journal of lnternal Medicine 1 9 9 0 ; 227: 317-24
Pre- and postoperative evaluation of renal function with five different tests in patients with primary hyperparathyroidism A. KRISTOFFERSSON, C. BACKMAN*, K. GRANQVISTt & J. JARHULT From the Department of Surgery. the *Department of Clinical Physiology and the fDepurtrnent of Clinical Chemistry, Umed University Hospital. Umed. Sweden
Abstract. Kristoffersson A, Backman C, Granqvist K, Jarhult J (Department of Surgery, Department of Clinical Physiology and Department of Clinical Chemistry, UmeB University Hospital, Umed, Sweden). Pre- and postoperative evaluation of renal function with five different tests in patients with primary hyperparathyroidism. Journal of Internal Medicine 1 9 9 0 : 227: 317-24.
Renal function was investigated immediately before and 1 year following parathyroidectomy in 1 9 patients with moderate hypercalcaemia. On both occasions, all patients underwent five different tests of glomerular and tubular function : plasma creatinine, creatinine clearance, 5'Cr-EDTA-clearance, p,-microglobulin excretion and the desmopressin test. Glomerular filtration rate. as assessed by plasma creatinine and clearance of both creatinine and 51Cr-EDTA, was normal in most patients. and was little affected by restoration of normocalcaemia. Renal concentrating capacity, as determined by the desmopressin test, was abnormally low in 14 of 1 9 patients, but increased significantly after surgery. It is concluded that serious renal damage is seldom encountered in present-day HPT patients, but that a treatable decrease in renal concentrating capacity often exists.
Keywords: glomerular filtration, hyperparathyroidism. renal concentrating capacity, renal function.
Introduction Impaired renal function is a well-known complication of primary hyperparathyroidism (HPT), but the incidence and severity of this impairment vary considerably in different reports. Such variation is probably due to both the heterogeneity of the patient sample studied and the different techniques used for estimation of renal function. In 1962, Hellstrom [l]reported that more than 90% of his HPT patients showed some degree of impaired renal function, and that parathyroidectomy improved renal concentrating capacity in 65% of patients. Whether or not present-day HPT patients also suffer from renal damage is not known. The main aims of this study were therefore (a) to define, using modern laboratory facilities, both glomerular
filtration and proximal and distal tubular function in HPT patients and (b) to determine whether any depression of renal function could be reversed by successful parathyroid surgery.
Material and methods Nineteen patients with verified HPT (median age 61 years, range 39-71 years) agreed to participate in the study. All patients harboured a single parathyroid adenoma and were relieved from hypercalcaemia postoperatively. The initial serum biochemistry of each patient, as well as age, sex and clinical presentation, is shown in Table 1. Eight patients had a history of renal lithiasis, but the preoperative intravenous pyelography revealed an intrarenal calculus (2 x 3 mm) in only one of them. No patient had 317
50 55 39 53
63 70 66
50
70 42
56
55
66
68
F
F F M F
F F
M F F
F
F
M
M
F
F
F
F
F
EA
AA VB JE HG
BG MJ
JL
ML SL
ML
KM
uo
EP
FP
Ep
MS
MS
vv
61
54
65 71
67
Sex
Patient
14 14 9 11
72 77 75 93 68
33 30 26 15 20 37 17 31
0.90 0.65
1.40 1.38 1.34
2.75 2.70 2.74 2.89
1.08-1.29 1.38
2.10-2.60 2.84
Normal range
Median value
5.9 1.5-7.5 5.3
0.82-1.50 0.73
24
< 50
4
4.2
0.78
1.33
2.66
0.65
3.1 0.83
1.44
2.68
-
76
24
6.6
0.76
-
2.92
2.98
66 17
5.1
0.73
1.29
35-80 (F) 80-100 (M) 75
91
75
27
3.3
0.71
4.5 16.0
3.6
0.79
2.84
83 72 72
22
1.41
-
2.62 2.71 2.92
70 98
-
-
10.0 11.0 5.3
1.38 1.34
2.67 2.86
11
< 10
12
7
7
20
8
11 6 12
10 21
3 2 11 14
72 74 87 90
37 14 24
13
Plasma PTH (pmol 1-l)
0.9 5.9 11.0
-
0.70 0.80 0.73
1.35 -
2.80 2.87 2.98 3.04
Plasma creatinine (pmol l-l) 98
Urinary phosphate (mmol 24 h-l) 9
2.4
6.4
0.73 0.55 0.59 0.66
1.37 1.46 1.53 1.51
3.05
Fatigue and neuromuscular Fatigue Arthralgia Hypertension Fatigue and neuromuscular Renal stone Fatigue and neuromuscular No symptoms Fatigue Fatigue and neuromuscular Fatigue and depression No symptoms Fatigue and arthralgia Fatigue and renal stone Fatigue and depression Fatigue and neuromuscular Fatigue and neuromuscular Fatigue and neuromuscular Fatigue and depression
Urinary calcium (mmol 24 h-')
0.65 0.88
0.77
1.52
Plasma calcium (mmol l-l)
Signs and symptoms at referral
Plasma phosphate (mmol I-')
Plasma ionized calcium (mmol 1-l)
Table 1. Preoperative symptoms and signs and serum and urinary biochemistry in 19 patients with primary hyperparathyroidism
I-
W
LD
03
R E N A L FUNCTION IN HPT
a renal disease or was suffering from any other serious disorder at the time of operation. Ten patients had arterial hypertension, eight of whom were under permanent medication. All patients were examined immediately before surgery and 12 months postoperatively. At follow-up all patients were normocalcaemic without calcium or vitamin D substitution. All pre- and postoperative investigations were performed during hospitalization. Serum and urinary calcium and phosphate concentrations were determined by standard laboratory methods. Serum ionized calcium was measured with an ion selective electrode (Kone Microlyte, Kone Corp., Espoo, Finland). Serum parathyroid hormone concentration was analysed by radioimmunoassay using an antibody directed against the N-terminal portion of the parathyroid molecule (N-tact PTH RIAR, Immunoclear Corp., USA). Serum and urinary creatinine concentrations were measured on an automated multichannel analyser by a method based on the reaction of saturated picric acid with creatinine under alkaline conditions. The following renal tests were carried out for each patient on both occasions : plasma creatinine level, creatinine clearance, "Cr-EDTA-clearance, p2microglobulin excretion and desmopressin test. Renal concentrating capacity was measured the morning after a 12-h overnight fast by administering 4 0 p g of desmopressin-acetate (Minirin, Ferring, Sweden) intranasally. The patients then provided two urinary specimens after 1 5 and 180 min, respectively. Reference values were obtained from Tryding et al. [2]. Clearance of endogenous creatinine was calculated on the basis of m1/1.73 m2 body surface area by measuring the creatinine concentration in urine collected over a period of 24 h and in a single blood sample. The normal value is assumed to be > 65 ml min-'. Urine µglobulin was measured with a competitive, double-antibody radioimmunoassay (Pharmacia Diagnostics, Uppsala, Sweden). The normal range of detection using this method is 4-3 70 p g I-'. Clearance of 'lCr-EDTA (ethylene-diamine tetraacetic acid) was calculated from a one-pool system as a single injection of Cr-EDTA labelled with 51Cr. Blood samples were withdrawn 180. 210, 240 and 2 70 min after injection of the isotope. The activity of the plasma, the injected solution and the background
319
was determined using a scintillation counter. Clearance was calculated as the ratio between the amount of 51Cr-EDTA injected and the total area under the plasma concentration curve according to BrochnerMortensen [3]. Clearance was expressed as ml/ 1.73 m2 body surface area, and normal values were obtained from Granerus [4].Statistical significance was assessed by Student's paired t-test and Wilcoxon's signed rank test for paired samples. Correlation was determined by means of Pearson's correlation coefficient.
Results The median plasma calcium concentration decreased from 2.84 mmol I-' to 2.32 mmol I-' postoperatively ( P < 0.001). The pre- and postoperative data on renal function are presented in Table 2 and summarized graphically in Fig. 1. There was no significant change in plasma creatinine concentration, creatinine clearance, 51CrEDTA clearance or urinary D,-microglobulin excretion in response to the correction of hypercalcaemia. Fourteen patients showed a depressed renal concentrating capacity preoperatively. One year after parathyroid surgery, complete normalization had occurred in seven patients, nine patients showed noticeable improvement, one patient's condition was unchanged, and a slight impairment was observed in two patients. With regard to the whole group, renal concentrating capacity was significantly improved one year postoperatively (P < 0.004). In the hypercalcaemic state before surgery there was no significant correlation between age and renal concentrating capacity. However, a significant relationship was observed between plasma calcium and urinary osmolality after desmopressin before surgery ( P < 0.05). Review of the literature Previous studies on renal function in HPT are summarized in Tables 3, 4 and 5. Reported data for improvement or impairment of renal function after parathyroidectomy, as assessed by the different renal function tests, are based on the judgements of the different authors.
A. KRISTOFFERSSON et al.
320
Table 2. Plasma creatinine. urinary osmolality after desmopressin. clearance of "Cr-EDTA and creatinine and excretion of /7,-microglobulin in 19 HPT patients before and after successful parathyroid surgery Creatinine clearance (ml min-')
P-creatinine (fimol I-')
"Cr-EDTA clearance (mi min-')
Urinary osmolality ( m o m kg-')
Urinary P,-microglobulin (fig
~~
Patient
Preop.
Postop.
FA AA VB JE HG BG MJ JL ML SL ML KM
98* 72 74 87 90' 70 98* 83 72 72 72 77 75 93 68 75 66 76 91*
114* 72 79 101* 80 78 91' 80 92* 77 63 67 84 105' 9 7* 77 90* 88* 96*
75
84
uo EP EP EP MS MS
vv Median value
Preop. -
96 155 71 90 52* 109 89 72 54* 195 95 118 85 95 88 77 90
Postop.
Preop.
Postop.
Preop.
Postop.
Preop.
Postop.
66
41 * 100 102 102 76 79 44* 95 65 71 137 60 117 85 60* 69 76 69* 58*
431* 624' 520' 643* 61 9' 747 614' 990 74 5 41 2* 699' 482' 746* 580* 409* 533' 71 4 637' 880
587. 779 760 782* 768 830 639* 981 784 678 745' 61 3' 872 446* 51 5' 789 588* 856 996
57 134 108 87 90 94 114 528' 117 148 105 105 79 78 75 4431 259 144 50
68 185 84
62' 53' 63*
41* 96 102 106 85 83 44; 82 68 70 112 53 103 75 79 61 63 68* 59'
80 88 52 65 82 173 127 16 93 132 216 212 1 I7 176
87
75
76
624
768
108
117
160 101
137 79 110 106 163 72 86 87 82 132 69 125 -
1 01
*Abnormal value.
Urinary
Creatinine
5'Cr -EDTA
Urinary
Plasma creatinine
P-2-microglobulin
clearance
clearance
osmolality
(pmol I-')
(pq I - ' )
( m l min-')
(ml min-')
(mosm k g - ' )
110
IT
'.'I T I
4
1000
-
90
80 70 60
800 -
600 -
50
40
400
-
200
-
30
20 I0
Fig. 1 . Concentrations of plasma creatinine and urinary &-microglobulin, clearance values of endogenous creatinine and "Cr-EDTA and urinary osmolality after desmopressin in 19 hypercalcaemic patients before and after parathyroidectomy. Median values and ranges are depicted. Asterisks indicate a significant ( P < 0.004) difference between the pre- and postoperative values. ( 0 )= before surgery. (M) = after surgery.
RENAL FUNCTION I N HPT
321
Table 3. Reported studies on serum creatinine concentration in patients with primary hyperparathyroidism
Author(s)
Year
N
Abnormal creatinine preop. (%)
Mathiesen et al. [20] Britton et al. [I 61 Johansson et al. [21] Chowdbury & Gray [22] Werner et a/. [23] Freany et a/. [24] Lins [25] Falkheden et a/. [26] Heath et al. [27] Lueg [28] Jones et al. [29] Ronni-Sivula & Sivula [30] Diamond et a/. 1311 Kristoffersson et al. [32] Niederle et a/. [33] Augustin et a/. [I 51 Present series
1967 1971 1972 1973 1974 1978 1978 1980 1980 1982 1983 1985 1986 1987 1986 1987 1988
60 52 208 15 129 40 5 64 90 23 62 334 35 311 176 31 19
35 6 25 27 19 33 60 13 16 17 27 12 37 8 15 16 21
Median value
Time after operation (months) 6-2 88 12-264 12-168 8-60 3-108 60 (mean) 41-180 12-72 24-240 12-312 3-108 6-264 6-168 12
Improved POStOP. (%I
Impaired POStOP. (%I
8 0 0 3 100
18 10
11
-
12 43 62 3 40 25 12
19
-
7 16 0 3
9 9 38 -
11 -
0
9
Table 4. Reported series on renal concentrating capacity as assessed by urine osmolality after thirst or desmopressin in patients with primary hyperparathyroidism
Author(s)
Year
N
Abnormal preop. value (%)
Edwall [5] Hellstrom & Ivemark [ l ] Lovice & Connor [34] Johansson et a/. [21] Olsson [6] Baylis et al. [7] Marx el al. [35] Kristoffersson et al. [32] Present series Median value
1958 1962 1963 1972 1970 1981 1981 1987 1988
20 104 15 208 22 10 18 114 19
100 80 93 20 86 60 70 70 74
-
74
-
Discussion This study has shown that HPT patients with moderate hypercalcaemia have a depressed renal concentrating capacity but a well maintained glomerular function. The decreased concentrating capacity had normalized in 50% of patients within 1 year after surgery, and in all other patients except three an improvement was observed when normocalcaemia was achieved. These findings are in agreement with other clinical studies [ l , 5-71. Inability of the kidneys to conserve water occurs both in HPT and in other forms of hypercalcaemia
Time after operation (months) 114-1 6 14 1/4-60 12-168 36-108 6