Acta Med Scand 206: 507-510. 1979
Hyperparathyroidism Associated with Distal Tubular Dysfunction but Intact Reabsorption of Protein in the Proximal Tubules Lars Wibell, Per Anders Dahlberg and Anders Karlsson From the Department of Internal Medicine, University Hospital, Uppsala Sweden
ABSTRACT. The urinary output of /3,-microglobulin was measured in ten hypercalcemic patients undergoing surgery because of hyperparathyroidism. In three subjects the &-microglobulin excretion was abnormally increased and in seven patients it was normal before surgery. Three of these seven patients displayed markedly impaired distal tubular function with a reduced urinary concentrationcapacity. After surgery all patients became normocalcemic and the urinary concentrating capacities improved. The P,-mciroglobulin excretion, on the other hand, remained unchanged. Thus, hypercalcemia per se does not readily affect the proximal tubular function of reabsorbing low molecular weight proteins. “Tubular proteinuria”, if found in patients with hypercalcemia, should he suspected to reflect damage to the kidney by additional mechanisms.
et al. (20) have found mixed proteinuric patterns by electrophoresis of urinary protein in five patients with parathyroid adenomas. We have investigated the influence of hypercalcemia on the proximal renal tubules by following the urinary output of P,-microglobulin in patients undergoing surgery because of HPT. p2microglobulin (mol. wt. 11 800), first isolated from the urine of patients with renal tubular disorders (4), is one of the major LMW proteins of “tubular proteinuria”, and as such, a sensitive marker of protein reabsorption in the proximal renal tubules (19, 23).
PATIENTS Ten patients with hypercalcemia and probable HPT were selected for the study. Patients with a history of recurrent Key words: hyperparathyroidism, hypercalcemia, p2- kidney stones or infections in the urinary pathways were excluded since obstruction and infection, particularly if microglobulin, kidney function. connected with hypercalciuria or renal tubular acidosis, Acta Med Scand 206: 507. 1979. may be associated with an abnormal excretion of LMW proteins ( 5 , 12, 13, 15). In seven of the patients a diagnosis of HPT was not suspected until a routine serum calcium determination was performed and disclosed a high value. Hyperparathyroidism (HPT) is sometimes ac- Patients 3 and 8 had suffered single episodes of renal colic. companied by kidney dysfunction, in general attrib- These patients and patient 9 had minimal kidney calcificauted to a diffuse calcium nephropathy (8). When tions at urography. Patient 5 had a non-functioning left kidney after a complicated nephrolithotomy 15 years ago. the glomerular filtration rate is impaired (14, 18), it In all other patients X-ray investigations of the kidneys seldom improves after parathyroidectomy . In con- were normal. Laboratory findings are presented in Table I. Protrast, the common impairment of the renal concentrating ability is often reversed after correction nounced hypercalciuria was present in patients 1-3 and moderate hypercalciuria in two of the other seven subof the hypercalcemia (7, 11). jects. Most patients had an increased phosphate excretion, It has been claimed (6) that a selective urinary and, when tested in patients 5-10, pathological urine phosexcretion of low molecular weight (LMW) proteins, phate responses to calcium infusion, as in HPT (22), were “tubular proteinuria” , can be present in patients found in five cases. The ability to produce concentrated with HPT-and be reversible during the months urine was subnormal in all subjects, and markedly low urinary osmolalities were noted after pitressin tannate adfollowing parathyroidectomy . Hayslett et al. (13) ministration in patients 1-3. Serum alkaline phosphatase have described three hyperparathyroid subjects with normal serum creatinine values and increased Abbreviations: HPT = hyperparathyroidism, LMW = low excretions of lysozyme (mol. wt. 14000). Revillard molecular weight. Aclu
Mrd SrNnd 206
SO8
L. Wibell et cil.
Table I . Laboratory,finding.s With the exception of tubular reabsorption of phosphate (TRP) and maximal osmolality, the laboratory data represent th mean of 2-5 determinations S-Ca (mmol/l) Pat. no.
Sex
(Y.)
Preop.
Postop."
U-Ca (mmoll 24 h)
P P 0
53 51 52 73 66 72 68 26 64 69
3.4 3.3 3.1 3.0 3.0 2.9 2.9 2.9 2.9 2.8
2.3 2.4 2.5 3.5 2.5 2.5 2.3 2.4 2.3 2.4
15 17 15 5 2 4 10 8 6 3
Age
1
2 3 4
0
Y
6
6 7 8 9 10
0 0 0
6 0
Reference values
2.2-2.6
Max. osmol! S-creat. (mOsm/kg) (pmol/l) 375 530 465 670 630 690 600 780 680 710
0.6-5.0
>750
CC,,,, (ml/min/ I .73 m')
S-P (mmol/l)
82 70 72 110 187 83 75 75 76 106
80 120 140 70 45 70 115 95 55
0.6 0.6 0.7 0.8 0.8 0.8 0.6 0.8 0.8 0.8
64-106
75-150
0.8-1.4
60
Determined 5 months after surgery. Determined with a Knaur Osmometer. Urine collected after water restriction and injection of pitressin tannate. ' Determined after infusion of calcium (22), N = normal, P =pathological. This patient, who had only one functioning kidney, displayed moderate proteinuria (0.5 g albumid24 h) and reducec glomerular filtration rate.
was slightly elevated in two patients. X-ray investigations of the skeleton revealed an unequivocal bone disease in patient 10, with osteopenia and subperiosteal erosions. Vascular calcifications of the Moenckeberg type (21) were apparent in patient 3. The diagnosis of HPT was corroborated in all patients by thorough examination of removed parathyroid tissues. Expert evaluation of parathyroid glands was performed by L. Grimelius. Single adenomas were found in 9 patients, one of whom also had two hyperplastic glands, one patient had two hyperplastic and two normal glands. Postoperatively, the levels of serum and urinary calcium were normalized in all patients. When investigated five months postoperatively, the urinary concentration ability after pitressin tannate administration was improved in all ten subjects, although in six patients the values of urinary osmolality were still subnormal, in the range of 650-750 mOsm/kg.
METHODS &-Microglobulin was determined with a radioimmunoassay kit (9) (Phadebas, Pharmacia, Uppsala). All other analyses were carried out with the routine procedures in use at the Laboratory of Clinical Chemistry, University Hospital, Uppsala. Only single urine specimens with a pH above 5.8 were accepted for study, since at low pH degradation of /32-microglobulin frequently occurs (10). Urines were stored at -20°C until analysis. The urinary excretion of &-microglobulin was expressed as a ratio of p2microglobulin to creatinine in order to minimize the variation among samples caused by differences in diuresis (23). Ai'ltr
Mod
Swiid
206
RESULTS AND DISCUSSION The urinary /3,-microglobulin/creatinine ratio before parathyroidectomy , during the postoperative days and at the follow-up five months postoperatively, are shown in Fig. 1. Before surgery the excretion of /3,-microglobulin was of normal magnitude in seven patients. Three of these patients (nos. 1-3) had the most pronounced hypercalcemia and hypercalciuria, and the lowest maximal urinary osrnolality after pitressin tannate administration. At the follow-up these seven patients had p2microglobulin excretion similar to that found before the operation. Thus, patients with HPT may have hypercalcemia, hypercalciuria and a reduced concentration capacity but still retain a normal capacity for reabsorption of LMW proteins in the proximal renal tubules. Three of the investigated patients, cases 5 , 7 and 10, had an abnormal excretion of /3,-rnicroglobulin. It is clear that the amount of &-microglobulin in the urine of these cases did not correlate to the serum calcium level or to the maximal urinary osmolality. This supports the concept that an impaired concentrating capacity is secondary to hypercalcemia, and in part due to functional changes, rather than to structural alterations and microscopic nephrocalcinosis in the kidney (3, 8, 11).
Hyperparathyroidism and tubular dysfunction PREOP
POSTOP I I
02 p I CREATlNlNE
(pglmg
3asal
After Ca+“
S-alk. phosph. (pkat/l)
)4 i4 14 ,5 ,5 8 44
15 N 87 P 17 P 83 P 86 P 77 P
4.5 4.5 4.3 2.6 2.2 6.4 3.4 2. I 8.6 5.5
70 37
34 38 85-95
5000
first week I 5 months
I I
103)
FRP (%)
509
I
-
2000 I
/
\ ;
1000 -
500 -
0.8-4.8
200 NO& AL RANGE
I
I
loo -I
I
I
I
I
Fig. I . Urinary excretion of @,-microglobulin before and A temporary postoperative increase in the µglobulin excretion was observed in three patients (nos. l , 6 and 7). This finding may be analogous to the high excretion of LMW proteins observed in patients after major surgical intervention (24) and in patients with large burns (1). The mechanism of such proteinuria is not known. Possibly, the postoperative catabolic phase induces a load on the kidney of LMW substances. Such molecules could interfere with proximal tubular function in much the same way as an infusion of basic amino acids causes tubular proteinuria (17). In previous reports (6, 13, 20) on LMW proteinuria in patients with HPT, no details were given concerning renal stones or associated kidney disease. In patients with kidney stones, but without HPT, a surprisingly high incidence-up to 80 %-of LMW proteinuria has been reported as lysozymuria (15) or hyperinsulinuria (5). In the latter of these studies, all patients had spinal cord injuries. Thus, bacterial pyelonephritis is likely to have been a common finding. In a recent study of consecutive subjects with recurrent stone disease, seen in an outpatient clinic ( 2 ) , less than 10% of the patients displayed an elevated excretion of p,-microglobulin. Our results suggest that hypercalcemia per se
after parathyroidectomy in ten patients with primary HPT. The data are presented as the ratio of @,-microglobulinlcreatinine.
does not interfere with the protein reabsorbing capacity of the kidney tubules. As reabsorption of filtered proteins mainly occurs in the proximal tubules (16), our findings are consistent with the observations that pathological calcifications in hypercalcemia first occur in the distal part of the nephron, such as the collecting ducts and the ascending limb of Henle’s loop (8). Clearly, “tubular proteinuria” is not an early or obligatory finding in patients with HPT. When LMW proteinuria is found, a complicating kidney disorder should be looked for.
ACKNOWLEDGEMENT This study was supported by a grant from Tore Nilsson Foundation.
REFERENCES I . Arturson, G., Evrin, P. E. & Wibell, L.: Renal function studies in patients with extensive burns. Medicinsk Riksst2imma 1973. Svenska Lakarsallskapet, Stockholm, Abstract KI 40: 196, 1973. Acta
Med Scrrnd 206
510
L . Wibell et
cil.
2. Backman, U., Danielsson, B. G. & Sothell, M.: Urinary excretion of P,-microglobulin in renal stone patients under normal conditions and during acidosis and alkalosis. Scand J Urol Nephrol (Suppl) 35: 79, 1976. 3 . Bech, N., Singh, H., Reed, S. W., Murdangli, H . V. & Davis, B. B.: Pathogenic role of cyclic AMP in the impairment of urinary concentrating ability in acute hypercalcemia. J Clin Invest 54: 1049, 1974. 4. Bergghd, I. & Bearn, A. G.: Isolation and properties of a low molecular weight P,-globulin occurring in human biological fluids. J Biol Chem 243: 4095, 1968. 5 . Ching, K. N . , Karam, J. H., Choy, F. B., Kolb, F. O., Grodsky, G. M. & Forsham, P. H.: Hyperinsulinuria in patients with renal calculi. Clin Chim Acta 5217: 383, 1972. 6. Dent, C. E.: The Balkan nephropathy (ed. G. E. Wolstenholme and J . Knight), p. 108. Ciba Foundation, Boston 1967. 7. Edvall, C. A,: Renal function in hyperparathyroidism. Acta Chir Scand (Suppl) 229, 1958. 8. Epstein, F. H.: Calcium and the kidney. Am J Med 45: 700, 1968. 9. Evrin, P. E., Peterson, P. A., Wide, L. & BerggArd, I.: Radioimmunoassay of P,-microglobulin in human biological fluids. Scand J Clin Lab Invest 28:439, 1971. 10. Evrin, P. E. & Wibell, L.: The serum level of p2microglobulin in apparently healthy subjects. Scand J Clin Lab Invest 29: 69, 1972. 1 1 . Gill, J. R. & Bartter, F. C.: On the impairment of renal concentration ability in prolonged hypercalcemia and hypercalciuria in man. J Clin Invest 40: 716, 1961. 12. Hall, P. W. & Vasiljevic, M.: Beta,-microglobulin excretion as an index of renal tubular disorders with special reference to endemic Balkan nephropathy. J Lab Clin Med 81: 897, 1973. 13. Hayslett, J. P., Perillie, P. E. & Finch, S . C.: Urinary muramidase and renal disease. N Engl J Med 279: 506, 1968. 14. Hellstrom, J., Birke, G. & Edvall, C. A,: Hypertension in hyperparathyroidism. Br J Urol 30: 13, 1958.
15. Kregzde, J., Lamberg, L. L. & Davidson, W. D.: Lysozymuria in renal calculosis following spinal cord injury. Urol Int 24: 310, 1969. 16. Maunsbach, A. B.: Ultrastructure and digestive activity of lysosomes from proximal tubular cells. In: Proc. 4th Int. Congr. Nephrol., vol 1, pp. 102-115. Karger, Basel 1969. 17. Mogensen, C. E., Solling, K. & Vittinghus, E.: Increased urinary excretion of albumin, light chains and &-microglobulin after intravenous arginine administration in normal man. Lancet 2: 581, 1975. 18. Olsson, L.: Primary hyperparathyroidism, a study of 160 patients. University of Gothenburg dissertation, Gothenburg 1975. 19. Peterson, P. A,, Evrin, P. E. & BerggBrd, 1.: Differentiation of glomerular, tubular, and normal proteinuria: determinations of urinary excretion of & microglobulin, albumin, and total protein. J CIin Invest 48: 1189, 1969. 20. Revillard, J. P., Manuel, Y., Francois, R. & Traeger, J.: Renal diseases associated with tubular proteinuria. In: Proteins in normal and pathological urine (ed. Y. Manuel, J. P. Revillard and H. Betuel), pp. 209-219. Karger, Basel 1970. 21. Tatler, G. L. V., Baillod, R. A., Varghese, Z., Young, W. B., Farrow, S., Wills, M. R. & Moorhead, J. F.: Evolution of bone disease over 10 years in 135 patients with terminal renal failure. Br Med J 4:315, 1973. 22. Wibell, L., Johansson, H. & Werner, I.: The use of calcium infusion test in the diagnosis of hyperparathyroidism. Scand J Clin Lab Invest 30: 183, 1972. 23. Wibell, L. & Karlsson, F. A,,: The urinary excretion of P,-microglobulin after the induction of a diuresisa study in healthy subjects. Nephron 17: 343, 1976. 24. Wide, L. & Thoren, L.: Increased urinary clearance for albumin, &-microglobulin, insulin and luteinizing hormone following surgical or accidental trauma. Scand J Clin Lab Invest 30: 275, 1972.
Hyperparathyroidism Associated with Distal Tubular Dysfunction but Intact Reabsorption of Protein in the Proximal Tubules Lars Wibell, Per Anders Dahlberg and Anders Karlsson From the Department of Internal Medicine, University Hospital, Uppsala Sweden
ABSTRACT. The urinary output of /3,-microglobulin was measured in ten hypercalcemic patients undergoing surgery because of hyperparathyroidism. In three subjects the &-microglobulin excretion was abnormally increased and in seven patients it was normal before surgery. Three of these seven patients displayed markedly impaired distal tubular function with a reduced urinary concentrationcapacity. After surgery all patients became normocalcemic and the urinary concentrating capacities improved. The P,-mciroglobulin excretion, on the other hand, remained unchanged. Thus, hypercalcemia per se does not readily affect the proximal tubular function of reabsorbing low molecular weight proteins. “Tubular proteinuria”, if found in patients with hypercalcemia, should he suspected to reflect damage to the kidney by additional mechanisms.
et al. (20) have found mixed proteinuric patterns by electrophoresis of urinary protein in five patients with parathyroid adenomas. We have investigated the influence of hypercalcemia on the proximal renal tubules by following the urinary output of P,-microglobulin in patients undergoing surgery because of HPT. p2microglobulin (mol. wt. 11 800), first isolated from the urine of patients with renal tubular disorders (4), is one of the major LMW proteins of “tubular proteinuria”, and as such, a sensitive marker of protein reabsorption in the proximal renal tubules (19, 23).
PATIENTS Ten patients with hypercalcemia and probable HPT were selected for the study. Patients with a history of recurrent Key words: hyperparathyroidism, hypercalcemia, p2- kidney stones or infections in the urinary pathways were excluded since obstruction and infection, particularly if microglobulin, kidney function. connected with hypercalciuria or renal tubular acidosis, Acta Med Scand 206: 507. 1979. may be associated with an abnormal excretion of LMW proteins ( 5 , 12, 13, 15). In seven of the patients a diagnosis of HPT was not suspected until a routine serum calcium determination was performed and disclosed a high value. Hyperparathyroidism (HPT) is sometimes ac- Patients 3 and 8 had suffered single episodes of renal colic. companied by kidney dysfunction, in general attrib- These patients and patient 9 had minimal kidney calcificauted to a diffuse calcium nephropathy (8). When tions at urography. Patient 5 had a non-functioning left kidney after a complicated nephrolithotomy 15 years ago. the glomerular filtration rate is impaired (14, 18), it In all other patients X-ray investigations of the kidneys seldom improves after parathyroidectomy . In con- were normal. Laboratory findings are presented in Table I. Protrast, the common impairment of the renal concentrating ability is often reversed after correction nounced hypercalciuria was present in patients 1-3 and moderate hypercalciuria in two of the other seven subof the hypercalcemia (7, 11). jects. Most patients had an increased phosphate excretion, It has been claimed (6) that a selective urinary and, when tested in patients 5-10, pathological urine phosexcretion of low molecular weight (LMW) proteins, phate responses to calcium infusion, as in HPT (22), were “tubular proteinuria” , can be present in patients found in five cases. The ability to produce concentrated with HPT-and be reversible during the months urine was subnormal in all subjects, and markedly low urinary osmolalities were noted after pitressin tannate adfollowing parathyroidectomy . Hayslett et al. (13) ministration in patients 1-3. Serum alkaline phosphatase have described three hyperparathyroid subjects with normal serum creatinine values and increased Abbreviations: HPT = hyperparathyroidism, LMW = low excretions of lysozyme (mol. wt. 14000). Revillard molecular weight. Aclu
Mrd SrNnd 206
SO8
L. Wibell et cil.
Table I . Laboratory,finding.s With the exception of tubular reabsorption of phosphate (TRP) and maximal osmolality, the laboratory data represent th mean of 2-5 determinations S-Ca (mmol/l) Pat. no.
Sex
(Y.)
Preop.
Postop."
U-Ca (mmoll 24 h)
P P 0
53 51 52 73 66 72 68 26 64 69
3.4 3.3 3.1 3.0 3.0 2.9 2.9 2.9 2.9 2.8
2.3 2.4 2.5 3.5 2.5 2.5 2.3 2.4 2.3 2.4
15 17 15 5 2 4 10 8 6 3
Age
1
2 3 4
0
Y
6
6 7 8 9 10
0 0 0
6 0
Reference values
2.2-2.6
Max. osmol! S-creat. (mOsm/kg) (pmol/l) 375 530 465 670 630 690 600 780 680 710
0.6-5.0
>750
CC,,,, (ml/min/ I .73 m')
S-P (mmol/l)
82 70 72 110 187 83 75 75 76 106
80 120 140 70 45 70 115 95 55
0.6 0.6 0.7 0.8 0.8 0.8 0.6 0.8 0.8 0.8
64-106
75-150
0.8-1.4
60
Determined 5 months after surgery. Determined with a Knaur Osmometer. Urine collected after water restriction and injection of pitressin tannate. ' Determined after infusion of calcium (22), N = normal, P =pathological. This patient, who had only one functioning kidney, displayed moderate proteinuria (0.5 g albumid24 h) and reducec glomerular filtration rate.
was slightly elevated in two patients. X-ray investigations of the skeleton revealed an unequivocal bone disease in patient 10, with osteopenia and subperiosteal erosions. Vascular calcifications of the Moenckeberg type (21) were apparent in patient 3. The diagnosis of HPT was corroborated in all patients by thorough examination of removed parathyroid tissues. Expert evaluation of parathyroid glands was performed by L. Grimelius. Single adenomas were found in 9 patients, one of whom also had two hyperplastic glands, one patient had two hyperplastic and two normal glands. Postoperatively, the levels of serum and urinary calcium were normalized in all patients. When investigated five months postoperatively, the urinary concentration ability after pitressin tannate administration was improved in all ten subjects, although in six patients the values of urinary osmolality were still subnormal, in the range of 650-750 mOsm/kg.
METHODS &-Microglobulin was determined with a radioimmunoassay kit (9) (Phadebas, Pharmacia, Uppsala). All other analyses were carried out with the routine procedures in use at the Laboratory of Clinical Chemistry, University Hospital, Uppsala. Only single urine specimens with a pH above 5.8 were accepted for study, since at low pH degradation of /32-microglobulin frequently occurs (10). Urines were stored at -20°C until analysis. The urinary excretion of &-microglobulin was expressed as a ratio of p2microglobulin to creatinine in order to minimize the variation among samples caused by differences in diuresis (23). Ai'ltr
Mod
Swiid
206
RESULTS AND DISCUSSION The urinary /3,-microglobulin/creatinine ratio before parathyroidectomy , during the postoperative days and at the follow-up five months postoperatively, are shown in Fig. 1. Before surgery the excretion of /3,-microglobulin was of normal magnitude in seven patients. Three of these patients (nos. 1-3) had the most pronounced hypercalcemia and hypercalciuria, and the lowest maximal urinary osrnolality after pitressin tannate administration. At the follow-up these seven patients had p2microglobulin excretion similar to that found before the operation. Thus, patients with HPT may have hypercalcemia, hypercalciuria and a reduced concentration capacity but still retain a normal capacity for reabsorption of LMW proteins in the proximal renal tubules. Three of the investigated patients, cases 5 , 7 and 10, had an abnormal excretion of /3,-rnicroglobulin. It is clear that the amount of &-microglobulin in the urine of these cases did not correlate to the serum calcium level or to the maximal urinary osmolality. This supports the concept that an impaired concentrating capacity is secondary to hypercalcemia, and in part due to functional changes, rather than to structural alterations and microscopic nephrocalcinosis in the kidney (3, 8, 11).
Hyperparathyroidism and tubular dysfunction PREOP
POSTOP I I
02 p I CREATlNlNE
(pglmg
3asal
After Ca+“
S-alk. phosph. (pkat/l)
)4 i4 14 ,5 ,5 8 44
15 N 87 P 17 P 83 P 86 P 77 P
4.5 4.5 4.3 2.6 2.2 6.4 3.4 2. I 8.6 5.5
70 37
34 38 85-95
5000
first week I 5 months
I I
103)
FRP (%)
509
I
-
2000 I
/
\ ;
1000 -
500 -
0.8-4.8
200 NO& AL RANGE
I
I
loo -I
I
I
I
I
Fig. I . Urinary excretion of @,-microglobulin before and A temporary postoperative increase in the µglobulin excretion was observed in three patients (nos. l , 6 and 7). This finding may be analogous to the high excretion of LMW proteins observed in patients after major surgical intervention (24) and in patients with large burns (1). The mechanism of such proteinuria is not known. Possibly, the postoperative catabolic phase induces a load on the kidney of LMW substances. Such molecules could interfere with proximal tubular function in much the same way as an infusion of basic amino acids causes tubular proteinuria (17). In previous reports (6, 13, 20) on LMW proteinuria in patients with HPT, no details were given concerning renal stones or associated kidney disease. In patients with kidney stones, but without HPT, a surprisingly high incidence-up to 80 %-of LMW proteinuria has been reported as lysozymuria (15) or hyperinsulinuria (5). In the latter of these studies, all patients had spinal cord injuries. Thus, bacterial pyelonephritis is likely to have been a common finding. In a recent study of consecutive subjects with recurrent stone disease, seen in an outpatient clinic ( 2 ) , less than 10% of the patients displayed an elevated excretion of p,-microglobulin. Our results suggest that hypercalcemia per se
after parathyroidectomy in ten patients with primary HPT. The data are presented as the ratio of @,-microglobulinlcreatinine.
does not interfere with the protein reabsorbing capacity of the kidney tubules. As reabsorption of filtered proteins mainly occurs in the proximal tubules (16), our findings are consistent with the observations that pathological calcifications in hypercalcemia first occur in the distal part of the nephron, such as the collecting ducts and the ascending limb of Henle’s loop (8). Clearly, “tubular proteinuria” is not an early or obligatory finding in patients with HPT. When LMW proteinuria is found, a complicating kidney disorder should be looked for.
ACKNOWLEDGEMENT This study was supported by a grant from Tore Nilsson Foundation.
REFERENCES I . Arturson, G., Evrin, P. E. & Wibell, L.: Renal function studies in patients with extensive burns. Medicinsk Riksst2imma 1973. Svenska Lakarsallskapet, Stockholm, Abstract KI 40: 196, 1973. Acta
Med Scrrnd 206
510
L . Wibell et
cil.
2. Backman, U., Danielsson, B. G. & Sothell, M.: Urinary excretion of P,-microglobulin in renal stone patients under normal conditions and during acidosis and alkalosis. Scand J Urol Nephrol (Suppl) 35: 79, 1976. 3 . Bech, N., Singh, H., Reed, S. W., Murdangli, H . V. & Davis, B. B.: Pathogenic role of cyclic AMP in the impairment of urinary concentrating ability in acute hypercalcemia. J Clin Invest 54: 1049, 1974. 4. Bergghd, I. & Bearn, A. G.: Isolation and properties of a low molecular weight P,-globulin occurring in human biological fluids. J Biol Chem 243: 4095, 1968. 5 . Ching, K. N . , Karam, J. H., Choy, F. B., Kolb, F. O., Grodsky, G. M. & Forsham, P. H.: Hyperinsulinuria in patients with renal calculi. Clin Chim Acta 5217: 383, 1972. 6. Dent, C. E.: The Balkan nephropathy (ed. G. E. Wolstenholme and J . Knight), p. 108. Ciba Foundation, Boston 1967. 7. Edvall, C. A,: Renal function in hyperparathyroidism. Acta Chir Scand (Suppl) 229, 1958. 8. Epstein, F. H.: Calcium and the kidney. Am J Med 45: 700, 1968. 9. Evrin, P. E., Peterson, P. A., Wide, L. & BerggArd, I.: Radioimmunoassay of P,-microglobulin in human biological fluids. Scand J Clin Lab Invest 28:439, 1971. 10. Evrin, P. E. & Wibell, L.: The serum level of p2microglobulin in apparently healthy subjects. Scand J Clin Lab Invest 29: 69, 1972. 1 1 . Gill, J. R. & Bartter, F. C.: On the impairment of renal concentration ability in prolonged hypercalcemia and hypercalciuria in man. J Clin Invest 40: 716, 1961. 12. Hall, P. W. & Vasiljevic, M.: Beta,-microglobulin excretion as an index of renal tubular disorders with special reference to endemic Balkan nephropathy. J Lab Clin Med 81: 897, 1973. 13. Hayslett, J. P., Perillie, P. E. & Finch, S . C.: Urinary muramidase and renal disease. N Engl J Med 279: 506, 1968. 14. Hellstrom, J., Birke, G. & Edvall, C. A,: Hypertension in hyperparathyroidism. Br J Urol 30: 13, 1958.
15. Kregzde, J., Lamberg, L. L. & Davidson, W. D.: Lysozymuria in renal calculosis following spinal cord injury. Urol Int 24: 310, 1969. 16. Maunsbach, A. B.: Ultrastructure and digestive activity of lysosomes from proximal tubular cells. In: Proc. 4th Int. Congr. Nephrol., vol 1, pp. 102-115. Karger, Basel 1969. 17. Mogensen, C. E., Solling, K. & Vittinghus, E.: Increased urinary excretion of albumin, light chains and &-microglobulin after intravenous arginine administration in normal man. Lancet 2: 581, 1975. 18. Olsson, L.: Primary hyperparathyroidism, a study of 160 patients. University of Gothenburg dissertation, Gothenburg 1975. 19. Peterson, P. A,, Evrin, P. E. & BerggBrd, 1.: Differentiation of glomerular, tubular, and normal proteinuria: determinations of urinary excretion of & microglobulin, albumin, and total protein. J CIin Invest 48: 1189, 1969. 20. Revillard, J. P., Manuel, Y., Francois, R. & Traeger, J.: Renal diseases associated with tubular proteinuria. In: Proteins in normal and pathological urine (ed. Y. Manuel, J. P. Revillard and H. Betuel), pp. 209-219. Karger, Basel 1970. 21. Tatler, G. L. V., Baillod, R. A., Varghese, Z., Young, W. B., Farrow, S., Wills, M. R. & Moorhead, J. F.: Evolution of bone disease over 10 years in 135 patients with terminal renal failure. Br Med J 4:315, 1973. 22. Wibell, L., Johansson, H. & Werner, I.: The use of calcium infusion test in the diagnosis of hyperparathyroidism. Scand J Clin Lab Invest 30: 183, 1972. 23. Wibell, L. & Karlsson, F. A,,: The urinary excretion of P,-microglobulin after the induction of a diuresisa study in healthy subjects. Nephron 17: 343, 1976. 24. Wide, L. & Thoren, L.: Increased urinary clearance for albumin, &-microglobulin, insulin and luteinizing hormone following surgical or accidental trauma. Scand J Clin Lab Invest 30: 275, 1972.
