Renal scintigraphy in insulin-dependent diabetes mellitus: Early glomerular and urologic dysfunction

Original Articles

Renal Scintigraphy in Insulin-Dependent Mellitus: Early Glomerular and lirologic

Jean-Yves Poirier, MD Annick Moisan, PhD Joseph Le Cloirec, MD Christine Siemen, MD Jacqueline Yaouanq, MD Gilles Edan, MD Jean-Yves Heny, MD, PhD Clinique Mkdicale B, Hopital-Sud, Rennes, France Service de Me’decine Nuckaire Pontchaillou, Rennes, France

Diabetes Dysfunction

ABSTRACT Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by intravenous injection of ssmTc-diethylenetriaminepentaacetic acid (DTPA) and ‘311-Hippuran in 115 insulin-dependent diabetic patients with albumin excretion rates (AER) <200 Pglmin, and in 45 normal subjects. Separate kidney function and urinary elimination were estimated by renography. GFR was increased in the diabetic patients (152 f 24 ml/min/l.73m2 vs. 128 & 15) and correlated significantly with RPF (r = 0.5; p < lo-‘). No relationship was found between GFR and the duration of diabetes, blood glucose, HbA,,, or AER. Fifty patients were hyperfiltering with RPF and filtration fraction higher than those in the normofiltering group. Slow intrarenal or pyeloureteral elimination, either unilateral or bilateral, was observed in 3 controls and 80 diabetic subjects (24 hyperfiltering; 38 normofiltering) and did not disappear with the patient in the standing position. In these 80 patients, mean age, duration of diabetes, blood glucose, HbA,,, 24 h albumin excretion rate, and frequency of peripheral or autonomic neuropathy did not differ from patients with normal scintigraphy; GFR was lower in the group with slow elimination, but not significantly so. ““Tc-DTPA renal uptake was symmetric in all the controls; asymmetric renal uptake with asymmetric GFR was observed in 13 patients (7 hyperfiltering; 6 normofiltering) and often associated with slower elimination. No evidence for renal stenotic atheroma or parenchymatous disease was found on the angiopyeloureterography. The results suggest that incipient uropathy is a very common phenomenon that occurs irrespective of glomerular dysfunction. (The Journal of Diabetic Complications 4; 3:113-118, 1990.)

INTRODUCTION

Reprint requests: Dr. Jean-Yves Poirier. Clinique Mbdicale B; Hopital-Sud; Boulevard de Bulgarie, BP 22129, 35056 Rennes, France. Submitted for publication on August 1989: accepted in revised form February i. ac8n “I”.

0 1990 Elsevier Science Publishing 0891~6632/90/$3.50

Co., Inc.

The glomerular filtration rate (GFR) may be elevated in insulin-dependent diabetic patients.‘,’ A recent study suggests that increased GFR plays a role in the initiation and progression of clinical nephropathy and that glomerular function declines at a much faster rate in hyperfiltering than in normofiltering patients.3 On the other hand, many reports suggest that bladder dysfunction is quite common in diabetic patients many years before atony and urinary retention appear.4l5 This study was undertaken to evaluate, by renal scintigraphy, the glomerular hemodynamics and urinary excretion of 99mT~-DTPA in 115 Type I insulin-dependent diabetic patients without overt nephropathy.

SUBJECTS AND METHODS Subjects:

Type I insulin-dependent diabetic pawere entered into the study from September 1985 to March 1989. The criteria for inclusion were: 1) age less than 50 years (mean: 33 2 10.6); 2) duration of diabetes exceeding 1 year (mean: 11 * 8); 3) no history of uropathy or nephropathy; 4) albumin excretion rate less than 200 pg/min; 5) no medication other than insulin; and 6) blood pressure less than 150/85 mmHg. At the time of tients

One hundred

fifteen

(56 men and 59 women)

113

114

POIRIERET/IL.

exploration none of the patients had ketonuria. Diabetic retinopathy was present in 30 patients; 15 had peripheral neuropathy (decrease or loss of at least one of the lower limb reflexes). None had clinically evident signs of autonomic neuropathy. The control group consisted of 45 subjects with no history of uropathy or arterial hypertension (men: 29; women: 16; age: 29 i- 6.2 years).

dent’s t-test. Wilcoxon rank test was used for values that are not normally distributed; linear regression was used when appropriate. The frequency of morphologic abnormalities was studied by Chi-square test. Statistical significance was set at p < 0.05.

Methods:

Mean GFR and FF were higher in the diabetic group than in the control group (152 + 24 mllmin vs. 128 ? 15; t = 6.328; p < lo-’ and 27.7% 2 4.8 vs. 25 ? 4.6: t = 3.241; p < 0.01); RPF was not significantly different (558 2 104 ml/min vs. 518 2 89). A significant relationship was found between GFR and RPF (r = 0.50; p < lo-‘), but there was no correlation between GFR and blood glucose, HbA,,, AER, or duration of diabetes. The upper normal limit for GFR in diabetic patients was defined as the mean of the control group + 2 SD (158 ml/min). This limit was used to separate two groups: a hyperfiltering one with GFR 2 158 (Group I: 50 patients) and a normofiltering one with GFR < 158 (Group II: 65 patients). No difference was observed between these two groups with regard to age, duration of diabetes, blood glucose, HbA,,, or AER (Table 1). RPF and FF glucose were significantly higher in Group I than in Group II (t = 3.843, p < 10p3; t = 4.4, p < 10p4). Mean plasma creatinine was lower in the hyperfiltering patients (t = 3.254, p < 0.01). The correlation between GFR and RPF was higher in Group II (r = 0.57; t = 5.506; p < lo-‘) than in group I (r = 0.28; t = 2.02; p < 0.04). Renal QQmT~DTPA excretion was normal and symmetric in 51 diabetic patients (Figure 1). Slow intrarenal or pyeloureteral elimination (Figure 2a) was found in 60 patients, but only 3 control subjects (Chi-square = 29,8, p < lo-‘). In the diabetic patients, stasis was bilateral (n : 23) or unilateral (right kidney = 24; left kidney = 13). In the standing position the stasis was still present in the diabetic patients (Figure 2b) but dissappeared quickly in the 3 control subjects in which it was seen. As shown in Table 2, neither age, duration of diabetes, blood glucose, HbA,,, nor AER was significantly different relative to the results of renal QQmTc-DTPAelimination. GFR was lower in the patients with slow renal elimination than in those with normal scintigraphy, but the difference was not significant (t = 1.325). The frequency of slow renal elimination was: 1) similar in Groups I(48%) and II (59%) (Chi-square = 1.668; NS); and 2) slightly higher in women (n = 36) than in men (n = 24; Chi-square = 3.91; p < 0.05). The

The subjects were supine on the examination table above the gamma camera, with the heart and kidneys within the detection field. Ten MBq of ‘311-Hippuran followed by 300 MBq of QgmTc-DTPA (diethylenetriaminepentaacetic acid) were administered by bolus injection after blood sampling to measure plasma glucose. The absence of radioactivity at the site of injection was visualized by the gamma camera. Blood samples were drawn from the contralateral arm at 3, 5, 7, and 10 min postinjection, and then every 10 min for 1 hr. Each sample was divided into 2 aliquots of 1 ml of plasma, and the radioactivity measured. The plasma curve representing the decrease of ‘3’I-Hippuran expresses renal plasma flow (RPF); that of ““Tc-DTPA, the GFR. The GFR/RPF ratio corresponds to the filtration fraction (FF). All results were calculated for a standard body surface of 1.73m2. Sapirstein’s bicompartmental model6 was used to calculate 13’1-Hippuran and ““Tc-DTPA clearances. Clearance for each kidney was calculated from the overall plasma clearance, as was the ratio of the slopes on the nephrogram between the first and third min.‘,* The gamma camera was set at the ggmT~peak of 140 kev and was interfaced with a data-processing system. Ninety images at 20 set each were recorded, and the scans were printed on a multi-imager. At the 60th min, a static image lasting 2 min was obtained with the patient standing. Renal scintigraphy was performed in 111 of the 115 patients (54 men; 57 women). HbA,, was measured by ion exchange chromatography on microcolumns, with temperature controlled, at three points (normal range: 3.4-6.1%). Albumin excretion rate (AER) was measured by immunonephelemetry laser' from a 24 h urine collection obtained on the day before renal scintigraphy. If necessary, renal scintigraphy was completed by conventional cardiovascular tests to check autonomic neuropathy” and venous angiopyelourography.

Statistical Analysis: The results are expressed as mean values ? SD. Means were compared by the unpaired StuTABLE 1

Characteristics

n Group I GFR 2158 Group II GFR ~158

50

Patients

Age

Diabetic duration

HbA,,

Blood glucose

(years)

(years)

(%)

(mg/dL)

AER (pg/min)

32 9.5 34 k11.5

11 28 12 k8

7.85 k2.18 7.65 11.56

194 z!I 76 205 2171

10.4 + 19.3 13.5 Ik31

i 65

of the 115 Diabetic

* p < 0.01. t p < 0.001. * p < 0.0001. Note: Renal scintigraphy

performed

RESULTS

Creatinine (mg/dL) 840 2169 949* k-158

GFR

RPF

(ml/min 1.73 m’)

(ml/min 1.73 m’)

175.2 15.5 134.6 + 12

k

598 93 527t 2102

k

Slow elimination

Asymmetric

FF

n

%

GFR n

29.8 4.8 26.14 4 4.2

23

48

7

37

59

6

i

in 111 patients (Group I, n = 48; Group II, n = 63). p values from Student’s

t-tests.

115

RENAL SCINTIGRAPHY IN IDDM

FIG. 1 Normal ggmTc-DTPA renal scintigraphy (posterior view); symmetric renal uptake (l-3 min) and normal excretion (28-30 min).

tests for autonomic neuropathy were normal in all but one of the patients with slow excretion. was symmetric in 98 paRenal uptake of ““Tc-DTPA tients and in all the control subjects. An asymmetric renal with asymmetric GFR was found uptake of ““Tc-DTPA, on renal scintigraphy in 13 diabetic patients (4 men and 9 women; Chi-square = 1.88; NS) (Figure 3). Their mean GFR, RPF, and FF did not differ from those of the 98 patients with symmetric renal uptake (Table 2). Seven were hyperfiltering, and six were normofiltering. GFR was lower in the right (69.4 +- 19.6) than in the left kidney (90.8 2 21.7) for 12 of these patients (t = 2.638 p < 0.02). Slow intrarenal or pyeloureteral excretion was associated in 10 of these 13 patients, particularly in the kidney with the lower GFR (Figure 3).

DISCUSSION To our knowledge, this is the first study showing impaired renal excretion and asymmetric GFR in insulin-dependent diabetic patients without overt nephropathy. Our

TABLE 2

Characteristics

of the 111 Diabetic

Patients

data demonstrate that slow intrarenal or pyeloureteral elimination is frequent, although the underlying mechanisms are not clearly understood. The supine position may cause abnormalities in the excretory phase of the renogram, but this does not account for the fact that slow elimination is statistically less frequent in the control subjects in the same position. It should be emphasized that the standing position failed to accelerate renal excretion in the diabetic group, whereas it did so in control subjects. Early functional uropathy is frequent in diabetes mellitus, but the only one reported to date is bladder distention found in streptozotocin-diabetic rats 8 weeks after the onset of diabetes5 and in diabetic patients with or without neurologic dysfunction.4,” It has been suggested that osmotic polyuria may result in bladder distention, and that autonomic neuropathy could later lead to bladder atony and urinary retention.” Several studies1’.13.14 have reported a correlation between the presence of bladder dysfunction and signs of peripheral neuropathy. In the present study, we demonstrate a new sign of functional uropathy. We did not, however, find a

According to ““Tc-DTPA

Scintigraphy

g9mT~-DTPA Renal Uptake

Statistical significance

gOmT~-DTPA Elimination

Symmetric

Asymmetric

33YlO 11.2 ? 8.2 7.80 + 1.95 205 -c_90 13.4 k 28 915 ” 169 150 2 23.8 550 k 100 27.8 5 5

31.6 10.7 7.66 180 4.72 892 160 578 27.5

Patients (n) Age (yr) Diabetes duration (yr) HbA,, (%) Blood glucose (mgldl) AER (pgimin) Creatinine (mg/dL) GFR (ml/min, 1.73 m*) RPF (ml/mm, 1.73 m*) FF (GFWRPF)

NS

13 2 f -t+ ” + 2 t i

Results

11.2 5.4 1.3 173 5.9 135 30 83 3

Normal

32 11 7.85 211 13 915 154 565 27.8

Slow

51 2 9.3 -c 7.6 2 2.2 + 86 k 33 of: 180 2 23.5 * 98 2 5.1

31.5 11.3 7.70 194 12 892 148 544 27.7 NS

60 * 12 % 8.3 * 1.6 + 92 ‘- 20 f 158 k 24 r+_99 _’ 4.6

116

POIRIERET/IL.

FIG. 2 (a) Bilateral stasis (po sterior view, supine position). &I) The standTc ing position fails to accelerate 99rn excretion in the left kidney.

relationship between slow renal excretion and peripheral or cardiovascular autonomic neuropathy, although we cannot completely rule out the possibility of an incipient autonomous neuropathy of the urinary tract. Another possible explanation of the incidence of stasis in diabetic patients could be kidney enlargement, which results n distention of the collecting system. Asymmetric renal uptake, with asymmetric GFRs, is the other original result of our study. Such images are usual in cases of stenotic renal artery atheroma, obstruction of

the urinary tract, and after pyelonephritis. The 13 patients with asymmetric GFRs had no medical history of such disorders. Furthermore, angiopyelourography revealed no arterial or parenchymatous abnormalities, apart from the asymmetric kidney size and slow excretion demonstrated by renal scintigraphy. A significant positive correlation between GFR and kidney size has been noted in short-term diabetic patients.2B’5 The extent to which this morphologic change contributes to the increased glomerular filtration rate remains to be determined, espe-

117

RENAL SCINTIGRAPHYIN IDDM

ggmT~-DTPA FIG. 3 Asymmetric renal uptake (posterior view; left kidney larger than right one) and sfasis in the ieft kidney.

cially since the fall in GFR induced by initial insulin treatmenti or by long-term improvement of metabolic control” appears without or before a reduction in kidney size. Our data, showing an increased glomerular filtration rate in diabetic patients without overt nephropathy, are lz51similar to those obtained with other markers: inulin,’ iothalamate,21’8 and 5’Cr-EDTA.‘g.20 ““Tc-DTPA is a well known marker of GFR, and its reliability has been demonstrated by comparison with the same methods.2’-23 It should be stressed that its accuracy depends upon the use of a bicompartmental system6f24 and strict adherence to the time interval between blood sampling over the 1 hr period. When compared with other methods of renal ““Tc-DTPA combines three advantages: investigation, simultaneous measurement of renal plasma flow with ‘3’l-Hippuran, information on the urinary tract by renal scintigraphy, and above all, measurement of GFR without urine collection. This last point is of interest in view of the high frequency of urinary stasis in our patients. In the present study, we found no relationship between GFR and the duration of diabetes; furthermore, we observed an increased GFR in several long-term diabetic patients with normal albumin excretion rates. This particularity has been reported by Mogensen”25 and raises the question as to whether elevated GFR is of predictive value in such patients since the risk of nephropathy decreases 30 years after the onset of insulin-dependent diabetes.26 The relationship between GFR and blood glucose remains controversial. Mogensen found no correlation,’ but other authors have described a significant correlation between GFR and plasma glucose values of less than 14 mmol/L. *’ Our findings are in agreement with those reported by Mogensen, even if we separate severe from mild hyperglycemia. Moreover, there was no correlation between GFR and HbA,,; this result is not

surprising in view of the potentially acute changes in renal hemodynamic parameters. In conclusion, urinary tract dysfunction is very common in insulin-dependent diabetic patients without any signs of overt nephropathy or uropathy. Slow excretion occurs irrespective of the increased glomerular filtration rate, renal plasma flow, or duration of diabetes. The relevance of this urinary dysfunction in the progression of diabetic nephropathy deserves further investigation.

ACKNOWLEDGMENTS This work was supported by grants from the University of Rennes (Recommandation Bl*-Direction de la Recherche). The technical assistance of Anne Trichet and Raymonde Kiner is gratefully acknowledged.

REFERENCES 1. Mogensen CE: Glomerular filtration rate and renal plasma flow in short-term and long-term juvenile diabetes &ellitus. Stand J C/in Lab invest 28:91-100. 1971. 2. Christiansen JS, Gammelgaard J, irandsen M, Parving HH: Increased kidney size, glomerular filtration rate and renal plasma flow in short-term insulin-dependent diabetics. Diabetologia 20:451-456, 1981. 3. Mogensen CE, Christensen CK: Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med 311:8993, 1984. 4. Ellenberg M, Weber H: The incipient asymptomatic diabetic bladder. Diabetes 16:331-335, 1967. 5. Lincoln J, Crockett M, Haven AJ, Burnstock G: Rat bladder in the early stages of streptozotocininduced diabetes: Adrenergic and cholinergic innervation. Diabetologia 26:8187, 1984. 6. Sapirstein LA, Vidt DG, Mandel M: Volumes of distribution

and clearances of intravenously injected creatinine in the dog. Am J Physiol181:330-336, 1955.

POIRIERETAL.

7. Chevet D, Moisan A, Le Pogamp P, Le Cloirec J, Wehbe B, Herry JY: Correlation between ggmT~-DTPAclearance, percentage ggmT~-DMSAfixation and creatinine clearance. Nephrologie 521-25, 1984. 8. Chanard J, Ruiz JC, Liehn JC, et al: Assessment of divided renal function by renography: Validation in patients with separate urine collections from each kidney. C/in Nephrol 18:291-296, 1982. 9. Dezier JF, Le Reun M, Leguerrier AM, Baudouard C, Jouanolle AM: Laser immunonephelemetry: A new method to measure microalbuminuria. Nouv Presse Med 15:398, 1986. 10. Edwing DJ, Campbell IW, Clarke BF: Assessment of cardiovascular effects in diabetic autonomic neuropathy and prognostic implications. Ann intern Med 92:308-311, 1980. 11. Ellenberg M: Development of urinary bladder dysfunction in diabetes mellitus. Ann Intern Med 92:321-323, 1980. 12. Buck AC, MC Rae CU, Reed PI, Chisholm GD: The diabetic bladder. Proc R Sot Med 67:81-83, 1974. 13. Bartley 0, Brolin I, Fagerberg SE, Wilhemsen L: Neurogenic disorders of the bladder in diabetes mellitus: A clinical roentgenological investigation. Acta Med Stand 180:187-199, 1966. 14. Buck AC, Reed PI, Siddiq YK, Chisholm GD, Fraser T: Bladder dysfunction and neuropathy in diabetes. Diabetologia 12:251-258, 1976. 15. Puig JG, Anton FM, Grande C, et a/: Relation of kidney size to kidney function in early insulin-dependent diabetes. Diabetologia 211363-367, 1981. 16. Mogensen CE, Andersen MJF: Increased kidney size and gtomerular filtration rate in untreated juvenile diabetes: Normalisation by insulin treatment. Diabetoiogia 11:221-224, 1975. 17. Wiseman MJ, Saunders AJ, Keen H, Viberti GC: Effect of blood glucose control on increased glomerular filtration rate and kidney size in insulin-dependent diabetes. N EnglJ Med 312:617-621, 1985.

18. Esmatjes E, Fernandez MR, Halperin I. et a/: Renal hemodynamic abnormalities in patients with short term insulindependent diabetes mellitus: Role of renal prostaglandins. J C/in Endocrinol Metab 60:1231-l 236, 1985. 19. Christiansen JS, Gammelgaard J, Tronier B, Svendsen PA, Parving HH: Kidney function and size in diabetics before and during initial insulin treatment. KidneyInt21:683-688,1982. 20. Wiseman MJ, Mangili R, Alberetto M, Keen H, Viberti GC: Glomerular response mechanisms to glycemic changes in insulin-dependent diabetics. Kidney/nt31:1012-1018, 1987. 21. Hilson AJ, Chir 8, Mistry RD, Maisey MN: ggmT~-DTPAfor the measurement of glomerular filtration rate. Br J Radio/ 49:794-796, 1976. 22. Barbour GL, Crumb CK, Boyd CM, Reeves RD, Rastogi SP. Patterson RM: Comparison of inulin, iothalamate and s9mTcDTPA for measurement of glgmerular filtration rate. J Nucl Med 17:317-320, 1976. 23. Bianchi C, Bonadio M, Donadio C: Measurement of glomerular filtration rate in man using DTPA-gQmT~.Nephron 24:174-178, 1979. 24. Walter DG, Keast CM, Fleming JS, Ackery DM: Measurement of glomerular filtration rate with Technetium QgmDTPA:Comparison of plasma clearance techniques. JNucl Med28:372377, 1987. 25. Mogensen CE: Glomerular filtration rate and renal plasma flow in long-term juvenile diabetics without proteinuria. Br Med J 4:257-259, 1972. 26. Andersen AR, Christiansen JS, Andersen JK, Kreiner S, Deckert T: Diabetic nephropathy in type I (insulin-dependent) diabetes: An epidemiological study. Diabetologia 25:496-501, 1983. 27. Wiseman MJ, Viberti GC, Keen H: Threshold effect of plasma glucose in the glomerular hyperfiltration of diabetes. Nephron 38:257-260, 1964.