Acta Med Scand 203: 131-134, 1978
Prognosis for Juvenile Diabetics with Nephropathy and Failing Renal Function Allan Renard Andersen, Jane Kock Andersen, Jens Sandahl Christiansen and Torsten Deckert From the Steno Memorial Hospital, Gentofte, Denmark
ABSTRACT. A total of 157 consecutive patients with juvenile diabetes (onset before the 31st birthday), diabetic nephropathy, and impaired renal function were followed up until 1.1.1976. All the patients had been admitted to the Steno Memorial Hospital, Copenhagen, between 1934 and 1972. Independently of the patients’ age at onset of diabetes, it was found that persistent proteinuria appeared after an average of 19 years, and that death ensued 5-6 years thereafter. Division of the patients into two groups, according to whether the diabetes had set in before or after 1940, showed no signs of an improved prognosis during the past few decades. Once the serum creatinine has started to rise, the prognosis is very grave. Only 50% were alive 21 months after serum creatinine leveb of 2-5 mg/100 ml had been ascertained. Among patients whose serum creatinine exceeded 5 mg/100 ml, 50% succumbed in 9 months. It is concluded that rend transplantation, if it is to be done, should be instituted early.
It is well known that patients with long-standing diabetes mellitus develop generalized angiopathy and neuropathy which may lead to organic lesions in the form of retinopathy, nephropathy , myocardial infarction, gangrene, and brain damage. Diabetic nephropathy is clinically fairly silent, but in most young patients it will sooner or later result in renal failure (2). So far, treatment with renal transplantation has not been a routine, as the state of terminal uraemia in patients with diabetic nephropathy is frequently associated with other complications of advanced diabetes, such as myocardial infarction, stroke, gangrene, neuropathy, and blindReprint requests to: T . Deckert, M.D., Niels Steensens Hospital,DK-2820Gentofte, Denmark.
ness. According to some studies, however, development of the advanced diabetic organic lesions seems to be accelerated by the uraemia (4). This raises the question of whether the development of these disabling lesions can be delayed by performing renal transplantation on juvenile diabetics exhibiting nephropathy at an early stage of the uraemia. However, there have been only a few reports on the prognosis of diabetic nephropathy in juvenile diabetics, once failing renal function has been diagnosed by methods of clinical chemistry (597).
As knowledge on this item is needed to assess whether it is reasonable to consider renal transplantation in the treatment of diabetic nephropathy, and if so, at which state of the progress of the disease it should be applied, we analysed the course of the disease in 157 patients with diabetic nephropathy in whom renal failure had been verified. STUDY POPULATION AND METHOD The study comprises all patients with juvenile diabetes mellitus (onset before the 31st birthday) who had diabetic nephropathy with impaired renal function when admitted to the Steno Memorial Hospital between 1934 and 1972. Of the 157 patients, 100 (64%) were males and 57 (36%) females, male :female mtio 1.75 : 1. In 56 patients diabetes mellitus had been diagnosed between the ages of 0 and 10 years, in 61 between 11 and 20, and in 40 between 21 and 30 years of age. All were on insulin. Diabetic nephropathy was defined as persistent proteinuria (proteinuria at four successive controls with an interval of at least one month) in a diabetic without clinical evidence or a history of other renal disease. The diagnosis of proteinuria was confirmed by qualitative examination of the 24-hour urine using Heller’s test (1) (after 1965 Albustix) and measured quantitatively by the Tsuchya Acta Med Scand 203
132
A . R . Andersen et al.
Table I . Intervals between onset of diabetes and proteinuria and between start of proteinuria and death Age (y.) at onset of diabetes
No. of years between onset of diabetes and persistent proteinuria Mean? S.D. Range No. of years between start of persistent proteinuria and death Mean? S.D. Range
0-10
11-20
2 1-30
0-30
19.1k8.8 (0) 5-37"
18.2k5.7 7-33
19.7k7.9 4-41
18.9t6.9 (0)4-11
6.8k6.6 0-3 2
5.2k4.9 0-20
4.4f5.8 0-19
5.6t5.5 0-32
One patient had proteinuria on first admission (at onset of disease). No information available until next admissi4 in terminal uraemia.
Table 11. Causes of death in 157 patients with juvenile diabetes, diabetic nephropathy, and increased serum creatinine
Uraemia Acute myocardial infarction Pulmonary oedema Pneumonia Pericarditis Stroke Others
n
%
119 14 6
76 9 4 3 2 2
5
3 3 7
serum urea levels at first admission. Initial serum creatinine levels of 2.04.0 mg/lOO ml were found in 123 (78%) of the patients (serum urea 60-149 mg/100 mi). The analysis was concluded on 1.1.1976. At that time all the patients had died. Sex, age, time of onset of diabetes mellitus, start of persistent proteinuria, and time of death were recorded. So were the serum urea and serum creatinine values, the cause of death given on the death certificate, and whether blindness had been diagnosed by an ophthalmologist.
4
RESULTS method ( I ) . Impaired renal function was diagnosed when the patients persistently had serum creatinine levels of 82.0 mg1100 mi or serum urea levels of 2-60 mg/100 ml. These values were chosen in order to disregard minor variations in kidney function. Serum creatinine was determined by Jaffe's reaction after protein precipitation and serum urea by the van Slyke method (1). Fig. 1 gives the distribution of serum creatinine and
The number of years elapsing from the onset of diabetes until the finding of persisting proteinuria and from the diagnosis of proteinuria until death are given in Table I . Despite considerable individual variation, it is seen that proteinuria sets in and death occurs after the lapse of about 18-20 years and about 23-26 years, respectively, independently
NUMBER OF PATIENTS
LO
Fig. I. Renal function expressed in serum creatinine or serum urea at
20
the beginning of the study of 157 juvenile diabetics with diabetic nephropathy and impaired renal
Acta Med Scand 203
Prognosis in diabetic nephropathy with failing renal function
133
Table 111. Prognosis in diabetic nephropathy with impaired renal function before and during the penicillin era Diabetes mellitus diagnosed
Before 1941
After 1940
21.0k7.9 (0) 5-370
14.3f5.5 4-25
5.7f5.7 0-32
5.3k4.9 0-16
1.4f 1.8 0-12
1.8f 1.6 0-9
No. of years between onset of diabetes and persistent proteinuria MeanfS.D. Range No. of years between start of persistent proteinuria and death MeanfS.D. Range No. of years between diagnosis of impaired renal function and deathb Mean? S.D. Range
a One patient had proteinuria on first admission (at onset of disease). No information available until next admission in terminal uraemia. Serum creatinine 2 2 . 0 mgjl00 ml, serum urea 360.0 mgll00 ml.
of age at the time of diagnosis. The prognosis proved to be the same for both sexes. All the patients had died before the end of 1975. The causes of death are presented in Table 11. Uraemia was stated as the cause of 76% of the deaths. Other causes of death were particularly pulmonary oedema, stroke, pneumonia, and pericarditis. Forty-one (41%) of the males and 25 (44%) of the females, i.e. 66 (42%) of the 157 patients became blind. Fig. 2 gives the mortality rate for the total series. It shows that 50% had died 18 months, 83% three years, and 95% six years after the examination which first disclosed serum creatinine levels of 3 2 mgll00 ml or serum urea levels of 360 mg/lOO ml. Fig. 3 sets out the mortality rate for patients whose serum creatinine level was 2-5 mg/100 ml and for patients in whom it exceeded 5.0 mg/lOO ml. Of the patients with serum creatinine levels between 2 and 5 rngll00 ml, 50% were alive 21 months, 18% three years, and 5 % 11 years after the examination which first revealed serum creatinine 32.0 mg/100 ml or serum urea 360 mg1100 ml. Of the patients with serum creatinine levels above 5 mg/lOO ml, 50% had died in 9 months, and all had died in 3 years. Division of the series according to onset of diabetes before and after 1940 showed that patients whose diabetes had been diagnosed prior to 1941 had a longer duration of diabetes before the occurrence of persistent proteinuria than patients with an onset of diabetes after 1940 (Table 111).
DISCUSSION The ratio males : females (1.75 : 1) in the present series is surprising, as the incidence of juvenile diabetes mellitus is only about 20% higher in males than in females. Whether diabetic males are more apt than diabetic females to develop nephropathy is not known. Age at onset of diabetes proved to have no influence on the number of years elapsing until proteinuria occurred or until death. That juvenile diabetics developing renal complications acquire persistent proteinuria after having had diabetes for about 18-20 years, and that death occurs 5-6 years thereafter accords with the course described by Kussman et al. (6), Knowles (5) and Shapiro et al. (7), but the prognosis is not so poor as found by Wilson et al. (9). PERCENT OF ACTWL POPULATION
t
Fig. 2. Cumulative death rate for 157 juvenile diabetics with diabetic nephropathy after impaired renal function (serum creatinine 2 2 . 0 mg/100 ml or serum urea 360 mg/l00 ml) had been diagnosed. Acta Med Scond 203
134
A . R . Andersen et al.
PERCENT OF ACTUAL POPULATION 6
. -. . -
100 -
0
80 60 LO-
0-0
S c - CREATlNlNE
x-x
S r - CREAllNlNE
20
- 5 0 mg I100 ml
5 0 mgllOO m l
20-
Fig. 3. Cumulative death rate for juvenile diabetics with diabetic nephropathy after impaired renal function had been diagnosed. n=130 ( O ) , n=55 (XI.
1
2
3
L
5
6
7
8
9
Evaluation of the dependence of the prognosis upon whether the diabetes set in before or after 1940 (before and during the antibiotic era) showed that patients who have developed their diabetes after 1940 apparently are worse off than those with an onset prior to 1940, the latter dying after an average duration of 26.3 years, and the former after 19.6 years (Table 111). These values presumably indicate that admission of patients with severe nephropathy to the Steno Memorial Hospital was not as common before as after 1940. That the survival time after the appearance of persistent proteinuria and incipient impairment of renal function was unchanged in patients whose diabetes set in before or after 1940 (Table 111) shows that the more intensive conservative treatment of the uraemia during the past few decades has not given better results. Acute myocardial infarction proved to be the cause of death in only 9% of the patients. This rate is considerably below the percentage of 38% in the series of Kussman et al. (6). But their series was smaller and the follow-up period appreciably shorter. That 42% of the patients became blind confirms previous findings (4) showing that only 2 years passed before 50% of juvenile diabetics with proliferative retinopathy and proteinuria became blind, as compared with 5 years for 50% of those without proteinuria. Only 12% of juvenile diabetics with normal serum creatinine became blind after a duration of diabetes of more than 40 years (3). The present study has confirmed that diabetic nephropathy is a very serious disease and that the
10
11YEARS
prognosis is exceptionally poor when renal function starts failing. Intensive nephrological treatment of this group of patients is still in an experimental stage, and the indication for renal transplantation in diabetic nephropathy is a matter of discussion. However, the present material indicates that intensive treatment, including transplantation, should be instituted earlier in diabetic nephropathy than in renal failure due to other causes. REFERENCES I . Astrup, P., Brprchner Mortensen, K. & Faber, M.: Klinisk laboratorieteknik. August Bang, Copenhagen 1959. 2. Deckert, T. & Poulsen, J. E.: Prognosis for juvenile
diabetics with late diabetic manifestations. Acta Med Scand 183:351, 1%5. 3. Deckert, T., Poulsen, J. E. & Larsen, M.: Prognosis in juvenile diabetes mellitus. Acta Endocrinol (Suppl) 203: 15, 1976. 4. Deckert, T., Simonsen, S. E. & Poulsen, J. E.: Prog-
nosis of proliferative retinopathy in juvenile diabetes. Diabetes 16: 728, 1%7. 5 . Knowles, H. C.: Long-term juvenile diabetes treated with unmeasured diet. Trans Assoc Am Physicians 84:95, 1971. 6. Kussman, M. J., Goldstein, H. H. & Ray, E. G.: Clinical course of diabetic nephropathy. Diabetes 23: 357, 1974. 7. Shapiro, F. L., Kjellstrand, C. M. & Goetz, F. C. (ed.):
End stage diabetic nephropathy. Kidney Int (Suppl) I , 1-186, 1974.
8. Watkins, P. J., Blainey, J. D., Brewer, D. B., Fitzgerald, M. G., Malins, J. M.,OSullivan, D. J. &Pinto, J. A.: The natural history of diabetic renal disease. Q J Med 164:437, 1972. 9. Wilson, J. L., Root, H. F. & Marble, A.: Diabetic nephropathy: A clinical syndrome. N Engl J Med 245:513, 1951.
Acta Med Scand 203
Prognosis for Juvenile Diabetics with Nephropathy and Failing Renal Function Allan Renard Andersen, Jane Kock Andersen, Jens Sandahl Christiansen and Torsten Deckert From the Steno Memorial Hospital, Gentofte, Denmark
ABSTRACT. A total of 157 consecutive patients with juvenile diabetes (onset before the 31st birthday), diabetic nephropathy, and impaired renal function were followed up until 1.1.1976. All the patients had been admitted to the Steno Memorial Hospital, Copenhagen, between 1934 and 1972. Independently of the patients’ age at onset of diabetes, it was found that persistent proteinuria appeared after an average of 19 years, and that death ensued 5-6 years thereafter. Division of the patients into two groups, according to whether the diabetes had set in before or after 1940, showed no signs of an improved prognosis during the past few decades. Once the serum creatinine has started to rise, the prognosis is very grave. Only 50% were alive 21 months after serum creatinine leveb of 2-5 mg/100 ml had been ascertained. Among patients whose serum creatinine exceeded 5 mg/100 ml, 50% succumbed in 9 months. It is concluded that rend transplantation, if it is to be done, should be instituted early.
It is well known that patients with long-standing diabetes mellitus develop generalized angiopathy and neuropathy which may lead to organic lesions in the form of retinopathy, nephropathy , myocardial infarction, gangrene, and brain damage. Diabetic nephropathy is clinically fairly silent, but in most young patients it will sooner or later result in renal failure (2). So far, treatment with renal transplantation has not been a routine, as the state of terminal uraemia in patients with diabetic nephropathy is frequently associated with other complications of advanced diabetes, such as myocardial infarction, stroke, gangrene, neuropathy, and blindReprint requests to: T . Deckert, M.D., Niels Steensens Hospital,DK-2820Gentofte, Denmark.
ness. According to some studies, however, development of the advanced diabetic organic lesions seems to be accelerated by the uraemia (4). This raises the question of whether the development of these disabling lesions can be delayed by performing renal transplantation on juvenile diabetics exhibiting nephropathy at an early stage of the uraemia. However, there have been only a few reports on the prognosis of diabetic nephropathy in juvenile diabetics, once failing renal function has been diagnosed by methods of clinical chemistry (597).
As knowledge on this item is needed to assess whether it is reasonable to consider renal transplantation in the treatment of diabetic nephropathy, and if so, at which state of the progress of the disease it should be applied, we analysed the course of the disease in 157 patients with diabetic nephropathy in whom renal failure had been verified. STUDY POPULATION AND METHOD The study comprises all patients with juvenile diabetes mellitus (onset before the 31st birthday) who had diabetic nephropathy with impaired renal function when admitted to the Steno Memorial Hospital between 1934 and 1972. Of the 157 patients, 100 (64%) were males and 57 (36%) females, male :female mtio 1.75 : 1. In 56 patients diabetes mellitus had been diagnosed between the ages of 0 and 10 years, in 61 between 11 and 20, and in 40 between 21 and 30 years of age. All were on insulin. Diabetic nephropathy was defined as persistent proteinuria (proteinuria at four successive controls with an interval of at least one month) in a diabetic without clinical evidence or a history of other renal disease. The diagnosis of proteinuria was confirmed by qualitative examination of the 24-hour urine using Heller’s test (1) (after 1965 Albustix) and measured quantitatively by the Tsuchya Acta Med Scand 203
132
A . R . Andersen et al.
Table I . Intervals between onset of diabetes and proteinuria and between start of proteinuria and death Age (y.) at onset of diabetes
No. of years between onset of diabetes and persistent proteinuria Mean? S.D. Range No. of years between start of persistent proteinuria and death Mean? S.D. Range
0-10
11-20
2 1-30
0-30
19.1k8.8 (0) 5-37"
18.2k5.7 7-33
19.7k7.9 4-41
18.9t6.9 (0)4-11
6.8k6.6 0-3 2
5.2k4.9 0-20
4.4f5.8 0-19
5.6t5.5 0-32
One patient had proteinuria on first admission (at onset of disease). No information available until next admissi4 in terminal uraemia.
Table 11. Causes of death in 157 patients with juvenile diabetes, diabetic nephropathy, and increased serum creatinine
Uraemia Acute myocardial infarction Pulmonary oedema Pneumonia Pericarditis Stroke Others
n
%
119 14 6
76 9 4 3 2 2
5
3 3 7
serum urea levels at first admission. Initial serum creatinine levels of 2.04.0 mg/lOO ml were found in 123 (78%) of the patients (serum urea 60-149 mg/100 mi). The analysis was concluded on 1.1.1976. At that time all the patients had died. Sex, age, time of onset of diabetes mellitus, start of persistent proteinuria, and time of death were recorded. So were the serum urea and serum creatinine values, the cause of death given on the death certificate, and whether blindness had been diagnosed by an ophthalmologist.
4
RESULTS method ( I ) . Impaired renal function was diagnosed when the patients persistently had serum creatinine levels of 82.0 mg1100 mi or serum urea levels of 2-60 mg/100 ml. These values were chosen in order to disregard minor variations in kidney function. Serum creatinine was determined by Jaffe's reaction after protein precipitation and serum urea by the van Slyke method (1). Fig. 1 gives the distribution of serum creatinine and
The number of years elapsing from the onset of diabetes until the finding of persisting proteinuria and from the diagnosis of proteinuria until death are given in Table I . Despite considerable individual variation, it is seen that proteinuria sets in and death occurs after the lapse of about 18-20 years and about 23-26 years, respectively, independently
NUMBER OF PATIENTS
LO
Fig. I. Renal function expressed in serum creatinine or serum urea at
20
the beginning of the study of 157 juvenile diabetics with diabetic nephropathy and impaired renal
Acta Med Scand 203
Prognosis in diabetic nephropathy with failing renal function
133
Table 111. Prognosis in diabetic nephropathy with impaired renal function before and during the penicillin era Diabetes mellitus diagnosed
Before 1941
After 1940
21.0k7.9 (0) 5-370
14.3f5.5 4-25
5.7f5.7 0-32
5.3k4.9 0-16
1.4f 1.8 0-12
1.8f 1.6 0-9
No. of years between onset of diabetes and persistent proteinuria MeanfS.D. Range No. of years between start of persistent proteinuria and death MeanfS.D. Range No. of years between diagnosis of impaired renal function and deathb Mean? S.D. Range
a One patient had proteinuria on first admission (at onset of disease). No information available until next admission in terminal uraemia. Serum creatinine 2 2 . 0 mgjl00 ml, serum urea 360.0 mgll00 ml.
of age at the time of diagnosis. The prognosis proved to be the same for both sexes. All the patients had died before the end of 1975. The causes of death are presented in Table 11. Uraemia was stated as the cause of 76% of the deaths. Other causes of death were particularly pulmonary oedema, stroke, pneumonia, and pericarditis. Forty-one (41%) of the males and 25 (44%) of the females, i.e. 66 (42%) of the 157 patients became blind. Fig. 2 gives the mortality rate for the total series. It shows that 50% had died 18 months, 83% three years, and 95% six years after the examination which first disclosed serum creatinine levels of 3 2 mgll00 ml or serum urea levels of 360 mg/lOO ml. Fig. 3 sets out the mortality rate for patients whose serum creatinine level was 2-5 mg/100 ml and for patients in whom it exceeded 5.0 mg/lOO ml. Of the patients with serum creatinine levels between 2 and 5 rngll00 ml, 50% were alive 21 months, 18% three years, and 5 % 11 years after the examination which first revealed serum creatinine 32.0 mg/100 ml or serum urea 360 mg1100 ml. Of the patients with serum creatinine levels above 5 mg/lOO ml, 50% had died in 9 months, and all had died in 3 years. Division of the series according to onset of diabetes before and after 1940 showed that patients whose diabetes had been diagnosed prior to 1941 had a longer duration of diabetes before the occurrence of persistent proteinuria than patients with an onset of diabetes after 1940 (Table 111).
DISCUSSION The ratio males : females (1.75 : 1) in the present series is surprising, as the incidence of juvenile diabetes mellitus is only about 20% higher in males than in females. Whether diabetic males are more apt than diabetic females to develop nephropathy is not known. Age at onset of diabetes proved to have no influence on the number of years elapsing until proteinuria occurred or until death. That juvenile diabetics developing renal complications acquire persistent proteinuria after having had diabetes for about 18-20 years, and that death occurs 5-6 years thereafter accords with the course described by Kussman et al. (6), Knowles (5) and Shapiro et al. (7), but the prognosis is not so poor as found by Wilson et al. (9). PERCENT OF ACTWL POPULATION
t
Fig. 2. Cumulative death rate for 157 juvenile diabetics with diabetic nephropathy after impaired renal function (serum creatinine 2 2 . 0 mg/100 ml or serum urea 360 mg/l00 ml) had been diagnosed. Acta Med Scond 203
134
A . R . Andersen et al.
PERCENT OF ACTUAL POPULATION 6
. -. . -
100 -
0
80 60 LO-
0-0
S c - CREATlNlNE
x-x
S r - CREAllNlNE
20
- 5 0 mg I100 ml
5 0 mgllOO m l
20-
Fig. 3. Cumulative death rate for juvenile diabetics with diabetic nephropathy after impaired renal function had been diagnosed. n=130 ( O ) , n=55 (XI.
1
2
3
L
5
6
7
8
9
Evaluation of the dependence of the prognosis upon whether the diabetes set in before or after 1940 (before and during the antibiotic era) showed that patients who have developed their diabetes after 1940 apparently are worse off than those with an onset prior to 1940, the latter dying after an average duration of 26.3 years, and the former after 19.6 years (Table 111). These values presumably indicate that admission of patients with severe nephropathy to the Steno Memorial Hospital was not as common before as after 1940. That the survival time after the appearance of persistent proteinuria and incipient impairment of renal function was unchanged in patients whose diabetes set in before or after 1940 (Table 111) shows that the more intensive conservative treatment of the uraemia during the past few decades has not given better results. Acute myocardial infarction proved to be the cause of death in only 9% of the patients. This rate is considerably below the percentage of 38% in the series of Kussman et al. (6). But their series was smaller and the follow-up period appreciably shorter. That 42% of the patients became blind confirms previous findings (4) showing that only 2 years passed before 50% of juvenile diabetics with proliferative retinopathy and proteinuria became blind, as compared with 5 years for 50% of those without proteinuria. Only 12% of juvenile diabetics with normal serum creatinine became blind after a duration of diabetes of more than 40 years (3). The present study has confirmed that diabetic nephropathy is a very serious disease and that the
10
11YEARS
prognosis is exceptionally poor when renal function starts failing. Intensive nephrological treatment of this group of patients is still in an experimental stage, and the indication for renal transplantation in diabetic nephropathy is a matter of discussion. However, the present material indicates that intensive treatment, including transplantation, should be instituted earlier in diabetic nephropathy than in renal failure due to other causes. REFERENCES I . Astrup, P., Brprchner Mortensen, K. & Faber, M.: Klinisk laboratorieteknik. August Bang, Copenhagen 1959. 2. Deckert, T. & Poulsen, J. E.: Prognosis for juvenile
diabetics with late diabetic manifestations. Acta Med Scand 183:351, 1%5. 3. Deckert, T., Poulsen, J. E. & Larsen, M.: Prognosis in juvenile diabetes mellitus. Acta Endocrinol (Suppl) 203: 15, 1976. 4. Deckert, T., Simonsen, S. E. & Poulsen, J. E.: Prog-
nosis of proliferative retinopathy in juvenile diabetes. Diabetes 16: 728, 1%7. 5 . Knowles, H. C.: Long-term juvenile diabetes treated with unmeasured diet. Trans Assoc Am Physicians 84:95, 1971. 6. Kussman, M. J., Goldstein, H. H. & Ray, E. G.: Clinical course of diabetic nephropathy. Diabetes 23: 357, 1974. 7. Shapiro, F. L., Kjellstrand, C. M. & Goetz, F. C. (ed.):
End stage diabetic nephropathy. Kidney Int (Suppl) I , 1-186, 1974.
8. Watkins, P. J., Blainey, J. D., Brewer, D. B., Fitzgerald, M. G., Malins, J. M.,OSullivan, D. J. &Pinto, J. A.: The natural history of diabetic renal disease. Q J Med 164:437, 1972. 9. Wilson, J. L., Root, H. F. & Marble, A.: Diabetic nephropathy: A clinical syndrome. N Engl J Med 245:513, 1951.
Acta Med Scand 203
