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PROGRESSION OF DIABETIC NEPHROPATHY
1105
PROGRESSION OF DIABETIC
dependent from the time of diagnosis and all had diabetic retinopathy (8 proliferative, 1 background). All had had prosulin
NEPHROPATHY R. H. JONES
J. D. MACKAY P.
J.
H. HAYAKAWA V. PARSONS WATKINS
Diabetic and Renal Departments, King’s
College Hospital,
London SE5
Summary
Although deterioration of renal function in diabetic nephropathy varies consider-
teinuria for several years before our observations were made, and there was no evidence of disease of the renal tract other than diabetic nephropathy. Observations were made only when serum-creatinine levels were >200 umol/l; below this value, small fluctuations in creatinine produce large changes in log Cr and I/Cr. The time, either measured or projected, at which serum-creatinine reached 200 µmol/1, wastaken as zero time for each patient (fig. 1), and the study continued until death (6 patients) or
ably from one diabetic to another, its rate is constant in individuals. For each patient there is a linear relation between period (months) which elapses from the time creatinine becomes >200 µmol/l and the inverse the inverse of the serum-creatinine. The observation is of practical importance in predicting the time at which end-stage renal failure will develop, so that treatment can be planned in advance.
serum
Introduction CHRONIC renal failure (C.R.F.) progresses in an orderly way which can be mathematically defined. Linear relations between duration (months or years) of renal impairment and the logarithm of serum-creatinine (log Cr) or the inverse of serum-creatinine (1/Cr) have been demonstrated in patients with C.R.F. from various causes.1,2 Rutherford et al. described these relations in 8 diabetics, but no details of these patients were given and it is not even clear whether they had diabetic glomerulosclerosis or other forms of renal disease. We have studied a group of patients with C.,R.F. due to diabetic nephropathy, both in order to discover whether these linear relations can be demonstrated in diabetics, and to determine any factors which might be responsible for the very different rates of decline of renal function in different individuals.
Patients and Methods 9 patients (5 men and 4 women) were studied (table i). At the time the serum-creatinine reached 200 µmol/1 (2-3mg/dl) their mean age was 32.8 (range 23-52) years and the mean duration of diabetes was 21.2 (range 13-32) years. All were in-
Time (months)
Fig. 1-Progression of renal failure in 9 diabetics-inverse of serum-creatinine (µmol/1) plotted against time. for end-stage c.R.F. (3 patients). Regular blood-presrecordings were made in all patients, and details of drug therapy, body-weight, and presence of absence of oedema were
treatment sure
recorded.
Serum-creatinine concentrations were measured on or SMAC ’AutoAnalyzers’. Linear regression
SMA12/60
of the relation between time since serum-creatinine reaches 200 µmol/1 and both I/Cr and log Cr was done on the data from each patient. In order to assess factors which might determine the rate of deterioration of renal function we examined the relation between the slopes of the regression lines and attempted to relate them to (a) age at diagnosis, (b) duration of diabetes from diagnosis to a creatinine level of 200 µmol/1, (c) mean diastolic blood-pressure (M.D.B.P.), and (d) mean blood-pressure recording all blood-pressure readings after the serumcreatinine levels had reached 200 µmol/1.
analysis
,
Results A linear relation between both log Cr time has been shown in all these patients
TABLE I-CLINICAL DATA
’On treatment for hypertension.
B.P.
readings are given as mean ± S.D.
I/Cr and (table n, fig. or
1106 TABLE II—LINEAR REGRESSION ANALYSES BETWEEN SERUM-CREATININE AND TIME IN DIABETIC NEPHROPATHY
1).
In 1
patient (case 5), terminal acceleration of the de-
cline of renal function
observed when the creatinine became >500 p.mol/1 (fig. 2). The acceleration began when diuretic therapy was started. There was no relation between the rate of decline of renal function and age at diagnosis of diabetes, interval between diagnosis and serum-creatinine of 200 µmol/1, or blood-pressure (either mean blood-pressure or diastolic pressure). was
Discussion of deterioration of renal function in diabetic varies considerably from one patient to another.3-6 The present study has shown that in 7 patients 5-43 months elapsed between the, time at which the serum-creatinine level reached 200 µmol/1 and the occurrence of end-stage renal failure, while in the 2 other patients renal function had declined-only slightly after 35 and 47 months, respectively. There is thus a remarkable variation in- the progression of this disease entity. The progression of renal failure in each individual patient is, however, constant, and once the serumcreatinine is > 200 µmol/1, the inverse of the creatinine concentration shows a straight-line correlation with time. A similar but slightly less satisfactory correlation has been shown with the logarithm of the creatinine. Mogensen3has also observed a linear decline of glomerular-filtration rates in diabetics. 1 of our patients had -an accelerated terminal phase of renal failure after the creatinine became >500 µmol/1; such a change has been of reported in other forms chronic renal disease.? , The
rate
nephropathy
straight-line relation would occur between the logarithm of the creatinine and time if fractional los of nephrons, for example 10% per year, occurs, anc if there was a direct relation between glomerular-filt ration rate and nephron number. Alternatively, if th( number of nephrons lost remained constant there woulc be a straight-line relation between inverse creatinine anc time. In the present study and that of Rutherford et al. A
linear relations have been shown between time and both the logarithm and the inverse of the creatinine. Thi; apparent mathematical incompatibility can probably b( explained by the presence of many factors which can in. fluence the progression of renal failure as well as b3 experimental error. Thus the resulting regression line’ are insufficiently exact to provide a mathematical mode for the progression of renal failure. The problem i further complicated by the "magnification phenom enon",7 whereby even after glomerular atrophy ha occurred tubules may retain a blood-supply (and there fore some function) from neighbouring glomeruli. On( can no longer therefore assume that there is a direc relation between glomerular-filtration rate and nephror number. Factors which might influence the rate of progressior of diabetic renal disease are not known. In our patients the rate of decline of renal function was not related t( age at diagnosis of diabetes, the duration of diabetes ul to time a serum-creatinine level of 200 µmol/1 wa!
reached,
or
blood-pressure (either
mean or
diastolic)
This study was not designed to test the effect of hypoten sive treatment on renal function, and we cannot confirn Mogensen’s observation that hypotensive treatmen slows the rate of deterioration of glomerular filtration. The cause of the terminal acceleration of renal failun which is, occasionally seen is also unknown. These observations are of considerable practical im portance because they can be used to predict the time a which a patient will approach end-stage renal failure. We now keep a chart showing the inverse ofserum-creatinim plotted against time in the records of every diabeti patient whose renal function is beginning to decline Plans for treatment, preferably transplantation,8 are made for suitable patients when the serum-creatinine i approximately 500 µmol/1, and transplantation is recom mended when it is 700-8’00 p.mol/1, when the prognosi for survival in untreated patients is only a few months R. H. J. was supported by a grant from Servier Laboratories Ltd. H. H. was a British Council Fellow, and J. D. M. was supported b grants from Winthrop Laboratories Ltd and the King’s College Hospi tal Voluntary Research Trust.
Requests for reprints should be addressed Dulwich Hospital, London SE22 8PT.
to
R. H.
J., Renal Uni
REFERENCES
1. Mitch, W. E., Walser, M., Buffington, G. A., Lemann, J. Lancet, 1976, ii, 1326. 2. Rutherford, W.
2-Terminal acceleration of renal failure-inverse of serum-creatinine (µmol/1) plotted against time.
Fig.
E., Blondin, J., Miller, J. P., Greenwalt, A. S., Vavra, J. D. Kidney Int. 1977, 11, 62. 3. Mogensen, S. E. Scand. J. clin. Lab. Invest. 1976, 36, 383. 4. Watkins, P. J., BLainey, J. D., Brewer, D. B., Fitzgerald, M. G., Malins, J. M., O’Sullivan, D. J., Pinto, J. A. Q. Jl Med. 1972, 41, 437. 5. Cameron, J. S., Ireland, J. T., Watkins, P. J. in Complications of Diabetes (edited by H. Keen and J. Jarrett); p.130. London, 1975. 6. Kussman, M. J., Goldstein, H. H., Gleason, R. E. J. Am. med. Ass. 1976, 236, 1861. 7. Brickler, N. S., Fine, L. G., Kaplan, M., Bourgoinie, J. J., Light, A. New Engl. J. Med. 1978, 299, 1287. 8. Najarian, J. S., Sutherland, D. E. R., Simmons, R. L., et al. Surgery Gynec. Obstet. 1977, 144, 682.
PROGRESSION OF DIABETIC
dependent from the time of diagnosis and all had diabetic retinopathy (8 proliferative, 1 background). All had had prosulin
NEPHROPATHY R. H. JONES
J. D. MACKAY P.
J.
H. HAYAKAWA V. PARSONS WATKINS
Diabetic and Renal Departments, King’s
College Hospital,
London SE5
Summary
Although deterioration of renal function in diabetic nephropathy varies consider-
teinuria for several years before our observations were made, and there was no evidence of disease of the renal tract other than diabetic nephropathy. Observations were made only when serum-creatinine levels were >200 umol/l; below this value, small fluctuations in creatinine produce large changes in log Cr and I/Cr. The time, either measured or projected, at which serum-creatinine reached 200 µmol/1, wastaken as zero time for each patient (fig. 1), and the study continued until death (6 patients) or
ably from one diabetic to another, its rate is constant in individuals. For each patient there is a linear relation between period (months) which elapses from the time creatinine becomes >200 µmol/l and the inverse the inverse of the serum-creatinine. The observation is of practical importance in predicting the time at which end-stage renal failure will develop, so that treatment can be planned in advance.
serum
Introduction CHRONIC renal failure (C.R.F.) progresses in an orderly way which can be mathematically defined. Linear relations between duration (months or years) of renal impairment and the logarithm of serum-creatinine (log Cr) or the inverse of serum-creatinine (1/Cr) have been demonstrated in patients with C.R.F. from various causes.1,2 Rutherford et al. described these relations in 8 diabetics, but no details of these patients were given and it is not even clear whether they had diabetic glomerulosclerosis or other forms of renal disease. We have studied a group of patients with C.,R.F. due to diabetic nephropathy, both in order to discover whether these linear relations can be demonstrated in diabetics, and to determine any factors which might be responsible for the very different rates of decline of renal function in different individuals.
Patients and Methods 9 patients (5 men and 4 women) were studied (table i). At the time the serum-creatinine reached 200 µmol/1 (2-3mg/dl) their mean age was 32.8 (range 23-52) years and the mean duration of diabetes was 21.2 (range 13-32) years. All were in-
Time (months)
Fig. 1-Progression of renal failure in 9 diabetics-inverse of serum-creatinine (µmol/1) plotted against time. for end-stage c.R.F. (3 patients). Regular blood-presrecordings were made in all patients, and details of drug therapy, body-weight, and presence of absence of oedema were
treatment sure
recorded.
Serum-creatinine concentrations were measured on or SMAC ’AutoAnalyzers’. Linear regression
SMA12/60
of the relation between time since serum-creatinine reaches 200 µmol/1 and both I/Cr and log Cr was done on the data from each patient. In order to assess factors which might determine the rate of deterioration of renal function we examined the relation between the slopes of the regression lines and attempted to relate them to (a) age at diagnosis, (b) duration of diabetes from diagnosis to a creatinine level of 200 µmol/1, (c) mean diastolic blood-pressure (M.D.B.P.), and (d) mean blood-pressure recording all blood-pressure readings after the serumcreatinine levels had reached 200 µmol/1.
analysis
,
Results A linear relation between both log Cr time has been shown in all these patients
TABLE I-CLINICAL DATA
’On treatment for hypertension.
B.P.
readings are given as mean ± S.D.
I/Cr and (table n, fig. or
1106 TABLE II—LINEAR REGRESSION ANALYSES BETWEEN SERUM-CREATININE AND TIME IN DIABETIC NEPHROPATHY
1).
In 1
patient (case 5), terminal acceleration of the de-
cline of renal function
observed when the creatinine became >500 p.mol/1 (fig. 2). The acceleration began when diuretic therapy was started. There was no relation between the rate of decline of renal function and age at diagnosis of diabetes, interval between diagnosis and serum-creatinine of 200 µmol/1, or blood-pressure (either mean blood-pressure or diastolic pressure). was
Discussion of deterioration of renal function in diabetic varies considerably from one patient to another.3-6 The present study has shown that in 7 patients 5-43 months elapsed between the, time at which the serum-creatinine level reached 200 µmol/1 and the occurrence of end-stage renal failure, while in the 2 other patients renal function had declined-only slightly after 35 and 47 months, respectively. There is thus a remarkable variation in- the progression of this disease entity. The progression of renal failure in each individual patient is, however, constant, and once the serumcreatinine is > 200 µmol/1, the inverse of the creatinine concentration shows a straight-line correlation with time. A similar but slightly less satisfactory correlation has been shown with the logarithm of the creatinine. Mogensen3has also observed a linear decline of glomerular-filtration rates in diabetics. 1 of our patients had -an accelerated terminal phase of renal failure after the creatinine became >500 µmol/1; such a change has been of reported in other forms chronic renal disease.? , The
rate
nephropathy
straight-line relation would occur between the logarithm of the creatinine and time if fractional los of nephrons, for example 10% per year, occurs, anc if there was a direct relation between glomerular-filt ration rate and nephron number. Alternatively, if th( number of nephrons lost remained constant there woulc be a straight-line relation between inverse creatinine anc time. In the present study and that of Rutherford et al. A
linear relations have been shown between time and both the logarithm and the inverse of the creatinine. Thi; apparent mathematical incompatibility can probably b( explained by the presence of many factors which can in. fluence the progression of renal failure as well as b3 experimental error. Thus the resulting regression line’ are insufficiently exact to provide a mathematical mode for the progression of renal failure. The problem i further complicated by the "magnification phenom enon",7 whereby even after glomerular atrophy ha occurred tubules may retain a blood-supply (and there fore some function) from neighbouring glomeruli. On( can no longer therefore assume that there is a direc relation between glomerular-filtration rate and nephror number. Factors which might influence the rate of progressior of diabetic renal disease are not known. In our patients the rate of decline of renal function was not related t( age at diagnosis of diabetes, the duration of diabetes ul to time a serum-creatinine level of 200 µmol/1 wa!
reached,
or
blood-pressure (either
mean or
diastolic)
This study was not designed to test the effect of hypoten sive treatment on renal function, and we cannot confirn Mogensen’s observation that hypotensive treatmen slows the rate of deterioration of glomerular filtration. The cause of the terminal acceleration of renal failun which is, occasionally seen is also unknown. These observations are of considerable practical im portance because they can be used to predict the time a which a patient will approach end-stage renal failure. We now keep a chart showing the inverse ofserum-creatinim plotted against time in the records of every diabeti patient whose renal function is beginning to decline Plans for treatment, preferably transplantation,8 are made for suitable patients when the serum-creatinine i approximately 500 µmol/1, and transplantation is recom mended when it is 700-8’00 p.mol/1, when the prognosi for survival in untreated patients is only a few months R. H. J. was supported by a grant from Servier Laboratories Ltd. H. H. was a British Council Fellow, and J. D. M. was supported b grants from Winthrop Laboratories Ltd and the King’s College Hospi tal Voluntary Research Trust.
Requests for reprints should be addressed Dulwich Hospital, London SE22 8PT.
to
R. H.
J., Renal Uni
REFERENCES
1. Mitch, W. E., Walser, M., Buffington, G. A., Lemann, J. Lancet, 1976, ii, 1326. 2. Rutherford, W.
2-Terminal acceleration of renal failure-inverse of serum-creatinine (µmol/1) plotted against time.
Fig.
E., Blondin, J., Miller, J. P., Greenwalt, A. S., Vavra, J. D. Kidney Int. 1977, 11, 62. 3. Mogensen, S. E. Scand. J. clin. Lab. Invest. 1976, 36, 383. 4. Watkins, P. J., BLainey, J. D., Brewer, D. B., Fitzgerald, M. G., Malins, J. M., O’Sullivan, D. J., Pinto, J. A. Q. Jl Med. 1972, 41, 437. 5. Cameron, J. S., Ireland, J. T., Watkins, P. J. in Complications of Diabetes (edited by H. Keen and J. Jarrett); p.130. London, 1975. 6. Kussman, M. J., Goldstein, H. H., Gleason, R. E. J. Am. med. Ass. 1976, 236, 1861. 7. Brickler, N. S., Fine, L. G., Kaplan, M., Bourgoinie, J. J., Light, A. New Engl. J. Med. 1978, 299, 1287. 8. Najarian, J. S., Sutherland, D. E. R., Simmons, R. L., et al. Surgery Gynec. Obstet. 1977, 144, 682.