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Many years ago Claude Bernard (1878) introduced the concepts of milieu extérieur (the environment where an organism lives) and a milieu intérieur (the environment in which the tissues of that organism live). He argued that the milieu intérieur varied very little and that there were vital mechanisms that functioned to maintain this internal environment constant. Walter B. Cannon later extended these concepts by recognizing that the constancy of the internal state, which he termed the homeostatic state, was evidence of physiologic mechanisms that act to maintain this minimal variability. In higher animals, the plasma is maintained remarkably constant in composition both within an individual and among individuals. The kidney plays a vital role in this constancy. The kidney changes the composition of the urine to maintain electrolyte and acid-base balance and can produce hormones that can maintain constancy of blood hemoglobin and mineral metabolism. When the kidney is injured, the remaining functional mass responds and attempts to continue to maintain the milieu intérieur. It is remarkable how well the residual nephrons can perform in this task so that in many cases homeostasis is maintained until the glomerular filtration rate (GFR) drops to very low levels. At this point, the functional tissue can no longer compensate. In this chapter, we will discuss a number of these compensatory adaptations that the kidney makes in response to injury in an attempt to protect itself and protect the milieu intérieur. A theme that permeates, however, is that these adaptive processes can often be maladaptive and contribute to enhanced renal dysfunction, facilitating a positive feedback process that is inherently unstable.


Renal disease is associated with a reduction in functional nephrons. The rest of the kidney adapts to this reduction by increasing blood flow to and the size of the remaining glomeruli and increasing size and function of the remaining tubules. Robert Platt, in 1936, argued that “…a high glomerular pressure, together with loss of nephrons (destroyed by disease) [is] an explanation of the peculiarities of renal function in this stage of kidney disease.” The raised glomerular pressure will increase the amount of filtrate produced by each nephron and thus compensate for a time for the destruction of part of the kidney. But eventually there are too few nephrons remaining to produce an adequate filtrate, even though they may work under the highest possible pressure, associated with a high systemic blood pressure. The responses to kidney injury can be both adaptive and maladaptive, and in many cases, the early adaptive responses can become maladaptive over time, leading to progressive decline in the anatomic and functional integrity of the kidney. As described previously, the early responses are likely in many cases motivated by attempts to maintain the constancy of the milieu intérieur for the survival of the organism (Claude Bernard).

Barry Brenner in the 1960s and 1970s ...

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