40-100 mL/hr

acid and ^-hydroxybutyric acid are weak acids that readily dissociate at physiological pH, leading to a metabolic acidosis; note that U.T.'s plasma pH was at the perilously low level of 7.1. Finally, insulin stimulates protein synthesis and inhibits protein degradation. In the absence of insulin, the reverse takes place, leading to severe protein catabolism, wasting, aminoacidemia, and elevated blood urea nitrogen.

The clinical picture of diabetic ketoacidosis arises from the combination of three pathophysiological conditions resulting from these metabolic derangements: (1) impaired renal ability to elaborate a maximally concentrated urine in spite of a hypertonic plasma and markedly elevated plasma levels of ADH, (2) metabolic acidosis, and (3) markedly increased solute load that must be excreted. The end result is diuresis, volume depletion, electrolyte imbalances, and life-threatening acidosis. We will consider the renal disturbance first.

As discussed in Chapter 26, glucose is freely filtered at the glomerulus and is then reabsorbed by a Na-coupled, carrier-mediated process located in the proximal tubule. As with all carrier-mediated reabsorptive processes, glucose reabsorption is characterized by a tubular maximum (Tm). Normally, the filtered load (glomerular filtration rate [GFR] x plasma glucose concentration) is well below the Tm so that all filtered glucose is reabsorbed in the first few millimeters of the proximal tubule. If, as in the case of U.T., the plasma glucose concentration is 900 mg/dL (=9 mg/mL) and assuming that the initial GFR is 120 mL/min, then U.T.'s filtered load of glucose is 1080 mg/min (GFR x plasma glucose concentration). If her Tm for glucose reabsorption initially is the normal 375 mg/min, then 705 mg/min (1080 — 375 mg/min) is not reabsorbed and must be excreted in the urine. This amounts to about 1000 g/day, or about 2 lb/day.

Now, as discussed in Chapter 26, the presence of a nonreabsorbable solute in the ''leaky'' proximal tubule results in the retention of its osmotic equivalent of water and, in turn, a reduction in the fractional reabsorption of Na, urea, and water by the proximal tubule. Thus, more volume enters the descending limb of the loop of Henle and this, in turn (see Chapter 27), results in a washout of the hypertonic renal medulla normally established by the countercurrent mechanism. In short, because of the reduced fractional reabsorption in the proximal tubule, due to the presence of glucose that could not be reabsorbed, the ability of the kidney to elaborate a maximally hypertonic urine-that is, to maximally concentrate filtered solutes-is reduced, and the osmolarity of the final urine may approach isotonicity with the plasma.

It should be noted that U.T.'s plasma level of ADH was very high because the enormous concentration of glucose (50 mM) rendered her plasma hypertonic; thus, the wall of the distal nephron was maximally permeable to water. The submaximal final urine osmolarity is prima facia evidence of the washout of the countercurrent multiplier system.

Now, the molecular weight of glucose is 180. Thus, the rate of solute excretion due to glucose alone is about 4 mOsm/min (705 mg/min divided by 180 g/mol), or about 5750 mOsm/day. If the normal concentrating ability is 1200 mOsm/L, then this amount of glucose must be accompanied by 4.8 L/day of water; however, if, as for U.T. (see Table 1), concentrating ability is reduced to 500 mOsm/L, then the minimum urinary volume is 10 L/day. Thus, an enormous amount of urine is required just to rid the body of nonreabsorbed glucose, and, as we will soon see, this is just the beginning.

As noted previously and discussed in greater detail in Chapter 41, the excessive breakdown of adipose stores and metabolism of lipids result in the production by the liver of large amounts of acetoacetic acid and hydroxybutyric acid. Both dissociate at physiological pHs to yield the anions acetoacetate and ^-hydroxybu-tyrate, respectively, as well as H + , which results in a metabolic acidosis. The respiratory response to the decline in plasma pH, sensed largely by peripheral chemoreceptors (Chapters 20 and 31), is an increase in minute volume due to increased respiratory rate and tidal volume ("Kussmaul" breathing), leading to a decline in plasma PCO2 (see Table 1) and partial compensation for the decline in pH. But, the lungs cannot rid the body of excess H + . That task remains for the kidneys and is accomplished in the proximal tubule by acceleration of the apical membrane Na+-H + exchanger, leading to a complete reabsorption of filtered HCO^ and in the distal nephron by acceleration of the apical membrane H + pump. But, because neither of these carrier-mediated processes can, for energetic reasons, continue to extrude H+ from the cell when the luminal pH falls below 4 (approximately a 10,000-fold H+ gradient across the apical membranes), the urine must be buffered if it is to accommodate much H + . Thus, buffers are elaborated initially in the form of titratable buffers (i.e., H+ bound with other anions to form weak acids). The anions in this case are phosphate and sulfate derived from the breakdown of cell proteins and, most importantly, acetoacetate and ^-hydroxybutyrate. If the acidosis persists, NH3 derived from the deamination of glutamine will contribute to the buffering capacity of the urine in the form of a nontitratable buffer (see Chapter 31).

But, while titratable and nontitratable buffers serve to assist, vitally, in ridding the plasma of H + , they add to the renal solute load that must be excreted. Thus, in addition to glucose, we have these buffers and a greater than normal quantity of urea due to enhanced muscle breakdown. All in all, the obligatory solute load that must be excreted is huge while the renal concentrating ability has been compromised. This results in a diuresis that may exceed 12 L/day and, if unmatched by fluid replacement, can lead to hypovolemia, circulatory collapse, and death.

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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