Pathophysiology

2. Pathophysiology

Most of the nephrons of the diseased kidney fall into one of two categories. They are either non-functioning nephrons, as a result of destruction of any portion of their structures, or they are intact nephrons that function normally. Changes in renal function occur as a result of a reduction in the number of functioning nephrons. As the number of functioning nephrons diminishes, there are adaptations that occur in a regular sequence. When nephrons are damaged and essentially rendered non functional, the remaining "healthy" nephrons increase their size and their work load to compensate for nephron loss. This is referred to as the hyperfiltration theory (Figure 3). Nephron hypertrophy and hyperfiltration is an adaptative mechanism to compensate for reduced nephron number.

Figure 3. Central role of glomerular hypertension in the initiation and progression of nephron injury.

Nevertheless the chronic increase in glomerular capillary pressure and/or glomerular plasma flow rate damages the endothelium, mesangium and epithelium. Mesangial matrix production, glomerular deposition of circulating lipid, and capillary thrombosis promote structural injury to the glomerulus. Tubulointerstitial damage, increased tubular ammoniagenesis, and soft tissue mineralization contribute to nephron injury and ultimately lead to nephron sclerosis. Continued nephron destruction initiates further compensation, promoting a self-perpetuating cycle of adaptation and injuries (Figure 4).

Figure 4. Illustration of the relationship between renal injury, loss of nephrons, renal compensatory adaptations, and the ultimate progression.

The progression of CRF has been described as occurring in four stages that are not sharply demarcated but rather, are phases in a continuing degenerative process with loss of more and more functioning nephrons (Table 2).

Given the large reserve capacity of the kidney at least 60 - 70% of normal renal function must be lost before azotemia increases, although there may be some nephron hypertrophy during the first phase of decreased renal reserve. At this stage, the patient does not have any clinical symptoms although decreased urine concentrating ability may be noted. In renal insufficiency, up to 75% of the nephrons may be lost. There is mild azotemia, loss of urine concentrating ability and the patient becomes more susceptible to the effects of stresses such as large changes in fluid intake, protein and electrolytes. The patient may remain symptom-free if no overwhelming metabolic stress occurs.

In renal failure nephron loss may reach 90%. There is moderate to severe azotemia, anemia, decreased urine concentration ability and impaired ability to maintain electrolyte and acid base balance.

The pathogenesis of the uremic syndrome is complex and not fully understood. Many toxins are involved and no single compound is likely to explain the diversity of the uremic symptoms. Nitrogenous waste products of protein digestion and catabolism (e.g. urea, creatinine, ammonia, middle molecules, guanidine and its derivatives) accumulate when renal function is reduced and some of them contribute to many of the clinical consequences of uremic intoxication associate with chronic renal failure (Table 3).