The current CKD classification is based on eGFR (see Chapter 3). The Modification of Diet in Renal Disease (MDRD) study equation and the more recently developed Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation are both commonly used equations to calculate eGFR; however, both are relatively inaccurate in reflecting measured glomerular filtration rate (mGFR) above 60 ml/min/1.73 m². This underestimation by eGFR of true mGFR can lead to misclassification of a large number of individuals as having CKD stage 3a, whereas in reality their true GFR is above 60 ml/min. Also, the inaccuracy of eGFR to reflect mGFR above 60 ml/min/1.73 m² makes the distinction between CKD stages 1 and 2 difficult and artificial. The limitations of using creatinine-based estimations have spurred the search for alternative filtration biomarkers, such as β-trace protein (βTP), cystatin C, and β₂-microglobulin (β₂M). (See Chapter 3 for alternative estimations of GFR.)

Impact of Chronic Kidney Disease on Morbidity and Mortality

A decrease in eGFR below 60 ml/min/1.73 m² and increased albuminuria are associated with increased cardiovascular as well as overall morbidity and mortality, and the effects of combined decreased GFR and increased albuminuria on mortality are synergistic (see Chapter 82).¹⁴ However, decreased GFR and increased albuminuria are markers of ill health, thus generally reflecting poor outcomes. Also, albuminuria is increasingly defined by a raised uACR. Interpretation of the predictive value of albuminuria as albumin-creatinine ratio (ACR) is confounded by the inclusion of urine creatinine because a fall in urinary creatinine excretion that causes a rise in ACR, may also reflect ill health and the associated sarcopenia. Sarcopenia may also be associated with a low serum creatinine and an elevation of eGFR (>120 ml/min) that has been associated with poor outcomes.¹⁴

The fall in GFR with age has been linked to underlying comorbidities such as lifelong hypertension and diabetes. The term cardio-kidney-damage has been coined to highlight the close links between cardiovascular and kidney damage.¹⁵ It is therefore not surprising that CKD in the elderly predicts cardiovascular morbidity and mortality.

Nevertheless, when the predictive values of albuminuria and/or eGFR on morbidity and mortality have been compared with or when these values have been added to well-established cardiovascular prognostic markers and scores, such as the Framingham Risk Score (FRS), they were found to add very little to the accuracy of risk prediction.¹⁶

Causes and Natural History of Community Chronic Kidney Disease

In the developed world, the majority of community CKD is identified in older people. The average rate of decline of GFR in this population is approximately 0.75 to 1 ml/min/yr after the age of 40 to 50 years.³ CKD affects those who have had a lifelong exposure to cardiovascular risk factors—hypertension and diabetes—that can also affect the kidneys. U.S. Medicare data demonstrate that 48% of patients with CKD have diabetes, 91% are hypertensive, and 46% have atherosclerotic heart disease. Given that more than one third of aging adults have systolic hypertension and about 20% have type 2 diabetes mellitus (T2DM), it is not surprising that up to 40% of such individuals have evidence of CKD. They also have a higher incidence of cardiovascular and atherosclerotic diseases. This has led to the formulation of prediction scores of incident community-based CKD, based on the presence of vascular risk factors such as hypertension and diabetes as well as peripheral vascular disease and heart failure—the SCORED model (Screening for Occult Renal Disease).¹⁷

In a large analysis of community-based CKD over 5 years, only 1% and 20% of patients with CKD G3 and G4 required RRT, whereas 24% and 45%, respectively, died, predominantly from CVD.¹⁸ Thus death rather than progression to ESRD is the predominant outcome in elderly community-based CKD.¹⁸

Community CKD in emerging countries is often multifactorial because of communicable and noncommunicable disease affecting the kidneys. In these countries, in addition to the poverty that has an impact on CKD, individuals often develop infections that can cause CKD (see Chapters 53 to 58). They are also subject to increased globalization and westernization of lifestyle that predispose them to obesity, diabetes, hypertension, and CVD, which can lead to CKD. The renal risk is increased further by unfavorable environmental factors, including maternal deprivation and malnutrition, which relate to CKD in later life¹⁹; air and water pollution; exposure to heavy metals and agricultural pollution; and aristolochic acid (see Chapter 64) and other herbal toxins, in particular in China and Taiwan (see Chapter 78). Reports of epidemics of CKD have emanated from a number of regions of the world, including Central American countries such as Salvador, among agricultural workers in sugar cane and cotton plantations who are exposed to excessive heat resulting in chronic dehydration, hypokalemia, and premature death.²⁰ These effects may be compounded by exposure to pesticides and consumption of nonsteroidal anti-inflammatory drugs (NSAIDs).

Causes and Natural History of Referred Chronic Kidney Disease

In contrast to community CKD, the causes and natural history of referred CKD vary considerably. Patients with referred CKD often present at an earlier age because of an underlying hereditary nephropathy (such as autosomal dominant polycystic kidney disease [ADPKD]) or acquired nephropathy (such as glomerulonephritis [GN], diabetic nephropathy, or tubulointerstitial disease) causing progressive damage and loss of function. Some present early with signs of kidney damage such as moderate albuminuria or hematuria in the absence of impaired kidney function (CKD stages G1 and G2, A1 and A2). The prognosis of such patients in the absence of hypertension, overt proteinuria, and/or impaired renal function is generally good because they can remain within these stages for years without progressing to CKD stage G3 or higher. However, some go on to progress with time, thus justifying vigilance and regular follow-up.

The rate of progression of referred CKD 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/yr. Control of systemic hypertension, hyperglycemia, and other factors slows the rate of GFR decline (see Chapter 80). In nondiabetic nephropathies, the rate of progression of CKD is usually faster in patients with chronic proteinuric GN than in those with chronic interstitial nephritis and low-level proteinuria. It is slowest in those with hypertensive nephrosclerosis with good blood pressure (BP) control and minimal proteinuria. Patients with ADPKD and impaired renal function, CKD stage G3b and beyond, may also have a fast rate of progression compared with patients with other nephropathies.

It is generally assumed that the majority of patients with underlying nephropathies reaching CKD stages G3 to G5 progress relentlessly to ESRD, yet even in the referred population progression is variable, with a sizable percentage of patients either having stable kidney function or dying prematurely of CVD. A Canadian study showed the natural history of referred CKD stages G3 and G4 to be variable, reflecting the patient’s risk factor profile.^21,22 Even some patients with CKD stage G5 remain stable for a number of years.

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