Elaine M. Kaptein
Thyrotoxicosis, particularly severe thyrotoxicosis, is associated with multiple alterations in cardiovascular function, renal hemodynamics, and renal tubular reabsorptive function. Renal function is altered due to a combination of direct and indirect effects of thyroid hormone excess on the kidney (Fig. 33.1). The indirect effects include changes in cardiovascular hemodynamics and the renin–angiotensin–aldosterone system. Reversible alterations in sodium and water metabolism, calcium, phosphate, vitamin D, and uric acid homeostasis also occur.
FIGURE 33.1. Diagram of the cardiovascular and other changes affecting renal function in patients with thyrotoxicosis.
HEMODYNAMIC CHANGES
Thyrotoxicosis results in a hyperkinetic circulation with increased heart rate and cardiac output, decreased peripheral vascular resistance, and increased blood flow to most organs, including the kidneys (see Chapter 31) (1). The decrease in peripheral vascular resistance may be due to relaxation of vascular smooth muscle cells, increased β-adrenergic receptor activity, and an increase in effective blood volume (2) (Fig. 33.1).
Nitric oxide is an important factor in regulating vascular tone, renal sodium excretion, and the renal pressure diuresis-natriuresis response, and therefore arterial blood pressure (3). Nitric oxide synthase activity is increased in the left ventricle, aorta and vena cava, and renal cortex and medulla of thyrotoxic rats (3). In thyrotoxic humans, decreased vascular resistance is largely due to increased endothelial production of nitric oxide and increased vascular sensitivity to acetylcholine, the endothelial-dependent vasodilator (4). Furthermore, the vasoconstrictor response to norepinephrine is increased, whereas plasma catecholamine concentrations are low (see Chapter 38) (4). These vascular abnormalities are corrected by correction of thyrotoxicosis (4). In addition, serum concentrations of the endothelial vasodilatory hormone adrenomedullin are high in patients with thyrotoxicosis (2). Thus, an increase in basal endothelial cell function and endothelial hyperresponsiveness to vasodilating stimuli provide an explanation for the decrease in peripheral vascular resistance and maintenance of a hyperkinetic state in patients with thyrotoxicosis (4). Activation of the renin–angiotensin–aldosterone system may play a causative role in development of cardiac hypertrophy in thyrotoxicosis (5,6).
HYPERTENSION
Systolic hypertension occurs in up to one third of patients with thyrotoxicosis (7). In one study, the mean systolic blood pressure was 10 mm Hg higher and diastolic blood pressure was 5 mm Hg lower during thyrotoxicosis than after euthyroidism was attained (1). Systolic blood pressure correlated with cardiac output, whereas diastolic blood pressure was related to systemic vascular resistance (1).
Thyrotoxicosis increases nitric oxide synthase activity, which as noted above regulates vascular tone, renal sodium excretion, and blood pressure (6). Thyrotoxicosis also results in activation of the renin–angiotensin system, the effects of which are blocked by angiotensin-converting enzyme inhibitors (6). In normal subjects, there is a functional balance between angiotensin II and nitric oxide production. In thyrotoxic rats, thyroxine (T4) administration increased blood pressure and plasma concentrations of angiotensin II and nitrates/nitrites (6). Simultaneous administration of T4 and subpressor doses of an inhibitor of nitric oxide synthesis caused a marked increase in blood pressure, which was attenuated by losartan, an angiotensin receptor–blocking drug (6). Plasma angiotensin II and nitric oxide concentrations were increased by T4, whereas both were reduced in the rats given T4 and the nitric oxide inhibitor (6). Impaired synthesis of nitric oxide results in increased sensitivity to the pressor effect of T4, and the latter is attenuated by losartan. Thus, increased nitric oxide synthase activity may play a protective homeostatic role in ameliorating the prohypertensive effects of T4 in thyrotoxicosis, as well as antagonizing the pressor actions of angiotensin II (6).
RENAL GLOMERULAR AND TUBULAR FUNCTION
In humans with thyrotoxicosis and animals treated with excess T4, renal plasma flow and glomerular filtration rate are increased, probably because of the increase in cardiac output and decrease in peripheral resistance (8,9). Intrarenal vasodilatation also occurs (8). The renal content of the endogenous vasoconstrictor substance endothelin is lower in thyrotoxic rats, which may contribute to renal vasodilatation (10).
The glomerular filtration rate, as measured by inulin clearance, and renal blood flow, as measured by paraaminohippurate clearance, are increased by 12% to 20% in patients with thyrotoxicosis and normalize during antithyroid treatment (9,11) (Fig. 33.1). Serum creatinine concentrations tend to be low in patients with thyrotoxicosis and increase during antithyroid treatment (11). Normal subjects given large doses of thyroid hormone have a decrease in serum creatinine concentrations before substantial muscle wasting occurs. Mean 24-hour urine creatinine excretion is significantly lower in patients with thyrotoxicosis due to loss of muscle mass, and it occurs despite an increase in the renal tubular secretion of creatinine (12,13,14).
Thyrotoxicosis induces both hypertrophy and hyperplasia of renal tubular epithelial cells. The increases are proportional to the increases in glomerular filtration rate and renal plasma flow. Intrarenal renin and angiotensin production are increased, as a result of increased renal renin messenger RNA expression, which leads to an increase in plasma renin activity and plasma angiotensin II concentrations and renal hypertrophy (15). The renal hypertrophy can be prevented by the angiotensin II antagonist losartan, indicating that it is dependent on intrarenal renin–angiotensin activation (15). Thyroid hormone also stimulates renal production of epidermal growth factor and renal growth in young animals (16), independent of protein intake and pituitary activity (8).
The functional and morphologic changes in renal tubules that occur in thyrotoxicosis are accompanied by an increase in renal tubular capacity for active transport. For example, transepithelial voltage and Na+,K+-adenosine triphosphatase (ATPase) activity are increased, with consequent increases in sodium transport. T4 also stimulates sodium-dependent phosphate transport in cultured renal tubular cells (17), without changing sodium-dependent transport of sulfate, glucose, or proline (18,19). In thyrotoxic rats, proximal tubular sodium-proton exchange is increased (19); in particular, the predominant isoform (NHE3) of the exchanger in proximal tubules is increased (20). These changes are not associated with clinically important increases in reabsorption of phosphate or bicarbonate.
WATER AND ELECTROLYTE METABOLISM
Patients with thyrotoxicosis rarely have discernible abnormalities in water metabolism. Serum electrolyte concentrations are usually normal. Occasional patients have polydipsia and polyuria, with 24-hour urine volumes as high as 3 or 4 L (21), associated at times with slightly hypotonic plasma. Some thyrotoxic patients have mild impairment in urinary concentrating ability (22), but this is not clinically important (23), and release of vasopressin in response to osmotic stimuli is normal (24). The polyuria is due to increased thirst, an explanation supported by observations in thyrotoxic animals (25,26). In patients with thyrotoxicosis, the sensation of thirst is initiated at a lower serum osmolality than when they are euthyroid (24). This increase in thirst may be secondary to the thirst-stimulating effect of high plasma angiotensin II concentrations (27). The increased thirst (polydipsia) and polyuria revert to normal after treatment of thyrotoxicosis.
Patients with thyrotoxicosis have high plasma renin activity and serum atrial natriuretic peptide concentrations (2,28,29,30). A higher cardiac preload in thyrotoxicosis may initiate secretion of atrial natriuretic peptide (2). The increase in plasma renin activity and serum atrial natriuretic peptide concentrations may also be due to a direct effect of T4 on gene expression (2). The high serum atrial natriuretic peptide concentrations may contribute to the decrease in peripheral vascular resistance in thyrotoxicosis (2).
Thyrotoxic patients have normal or low serum aldosterone concentrations, particularly in relation to their plasma renin activity (2,30). Urinary excretion of sodium and potassium is normal when patients consume usual amounts of those ions. Whereas total body exchangeable potassium is decreased in thyrotoxicosis, as a result of a decrease in total muscle mass (31), total exchangeable sodium is often increased. Thyrotoxicosis in rats reduces sodium retention (6), which may be caused by increased renal perfusion and perhaps high serum atrial natriuretic peptide concentrations.
EDEMA
Thyrotoxic patients may have pitting edema involving the ankles, legs, and sacrum (32). Periorbital edema is usually a manifestation of Graves' ophthalmopathy rather than of thyrotoxicosis. Edema in thyrotoxic patients results from renal salt and water retention in response to a reduction in effective arterial volume, and the sodium retention contributes to an increase in blood volume and venous pressure. The edema that develops under these circumstances does not imply the presence of congestive heart failure. In support of this concept, exercise testing in thyrotoxic patients with edema usually results in a substantial increase in cardiac output with little or no increase in right atrial or pulmonary artery pressure. If the additional circulatory load imposed by high cardiac output overwhelms myocardial reserve, or if myocardial function is impaired by organic heart disease or by the thyrotoxicosis itself, congestive failure ensues (see Chapter 31). Severe thyrotoxicosis also may be associated with protein-calorie malnutrition and hypoalbuminemia, an additional cause of plasma volume expansion and edema.
MINERAL METABOLISM
Thyrotoxicosis causes increased bone resorption, as evidenced by low bone density and an increase in markers of bone resorption, such as urinary excretion of hydroxyproline, pyridinoline and deoxypyridinoline cross-links, and N-telopeptide of type I collagen (33). There is a compensatory increase in bone formation, as evidenced by increased serum osteocalcin and bone-specific alkaline phosphatase concentrations (see Chapter 40) (33). The increase in bone resorption is greater than that of bone formation (33); the result is osteopenia, and in some patients osteoporosis. These changes in mineral metabolism result in an increase in serum calcium concentrations and occasionally in hypercalcemia. The increase in serum calcium concentrations inhibits parathyroid hormone secretion, resulting in hypercalciuria and decreased renal 1α-hydroxylation of 25-hydroxyvitamin D, and therefore decreased intestinal calcium absorption. Occasional patients have renal calculi, nephrocalcinosis, and reversible renal insufficiency (34).
All these changes, including osteoporosis, are reversible with treatment of thyrotoxicosis.
Thyrotoxicosis may result in magnesium deficiency, with decreased serum total and ionized magnesium concentrations, due to renal magnesium wasting (33). Low serum magnesium concentrations may contribute to the low serum parathyroid hormone concentrations in thyrotoxicosis.
URIC ACID METABOLISM
Patients with long-standing thyrotoxicosis may have high serum uric acid concentrations (11,35). In one study, 28% of patients with toxic nodular goiter and 39% of those with thyrotoxicosis caused by Graves' disease had hyperuricemia, as compared with 2% to 10% of normal subjects (11). Renal clearance of uric acid was increased in proportion to the increase in glomerular filtration rate, and therefore the fractional excretion of uric acid was normal (11). The occurrence of high serum uric acid concentrations in the presence of increased urinary clearance of uric acid indicates that production of uric acid is increased more than is renal uric acid clearance (11). The increase in uric acid production is most likely due to increased purine turnover. There are no reports of an increase in gout in thyrotoxic patients.
THYROTOXIC PERIODIC PARALYSIS
Thyrotoxic periodic paralysis is characterized by localized or generalized attacks of muscle weakness, even flaccid paralysis, that last for a few hours to several days. Most patients are men, with the male to female ratio being 20:1; Asian men are particularly susceptible to the disorder, but it has been described in many ethnic/racial groups (36,37,38,39). The episodes of muscle weakness are associated with a decrease in serum potassium concentrations, although the concentration is not always subnormal (40), and may be accompanied by hypophosphatemia and hypomagnesemia (41). Hypophosphatemia may be caused by cellular uptake of phosphate in conjunction with the cellular uptake of potassium. Total body potassium content is normal; the hypokalemia results from the shift of potassium into cells, and is associated with low urinary potassium excretion and a low transtubular potassium concentration gradient (41,42).
Thyrotoxicosis increases Na+, K+-ATPase activity in kidney, liver, and other tissues, and the activity of the enzyme increases in response to adrenergic stimulation (43,44,45). An increase in activity of this enzyme could explain the shift in potassium, but its periodic activation is unexplained. Na+,K+-ATPase-independent activation of potassium uptake may be more important (46). The epidemiology, clinical manifestations, and treatment of this unusual manifestation of thyrotoxicosis are discussed in more detail in Chapter 41.
RENAL TUBULAR ACIDOSIS
Occasional patients with thyrotoxicosis have renal tubular acidosis, which has been characterized as distal because there is failure to achieve maximal urinary acidification. Renal bicarbonate wasting (proximal renal tubular acidosis) has not been described; in fact, expression of the proximal tubular sodium proton exchanger is increased in patients with thyrotoxicosis (20,47). Hypokalemia, a common feature of distal renal tubular acidosis, may exacerbate a tendency to periodic paralysis. Renal tubular acidosis rarely results from hypercalcemia and hypercalciuria, which can cause nephrocalcinosis, tubular damage, and impairment of urinary acidification (34,48). Renal tubular acidosis also may occur in association with thyrotoxicosis caused by Graves' disease in the absence of nephrocalcinosis, and may persist after resolution of the thyrotoxicosis (49). The renal tubular acidosis in these patients may have an autoimmune basis; antibodies to renal tubular cells were demonstrated in the serum of one patient with Graves' thyrotoxicosis and renal tubular acidosis (50). Urine pH, serum bicarbonate concentrations, and urine calcium excretion should be measured in the occasional thyrotoxic patient who has nephrolithiasis (49). Some patients with autoimmune thyroid disease and renal tubular acidosis also have Sj□gren's syndrome, and this syndrome by itself may be associated with renal tubular acidosis (51).
PROTEINURIA AND IMMUNE COMPLEX GLOMERULONEPHRITIS
Some patients with autoimmune thyroid disease (Graves' disease or chronic autoimmune thyroiditis) have proteinuria, which is usually mild; it was found in 36% of patients in one study, most of whom were euthyroid (52,53) (Fig. 33.1). Administration of T4 induces proteinuria in rats, which is unaffected by partial blockade of nitric oxide synthase or losartan. Thus, proteinuria may be the result of a direct effect of T4 excess on glomerular permeability (6). Minimal change nephropathy has been reported in patients with autoimmune thyroid disease, including one patient who had multiple simultaneous relapses of Graves' thyrotoxicosis and the nephrotic syndrome (53,54).
Immune complex glomerulonephritis has been described in a few patients with thyrotoxicosis, with immune complexes containing thyroglobulin and antithyroglobulin antibodies implicated as a cause of the renal disease (55,56,57). The most common renal lesion was membranous glomerulonephritis, although proliferative changes also have been described (55,56,57,58). Similar patterns of immune complex deposition have been reported in patients with chronic autoimmune thyroiditis and hypothyroidism (59). The relative rarity of this entity contrasts with the frequency of circulating immune complexes in thyroid disease, estimated to be as high as 17% in thyrotoxicosis and higher in chronic autoimmune thyroiditis (60).
Proteinuria and even the nephrotic syndrome have been reported in rare patients with Graves' thyrotoxicosis after treatment with radioiodine (52,61). Biopsy findings have included membranous nephropathy, and immunofluorescence microscopy in several patients revealed thyroglobulin and thyroid peroxidase in the glomerular basement membrane and the mesangium (61). These changes could occur as a result of autoimmunization caused by radiation-induced release of thyroid antigens, but more likely are simply related to the autoimmune thyroid disease.
RENAL COMPLICATIONS OF ANTITHYROID DRUG THERAPY
Renal complications of antithyroid drug therapy are rare. Proteinuria has been reported in patients taking propylthiouracil or, rarely, methimazole, usually in patients with a drug-induced vasculitis (62,63,64) or lupuslike reaction (65). The full syndrome of lupus erythematosus with diffuse proliferative lupus nephritis was reported in one patient treated with propylthiouracil (66). Antineutrophil cytoplasmic antibody (ANCA)–positive vasculitis is an uncommon but well-recognized complication of therapy with propylthiouracil (see Chapter 45). Both C-ANCA (cytoplasmic) and P-ANCA (perinuclear) related disease has been described. Nephritis with or without systemic involvement is present in about two thirds of ANCA-positive patients (67,68,69,70). The duration of propylthiouracil therapy in these patients before onset of nephritis varied from weeks to years, more often the latter. Cessation of therapy may result in remission of the renal disease, but because of persistent renal disease, some patients have been treated with a glucocorticoid or cyclophosphamide, and a few patients have had permanent renal disease (70).
Two patients with thyrotoxicosis who developed severe allergic interstitial nephritis causing acute renal failure soon after initiation of propylthiouracil therapy have been reported. Both patients had a generalized rash, eosinophilia, and fever; both required hemodialysis and improved with glucocorticoid therapy (71,72). Another patient with amiodarone-induced thyrotoxicosis developed acute renal failure due to acute interstitial nephritis and fatal Stevens-Johnson syndrome while receiving propylthiouracil (73).
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