Endocrine dysfunction in the nephrotic syndrome

INTRODUCTION — The nephrotic syndrome is characterized by a marked increase in the glomerular permeability to macromolecules. The associated urinary losses of albumin and hormone-binding proteins are responsible for many of the metabolic derangements and endocrine abnormalities in these patients [1].

This topic review will emphasize the alterations in thyroid, vitamin D, calcium, and glucocorticoid metabolism. The effects on lipid metabolism are discussed elsewhere. (See "Lipid abnormalities in nephrotic syndrome".)

THYROID FUNCTION

Alterations in thyroid function — In patients with the nephrotic syndrome, thyroid function tests reveal variable results, primarily depending upon the level of protein losses in the urine. In addition, other factors that are frequently present in such patients, such as hypoalbuminemia, increased serum free fatty acid concentrations, and glucocorticoid and furosemide administration, can also affect thyroid function tests [1,2]. (See "Laboratory assessment of thyroid function".)

●Approximately 50 percent of nephrotic patients with relatively normal kidney function have low total thyroxine (T4) concentrations resulting from urinary losses of T4-binding globulin (TBG) and other thyroid hormone-binding proteins (transthyretin and albumin) and the T4 bound to them [3-5]. Serum triiodothyronine (T3) concentrations may also be low due to decreased binding. There is often a good correlation between the serum T4 and T3 and the serum albumin concentration [5]. Serum reverse T3 (rT3) concentrations are also low.

●When impaired kidney function complicates the nephrotic syndrome, the thyroid function test abnormalities are often more severe than when either kidney failure or the nephrotic syndrome is present alone [6]. However, most patients remain clinically euthyroid. (See "Thyroid function in chronic kidney disease" and "Thyroid function in nonthyroidal illness".)

●Glucocorticoids, which are often given to treat the nephrotic syndrome, can cause a small reduction in thyroid-stimulating hormone (TSH) secretion and inhibit the peripheral conversion of T4 to T3. The net effect may be persistently low serum T3 and basal serum TSH concentrations and a rise in serum rT3 concentrations [7]. Thus, the serum free T4 concentrations may be the best marker of thyroid status in patients receiving glucocorticoids, and such patients with low serum free T4 concentrations probably should be treated as if they were hypothyroid [8]. (See 'Assessment of thyroid function' below.)

In earlier studies, nephrotic patients were usually clinically euthyroid, as evidenced by normal free T3, T4, and TSH levels [5]. However, subsequent reports suggest that thyroid dysfunction may be more common among such patients than previously thought. In a study from China of 317 patients with the nephrotic syndrome, 82 percent had an abnormality on thyroid function testing; of these, 32 percent had hypothyroidism (low free T4 and T3, high TSH levels), 24 percent had subclinical hypothyroidism (normal free T4 and T3, high TSH levels), and 37 percent had euthyroid sick syndrome (low free T3, T4, or both T3 and T4 levels with low, normal, or slightly elevated TSH) [2]. Patients with thyroid dysfunction had higher urine protein levels and dyslipidemia, higher serum creatinine levels, and lower platelet counts.

Some causes of the nephrotic syndrome are associated with autoimmune thyroid disease. Membranous nephropathy, for example, has been associated with both autoimmune thyroiditis (Hashimoto's disease) [9] and Graves' disease [10]. Antithyroid antibodies have been reported in the glomerular immune deposits in Graves' disease [11], and, in this particular case, thyroidectomy was associated with disappearance of antithyroid antibodies, reduction of proteinuria (but not complete remission), and stabilization of glomerular filtration rate. Conversely, treatment of patients with Graves' disease with radioactive iodine has been associated with the appearance of membranous nephropathy and proliferative glomerulonephritis [12,13]. The mechanisms linking diseases of the kidney and thyroid are not clear.

Severe hypothyroidism may be associated with kidney function impairment and proteinuria, which reverse after treatment with thyroid hormone replacement [14,15].

Assessment of thyroid function — There are no specific guidelines on screening thyroid function in patients with the nephrotic syndrome. In patients with the nephrotic syndrome who do not have preexisting thyroid disease, some clinicians routinely test thyroid function by obtaining a serum TSH level when the nephrotic syndrome is first diagnosed and then perform serial testing (at least annually) in patients who remain nephrotic. However, other clinicians do not routinely test thyroid function in all patients with the nephrotic syndrome and reserve testing only for those who have preexisting thyroid disease. If hypothyroidism is suspected clinically in any patient, serum TSH should be measured. (See "Laboratory assessment of thyroid function", section on 'Evaluating for thyroid dysfunction' and "Diagnosis of and screening for hypothyroidism in nonpregnant adults", section on 'Clinical features'.)

Patients with preexisting hypothyroidism may experience higher thyroid hormone replacement requirements due to loss of thyroid binding globulin in the urine [16,17]. Such patients should have serum TSH levels tested every six to eight weeks until therapeutic and every six months thereafter. If levels of proteinuria change (eg, with remission of the nephrotic syndrome or with disease relapse), TSH levels should be repeatedly tested as above until stable.

In view of the possibility of suppressed TSH levels in patients on high doses of glucocorticoids, testing both TSH and free T4 is suggested in hypothyroid patients on thyroid hormone replacement to assess adequacy of replacement while on glucocorticoids. Similarly, both TSH and free T4 levels should be monitored in patients with preexisting hyperthyroidism who are receiving high doses of glucocorticoids to assess hormonal status. (See 'Alterations in thyroid function' above.)

Management — In general, nephrotic patients with abnormal thyroid function tests do not require thyroid hormone replacement unless they have overt hypothyroidism (ie, high TSH level and low free T4 level) [5]. In patients who have preexisting hypothyroidism, the development of nephrotic syndrome may be associated with increased thyroid hormone requirements. In one case report of a patient who developed clinical hypothyroidism due to refractory nephrotic syndrome, resolution of proteinuria following bilateral nephrectomy led to normalization of thyroid function and cessation of thyroid hormone replacement [18].

In addition, patients receiving glucocorticoid therapy who have low serum free T4 concentrations probably should be treated as if they were hypothyroid [8]. Interestingly, in a study of 73 nephrotic children with thyroid function abnormalities treated with glucocorticoids, treatment with thyroid replacement was associated with shorter time to remission and higher serum albumin than no thyroid replacement [19].

A detailed discussion on the treatment of hypothyroidism in adults and children is presented elsewhere. (See "Treatment of primary hypothyroidism in adults", section on 'Approach to treatment' and "Acquired hypothyroidism in childhood and adolescence", section on 'Treatment and prognosis'.)

VITAMIN D AND CALCIUM METABOLISM

Effects on vitamin D and calcium — The nephrotic syndrome is associated with urinary loss of vitamin-D-binding protein (VDBP), due to increased permeability of the slit diaphragm in patients with the nephrotic syndrome [20]. In serum, calcidiol (25-hydroxyvitamin D), the precursor of the most active metabolite calcitriol, is primarily bound to VDBP and is therefore also excreted in the urine [21,22] (see "Overview of vitamin D", section on 'Metabolism'). The net effect is a reduction in serum calcidiol concentrations, while those of calcitriol are normal or reduced [21,23,24]. However, the physiologically important serum free or bioavailable calcidiol concentration is usually normal, suggesting that reduced total concentrations are due to loss of hormone bound to VDBP [24,25].

The physiologic consequences of these changes in vitamin D metabolism on calcium homeostasis are uncertain. Hypocalcemia is a common finding in the nephrotic syndrome due primarily to hypoalbuminemia-induced reduction in calcium binding to albumin. In general, the serum total calcium concentration will fall approximately 0.8 mg/dL (0.2 mmol/L) for every 1 g/dL (10 g/L) reduction in serum albumin concentration. A low serum total calcium concentration induced by hypoalbuminemia does not affect the physiologically important free (or ionized) calcium concentration. Thus, measurement of the ionized calcium concentration is generally required to confirm hypocalcemia in nephrotic patients with a low total serum calcium.

Alternatively, the measured serum calcium (Ca) concentration can be corrected for the presence of hypoalbuminemia from the following equation:

where the serum calcium and albumin (alb) concentrations are measured in units of mg/dL and g/dL, respectively. Thus, if the measured values are 7.6 mg/dL and 2.5 g/dL:

A subset of patients has been reported with hypocalcemia out of proportion to hypoalbuminemia due to low serum calcitriol concentrations. These patients have a decline in ionized calcium concentrations [26,27] and a secondary elevation in serum parathyroid hormone (PTH) concentrations [28]. The hyperparathyroidism can then lead to bone disease characterized by mixed osteomalacia and osteitis fibrosa [24]. A review of the histologic changes that may be seen can be found elsewhere. (See "Evaluation of renal osteodystrophy".)

The frequency with which true hypocalcemia and bone disease occur in the nephrotic syndrome is unclear as many investigators have found relatively normal calcium and bone metabolism. One report, for example, evaluated six adults with the nephrotic syndrome and normal kidney function [29]. Although serum calcidiol concentrations were reduced, the serum ionized calcium, calcitriol, and PTH concentrations were normal, and there was no histologic evidence of bone disease. Other investigators have also noted normal intestinal calcium absorption and bone histology [30,31].

In summary, only a subset of patients with the nephrotic syndrome develops clinically important abnormalities in vitamin D, calcium, and bone metabolism. Suggested predisposing factors include increasing age, prolonged duration of disease, kidney function impairment, marked proteinuria, and glucocorticoid therapy [7]. Another possibility that has been demonstrated in experimental animals is impaired production of calcitriol due to tubular damage induced by heavy proteinuria [32].

Treatment — Vitamin D replacement therapy (with ergocalciferol or cholecalciferol) is not routinely given to all patients with the nephrotic syndrome but may be appropriate in certain settings. We check a baseline serum 25-hydroxyvitamin D level at the time of diagnosis of the nephrotic syndrome and repeat this test every four months if the patient is persistently nephrotic or is receiving treatment with glucocorticoids. We administer vitamin D replacement therapy in patients who are found to have a low serum 25-hydroxyvitamin D level at any time during the course of their disease. In patients who have normal serum 25-hydroxyvitamin D levels, we give vitamin D maintenance therapy to those with persistent or relapsing nephrotic syndrome or who are receiving glucocorticoid therapy. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Vitamin D replacement' and "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Calcium and vitamin D'.)

If vitamin D is given, oral therapy is probably sufficient. Studies in experimental animals with the nephrotic syndrome have found that calcidiol absorption is normal [33]. Similar findings have been noted in humans. In one study, for example, oral administration of calcidiol to nephrotic patients resulted in sustained normalization of the serum calcidiol concentrations and, if kidney function was normal, calcitriol; these changes were accompanied by correction of the low serum ionized calcium concentrations and of secondary hyperparathyroidism [34].

Patients with the nephrotic syndrome who develop chronic kidney disease will often be at an increased risk for vitamin D-related bone disease due to the associated reduction in calcitriol synthesis. This is discussed separately. (See "Overview of the management of chronic kidney disease in adults" and "Chronic kidney disease in children: Overview of management".)

Moreover, in patients treated with glucocorticoids, indications for prophylaxis against osteoporosis should be considered. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)

The effects of the chronic administration of glucocorticoids on bone mineral density in children with the nephrotic syndrome are discussed in detail separately. (See "Treatment of idiopathic nephrotic syndrome in children".)

GLUCOCORTICOID METABOLISM — Cortisol-binding globulin (CBG) also is lost in the urine of nephrotic patients, and serum cortisol concentrations may be reduced. As with thyroxine (T4), however, the percentage of unbound cortisol is increased, serum free cortisol concentrations are normal, and symptomatic hypocortisolism typically does not occur [35].

However, rare cases of primary adrenal insufficiency in the setting of congenital nephrotic syndrome have been reported, some with adrenal calcifications [36-38]. It has been postulated that severe hypovolemia in patients with congenital nephrotic syndrome could predispose to adrenal infarctions. In addition, a multisystem genetic abnormality (eg, WT1 or SGPL1 pathogenic variants) causing adrenal insufficiency and nephrotic syndrome may be responsible in some cases [38].

SUMMARY AND RECOMMENDATIONS

●Overview – The nephrotic syndrome is characterized by a marked increase in the glomerular permeability to macromolecules. The associated urinary losses of albumin and hormone-binding proteins are responsible for many of the metabolic derangements and endocrine abnormalities in these patients.

●Thyroid function

•Alterations in thyroid function – Approximately 50 percent of patients with the nephrotic syndrome and relatively normal kidney function have low total thyroxine (T4) concentrations resulting from urinary losses of T4-binding globulin (TBG) and other thyroid hormone-binding proteins and the T4 bound to them. Serum triiodothyronine (T3) concentrations may also be low due to decreased binding. While earlier studies suggested that nephrotic patients were usually clinically euthyroid, subsequent reports suggest that thyroid dysfunction may be more common than previously thought. (See 'Alterations in thyroid function' above.)

•Effects of glucocorticoids – Glucocorticoids, which are often given to treat the nephrotic syndrome, can also cause a small reduction in thyroid-stimulating hormone (TSH) secretion and inhibit the peripheral conversion of T4 to T3.

•Assessing thyroid function – In patients with the nephrotic syndrome who do not have preexisting thyroid disease, some clinicians routinely obtain a serum TSH level when the nephrotic syndrome is first diagnosed and then perform serial testing (at least annually) in patients who remain nephrotic. However, other clinicians reserve thyroid testing only for those who have preexisting thyroid disease. If hypothyroidism is suspected clinically in any patient, serum TSH should be measured. (See 'Assessment of thyroid function' above.)

•Management – In general, nephrotic patients with abnormal thyroid function tests do not require thyroid hormone replacement unless they have overt hypothyroidism (ie, high TSH level and low free T4 level), in which case the treatment is the same as in patients without nephrotic syndrome. In patients who have preexisting hypothyroidism, the development of nephrotic syndrome may be associated with increased thyroid hormone requirements. Patients receiving glucocorticoid therapy who have low serum free T4 concentrations probably should be treated as if they were hypothyroid. (See 'Management' above.)

●Vitamin D and calcium metabolism

•Effects on vitamin D and calcium – Serum calcidiol (25-hydroxyvitamin D) and calcitriol concentrations may be reduced in patients with nephrotic syndrome, but the physiologically important serum free or bioavailable calcidiol concentration is usually normal. Hypocalcemia is common, however, due to hypoalbuminemia; this does not affect the physiologically important free (or ionized) calcium concentration. Measurement of the ionized calcium concentration is generally required to confirm hypocalcemia in nephrotic patients with a low total serum calcium. (See 'Effects on vitamin D and calcium' above.)

•Treatment – Vitamin D replacement therapy is not routinely given to all patients with the nephrotic syndrome but may be appropriate in certain settings. We administer vitamin D replacement therapy in patients who are found to have a low serum 25-hydroxyvitamin D level at any time during the course of their disease. In patients who have normal serum 25-hydroxyvitamin D levels, we give vitamin D maintenance therapy to those with persistent or relapsing nephrotic syndrome or who are receiving glucocorticoid therapy. (See 'Treatment' above.)

●Glucocorticoid metabolism – Although serum cortisol concentrations may be reduced due to loss of cortisol-binding globulin (CBG) in the urine, serum free cortisol concentrations are normal, and symptomatic hypocortisolism does not occur. (See 'Glucocorticoid metabolism' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Nuhad Ismail, MD, who contributed to an earlier version of this topic review.