Thyroid Function Studies in the Nephrotic Syndrome M. ALI AFRASIABI, M.D.; N. DABIR VAZIRI, M.D.; GRANT GWINUP, M.D.; DARREL M. MAYS, M.D.; CYRIL H. BARTON, M.D.; RUSSEL L NESS, M.D.; and LUBOMIR J. VALENTA, M.D.; Irvine, California Total serum and urinary thyroxine (T4), triiodothyronine (T3), and thyroxine-binding globulin (TBG) as well as serum free T4 t thyroid-stimulating hormone (TSH), and T3 resin uptake (T3RU) were measured in seven patients with the nephrotic syndrome. The nephrotic syndrome was defined by proteinuria exceeding 3 g/24 h. All patients were clinically euthyroid. Most values for total serum T4, free T4, T3, T3RU, TBG, and TSH were within normal limits. However, the mean serum T3 and TBG values were significantly lower in patients compared with the control group. The values (mean ± 2 SD) for urinary T4 were 24.3 ± 20.3 in the patient group and 1.5 ± 0.7 ]Lig/24 h in the control group. Urinary T3 values for patients and the control group were 2 1 0 0 ± 856 and 8 4 8 ± 253 ng/ 24 h respectively. Urinary TBG was 2.1 ± 1.8 mg/24 h in the patients and undetectable in the control group. There was no correlation between daily urinary T3 and T4 and urinary TBG. There was a weak correlation between daily urinary protein excretion and urinary T4 (r = 0.5). A N U M B E R of abnormal results of thyroid function tests have been reported in patients with the nephrotic synd r o m e in the presence of clinical euthyroidism. T h e s e include low protein-bound iodine ( P B I ) (1), low thyroxinebinding globulin ( T B G ) (2), and increased urinary P B I and T B G levels (3-7). There is, therefore, the general ass u m p t i o n that standard thyroid function study results are abnormal in nephrotic patients. T h e present study w a s undertaken to examine thyroid function in the nephrotic s y n d r o m e with modern techniques. • F r o m the Divisions of Endocrinology and Nephrology, University of California, Irvine, California College of Medicine; Irvine, California.
Materials and Methods Seven nephrotic patients were studied (Table 1). The cause of the nephrotic syndrome was unknown in five of them. One patient had lupus nephritis and the other had postinfectious glomerulonephritis. They were all clinically euthyroid, lacking symptoms of cold intolerance, constipation, slow mentation, and physical findings such as dry skin, myxedema, loss of body hair, myoedema, bradycardia, slow relaxation phase of the deep tendon reflexes, and so forth. The nephrotic syndrome was simply defined as proteinuria exceeding 3 g/24 h. None of the patients was taking any medication. Total serum thyroxine (T4) and triiodothyronine (T3) were measured in unextracted plasma by specific radioimmunoassays. Free and bound hormones were separated by precipitation with ammonium sulfate. To inhibit binding of the hormones to thyroxine-binding globulin, 8-anilino-l-naphthalene sulfonic acid was added. The sensitivity of the assay was found to be 0.5 /xg/dl and 12.5 ng/dl for T4 and T3 respectively. To test recovery, known amounts of T4 and T3 were added to the serum from a hypothyroid patient. There was complete recovery of the added materials. The T3 resin uptake (T3RU) was measured by the method of Clark (8). Serum free T4 was measured by dialysis according to the method of Sterling and Brenner (9). The inter- and intra-assay coefficients of variation were 5.2% and 3.5%, respectively. Urinary T4 and T3 were measured by radioimmunoassay procedures analogous to those for the serum. Freshly voided urine was kept at 4 °C. When the 24-h collection was completed, the volume was measured, the specimen was thoroughly mixed, and an aliquot of 1 dl was frozen and stored at —10 °C until the time of analysis. Because the concentration of T4 in the urine is about 1/100 of that of the serum, the sample size was increased from 20 to 200 ul, and the concentration of both
Annals of Internal Medicine 90:335-338, 1979
Downloaded From: https://annals.org/ by a Leiden University Med Centrum User on 10/26/2018
©1979 American College of Physicians
335
the antiserum and the 125I-iodothyronine tracer was adjusted so that the sensitivity of the standard curve was augmented about five times. With these modifications, the sensitivity of the assay was lower than 0.5 jug/litre for T4 and 100 ng/litre for T3. Serum and urine TBG was measured by radioimmunoassay using the method of Chopra, Solomon, and Ho (10). The urine was concentrated three times by dialysis against distilled water before the assay. Added TBG was quantitatively recovered. Sensitivity of the assay was 0.5 mg/dl. Normal serum values were between 1.8 and 4.2 mg/dl. Thyroxine-binding globulin was undetectable in the concentrated (three times) urine of control subjects. Serum thyroid-stimulating hormone (TSH) was measured by a specific human TSH radioimmunoassay using a double antibody technique (11).
The serum T B G level was low in Patient 2 and borderline low in Patients 3 and 4. It was normal in other nephrotic patients. The mean T B G value in the patients was 2.4 ± 1.2 m g / d l (range, 0.5 to 4.2), which was significantly lower than the control value of 3.3 ± 0.3 m g / dl. The T 3 R U level was within the normal range in most nephrotic patients but was elevated in two of the patients who had low serum T B G levels (Patients 3 and 4). Patient 2 had a markedly reduced T B G value and a slightly reduced T 3 R U level. In the nephrotic patients the urinary T4 excretion was markedly elevated with a mean of 24.3 jug/24 h (range, 12 to 70), compared with that of the control subjects in which the range was 0.5 to 3.7 jag/24 h. Furthermore, T B G was invariably present in the urine and ranged between 1 and 6 m g / 2 4 h (mean, 2.1 ± 1.8), whereas in the control subjects, TBG was consistently absent. There was no significant correlation between urinary T B G and urinary T4 levels, but a weak correlation (r = 0.5) existed between urinary T4 with total urinary protein values. A significant correlation was found between values for creatinine clearance and urinary T4 and T3 (r = 0.9). However, because of the narrow range of creatinine clearances, no correlation can be established with certainty.
CONTROL SUBJECTS
Forty-five healthy euthyroid subjects served as controls for all serum and urinary assays. They were 19 men and 26 women, aged 20 through 50 years. The only significant sex-dependent difference was in serum TBG levels, which ranged between 2.5 and 4.0 mg/dl in women and 2.0 and 3.6 mg/dl in men. Pooled serum or urine with known amounts of the measured substances was used for the assessment of both intra- and interassay variation, which was maximally about 5% in all instances. Also, known amounts of the measured substances were added to the serum or urine in at least four different concentrations, and their recovery was studied. It was found to be within the range of ± 10% in all instances. All assays were run in duplicate and the mean of the two values was entered into the statistical analysis. The "Student's" t-test and linear regression were used in analysis of data.
Discussion
Our study shows that patients with the nephrotic syndrome are clinically euthyroid, and their thyroid function tests are generally normal except for low serum T3 levels and occasionally low serum T B G values. Impaired peripheral T4-to-T3 conversion has been observed in many chronic diseases including renal failure (12-14), and this may be responsible for the decreased serum T3 levels in our patients. However, a low serum T B G level may also contribute to reduction of serum T3 level in nephrotic syndrome. The mean serum T B G level in our patients was significantly lower than in the control subjects. This may be because of decreased synthesis, increased extravascular distribution, or increased losses and degradation. In the absence of malnutrition and liver disease, decreased synthesis is unlikely. Furthermore, protein synthesis is generally enhanced in the nephrotic syndrome. Edema and effusions in various serosal cavities, as they occur in the
Results
The results of the patients' thyroid function tests are summarized in Table 2, where they are compared with the values of normal control subjects. In the nephrotic patients the serum T4 value was 7.2 ± 1 . 7 /xg/dl (range, 5.0 to 9.6). In the control subjects, it was 7.6 ± 0.4. The serum T3 level was 92.4 ± 3 1 . 9 ng/dl (range, 56 to 150) compared with 133 ± 5.7 in the control subjects. The difference was not statistically significant for T4 but was significant for T3. The free T4 level was 1.9 ± 0.3 ng/dl (range, 1.4 to 2.5) in the nephrotic patients and essentially identical at 1.9 ± 0.2 ng/dl in the control subjects. The serum TSH values were less than 8 /xU/ml in all nephrotic patients. The mean of 4.0 ± 1.6 jnU/ml was not significantly different from that of the average control value of 3.8 JLLU/ ml. Table 1 . Clinical Data and Pertinent Renal Variables
Patients
Age
Sex
yrs 1 2 3 4 5 6 7
26 51 20 31 20 50 39 Mean
34
F F M F M F F
24-h Urinary Protein Excretion
Serum Albumin
Blood Urea Nitrogen
Creatinine Clearance
Cholesterol
g 5.2 6.9 7.1 5.8 3.5 4.0 3.7
g/dl 2.7 2.2 1.8 2.1 1.7 3.3 3.6
mg/dl
ml/min
mg/dl
23 35 20 26 14 31 10
48 52 68 51 55 50 55
250 276 493 297 350 267 226
5.1
2.5
23
54
308
* MPGN = membranoproliferative glomerulonephritis. 336
March 1979 • Annals of Internal Medicine • Volume 90 • Number 3
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Renal Histology*
MPGN MPGN Minimal change Not biopsied Minimal change Not biopsied Immune complex glomerulonephritis
Table 2. Thyroid Function Tests in Seven Nephrotic Patients
Patients
1 2 3 4 5 6 7 Mean ± 2SD Normal mean ± 2SD P Value*
Urine
Serum Thyroxine
Triiodothyronine
ng/dl 9.5 6.8 7.0 5.0 6.0 6.8 9.6 7.2 1.7 7.6 0.4 NS
ng/dl 150 86 56 85 75 75 120 92.4 31.9 133 5.7 < 0.001
Triiodothyronine Uptake
% 42.7 34.0 54.3 54.0 31.0 26.0 29.0 38.7 11.7 40.0 1.2 NS
ThyroidStimulating Hormone
ThyroxineBinding Globulin
Free Thyroxine
Thyroxine
Triiodothyronine
ThyroxineBinding Globulin
v.g/ml 6.5 2.8 6.4 2.9 2.5 3.5 4.6 4.0 1.6 3.8 1.9 NS
mg/dl 4.2 0.5 1.6 1.8 2.6 2.9 3.5 2.4 1.2 3.31 0.31 < 0.001
ng/dl 1.9 2.5 2.3 1.8 1.4 1.6 2.0 1.9 0.3 1.9 0.2 NS
ng/24 h 12.0 16.5 70.0 18.0 15.0 20.0 19.0 24.3 20.3 1.5 0.7 < 0.001
ng/24h 1500 1600 3600 2500 2000 1000 2500 2100 856 848 253 0.001
mg/24 h 1.0 2.2 2.0 Not done 6.0 2.5 1.6 2.1 1.8
< aooi
* NS = not signdficant.
nephrotic syndrome, may lead to increased extravascular distribution of TBG. However, the most likely cause of the low serum T B G level is its renal loss. In our patients suffering from relatively mild proteinuria, urinary excretion seems to be insufficient to explain the observed low serum TBG levels. However, it should be noted that proteinuria may represent only a fraction of the total protein loss in the kidney, because a substantial portion of the filtered protein is catabolized by the renal tubular cells and thereby lost in the kidney without appearing in the urine (15, 16). In Patient 2, and to a certain degree, Patients 5 and 6, there was some disparity between the serum T B G and T 3 R U values, in that relatively low T B G levels were not associated with increased T3RU. We do not have a definite explanation for this observation. It is possible, however, that in some patients T 4 is bound to a significant degree by proteins other than TBG. This would also explain why, in the same patients, total serum T4 was normal in the face of low T B G concentration. A discrepancy between total T 4 and T B G binding capacity was also observed in patients in renal failure (17) where it was reversible upon renal transplantation. In our nephrotic patients, both urinary T4 and T3 were markedly increased. This could be correlated to some extent with the degree of proteinuria but not with urinary losses of TBG. Thyroxine-binding prealbumin (TBPA) is a smaller molecule than TBG, and TBPAbound T4 as well as free T4 may be a significant source of urinary T4 in nephrotic subjects in addition to the TBGT4 complex. In normal persons, the urinary/serum ratio is higher for T3 than T4. This reflects differential binding to the plasma proteins. Because of the greater proportion of unbound T3, a greater fraction of T3 is filtered in the glomeruli, compared with T4. In addition, it has been shown that the urinary excretion of T3 involves glomerular filtration and tubular secretion, whereas T4 is subject to glomerular filtration and tubular reabsorption (18). Finally, deiodination of iodothyronines occurs in the kidney with the derived iodine preferentially excreted in the
urine (19, 20). It seems plausible that some of the urinary T3 is derived from partial deiodination of T4 in the tubular cells. In contrast to findings in the control subjects, the urinary T3 level was increased only slightly and the urinary T4 level was increased considerably. Because T 3 does not bind to TBPA while a substantial part of T 4 is TBPA bound, the reversal of the usual urinary T4-to-T3 ratio further suggests the possibility that TBPA-bound T4 is a significant source of urinary T4. The lack of correlation of urinary T 4 and T B G was recently reported by Gavin and associates (21). However, they found a correlation between daily total proteinuria and urinary T4, and they reported increased serum free T4 in their patients. In our study, free T4 was normal and no statistical difference (P = 0.1) was found between free T4 levels of patients with low and normal T B G values. The discrepancy between our findings and those of Gavin and associates may be due to the more severe proteinuria and a greater degree of renal failure in the patients studied by Gavin and associates. Furthermore, seven of their 10 nephrotic patients suffered from diabetes, which is associated with a different form of renal pathologyACKNOWLEDGMENTS: Presented in part at the Sixtieth Annual Meeting of The American Endocrine Society; 14 June 1978; Miami Beach, Florida. • Requests for reprints should be addressed to Ludomir J. Valenta, M.D.; Endocrinology and Metabolism Division, University of California, Irvine, School of Medicine; 101 City Drive, S.; Orange, CA 92668. Received 19 June 1978; revision accepted 11 December 1978.
References 1. PETERMAN JB, M A N EB: The relation of albumin to precipitable iodine of serum. / Clin Invest 27:397-405, 1948 2. ROBBINS J, R A L L JE, P E T E R M O N ML: Thyroxine binding by serum and
urine proteins in nephrosis. Qualitative aspects. / Clin Invest 36:13331342, 1957 3. R E C A N T L, RIGG DS: Thyroid function in nephrosis. / Clin Invest 31:789-797, 1952 4. RASMUSSEN H, R A P P B: Thyroxine metabolism in the nephrotic syndrome. / Clin Invest 35:792-799, 1956 5. M U S A BU, SEAL US, D O E RP: Excretion of corticosteroid-binding glob-
ulin, thyroxine-binding globulin and total protein in adult males with Afrasiabi
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etal.
• Thyroid Function and Nephrotic Syndrome
337
nephrosis: effects of sex hormones. J Clin Endocrinol 27:768-774, 1967 6. B O R N E R E, K A M M E N H U B E R K, M E I S S N E R H P : Renaler Thyroxin-Ver-
lust bei nephrotischem Syndrom. Klin Wochenschr 48:1320-1328, 1970 7. H E R M A N N J, B A H L M A N N J, K R U S K E M P E R
8. 9.
10.
11.
HL: Das Verhalten des
Thyroxins sowie des Thyroxine-bindenden Globulins in Serum und Urin von Patienten mit renalen Thyroxin-Verlusten infolge Nephrotischen Syndroms unterschiedlicher Genese. Acta Endocrinol 69:13-28, 1972 CLARK F, BROWN HJ: Evaluation of Thyopac-3 in the in vitro assessment of thyroid function. Br Med J 1:713-715, 1970 STERLING K, BRENNER MA: Free thyroxine in human serum: simplified measurement with aid of magnesium precipitation. / Clin Invest 45:153, 1966 CHOPRA IJ, SOLOMON DH, H O RS: Competitive ligand-binding assay for measurement of thyroxine-binding globulin (TBG). / Clin Endocrinol Metab 35:565-573, 1972 H A L L R, A M O S J, ORMSTON BJ: Radioimmunoassay of human serum thyrotrophin. Br Med J 1:582-585, 1971
12. N O M U R A S, P I T T M A N CS, C H A M B E R S JB J R , BUCK MW, S H I M I Z U T:
Reduced peripheral conversion of thyroxine to triiodothyronine in patients with hepatic cirrhosis. / Clin Invest 56:643-652, 1975 13. CHOPRA IJ: An assessment of daily production and significance of thyroidal secretion of 3,3',5'-triiodothyronine (reverse T?) in man. J Clin Invest 58:32-40, 1976
338
14. SPECTOR DA, D A V I S PJ, H E L D E R M A N JH, B E L L B, U T I G E R R D : Thy-
roid function and metabolic state in chronic renal failure. Ann Intern Med 85:724-730, 1976 15. OLIVER J, M A C D O W E L L M: Cellular mechanisms of protein metabolism in the nephrotic. J Exp Med 107:731-754, 1958 16. SPECTOR WG: The reabsorption of labeled proteins by the normal and nephrotic rat kidney. J Pathol 68:187-196, 1954 17. L I M VS, F A N G VS, K A T Z AI, R E F E T O F F S: Thyroid dysfunction in
chronic renal failure. A study of the pituitary-thyroid axis and peripheral turnover kinetics of thyroxine and triiodothyronine. / Clin Invest 60:522-534, 1977 18. BURKE CW, SHAKESPEAR RA: Triiodothyronine and thyroxine in urine. II. Renal handling, and effect of urinary protein. / Clin Endocrinol Metab 42:504-513, 1976 19. SHIMODA S, G R E E R MA: Iodine metabolism: Preferential renal excretion of iodide derived from triiodothyronine deiodination. Science 175:1266-1267, 1972 20.
SHIMODA S-I, KASAI K, K I K U C H I T, IEIRI T: Preferential renal excre-
tion of iodide derived from thyroxine and triiodothyronine deiodination in man. / Clin Endocrinol Metab 44:137-141, 1977 21. G A V I N LA, M C M A H O N FA, C A S T L E JN, C A V A L I E R I RR: Alterations
in serum thyroid hormones and thyroxine-binding globulin in patients with nephrosis. / Clin Endocrinol Metab 46:125-130, 1978
Annals of Internal Medicine 90:338-340, 1979
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©1979 American College of Physicians
Materials and Methods Seven nephrotic patients were studied (Table 1). The cause of the nephrotic syndrome was unknown in five of them. One patient had lupus nephritis and the other had postinfectious glomerulonephritis. They were all clinically euthyroid, lacking symptoms of cold intolerance, constipation, slow mentation, and physical findings such as dry skin, myxedema, loss of body hair, myoedema, bradycardia, slow relaxation phase of the deep tendon reflexes, and so forth. The nephrotic syndrome was simply defined as proteinuria exceeding 3 g/24 h. None of the patients was taking any medication. Total serum thyroxine (T4) and triiodothyronine (T3) were measured in unextracted plasma by specific radioimmunoassays. Free and bound hormones were separated by precipitation with ammonium sulfate. To inhibit binding of the hormones to thyroxine-binding globulin, 8-anilino-l-naphthalene sulfonic acid was added. The sensitivity of the assay was found to be 0.5 /xg/dl and 12.5 ng/dl for T4 and T3 respectively. To test recovery, known amounts of T4 and T3 were added to the serum from a hypothyroid patient. There was complete recovery of the added materials. The T3 resin uptake (T3RU) was measured by the method of Clark (8). Serum free T4 was measured by dialysis according to the method of Sterling and Brenner (9). The inter- and intra-assay coefficients of variation were 5.2% and 3.5%, respectively. Urinary T4 and T3 were measured by radioimmunoassay procedures analogous to those for the serum. Freshly voided urine was kept at 4 °C. When the 24-h collection was completed, the volume was measured, the specimen was thoroughly mixed, and an aliquot of 1 dl was frozen and stored at —10 °C until the time of analysis. Because the concentration of T4 in the urine is about 1/100 of that of the serum, the sample size was increased from 20 to 200 ul, and the concentration of both
Annals of Internal Medicine 90:335-338, 1979
Downloaded From: https://annals.org/ by a Leiden University Med Centrum User on 10/26/2018
©1979 American College of Physicians
335
the antiserum and the 125I-iodothyronine tracer was adjusted so that the sensitivity of the standard curve was augmented about five times. With these modifications, the sensitivity of the assay was lower than 0.5 jug/litre for T4 and 100 ng/litre for T3. Serum and urine TBG was measured by radioimmunoassay using the method of Chopra, Solomon, and Ho (10). The urine was concentrated three times by dialysis against distilled water before the assay. Added TBG was quantitatively recovered. Sensitivity of the assay was 0.5 mg/dl. Normal serum values were between 1.8 and 4.2 mg/dl. Thyroxine-binding globulin was undetectable in the concentrated (three times) urine of control subjects. Serum thyroid-stimulating hormone (TSH) was measured by a specific human TSH radioimmunoassay using a double antibody technique (11).
The serum T B G level was low in Patient 2 and borderline low in Patients 3 and 4. It was normal in other nephrotic patients. The mean T B G value in the patients was 2.4 ± 1.2 m g / d l (range, 0.5 to 4.2), which was significantly lower than the control value of 3.3 ± 0.3 m g / dl. The T 3 R U level was within the normal range in most nephrotic patients but was elevated in two of the patients who had low serum T B G levels (Patients 3 and 4). Patient 2 had a markedly reduced T B G value and a slightly reduced T 3 R U level. In the nephrotic patients the urinary T4 excretion was markedly elevated with a mean of 24.3 jug/24 h (range, 12 to 70), compared with that of the control subjects in which the range was 0.5 to 3.7 jag/24 h. Furthermore, T B G was invariably present in the urine and ranged between 1 and 6 m g / 2 4 h (mean, 2.1 ± 1.8), whereas in the control subjects, TBG was consistently absent. There was no significant correlation between urinary T B G and urinary T4 levels, but a weak correlation (r = 0.5) existed between urinary T4 with total urinary protein values. A significant correlation was found between values for creatinine clearance and urinary T4 and T3 (r = 0.9). However, because of the narrow range of creatinine clearances, no correlation can be established with certainty.
CONTROL SUBJECTS
Forty-five healthy euthyroid subjects served as controls for all serum and urinary assays. They were 19 men and 26 women, aged 20 through 50 years. The only significant sex-dependent difference was in serum TBG levels, which ranged between 2.5 and 4.0 mg/dl in women and 2.0 and 3.6 mg/dl in men. Pooled serum or urine with known amounts of the measured substances was used for the assessment of both intra- and interassay variation, which was maximally about 5% in all instances. Also, known amounts of the measured substances were added to the serum or urine in at least four different concentrations, and their recovery was studied. It was found to be within the range of ± 10% in all instances. All assays were run in duplicate and the mean of the two values was entered into the statistical analysis. The "Student's" t-test and linear regression were used in analysis of data.
Discussion
Our study shows that patients with the nephrotic syndrome are clinically euthyroid, and their thyroid function tests are generally normal except for low serum T3 levels and occasionally low serum T B G values. Impaired peripheral T4-to-T3 conversion has been observed in many chronic diseases including renal failure (12-14), and this may be responsible for the decreased serum T3 levels in our patients. However, a low serum T B G level may also contribute to reduction of serum T3 level in nephrotic syndrome. The mean serum T B G level in our patients was significantly lower than in the control subjects. This may be because of decreased synthesis, increased extravascular distribution, or increased losses and degradation. In the absence of malnutrition and liver disease, decreased synthesis is unlikely. Furthermore, protein synthesis is generally enhanced in the nephrotic syndrome. Edema and effusions in various serosal cavities, as they occur in the
Results
The results of the patients' thyroid function tests are summarized in Table 2, where they are compared with the values of normal control subjects. In the nephrotic patients the serum T4 value was 7.2 ± 1 . 7 /xg/dl (range, 5.0 to 9.6). In the control subjects, it was 7.6 ± 0.4. The serum T3 level was 92.4 ± 3 1 . 9 ng/dl (range, 56 to 150) compared with 133 ± 5.7 in the control subjects. The difference was not statistically significant for T4 but was significant for T3. The free T4 level was 1.9 ± 0.3 ng/dl (range, 1.4 to 2.5) in the nephrotic patients and essentially identical at 1.9 ± 0.2 ng/dl in the control subjects. The serum TSH values were less than 8 /xU/ml in all nephrotic patients. The mean of 4.0 ± 1.6 jnU/ml was not significantly different from that of the average control value of 3.8 JLLU/ ml. Table 1 . Clinical Data and Pertinent Renal Variables
Patients
Age
Sex
yrs 1 2 3 4 5 6 7
26 51 20 31 20 50 39 Mean
34
F F M F M F F
24-h Urinary Protein Excretion
Serum Albumin
Blood Urea Nitrogen
Creatinine Clearance
Cholesterol
g 5.2 6.9 7.1 5.8 3.5 4.0 3.7
g/dl 2.7 2.2 1.8 2.1 1.7 3.3 3.6
mg/dl
ml/min
mg/dl
23 35 20 26 14 31 10
48 52 68 51 55 50 55
250 276 493 297 350 267 226
5.1
2.5
23
54
308
* MPGN = membranoproliferative glomerulonephritis. 336
March 1979 • Annals of Internal Medicine • Volume 90 • Number 3
Downloaded From: https://annals.org/ by a Leiden University Med Centrum User on 10/26/2018
Renal Histology*
MPGN MPGN Minimal change Not biopsied Minimal change Not biopsied Immune complex glomerulonephritis
Table 2. Thyroid Function Tests in Seven Nephrotic Patients
Patients
1 2 3 4 5 6 7 Mean ± 2SD Normal mean ± 2SD P Value*
Urine
Serum Thyroxine
Triiodothyronine
ng/dl 9.5 6.8 7.0 5.0 6.0 6.8 9.6 7.2 1.7 7.6 0.4 NS
ng/dl 150 86 56 85 75 75 120 92.4 31.9 133 5.7 < 0.001
Triiodothyronine Uptake
% 42.7 34.0 54.3 54.0 31.0 26.0 29.0 38.7 11.7 40.0 1.2 NS
ThyroidStimulating Hormone
ThyroxineBinding Globulin
Free Thyroxine
Thyroxine
Triiodothyronine
ThyroxineBinding Globulin
v.g/ml 6.5 2.8 6.4 2.9 2.5 3.5 4.6 4.0 1.6 3.8 1.9 NS
mg/dl 4.2 0.5 1.6 1.8 2.6 2.9 3.5 2.4 1.2 3.31 0.31 < 0.001
ng/dl 1.9 2.5 2.3 1.8 1.4 1.6 2.0 1.9 0.3 1.9 0.2 NS
ng/24 h 12.0 16.5 70.0 18.0 15.0 20.0 19.0 24.3 20.3 1.5 0.7 < 0.001
ng/24h 1500 1600 3600 2500 2000 1000 2500 2100 856 848 253 0.001
mg/24 h 1.0 2.2 2.0 Not done 6.0 2.5 1.6 2.1 1.8
< aooi
* NS = not signdficant.
nephrotic syndrome, may lead to increased extravascular distribution of TBG. However, the most likely cause of the low serum T B G level is its renal loss. In our patients suffering from relatively mild proteinuria, urinary excretion seems to be insufficient to explain the observed low serum TBG levels. However, it should be noted that proteinuria may represent only a fraction of the total protein loss in the kidney, because a substantial portion of the filtered protein is catabolized by the renal tubular cells and thereby lost in the kidney without appearing in the urine (15, 16). In Patient 2, and to a certain degree, Patients 5 and 6, there was some disparity between the serum T B G and T 3 R U values, in that relatively low T B G levels were not associated with increased T3RU. We do not have a definite explanation for this observation. It is possible, however, that in some patients T 4 is bound to a significant degree by proteins other than TBG. This would also explain why, in the same patients, total serum T4 was normal in the face of low T B G concentration. A discrepancy between total T 4 and T B G binding capacity was also observed in patients in renal failure (17) where it was reversible upon renal transplantation. In our nephrotic patients, both urinary T4 and T3 were markedly increased. This could be correlated to some extent with the degree of proteinuria but not with urinary losses of TBG. Thyroxine-binding prealbumin (TBPA) is a smaller molecule than TBG, and TBPAbound T4 as well as free T4 may be a significant source of urinary T4 in nephrotic subjects in addition to the TBGT4 complex. In normal persons, the urinary/serum ratio is higher for T3 than T4. This reflects differential binding to the plasma proteins. Because of the greater proportion of unbound T3, a greater fraction of T3 is filtered in the glomeruli, compared with T4. In addition, it has been shown that the urinary excretion of T3 involves glomerular filtration and tubular secretion, whereas T4 is subject to glomerular filtration and tubular reabsorption (18). Finally, deiodination of iodothyronines occurs in the kidney with the derived iodine preferentially excreted in the
urine (19, 20). It seems plausible that some of the urinary T3 is derived from partial deiodination of T4 in the tubular cells. In contrast to findings in the control subjects, the urinary T3 level was increased only slightly and the urinary T4 level was increased considerably. Because T 3 does not bind to TBPA while a substantial part of T 4 is TBPA bound, the reversal of the usual urinary T4-to-T3 ratio further suggests the possibility that TBPA-bound T4 is a significant source of urinary T4. The lack of correlation of urinary T 4 and T B G was recently reported by Gavin and associates (21). However, they found a correlation between daily total proteinuria and urinary T4, and they reported increased serum free T4 in their patients. In our study, free T4 was normal and no statistical difference (P = 0.1) was found between free T4 levels of patients with low and normal T B G values. The discrepancy between our findings and those of Gavin and associates may be due to the more severe proteinuria and a greater degree of renal failure in the patients studied by Gavin and associates. Furthermore, seven of their 10 nephrotic patients suffered from diabetes, which is associated with a different form of renal pathologyACKNOWLEDGMENTS: Presented in part at the Sixtieth Annual Meeting of The American Endocrine Society; 14 June 1978; Miami Beach, Florida. • Requests for reprints should be addressed to Ludomir J. Valenta, M.D.; Endocrinology and Metabolism Division, University of California, Irvine, School of Medicine; 101 City Drive, S.; Orange, CA 92668. Received 19 June 1978; revision accepted 11 December 1978.
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Annals of Internal Medicine 90:338-340, 1979
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©1979 American College of Physicians
