Clinical Note

Proteinuria Due to Other Small Proteins

Other than the low concentrations of the hormones noted earlier, plasma normally contains no significant amounts of low molecular weight peptides or proteins. However, some disease states are associated with the production or release of small peptides into the plasma. These include (1) multiple myeloma, in which large concentrations of the light chains of immunoglo-bulins appear in the plasma; (2) hemoglobinemia, in which hemoglobin is released from red blood cells due to hemolysis, as in a transfusion reaction; and, (3) myoglobinemia, in which the myoglobin normally present in muscle cells is released, as occurs in trauma and in the presence of toxins including chemotherapeutic agents.

The presence of significant concentrations of any of these peptides in the plasma results in a filtered load that far exceeds the protein reab-sorptive capacity of the proximal tubules. Consequently, these proteins appear in the urine, but because they become concentrated as fluid is reabsorbed along the tubules, they may precipitate and occlude the lumens of the nephrons. Protein precipitates can be seen as cylindrical casts when the urinary sediment is examined under the microscope. Also, as these proteins are reabsorbed in proximal tubule cells, they are degraded to smaller peptides and amino acids. For reasons that are not completely understood, the by-products of this degradation can be toxic to proximal tubule cells, especially in the case of certain light chains. Both the toxicity and the occlusion of nephrons by these small proteins can lead to acute renal failure as the number of functioning nephrons is reduced.

would be excreted per day. The kidney conserves this filtered protein by reabsorption so that the usual renal loss is less than 100 mg of albumin per day. This process is also Tm-limited. If the plasma albumin concentration increases above 6-7 g/dL, the rate of albumin excretion increases markedly and in proportion to the plasma concentration. Thus, the renal plasma albumin threshold is 6-7 g/dL, and the Tm is on the order of 30-40 mg/min. When the glomerular barrier is altered by disease so that more protein is filtered, massive amounts can appear in the urine, as seen in the nephrotic syndrome.

The kidney also reabsorbs the small amounts of low molecular weight peptides that are normally present in the plasma. These include hormones such as insulin, parathyroid hormone (PTH), glucagon, cal-citonin, vasopressin, and angiotensin. The peptides are taken up by specific transporters located in the brush border membrane and are degraded to amino acids within the cell. Renal metabolism of the filtered hormones is one of the primary routes of their normal turnover.

Phosphate and Sulfate

Both phosphate and sulfate anions are reabsorbed in the proximal tubule by cotransport with Na+, and their

FIGURE 14 Regulation of phosphate reabsorption in the proximal tubule. The ratio of the phosphate concentration in the tubular fluid compared with plasma (TF/P) is plotted as a function of the percent of the proximal tubule length. Under normal conditions, somewhat more than 70% of the filtered phosphate is actively reabsorbed along the proximal tubule by a Tm-limited mechanism. Consequently, the tubular fluid phosphate concentration falls below that in the plasma along the length of the proximal tubule. After acute parathyroidect-omy (lower line), an even greater fraction of the filtered phosphate is reabsorbed. Ingestion or infusion of large amounts of phosphate causes a decrease in phosphate reabsorption in the proximal tubule, with a corresponding rise in its luminal concentration.

FIGURE 14 Regulation of phosphate reabsorption in the proximal tubule. The ratio of the phosphate concentration in the tubular fluid compared with plasma (TF/P) is plotted as a function of the percent of the proximal tubule length. Under normal conditions, somewhat more than 70% of the filtered phosphate is actively reabsorbed along the proximal tubule by a Tm-limited mechanism. Consequently, the tubular fluid phosphate concentration falls below that in the plasma along the length of the proximal tubule. After acute parathyroidect-omy (lower line), an even greater fraction of the filtered phosphate is reabsorbed. Ingestion or infusion of large amounts of phosphate causes a decrease in phosphate reabsorption in the proximal tubule, with a corresponding rise in its luminal concentration.

reabsorption demonstrates the same Tm-limited transport as observed for the organic solutes. The reabsorption of phosphate is of particular interest because of its importance in maintaining a normal plasma phosphate concentration and, thus, a normal calcium-phosphate solubility product in the plasma. Furthermore, the plasma phosphate concentration (2-3 mmol/L) normally exceeds its renal plasma threshold, so that it is excreted continuously in the urine where it is normally the most important buffer anion. In fact, because the filtered load of phosphate is poised near the Tm, the excretion of phosphate rises in almost direct proportion to its plasma concentration. If the plasma phosphate concentration rises above normal levels, excretion increases, tending to reduce the excess. If the plasma phosphate concentration is too low, less is excreted. However, the Tm for phosphate can also be regulated physiologically. PTH (see Chapter 43) regulates phosphate reabsorption as shown in Fig. 14. Normally phosphate excretion is determined primarily by filtration, but high or low levels of PTH can alter this markedly. PTH has a phosphaturic action and reduces the Tm. In the patient with renal failure on hemodialysis, the management of plasma phosphate and calcium becomes one of the most difficult problems. Such a patient usually has a high plasma phosphate level that results in secondary hyperparathyroidism and osteodystrophy.

Sulfate is also reabsorbed by a Tm-limited mechanism. The usual plasma concentration of sulfate, 2-3 mmol/L, exceeds the renal plasma threshold so that sulfate appears in the urine. As in the case of phosphate, the filtered load is above or near the Tm so that the rate of sulfate excretion is proportional to its plasma concentration, and renal excretion serves as the main regulator of the plasma concentration. However, in contrast to phosphate, no known hormone regulates sulfate excretion.

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