Original Article
Increase in Glomerular Filtration Rate in Patients with Insulin-Dependent Diabetes and Elevated Erythrocyte Sodium–Lithium Countertransport
N Engl J Med 1990; 322:500-505February 22, 1990
- Abstract
- Abstract
Increased sodium–lithium countertransport in erythrocytes is found in patients with insulin-dependent diabetes mellitus (IDDM) and nephropathy. To determine whether such an increase precedes the onset of nephropathy and, if so, whether it is associated with changes in renal function, we measured erythrocyte sodium–lithium countertransport in 52 patients with IDDM but not nephropathy or hypertension and in 32 control subjects.
Seventeen of the 52 patients with IDDM (33 percent) had sodium–lithium countertransport activity that exceeded the maximal activity in the control subjects (0.39 mmol of lithium per hour per liter of cells). Eighteen of the 52 patients with IDDM were studied in more detail. The 7 patients with raised sodium–lithium countertransport values had glomerular filtration rates (median, 159 ml per minute per 1.73 m2 of body-surface area; range, 134 to 197) that were significantly higher (P<0.01) than those in the remaining 11 patients with IDDM and normal sodium–lithium countertransport (median, 126 ml per minute per 1.73 m2; range, 110 to 176) or in the 10 control subjects (median, 128 ml per minute per 1.73 m2; range, 93 to 151 ). In the seven patients with elevated sodium–lithium countertransport, the filtration fraction (median, 0.27; range, 0.22 to 0.37) was also greater (P<0.01) than that in control subjects (median, 0.22; range, 0.18 to 0.28). There were no differences in renal function between the patients with IDDM and normal sodium–lithium countertransport and the control subjects.
We conclude that sodium–lithium countertransport is increased in patients with IDDM before the onset of nephropathy and is associated with hyperfiltration. Thus, elevated sodium–lithium countertransport activity may be an early marker of diabetic nephropathy. (N Engl J Med 1990; 322:500–5.)
Media in This Article
Figure 1
Erythrocyte Sodium–Lithium Countertransport in 32 Control Subjects and 52 Normotensive Patients with IDDM.Figure 2
Sodium–Lithium Countertransport and the Glomerular Filtration Rate in 18 Patients with IDDM (Rs = 0.55, P<0.01, Spearman Correlation Coefficient).Article Activity
- Article
IT is not clear why diabetic nephropathy develops in approximately one third of patients with insulin-dependent diabetes mellitus (IDDM), usually during the second decade of their illness,1 , 2 but it has recently been suggested that this complication is most common in patients with a family history of hypertension.3 4 5 Patients with diabetic nephropathy often have an elevation in blood pressure, which has been presumed to be a consequence of renal damage. However, the blood pressure in patients with IDDM and microalbuminuria is often raised before there is evidence of an impairment in renal function.6 7 8 9 In addition, 25 percent of these patients may have renal hemodynamic abnormalities, leading to an increase in the glomerular filtration rate and renal plasma flow early in the course of their disease.10 , 11 Any further disturbance in renal hemodynamics in diabetic patients with a family history of hypertension may lead to increased intraglomerular pressure and renal damage.3 , 4
Sodium–lithium countertransport in erythrocytes is increased in some patients with essential hypertension.12 The activity of this transporter is related to the presence of a family history of hypertension,13 14 15 16 17 18 and its increased activity in normotensive persons may indicate a predisposition to hypertension. In two recent studies, increased sodium–lithium countertransport was found in patients with IDDM and nephropathy, so that it may also indicate a susceptibility to diabetic nephropathy, especially in the presence of poor control of the diabetes.3 , 4
We studied normotensive patients with IDDM who had no nephropathy or microalbuminuria to determine whether sodium–lithium countertransport may be increased before the onset of nephropathy and whether such patients, who may be genetically predisposed to hypertension, have detectable changes in renal function.
Methods
Subjects
The protocol was approved by the joint ethics committee of the University of Newcastle upon Tyne and Newcastle Health Authority, United Kingdom. All study subjects gave informed, written consent.
Venous blood samples were taken for the measurement of sodium–lithium countertransport from 52 normotensive patients with IDDM, normal renal function, and no proteinuria who were attending a hospital diabetic clinic during a three-month period. Normal renal function was defined as a plasma creatinine level less than 124 μmol per liter, and proteinuria was considered to be absent if no protein was detectable in the urine with the use of Albustix (Boehringer–Mannheim). Normal blood pressure was defined as a diastolic blood pressure below 90 mm Hg and a systolic blood pressure below 160 mm Hg.
Of the 52 patients, 18 volunteered to take part in a more detailed study. Five were women, and 13 were men. Their median age was 36.5 years (range, 20 to 72), diastolic blood pressure was 70 mm Hg (range, 60 to 90), systolic blood pressure was 115 mm Hg (range, 73 to 132), and body-mass index was 26.0 (range, 21 to 29). The median duration of diabetes in this group was 11 years (range, 1 to 29), and the median glycosylated hemoglobin level was 8.4 percent (range, 5.4 to 10.7). None had microalbuminuria (overnight urinary albumin excretion less than 15 μg per liter on two occasions), and none were taking any drugs or hormones other than insulin. The group of 18 patients did not differ significantly from the original group of 52 patients with IDDM, which consisted of 26 men and 26 women with a median age of 33.4 years (range, 19 to 72), diastolic blood pressure of 77 mm Hg (range, 60 to 90), body-mass index of 24.1 (range, 21 to 30), glycosylated hemoglobin level of 8.4 percent (range, 5.4 to 11.3), and duration of diabetes of 12.3 years (range, 1 to 33).
We also studied a control group of 32 normotensive, normoglycemic subjects (17 men and 15 women; median age, 35 years [range, 20 to 54]) seen at a local general practitioner's office for routine examination. The sodium–lithium countertransport values of 15 of the control subjects have been published previously.15 All control subjects had a body-mass index of less than 25. None were receiving regular medication. Ten of the control subjects volunteered to take part in the more detailed study. None had microalbuminuria.
For the detailed investigation of renal function, the patients and control subjects were admitted to the ward in a fasting state. The patients with IDDM had not taken their morning dose of insulin. Height and weight were recorded and the body-mass index was calculated (weight in kilograms divided by height in meters squared). Blood pressure was measured in the hospital with a random-zero sphygmomanometer. The mean systolic and diastolic pressures (fifth phase) were obtained by averaging three readings taken after 30 minutes of supine rest. Venous-blood samples were drawn for the measurement of plasma glucose (glucose oxidase method, Astra systems glucose reagent kit), glycosylated hemoglobin (Corning electroendosmosis method; reference range, 5.0 to 7.5 percent), blood 3-hydroxybutyrate,19 serum C peptide,20 and plasma urea and electrolytes (Astra systems reagent kits). After the patients had been supine for two hours, blood samples were taken for the measurement of plasma renin activity (Rianen angiotensin I [125I] radioimmunoassay kit).
Measurement of Sodium–Lithium Countertransport
The method used to measure sodium–lithium countertransport was similar to that described by Canessa et al.12 Venous blood was collected in tubes containing lithium—heparin and centrifuged. The red cells were then incubated in a lithium-loading solution for one hour (140 mmol of lithium chloride per liter, 10 mmol of lithium carbonate per liter, 10 mmol of glucose per liter, and 10 mmol of TRIS acetate per liter). The erythrocytes were washed once in isotonic magnesium chloride and twice with choline medium (139 mmol of choline chloride per liter, 1 mmol of magnesium chloride per liter, 10 mmol of glucose per liter, and 10 mmol of TRIS acetate per liter; pH 7.4; 290 mOsm per kilogram). After the final washing, the packed-cell volume was measured, and 0.1-ml aliquots were incubated in either 0.6 ml of choline medium plus 10−4 mol of ouabain (sodium-free) per liter or 0.6 ml of medium containing sodium (145 mmol of sodium chloride per liter, 1 mmol of magnesium chloride per liter, 10 mmol of glucose per liter, 10−4 mol of ouabain per liter, and 10 mmol of TRIS acetate per liter; pH 7.4; 290 mOsm per kilogram). The mixtures were incubated at 37°C for 30, 60, and 90 minutes. After centrifugation at 2000×g for three minutes, 200 μl of the supernatant was withdrawn and added to 2 ml of distilled water and 0.75 ml of cesium chloride (45 mmol per liter). The lithium content of the supernatant was measured with an IL943 flame photometer (Instrumentation Laboratory). The sodium–lithium countertransport was determined by calculating the difference in lithium efflux from erythrocytes in the sodium-free and sodium-containing mediums and expressed as millimoles of lithium per hour per liter of red cells.
Measurements
For the measurement of the glomerular filtration rate, EDTA labeled with chromium-51 (2.2 MBq) was injected intravenously, and blood samples were taken two and four hours later. The glomerular filtration rate was calculated according to the method described by Morgan et al.21 For the determination of effective renal plasma flow, [125I] O-iodohippurate sodium (Hippuran; 1 MBq) was injected intravenously while the subject was supine. A single blood sample was taken 44 minutes after the injection. The effective renal plasma flow was calculated according to the method described by Tauxe et al.21 , 22 To assess the level of control of diabetes in this group, the glycosylated hemoglobin values recorded during the two years before the study were obtained from the patients' records. For patients who had had diabetes for less than two years, all glycosylated hemoglobin values were used. At least eight values were available for each patient, and these were averaged. Finally, for the measurement of urinary albumin excretion, 12-hour urine samples were collected on two consecutive nights from the 18 patients with IDDM and 10 control subjects. The urinary albumin concentration was measured by radioimmunoassay (double antibody kit, Diagnostic Products).
Statistical Analysis
The results were analyzed by one-way analysis of variance or the Mann—Whitney U test where stated. All results are expressed as the median values unless otherwise stated. All P values of less than 0.05 were considered to indicate significance.
Results
The sodium–lithium countertransport in the 52 patients with IDDM who were normotensive without proteinuria was significantly greater than that in the 32 control subjects (median, 0.33 vs. 0.24 mmol of lithium per hour per liter of cells; range, 0.13 to 0.59 vs. 0.02 to 0.39; P<0.01) (Fig. 1Figure 1
Erythrocyte Sodium–Lithium Countertransport in 32 Control Subjects and 52 Normotensive Patients with IDDM.). Seventeen of the 52 patients with IDDM (33 percent) had sodium–lithium countertransport values in excess of 0.40 mmol of lithium per hour per liter of cells. According to previous studies, these patients may be at risk for the development of diabetic nephropathy.3 , 4 Therefore, in the 18 patients with IDDM who were studied further, renal function was compared in the patients with elevated and those with normal sodium–lithium countertransport.Table 1Table 1
Median Glomerular Filtration Rate, Effective Renal Plasma Flow, Plasma Renin Activity, and Urinary Electrolyte Measurements in Patients with IDDM and Elevated or Normal Sodium–Lithium Countertransport and Control Subjects. shows the results of renal-function tests in these two groups and in the 10 control subjects. When analysis of variance was used, the only indexes of renal function that varied among the three groups were the glomerular filtration rate (F = 9.44, P<0.001) and filtration fraction (F = 3.78, P<0.05). The glomerular filtration rate was significantly higher (P<0.01) in the 7 patients with IDDM and elevated sodium–lithium countertransport than in the 11 patients with IDDM and normal countertransport or in the 10 control subjects (Table 1). The glomerular filtration rates were similar in the patients with IDDM and normal sodium–lithium countertransport and the control subjects. There were no differences in effective renal plasma flow between either group of diabetic patients and the control group. Therefore, the filtration fraction (the glomerular filtration rate divided by effective renal plasma flow) was significantly higher in the patients with IDDM and elevated sodium–lithium countertransport than in the control subjects (0.27 vs. 0.22; P<0.01). The filtration fraction was similar in the control group and the group with IDDM and normal sodium–lithium countertransport.The occurrence of high sodium–lithium countertransport values in some patients with IDDM was not due to age or sex, since the median age was similar in the 32 control subjects (35 years [range, 20 to 54]) and the 52 diabetic patients (33.4 years [range, 19 to 72]), and the proportions of women and men in the two groups were similar. The median age was also similar in the two groups of patients with IDDM (Table 2)Table 2
Characteristics of 7 Patients with IDDM and Elevated Sodium–Lithium Countertransport and 11 with Normal Activity.*. The elevated sodium–lithium countertransport could not be explained by obesity, since the median body-mass indexes were similar in the control subjects and the patients with IDDM and either elevated or normal sodium–lithium countertransport. In addition, body-mass index was not correlated with sodium–lithium countertransport in the control group (Rs = 0.11) or the group with IDDM (Rs = 0.30), possibly because body-mass index varied within a narrow range. The elevated sodium–lithium countertransport was also not explained by poorer control of diabetes, since the median glycosylated hemoglobin and blood 3-hydroxybutyrate values were similar in the patients with IDDM and either elevated or normal sodium–lithium countertransport. The serum C-peptide levels were similar in the patients with IDDM and either elevated sodium–lithium countertransport (median, 0.02 nmol per liter; range, 0 to 0.07) or normal countertransport (median, 0.02 nmol per liter; range, 0 to 0.05 [reference range, 0.18 to 0.52 nmol per liter]). There were no differences in blood pressure between the two groups of patients with IDDM.Although the glomerular filtration rate was significantly correlated with sodium–lithium countertransport in the 18 patients with IDDM (Rs = 0.55, P<0.01) (Fig. 2Figure 2
Sodium–Lithium Countertransport and the Glomerular Filtration Rate in 18 Patients with IDDM (Rs = 0.55, P<0.01, Spearman Correlation Coefficient).), this was not a close relation (standard error of the estimate of glomerular filtration rate, 22.4 ml per minute per 1.73 m2). In addition, there was no indication that this relation existed separately in the groups of patients with IDDM and either raised sodium–lithium countertransport or normal countertransport (Rs = −0.32, Rs = −0.06). This finding suggests that the significant correlation in the 18 patients with IDDM was due mainly to a discrete difference between the two groups of patients with IDDM: the glomerular filtration rate was consistently higher in the patients with elevated sodium–lithium countertransport, but the actual glomerular filtration rate was dependent on other factors. The glomerular filtration rate was not related to the indicators of control of diabetes studied either in the patients with IDDM as a whole (Rs = 0.26) or separately in the patients with elevated sodium–lithium countertransport activity and those with normal activity (Rs = −0.08, Rs = 0.17).Discussion
It has recently been reported that sodium–lithium countertransport in erythrocytes is higher in patients with IDDM who have nephropathy3 , 4 and that patients with IDDM and a family history of hypertension are more prone to the development of nephropathy.5 Erythrocyte sodium–lithium countertransport is elevated in patients with essential hypertension,12 and such increased activity in normotensive persons has been related to the presence of a family history of hypertension.13 14 15 16 17 18
These results have led to the suggestion that increased sodium–lithium countertransport may identify a subgroup of patients with IDDM who are at particular risk for the development of nephropathy. However, it is not clear whether sodium–lithium countertransport is increased before the onset of clinical nephropathy.3 We therefore studied patients with IDDM who had normal blood pressure, no clinical evidence of nephropathy, and no microalbuminuria. Sodium–lithium countertransport activity was considered to be elevated if it was more than 0.40 mmol of lithium per hour per liter of cells. This value was established by Canessa et al.12 and has been accepted by subsequent authors23; in none of our control subjects was the value greater than 0.39 mmol of lithium per hour per liter of cells.
Using this definition, we found that 33 percent (17 of 52) of the patients with IDDM had elevated sodium–lithium countertransport. This value is the same as the proportion of patients with IDDM in whom nephropathy is expected to develop. Furthermore, in the detailed study of renal function we found an increase in the glomerular filtration rate in the patients with IDDM who had elevated sodium–lithium countertransport. Such hyperfiltration is well known to precede or even contribute to the development of nephropathy.24 , 25
There was a significant correlation between sodium–lithium countertransport and the glomerular filtration rate, but this is not evidence of a causal relation (Fig. 2). Indeed, in the group with IDDM and elevated sodium–lithium countertransport, in which the greatest effect may have been expected, the relation was almost reversed. In family studies of essential hypertension, elevated sodium–lithium countertransport is a marker of persons with a predisposition to the development of hypertension.13 14 15 16 17 18 However, there is only a poor link between the level of sodium–lithium countertransport and the level of blood pressure. By analogy, elevated sodium–lithium countertransport in patients with IDDM may predict which patients are at risk of nephropathy, but the actual values of countertransport activity and glomerular filtration rate are influenced by many other factors.
The increase in the glomerular filtration rate in diabetes has been attributed to a reduction in both afferent and efferent arteriolar tone with increased effective renal plasma flow and transcapillary pressure.26 In partial agreement, we found that our patients with IDDM and elevated sodium–lithium countertransport had a significant increase in filtration fraction, consistent with increased transcapillary pressure, but no indication of increased effective renal plasma flow. Therefore, if vasodilatation occurred, it must have involved the afferent arteriole to a greater extent than the efferent arteriole. We found no difference in plasma renin activity between the patients with IDDM who had hyperfiltration and those who did not to account for the relatively greater tone in the efferent arterioles. These results clearly suggest disturbed intrarenal regulation of blood flow through the glomerulus, resulting in hyperfiltration.
The prevalence of elevated sodium–lithium countertransport in our patients with IDDM was greater than that in the normal population and similar to that found in patients with essential hypertension. Therefore, either subjects with elevated countertransport are at markedly increased risk for IDDM (as they may be for hypertension) or sodium–lithium countertransport is elevated as a result of the diabetic state. However, elevated activity of the sodium—sodium exchanger is not known to have a pathophysiologic role in the development or maintenance of high blood pressure or diabetic nephropathy.
There was no difference in blood pressure between the patients with IDDM who had elevated sodium–lithium countertransport activity and those with normal activity (Table 2). This is surprising, since the normotensive offspring of patients with essential hypertension who have elevated sodium–lithium countertransport have higher blood pressures than the offspring with normal countertransport (unpublished data), and it would be consistent with a different cause of elevated sodium–lithium countertransport in diabetes mellitus.
In conclusion, normotensive patients with IDDM and elevated sodium–lithium countertransport had increased glomerular filtration rates and filtration fractions in the absence of microalbuminuria. Such changes in renal function are known to predispose patients with IDDM to the development of nephropathy.24 , 25 Creatinine-clearance measurement is an unreliable method of detecting hyperfiltration,27 , 28 and measurements of the clearance of EDTA labeled with chromium-51 are not feasible as a routine clinical test. Therefore, elevated sodium–lithium countertransport may be an early predictor of nephropathy in patients with IDDM.
Supported by the Northern Counties Kidney Research Fund, Newcastle upon Tyne, United Kingdom.
Source Information
From the Departments of Medicine and Nephrology (S.C., J.-C.M., T.T., K.G.M.M.A., R.W.) and Medical Physics (P.K.), Freeman Hospital, and the Department of Medicine, Royal Victoria Infirmary (R.T.), Newcastle upon Tyne, United Kingdom. Address reprint requests to Dr. Thomas at the Department of Nephrology, Freeman Hospital, Freeman Rd., Newcastle upon Tyne, NE7 7DN, United Kingdom.
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