of ESRD rates in different parts of the world. Disparities with developing countries are likely to reflect availability of and access to RRT in low and middle economies. The cost of treating patients with ESRD is substantial and has an impact on provision of care. In this context, it has been proposed that there is a clear and direct relationship between nations’ gross national product and the availability of RRT in most countries.5 It was pointed out that during the next decade, 907

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XV  Chronic Kidney Disease and the Uremic Syndrome

even the industrialized nations will struggle to meet the demands of expanding ESRD programs; in the United States, it has been estimated that the annual expenditure on ESRD will reach more than U.S. $52 billion by 2030.6 In the United Kingdom, renal services currently consume about 2% of the National Health Service budget, and this is set to rise with increasing numbers of individuals requiring RRT.7 Globally, it has been estimated that by 2010, more than 2 million individuals will be treated by RRT at a cost of $1 trillion during the decade.8 The great majority (90%) of those treated live in high economies. More than 100 of 212 countries worldwide with low and middle economies do not have any provision for RRT.9 Consequently, in many low and middle economy countries, ESRD is a death sentence.

Classification of CKD Based on GFR CKD Stage

Definition

1

Normal or increased GFR; some evidence of kidney damage reflected by microalbuminuria, proteinuria, and hematuria as well as radiologic or histologic changes

2

Mild decrease in GFR (89–60 ml/min per 1.73 m2) with some evidence of kidney damage reflected by microalbuminuria, proteinuria and hematuria as well as radiologic or histologic changes

3

3A 3B

GFR 59-30 ml/min per 1.73 m2 GFR 59 to 45 ml/min per 1.73 m2 GFR 44 to 30 ml/min per 1.73 m2

4

GFR 29-15 ml/min per 1.73 m2

5

GFR <15 ml/min per 1.73 m2; when renal replacement therapy in the form of dialysis or transplantation has to be considered to sustain life

SCREENING FOR CHRONIC KIDNEY DISEASE Current Screening Guidelines In view of the rising number of those suffering from ESRD and the perceived high prevalence of CKD in communities, interest has focused on the early detection of CKD and those at risk. Several guidelines for screening, mostly targeted to high-risk individuals, have been issued and implemented worldwide. Those include the U.S. KDOQI, the U.K. CKD NICE, and the Australian Caring for Australasians with Renal Impairment (CARI) guidelines, to name a few.1,4,10 There are few differences as to the recommended targeted populations, but they invariably include individuals with hypertension and diabetes mellitus. Other groups include those with a family history of CKD; obese individuals; those with cardiovascular diseases, especially congestive heart failure; people with multisystem diseases; ethnic groups with high prevalence of CKD; and those with urologic conditions, such as nephrolithiasis. The KDOQI guidelines additionally recommend screening those older than 65 years. Screening should consist of a urine albumin/protein estimation as well as measurement of serum creatinine and estimation of GFR (see Chapter 3). General population CKD screening is unlikely to be realistic or cost-effective. Targeted screening is the most costeffective approach (Fig. 75.4). Overall, CKD screening would best be associated with broader national strategies and programs to minimize cardiovascular disease (CVD). This is the essence of the U.K. national vascular campaign/strategy launched in 2009 and aiming to screen those older than 40 years for CVD risk, including, when appropriate, CKD. Similar strategies have been initiated by the Centers for Disease Control and Prevention in the United States and in Australia.

NATURAL HISTORY OF CHRONIC KIDNEY DISEASE

The suffix p to be added to the stage in proteinuric patients (proteinuria >0.5 g/24h)

Figure 75.1  Classification of CKD based on GFR as proposed by the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines and modified by NICE in 2008. (From references 1 and 4.)

The natural history of CKD stages 1 and 2 remains to be fully defined. It has generally been assumed that the majority of patients with CKD stages 3B to 5 progress relentlessly to ESRD.

Representative Population-based Studies on CKD Epidemiology

Figure 75.2  Representative population-based studies on CKD epidemiology. Outcome = subjects with chronic kidney disease (CKD) or micro­ albuminuria (MA). NHANES, National Health and Nutrition Evaluation Survey; PREVEND, Prevention of Renal and Vas­ cular Endstage Disease; NEOERICA, New Opportunities for Early Renal Inter­ vention by Computerised Assessment; HUNT, Nord-Trøndelag health study; EPIC, European Prospective Investiga­ tion into Cancer Study; AusDiab, Austra­ lian Diabetes, Obesity and Lifestyle study; CS, cross-sectional; F, female; L, longitudinal; M, male; N, number of par­ ticipants; service based, collecting patients’ data from general practitioner computer records.

Study

Country

Design

N

Outcome (%) MA

CKD

NHANES III

United Sates

CS/L

15,626

12

11

PREVEND

Netherlands

CS/L

40,000

7

NEOERICA

United Kingdom

CS/ service based

HUNT II

Norway

CS

65,181

6

EPIC-Norfolk

United Kingdom

CS

23,964

12

MONICA Augsburg

Germany

CS

2,136

8

AusDiab

Australia

CS

11,247

6

Taiwan

Taiwan

CS/L

Beijing

China

CS

13,925

Takahata

Japan

CS

2,321

11 (F), 6 (M)

130,226

462,293

10

10 12 13

14



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75  Epidemiology and Pathophysiology of Chronic Kidney Disease

Global Incidence and Prevalence of RRT (Per Million Population) in 2006 Country

Incidence

Prevalence

United States

360

1,626

Caucasians

279

1,194

African Americans

1,010

5,004

Native Americans

489

2,691

Asians

388

1,831

Hispanics

481

1,991

115

778

441

2,070

Japan

275

1,956

Europe

129

770

United Kingdom

113

725

France

140

957

Germany

213

1,114

Italy

133

1,010

Spain

132

991

Australia Aboriginal/Torres Strait

Figure 75.3  Global incidence and prevalence of RRT (per million population) in 2006. (Source: USRDS, ANZDATA, ERA-EDTA, and U.K. renal registries.)

International Recommendations for Targeted Screening for CKD Targeted group

Guidelines KDOQI UK NICE CARI

Elderly

•

Hypertension

•

Diabetes mellitus

•

•

•

CSN

•

•

•

•

Atherosclerotic

•

•

•

Cardiovascular disease heart failure

•

•

Urologic disease, stone disease, recurrent urinary infections

•

•

Systemic autoimmune conditions

•

•

•

Nephrotoxic drugs

•

•

•

High-risk ethnic groups

•

Family history of CKD

•

•

•

•

Other high-risk groups may include smokers, metabolic syndrome, obesity, low birth weight, systemic infections, reduced renal mass, and previous acute kidney injury Figure 75.4  International recommendations for targeted screening for CKD. KDOQI, Kidney Disease Outcomes Quality Initiative; U.K. NICE, U.K. National Institute of Health and Clinical Excellence; CARI, Australian Caring for Australasians with Renal Impairment; CSN, Cana­ dian Society of Nephrology.

909

This has recently been challenged as progression is variable, and a sizable percentage of these patients have stable kidney function or die prematurely of CVD.11 A Canadian study showed the natural history of CKD stages 3 and 4 to be variable and reflecting the patient’s risk factor profile.12 Many CKD patients with GFR below 60 ml/min per 1.73 m2 die from cardiovascular or other causes before reasing reaching ESRD. A straight-line relationship is often found between the reciprocal of serum creatinine (1/SCr) values or the estimated GFR and time (for methodologic aspects, refer to Chapter 76). However, a significant percentage of patients do not progress in a predictable linear fashion and have breakpoints in their progression slopes, suggesting acceleration or slowing down of the rate of progression of CKD. These breakpoints could be either spontaneous or secondary to events such as infections, dehydration, changes in the adequacy of systemic blood pressure control, and exposure to nephrotoxins, in particular nonsteroidal anti-inflammatory drugs (NSAIDs) or radiocontrast agents. Attention has also been drawn recently to the impact of intercurrent acute kidney injury (AKI) events on the rate of progression of CKD. It is also important to appreciate that some patients with mild to moderate CKD have stable renal function for sustained periods.11,12 The rate of progression of CKD also varies according to the underlying nephropathy and between individual patients. Historically, the rate of decline in GFR of patients with diabetic nephropathy has been among the fastest, averaging around −10 ml/min per year. Control of systemic hypertension slows the rate of GFR decline to −5 ml/min per year, with further improvement (−1 to −2 ml/min per year) expected in patients whose glycemia and hypertension are optimally controlled and in those treated with inhibitors of the renin-angiotensin-aldosterone system (RAS). In nondiabetic nephropathy, the rate of progression of CKD was 2.5 times faster in patients with chronic glomerulonephritis than in those with chronic interstitial nephritis and 1.5 times faster than in those with hypertensive nephrosclerosis. The association of proteinuria and faster progression of CKD was highlighted in a number of studies (reviewed in reference 13). Relief of obstruction, discontinuation of nephrotoxic agents, and control of hypertension often stabilize renal function in a large percentage of patients. Patients with polycystic kidney disease and impaired renal function, CKD stage 3B and beyond, may also have a faster rate of progression compared with other nephropathies. The rate of progression of CKD in the elderly has been associated with incident and progressive underlying cardiovascular disease. This is of interest as an increasing number of elderly patients reach ESRD, and renovascular disease has become one of the most common causes of ESRD in some countries.14

FACTORS AFFECTING INITIATION AND PROGRESSION OF CHRONIC KIDNEY DISEASE CKD is likely to be a multi-hit process. Risk factors for CKD include susceptibility, initiation, and progression factors. Susceptibility factors predispose to CKD, whereas initiation factors directly trigger kidney damage. Progression factors are associated with worsening of already established kidney damage. The aim of identifying susceptibility and initiation factors for CKD is to define individuals at high risk for development of CKD; with progression factors, the aim is to define individuals at high risk for worsening (CKD) kidney damage and subsequent loss of kidney function (Fig. 75.5).

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XV  Chronic Kidney Disease and the Uremic Syndrome

Summary of Risk Factors Associated with the Initiation and Progression of CKD Initiation Factors

Progression Factors

Systemic hypertension

Older age

Diabetes mellitus

Gender (male)

Cardiovascular disease

Race/ethnicity

Dyslipidemia

Genetic predisposition

Obesity/metabolic syndrome

Poor blood pressure control

Hyperuricemia

Poor glycemia control

Smoking

Proteinuria

Low socioeconomic status

Cardiovascular disease

Nephrotoxins exposure: NSAIDs, analgesics, traditional herbal use, heavy metals exposure (such as lead)

Dyslipidemia Smoking Obesity/metabolic syndrome Hyperuricemia Low socioeconomic status Alcohol consumption Nephrotoxins; NSAIDs, RCM, herbal remedies Acute kidney injury

Figure 75.5  Summary of risk factors associated with the initiation and progression of CKD. NSAIDs, nonsteroidal anti-inflammatory drugs; RCM, radiocontrast material.

These risk factors are further classified according to feasibility for intervention as modifiable and nonmodifiable (see Fig. 75.5). The classification can also be clinical (diabetes, hypertension, autoimmune diseases, systemic infections, drugs, or toxins) and sociodemographic (age, race, poverty/low income). A number of these risk factors have been identified in longitudinal communitybased studies (see Fig. 75.5). Known CKD susceptibility factors include genetic and familial predisposition, race (Afro-Caribbeans, Indo-Asians), maternalfetal factors (low birth weight, malnutrition in utero), age (elderly), and gender (male) (reviewed in references 1 and 15). Beyond the susceptibility to CKD, additional initiation factors are likely to trigger disease. These are listed in Figure 75.5.

CHRONIC KIDNEY DISEASE PROGRESSION FACTORS Once it is established, CKD (eGFR <60 ml/min) progression is influenced by a number of modifiable and nonmodifiable risk factors.16

Nonmodifiable Progression Risk Factors Age The rate of progression of CKD is influenced by age; elderly patients affected by glomerulonephritis seemingly have a faster rate of GFR decline. However, longitudinal studies of subjects without CKD have observed a decline in GFR with increasing age in some subjects, implying that nephron loss may be part of normal aging. This is corroborated by recently published longitudinal data from Norway.17 However, in one such study, the Baltimore Longitudinal Study, more than a third of indi­ viduals did not have a decline in kidney function with aging.

Age-related progression may be affected by underlying CVD and atherosclerosis.18 Gender This is an important demographic factor associated with development and progression of CKD. It has been reported that ESRD due to all causes occurs more frequently in men than in women. According to the USRDS Annual Data Report,6 there is preponderance in the prevalence of all-cause ESRD in favor of men, but this has not been reported to be so marked in Europe. In most CKD studies and meta-analyses, women have a slower rate of progression compared with men.6 Race In the United States, for all causes of ESRD, African Americans have a faster rate of progression than their Caucasian cohorts do. The incidence and prevalence of diabetic and hypertensive CKD are higher in African and Hispanic Americans compared with Caucasians.19 Their rate of CKD progression also seems faster, although few studies confirmed this by multivariate analysis. The mechanisms underlying these associations remain to be elucidated, but possible explanations include racial and genetic factors, lower nephron endowment, and increased susceptibility to saltsensitive hypertension as well as environmental, lifestyle, and socioeconomic differences. The last may have an impact on access to health care and compliance with treatment. Genetics Studies have demonstrated that genetic factors play a crucial role in CKD and ESRD, mostly through linkage and association analyses with candidate gene approaches. Recent technologic advancements in genome-wide association studies are likely to uncover new CKD susceptibility genes. Associations have been described between certain major histocompatibility complex loci and the rate of CKD progression. Patients with polycystic kidney disease carrying the genotype PKD1 are thought to have a worse prognosis than others. Progression of CKD may also be influenced by polymorphisms of genes coding for putative mediators of renal scarring, including those coding for the renin-angiotensin-aldosterone system (RAAS) (reviewed in reference 20). The human homologue of the rat renal failure (Rf ) gene has been localized to the long arm of chromosome 10. In African Americans with ESRD due a variety of nephropathies, an association between two markers (D10S1435 and D10S249) spanning 21 polymorphic regions of chromosome 10 approached significance in nondiabetic patients. It was also reported that genetic variation at the MYH9 locus or sequence variants in the APOL1 gene could explain the increased burden of focal segmental glomerulosclerosis and hypertensive ESRD among African Americans (see Chapter 19). Recent observations showed that single-nucleotide polymorphisms in the genes TCF7L221 and MTHFS22 are associated with CKD progression in population-based cohorts. Phenotypically, diabetic and nondiabetic nephropathies cluster in families, particularly in African Americans. In diabetes mellitus, a family history of CVD or hypertension is associated, respectively, with a twofold or fourfold increase in the risk for development of diabetic nephropathy. Loss of Renal Mass The threshold to natural progression after nephron loss is likely to be lowered by the presence of hypertension, obesity, hyperlipidemia, hyperglycemia, and black race. Recent evidence



CHAPTER

Renal Survival and Level of Proteinuria

1.00

1.00

0.95

0.95

0.90

0.90

Renal survival

Renal survival

Renal Survival and Blood Pressure

0.85 0.80 0.75

Mean blood pressure (mm Hg) <107 >107

0.70

911

75  Epidemiology and Pathophysiology of Chronic Kidney Disease

0.85 0.80 Proteinuria (g/24 h) <1 1–3 >3

0.75 0.70 0.65

0.65 0

6

12 18 Time (months)

24

30

0

6

12 18 Time (months)

24

30

Figure 75.6  Actuarial renal survival in relation to blood pressure. (Modified from reference 23.)

Figure 75.7  Actuarial renal survival in relation to proteinuria. (Modified from reference 23.)

also points to the impact of episodes of AKI on the decline in kidney function, with the elderly being more susceptible.24

Even low-grade albuminuria (below the current microalbuminuria threshold [albumin to creatinine ratio <3 mg/mmol]) in middle-aged nondiabetic and nonhypertensive individuals is associated with increased CVD risk. The risk associated with albuminuria in the general population matches, and sometimes exceeds, that attributed to better known risk factors of CVD, such as hypertension and hyperlipidemia. Diffuse endothelial and vascular dysfunction may be the common pathway linking albuminuria to the manifestations and prognosis of CKD and CVD (see also Chapter 78). Albuminuria has been linked in a number of studies to underlying systemic atherosclerosis, diffuse vascular stiffness, and maladaptive vascular remodeling.28,29 CKD is now defined as a CVD risk equivalent, and patients with moderate to severe CKD are taken to be in the “highest risk group” for development of CVD.1,30 Patients with CVD are also at a higher risk for development of CKD. Overall, these observations may, in part, be explained by the fact that CVD and CKD share many risk factors, including obesity, metabolic syndrome, hypertension, diabetes mellitus, dyslipidemia, and smoking. In addition, CVD may have direct hemodynamic effects on the kidneys that may promote initiation and progression of CKD, including decreased kidney perfusion in heart failure and atherosclerosis of the renal arteries, with subsequent ischemic nephropathy. Evidence is linking faster rate of CKD progression to severe atherosclerotic disease.18

Modifiable Progression Risk Factors These include systemic hypertension, proteinuria, and metabolic factors. In addition, interest has focused on the contribution of cigarette smoking, alcohol consumption, and recreational drug use to the risk for development of ESRD (see also Chapter 76). Hypertension Systemic hypertension is an important cause, consequence, and presenting feature of CKD. It is one of the leading causes of ESRD worldwide,6 the second leading cause in the United States after diabetes. Some experimental and epidemiologic studies have shown that sustained hypertension is indeed a significant contributor to the progression of CKD. Strong evidence links the progression of CKD to systemic hypertension in diabetic and nondiabetic nephropathies (reviewed in reference 1). It is believed that the transmission of systemic hypertension into the glomerular capillary beds and the resulting glomerular hypertension contribute to the progression of glomerulosclerosis (Fig. 75.6). Proteinuria A large number of studies in patients with diabetic and nondiabetic glomerular disease and nonglomerular diseases confirmed, by multivariate analysis, that heavy proteinuria is associated with a faster rate of CKD progression (Fig. 75.7).1,25 Furthermore, reduction of proteinuria by diet, angiotensin-converting enzyme inhibition, or angiotensin receptor blockade predicts a better outcome26 (see also Chapter 76); the extent of reduction in proteinuria is often proportional to the benefit accrued by such intervention on CKD progression. Experimental data suggest that proteinuria may contribute directly to the progression of CKD (see later discussion). The threshold for natural progression attributed to proteinuria appears to be crossed when proteinuria exceeds 1 g/day. Albuminuria, Chronic Kidney Disease, and Cardiovascular Disease Urinary albumin excretion rate is independently associated with the presence and severity of CVD in the general population.27

Renin-Angiotensin System The links between systemic hypertension, proteinuria/ albuminuria, and CVD may be mediated by changes in the RAS in CKD. A number of experimental and clinical data have implicated the RAS in the pathogenesis of hypertension, proteinuria, and renal fibrosis throughout the course of CKD (reviewed in reference 31). Consequently, interventions aimed at inhibition of the RAS have proved extremely effective in slowing the progression of CKD (discussed in Chapter 76). Glycemia A number of observations as well as randomized clinical trials have demonstrated during the last 25 years that tight diabetes control can potentially slow the rate of progression of diabetic microvascular complications, including diabetic nephropathy in both type 1 and type 2 diabetes mellitus.32,33

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Obesity Several studies have linked obesity, and the associated metabolic syndrome, with increased risk of CKD. Excessive body weight and a raised body mass index have also been linked to a faster rate of progression of CKD. Anecdotal reports suggest that weight reduction reduces obesity-related renal hemodynamic changes as well as CKD-associated proteinuria. Recent data derived from general population studies suggest that body weight reduction reduces albuminuria, and increased weight gain is associated with its progression.34 Lipids Dyslipidemia may contribute to glomerulosclerosis and tubulointerstitial fibrosis. A number of studies of diabetic and nondiabetic nephropathies have confirmed by multivariate analysis that dyslipidemia is a risk factor for a faster rate of CKD progression.1 Smoking Smoking has been shown to increase the risk of albuminuria as well as that of progression of CKD (reviewed in reference 35). Possible mechanisms whereby cigarette smoking may contribute to kidney damage include sympathetic nervous system activation, hypertension, endothelial injury, and potential direct tubulotoxicity. Uric Acid Hyperuricemia has been associated with systemic hypertension, CVD, and CKD36 (see also Chapter 33). Hyperuricemia may cause hypertension and renal injury through crystal-independent pathways, notably a stimulation of the RAAS. In a small Japanese study, hyperuricemic patients with IgA nephropathy had a worse prognosis compared with those with normal serum uric acid levels, and a serum uric acid of 6.0 mg/dl or higher was an independent predictor of ESRD in women. However, a more recent observation from the United States suggested that in patients with CKD, hyperuricemia appears to be an independent risk factor for all-cause and CVD mortality but not for kidney failure.37

fibrosis. However, little is known about what determines the kidney’s predilection for one or the other pathway. Healing is characterized by recovery of kidney structure and function. It occurs primarily in AKI when acutely damaged tubules recover from the initial insult and replace lost tubular cells to reconstitute the integrity of the tubules and to restore kidney function. Healing also takes place in acute interstitial nephritis when treatment is instituted early in the course of the inflammatory process, leading to resolution of the inflammatory process and tubule recovery. Healing is also the hallmark of acute postinfectious glomerulonephritis, when the acute glomerular inflammation resolves through the death (apoptosis) of infiltrating leukocytes or their efflux from the glomeruli. Renal function typically recovers within a few weeks from the acute nephritic process. On the other hand, most forms of chronic kidney damage, such as those induced by diabetes, hypertension, chronic glomerulonephritis, or chronic exposure to infections or nephrotoxins, evolve to progressive scarring with loss of function and CKD. Scarring is characterized by the progressive loss of intrinsic renal cells and their replacement by fibrous tissue made of collagenous extracellular matrix (ECM; Fig. 75.8). This affects the glomeruli (glomerulosclerosis; Fig. 75.9), tubules and interstitium (tubulointerstitial fibrosis; Fig. 75.10), and vessels (vascular sclerosis). In this section, we describe the generic elements of renal scarring and fibrosis in an attempt to identify stages potentially amenable to future therapies.39

Renal Cell Loss, Activation, and Transformation Loss of intrinsic renal cells is one of the hallmarks of progressive renal scarring. Experimental and clinical models of glomerulo-

Schematic Representation of Pathways to Healing or Scarring after Renal Cell Injury Injury

Additional Factors Implicated in Progression of Chronic Kidney Disease n n n

Alcohol and recreational drugs Analgesics and NSAIDs Lead and heavy metals exposure

Kidney cell Glomerular/tubular

Cell death Necrosis/apoptosis

MECHANISMS OF PROGRESSION OF CHRONIC KIDNEY DISEASE The progression of CKD is associated with changes in kidney structure characterized by scarring associated with glomerulosclerosis, tubulointerstitial fibrosis, and vascular sclerosis. Whereas injury to the glomeruli, tubules, interstitium, or vessels may predominate initially, CKD progression is often associated with damage and scarring affecting all structural components of the kidney. The kidney responds to injury by adaptive changes that lead to remodeling evolving toward either healing and functional recovery or scarring with loss of kidney function and progressive CKD.38 During the last 25 years, considerable progress has been made in the understanding of the pathways leading to healing and recovery and those favoring the progression to scarring and

Atrophy

Healing

Cell transformation Reverse embryogenesis Embryonic phenotype

Recapitulated embryogenesis Mature phenotype

Myofibroblasts Proliferation Migration

Fibrosis scarring

ECM production Decreased clearance Renal fibroblasts

Figure 75.8  Schematic representation of pathways to healing or scarring after renal cell injury. Cell death through necrosis or apoptosis would ultimately lead to renal atrophy and favors replacement by fibrous tissue. Cell injury may lead to dedifferentiation as a step toward recovery and healing.



CHAPTER

75  Epidemiology and Pathophysiology of Chronic Kidney Disease

913

A A

B B

C

C

D Figure 75.9  Histologic development of glomerulosclerosis. A, Normal glomerulus. B, Mesangial hypercellularity. C and D, Glomeru­ losclerosis of increasing severity. Note the tubular atrophy and dilation in B to D, indicating the parallel development of tubulointerstitial scarring.

nephritis display a progressive loss of the fine glomerular capillary structure and the disappearance of the glomerular cellular elements with their replacement by an expanding ECM and fibrous tissue. Loss of glomerular cells through necrosis or apoptosis has been described and can be triggered by a severe glomerular inflammatory process, as in glomerulonephritis with glomerular endothelial and capillary damage, or by continuing damage to glomerular cells, as in subacute and chronic glomerulonephritis affecting the mesangium or the podocytes (Fig. 75.11). Similarly, progressive renal scarring is associated with progressive tubular cell loss and atrophy.

Figure 75.10  Histologic development of tubulointerstitial fibrosis. A, Normal tubulointerstitium. B, Mild tubulointerstitial scarring with tubular atrophy and interstitial edema. C, Segmental interstitial fibrosis. D, Diffuse interstitial fibrosis with tubular atrophy and dilation.

Endothelial Cells In acute and severe glomerulonephritis, damage to the glomerular endothelial lining triggers further injury. The endothelial capillary lining normally displays protective anticoagulant, antiinflammatory, and antiproliferative functions.40 Damage to the

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The Stages of Glomerulosclerosis Endothelial cell injury Hemodynamic Immune Metabolic

Endothelial cell injury Chemokine and cyctokine release

Chemokine and cytokine release

Cell adhesion molecule

Inflammation

Cell adhesion molecule expression

Platelet attraction/ aggregation

Platelet

Monocyte influx

Figure 75.11  The stages of glomerulosclerosis. ECM, extracellular matrix. Foam cell (lipid-laden monocyte) infiltration

Foam cell Monocyte

Proliferation Stretched epithelial cell

Stretched epithelial cell

Proliferating/dedifferentiated mesangial cells

Activated mesangial cell Fibroblast/ myofibroblast ECM

glomerular endothelium transforms this protective cellular layer to a proaggregatory, pro-inflammatory, and mitogenic surface, leading to the accumulation of inflammatory cells and platelets within glomerular capillaries as well as the stimulation of the proliferation of the mesangium. This process bears strong similarities to atherosclerosis with microthrombi formation, infiltration of the glomerular tufts by macrophages and foam cells, and proliferation of the smooth muscle cell equivalent, the mesangial cell. Glomerular endothelial damage can be clearly triggered by an acute inflammatory process but also by a metabolic insult, as in diabetes, or hemodynamic shear stress, as in hypertension. Mesangial Cells Mesangial cells are the glomerular capillary equivalent to the smooth muscle cell and in that capacity respond to injury in a similar fashion: death, transformation, proliferation, and migration as well as synthesis and deposition of ECM. Mesangial death through necrosis, lysis, and apoptosis has been well documented

ECM synthesis + deposition

Fibrosis Fibroblast/ myofibroblast Glomerulosclerosis

in response to injury. Injury is also followed by the engagement of the mesangial cells in the repair, healing, or scarring process. Dedifferentiation of mesangial cells into an embryonic phenotype with the acquisition of stress fibers and α-smooth muscle actin allows these cells to proliferate, to migrate, and to restore the glomerular structural integrity.38 They also lay down collagenous ECM to seal the wound and to repair structural damage. However, scarring is often characterized by uncontrolled mesangial proliferation and excessive deposition of mesangial matrix. These are the forebears of glomerulosclerosis. Mesangial activation, transformation, proliferation, migration, and ECM synthesis seem to be driven by a number of cytokines and growth factors, including transforming growth factor β1 (TGF-β1), platelet-derived growth factor (PDGF), and fibroblast growth factor.41 These growth factors activate, through their respective mesangial cell surface receptors, a number of intracellular signal transduction pathways. These in turn mediate mesangial events and scarring (see Fig. 75.11).



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75  Epidemiology and Pathophysiology of Chronic Kidney Disease

Podocytes The relative inability of podocytes to replicate in response to injury may lead to their stretching along the glomerular basement membrane, exposing areas of denuded glomerular basement membrane that would attract and interact with parietal epithelial cells, leading to the formation of capsular adhesions and subsequent segmental glomerulosclerosis.42 However, inability of podocytes to replicate was challenged by the hypothesis that glomerular parietal epithelial cells could differentiate into podocytes. It has also been suggested that changes in podocytes’ derived growth factors, including vascular endothelial growth factor (VEGF) and PDGF, may also be instrumental in contributing to intraglomerular injury. Capsular adhesions formed by contact between the glomerular basement membrane and the parietal epithelial lining of Bowman’s capsule may lead to misdirected filtration with the accumulation of amorphous material in the paraglomerular space and the subsequent disruption of glomerular-tubular junction, resulting in atubular glomeruli. Misdirected filtration may also contribute to tubular atrophy and interstitial fibrosis. Tuft-capsule adhesions may allow the influx of periglomerular fibroblasts into the glomerular tuft, thus contributing to glomerulosclerosis. Podocytopathy and ECM deposition in diabetic nephropathy are believed to be mediated by increased proinflammatory cytokines and growth factor production by podocytes, including VEGF, TGF-β1, macrophage migration inhibitory factor, and monocyte chemoattractant protein 1.43 Tubular Cells As with glomerular cells, injury to tubule cells is followed by an attempt at regeneration and repair.44 After an acute insult, some tubular cells die through necrosis or apoptosis. Apoptosis has been well documented during the course of experimental and clinical models of CKD. Surviving cells attempt to restore tubule integrity by dedifferentiation into an embryonic phenotype that allows them, through the acquisition of cytoplasmic α-smooth muscle actin and stress fibers, to proliferate, to migrate, and to repopulate acellular tubules. Healing and recovery of renal function ensue. On the other hand, repeated or sustained insult is likely to stimulate sustained epithelial mesenchymal transformation (EMT) of tubule cells into a myofibroblastic phenotype with excessive production and deposition of ECM, contributing to fibrosis. Thus, tubular injury with subsequent activation and transformation can directly contribute to renal fibrogenesis. A number of stimuli have been shown to induce tubular EMT, including cytokines (interleukins) and growth factors (TGF-β1, epidermal growth factor) as well as advanced glycation products. Also, recent evidence suggests that excessive exposure of tubule cells in culture to albumin, simulating albuminuria, has the capacity to induce EMT. It has been postulated that proteinuria/ albuminuria itself is capable of activating the proximal tubules to release proinflammatory mediators and to initiate interstitial inflammation (reviewed in reference 45). Inflammatory cells would lead to more damage and also stimulate resident renal fibroblasts to produce and deposit ECM (Fig. 75.12). Vascular Cells Vascular sclerosis is an integral feature of the renal scarring process. Renal arteriolar hyalinosis is present in CKD at an early stage, even in the absence of severe hypertension. Furthermore, these vascular changes are often out of proportion to the severity of systemic hypertension. Vascular sclerosis is associated with progressive kidney failure in glomerulonephritis. Hyalinosis of

915

Development of Tubulointerstitial Fibrosis Inflammatory mediators Chemokines Cytokines Growth factors

Lymphocyte Monocyte

MHC class II expression

Tubular cell injury Immune Hemodynamic Metabolic Absorption of luminal glucose, protein, lipid

Fibroblast Collagen I and III

Interstitial fibrosis

Cell adhesion molecules

Protein Lipid Glucose

Figure 75.12  Development of tubulointerstitial fibrosis. MHC, major histocompatibility complex.

afferent arterioles has been implicated in the pathogenesis of diabetic glomerulosclerosis. Changes in postglomerular arterioles and damage to peritubular capillaries may further exacerbate interstitial ischemia and fibrosis. Ischemia and the ensuing hypoxia are fibrogenic influences that stimulate tubular cells and kidney fibroblasts to produce ECM components and to reduce their collagenolytic activity.46 Loss of peritubular capillaries with the associated impaired angiogenesis has been linked in experimental models of renal scarring to a fall in the renal expression of the proangiogenic VEGF. Together with an overexpression by scarred kidneys of thrombospondin, an antiangiogenic factor, this would perpetuate microvascular deletion and ischemia.47 The administration of VEGF preserves peritubular capillaries and improves scarring and functional outcome. Finally, the vascular endothelium, adventitia, and pericytes may be a source of interstitial myofibroblasts, contributing to the development of interstitial renal fibrosis.48 Recent evidence also points to lymphatic neoangiogenesis in association with interstitial inflammation and progressive renal fibrosis.49 Such a process appears to be driven by macrophages that express the lymphangiotropic growth factor VEGF-C. It may play a role in interstitial remodeling as it provides an exit route for inflammatory cells involved in interstitial inflammation.

Inflammation and Infiltration by Extrinsic Cells Infiltration of the glomeruli and renal interstitium by inflammatory cells is an early and common pathway in the pathogenesis of glomerulosclerosis (see Fig. 75.11) and tubulointerstitial fibrosis (see Fig. 75.12). Platelets Platelets and their release products have been detected within glomeruli in experimental and clinical nephropathies. The stimulation of the coagulation cascade is likely to activate mesangial cells and to induce sclerosis. Thrombin stimulates glomerular TGF-β1 production, leading to production of mesangial ECM as well as that of inhibitors of metalloproteinases. The upre­ gulation within damaged glomeruli of plasminogen activator

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XV  Chronic Kidney Disease and the Uremic Syndrome

Experimental Interventions to Slow CKD with Potential for Clinical Translation Target Growth factors Fibrosismodulating growth factors (TBF–β1, HGF, BMP-7)

Intervention

Mechanism of Action

Evidence Level

Neutralizing anti–TGF–β1 antibodies ALK1 (TGF–β1 receptor) inhibitors Administration of bone morphogenic protein 7 (BMP-7) Administration of hepatocyte growth factor (HGF)

Neutralization of the growth factor (TGF–β1) Inhibition of receptor-mediated signal transduction Inhibitor of the TGF–β1–Smad signaling pathway

Experimental models of CKD Experimental models of CKD Experimental models of CKD

Inhibits nuclear translocation of receptor-regulated Smads and upregulates the expression of Smad corepressors Mediator of TGF-β1– induced fibrosis

Experimental models of CKD Clinical trials in promoting angiogenesis Experimental models of CKD Phase II clinical trial completed in diabetic nephropathy Experimental models of CKD Used in the treatment of hypertrophic scars and scleroderma Preliminary clinical data in diabetic nephropathy Experimental models of CKD Experimental data indicate potential of CR002 in mesangioproliferative disease

Inhibition of connective tissue growth factor (CTGF)

Proliferative growth factors (PDGF, EGF)

Tranilast

Inhibits TGF-β1–induced ECM synthesis

Decorin Neutralizing anti–platelet-derived growth factor CR002 (PDGF) antibodies including CR002 PDGF antagonists; aptamers, imatinib mesylate, trapidil Anti–epidermal growth factor (EGF) antibody Inhibition of epidermal growth factor receptor (EGF-R)

Sequesters TGF-β1 in the extracellular matrix CR002 monoclonal antibody targeting PDGF-D

Angiogenic growth factors (VEGF)

Administration of vascular endothelial growth factor

Intracellular transduction pathways

Ras-Raf-Mek-Erk pathway inhibition by: 1: Ras: prenylation inhibitors (statins), prenyltransferase inhibitors farnesylthiosalicylic acid (FTS) 2:Raf and Mek kinase inhibitors Rho kinase inhibition: fasudil

Cell cycle inhibitors Immuno suppressive agents

Other agents

Direct inhibition of PDGF; imatinib mesylate: tyrosine kinase inhibitor of PDGF transduction Neutralize EGF action Inhibition of EGF-R by ascofuranone, an isoprenoid antibiotic, that inhibits phosphorylation of EGFR and downstream kinases To stimulate/restore glomerular and peritubular capillary angiogenesis However, may also stimulate glomerular hypertrophy and albuminuria in models of diabetic nephropathy Inhibition of cellular proliferation, differentiation, and apoptosis

Phase I clinical trial completed in MPGN Clinical use limited by cardiotoxicity Inhibition of renal fibroblast proliferation and collagen expression Experimental models of CKD Experimental mesangioproliferative GN and diabetic nephropathy Experimental models of CKD Role of statins in progressive clinical CKD not yet defined

Interference with cell proliferation, tubulointerstitial fibrosis, and glomerular hemodynamics

p38 mitogen–activated protein kinase inhibitors

Inhibition of proinflammatory and profibrotic mediators

Protein kinase C inhibitors, such as ruboxistaurin

Inhibition of cell growth most evident in diabetic nephropathy

Cyclin-dependent kinase inhibitors, such as roscovitine Mycophenolate mofetil (MMF)

Inhibition of cell cycle progression Inhibitor of inosine monophosphate dehydrogenase; inhibiting cell proliferation

Sirolimus (rapamycin)

mTOR inhibitor; interference with cell proliferation by regulating ribosomal biogenesis and protein translation

Endothelin antagonists

Reduce cellular proliferation and intraglomerular hypertension; antiproteinuric effect

Pirfenidone

Inhibits ECM accumulation

Peroxisome proliferator-activated receptor γ agonists

Reduce cell growth, inflammation; antiproteinuric effect

Prolyl hydroxylase domain (PHD) inhibitors, e.g., cobalt chloride, FG-2216

Upregulation of HIF-regulated genes, such as VEGF and EPO

Pentoxifylline

Antioxidant

N–Acetylcysteine (NAC)

Antioxidant

Tocopherols

Antioxidant

Experimental models of CKD Phase II studies in ischemic heart disease Fasudil in clinical use in Japan for cerebral vasospasm Experimental models of CKD Clinical trials in rheumatoid arthritis and type 1 diabetes mellitus Experimental models of CKD Phase II clinical trials in diabetic nephropathy, reduce albuminuria Experimental models of CKD Experimental models of CKD Used in clinical CKD associated with vasculitis Variable data in experimental models of CKD but can induce/increase proteinuria Promising in experimental PDKD Clinical trials completed in PKD Experimental models of CKD Clinical trials in diabetic nephropathy Reduce albuminuria in diabetic nephropathy Risk of increased CVD mortality Experimental models of CKD Phase II trials in diabetic nephropathy Experimental models of CKD Reduces proteinuria in clinical diabetic nephropathy Risk of increased CVD mortality Experimental models of CKD Phase II clinical trials of FG-2216 for treatment of anemia Experimental models of CKD Phase II clinical trials assessing role in proteinuric CKD Experimental models of CKD Used for AKI prophylaxis in CKD Experimental models of CKD Tocopherols and α–lipoic acid in clinical trials in CKD

Figure 75.13  Experimental interventions to slow CKD with potential for clinical translation. AKI, acute kidney injury; CVD, cardiovascular disease; ECM, extracellular matrix; EPO, erythropoietin; GN, glomerulonephritis; HIF, hypoxia-inducible transcription factor; MPGN, membranoprolifera­ tive glomerulonephritis; PKD, polycystic kidney disease.



CHAPTER

75  Epidemiology and Pathophysiology of Chronic Kidney Disease

inhibitor 1 is also likely to affect outcome as its inhibition of the proteolytic enzyme plasmin may lead to ECM accumulation and glomerulosclerosis.50 Glomerulosclerosis may depend on the balance between thrombotic/antiproteolytic and anticoagulant/ proteolytic activities, with a key role played by the plasminogen regulatory system. Lymphocytes, Monocytes-Macrophages, and Dendritic Cells Lymphocytes, including helper and cytotoxic T cells, as well as monocytes-macrophages are often identified within damaged glomeruli.51 It has been postulated that the balance between proinflammatory Th1 and anti-inflammatory Th2 lymphocytes may be a key factor in the resolution or progression of glomerulosclerosis. The relevance of monocytes-macrophages to the initiation and progression of glomerulosclerosis has been supported by experiments in which depletion of these cells had a protective effect. The release by these cells of cytokines, growth factors, and procoagulant factors is likely to contribute to the pathogenesis of glomerulosclerosis. However, these cells may also contribute to the termination and resolution of the glomerular inflammatory response. Phenotypic and functional macrophage changes may determine the outcome of glomerular inflammation and sclerosis. Interstitial inflammation is a common precursor of tubu­ lointerstitial fibrosis. The severity of the interstitial inflammatory infiltrate correlates closely with the severity of renal dysfunction and predicts progressive CKD. Interstitial lymphocytes and monocytes have been implicated in the pathogenesis of renal fibrosis with variable degree of involvement. Limited evidence also implicates mast cells, but this area is more controversial.52 Dendritic cells, a subset of cells that play an essential role in immunopathology of the kidney and the crosstalk with other proinflammatory cells including T lymphocytes, also have a central role in the pathogenesis of kidney inflammation in different disease processes.53 In the interstitium, inflammatory infiltrates of B cells, T cells, and dendritic cells form nodular aggregates surrounded by neolymphatic vessels. Bone Marrow–Derived Cells Glomerular remodeling (repair-healing or scarring) may depend on the influx of hematopoietic stem cells with the potential for repair or scarring (reviewed in references 54 and 55). The detection of cells displaying embryonic mesenchymal characteristics in glomeruli has led to the hypothesis that hematopoietic stem cells may be involved in normal glomerular cell turnover as well as in the response of glomeruli to injury. Experiments based on bone marrow transplantation have demonstrated the potential involvement of bone marrow–derived cells in normal mesangium turnover and in glomerular repair-repopulation after experimental mesangial injury. It has also been postulated that bone marrow–derived mesenchymal stem cells may be involved in fibrogenesis by migrating into scarred kidneys and contributing to the pool of fibroblasts.

Extracellular Matrix Processing Loss of intrinsic renal cells and their transformation into fibroblastic phenotypes are likely to be key events in the pathogenesis of renal fibrosis.48 In addition to transformed tubular cells, there is growing evidence that other renal cells, including

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vascular endothelial and pericytic cells, have the capacity to transform into mesenchymal myofibroblasts, thus contributing to the renal fibroblastic pool. The other main source of renal fibroblasts is likely to be derived from quiescent renal fibroblasts activated by tubules and inflammatory cells through the release of a range of cytokines and growth factors. Finally, bone marrow– derived stem cells are also thought to participate in renal fibrogenesis.48 One of the most potent inducers of EMT and fibroblast activation is thought to be TGF-ß1. This growth factor is thought to be a key factor in wound healing and scarring. It acts through its type 1 and 2 receptors and activates a number of intracellular signal transduction pathways including STATs and Smads. Connective tissue growth factor is one of the TGFβ1 effectors that enhances TGF-β1 intracellular signaling pathways. Two growth factors, hepatocyte growth factor and bone morphogenic protein 7 (BMP-7), have so far been shown in vitro and in vivo to inhibit and even to reverse EMT and to counteract the fibrogenic influences of TGF-β1. Of interest, uterine sensitization–associated gene 1, the natural antagonist of BMP-7, is abundant in renal tissue and modulates many of the effects of BMP-7 on the kidney. Fibroblast activation, proliferation, migration, and synthesis of ECM constitute a major step in fibrogenesis and renal scarring. Deposited ECM undergoes quantitative and qualitative changes. For instance, within scarred glomeruli, interstitial type III collagen is deposited. Interstitial fibrosis is associated with excessive deposition of collagens I, III, and IV. The normal homeostasis of ECM turnover is likely to be compromised in the course of renal scarring through excessive synthesis, decreased breakdown, or resistance to breakdown. Renal ECM breakdown is regulated by a number of collagenolytic enzymes including the matrix metalloproteinases and the plasmin system. These are in turn regulated by a number of inhibitors, such as the tissue inhibitors of matrix metalloproteinases (TIMPs) and the plasminogen activator inhibitors. Decreased matrix metalloproteinase activities or increased TIMPs and plasminogen activator inhibitor 1 activity have been implicated in the deposition of ECM in CKD. Recent evidence points to another putative pathway to excessive deposition of ECM, namely, resistance to breakdown through structural modification and cross-link of deposited ECM by an enzyme called tissue transglutaminase. This enzyme is upregulated during the course of experimental and clinical nephropathies.56 Mice lacking this enzyme have reduced pro­ pensity to renal scarring. Synthetic inhibitors of this enzyme have been shown to considerably attenuate experimental renal fibrosis. A number of potential interventions affecting and modulating different pathways of renal fibrosis are under investigation with variable degrees of promise and success (Fig. 75.13).39

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