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Chronic kidney disease (CKD) encompasses a spectrum of pathophysiologic processes associated with abnormal kidney function, often with a progressive decline in glomerular filtration rate (GFR). The risk of worsening CKD is closely linked to both the GFR and the amount of albuminuria. Figure 311-1 provides a staging of CKD stratified by the estimates for further progressive decline of GFR based on these two parameters.

FIGURE 311-1

Kidney Disease Improving Global Outcome (KDIGO) classification of chronic kidney disease (CKD). Gradation of color from green to red corresponds to increasing risk and progression of CKD. GFR, glomerular filtration rate. (Reproduced with permission from KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl 3:5, 2013.)

The dispiriting term end-stage renal disease represents a stage of CKD where the accumulation of toxins, fluid, and electrolytes normally excreted by the kidneys leads to death unless the toxins are removed by renal replacement therapy, using dialysis or kidney transplantation. These interventions are discussed in Chaps. 312 and 313. End-stage renal disease will be supplanted in this chapter by the term stage 5 CKD.


The pathophysiology of CKD involves two broad mechanisms of damage: (1) specific initiating mechanisms particular to the underlying etiology (e.g., genetic abnormalities in kidney development, immune complex deposition, and inflammation in certain types of glomerulonephritis, or toxin exposure in certain diseases of the renal tubules and interstitium), and (2) nonspecific mechanisms involving hyperfiltration and hypertrophy of the remaining viable nephrons, which are common consequences of long-term reduction of renal mass, irrespective of underlying etiology. The responses to reduction in nephron number are mediated by vasoactive hormones, cytokines, and growth factors. Eventually, the short-term adaptations of hyperfiltration and hypertrophy to maintain GFR become maladaptive as the increased pressure and flow within the nephron predisposes to distortion of glomerular architecture, abnormal podocyte function, and disruption of the filtration barrier, leading to sclerosis and dropout of the remaining nephrons (Fig. 311-2). Increased intrarenal activity of the renin-angiotensin system (RAS) appears to contribute both to the initial compensatory hyperfiltration and to the subsequent maladaptive hypertrophy and sclerosis. This process explains why a reduction in renal mass from an isolated insult may lead to a progressive decline in renal function over many years and the efficacy of pharmacologic approaches that attenuate this response (Fig. 311-3).

FIGURE 311-2

Left: Schema of the normal glomerular architecture. Right: Secondary glomerular changes associated with a reduction in nephron number, including enlargement of capillary lumens and focal adhesions, which are thought to occur consequent to compensatory hyperfiltration and hypertrophy in the remaining nephrons. (From JR Ingelfinger: Is microanatomy destiny?. N Engl J Med 348:99, 2003. Copyright © 2003, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

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