Original Papers Nephron 79.* 311-321 (1977)
Phenacetin Abuse and Chronic Pyelonephritis J. Brod, K. W. Kühn, H. S. Stender and E. Stolle Department of Medicine, Division of Nephrology, and Institute of Clinical Radiology, Medical School, Hannover
Key Words. Phenacetin abuse • Chronic pyelonephritis • Phenacetin kidney • Interstitial nephritis
In 1953, Spuhler and Zollinger [35] noted that almost one third of the patients, in whom chronic pyelonephritis had been found on post mortem, gave a history of phenacetin abuse. A long argument as to whether phenacetin (and perhaps also some other analgesic agents like aspirin) is causally related to interstitial inflammation of the kidneys seems at present to be answered positively by numerous clinical and pathological [4, 6, 10, 11, 15-18, 33, 34], epidemiological [14a, 14b, 19, 20] and experimental [1-3, 5, 12, 23, 26, 28, 31] studies. In a previous study one of us [7] found
phenacetin abuse nearly seven times more fre quently in patients diagnosed as having chron ic pyelonephritis on clinical and functional grounds, than in other patients suffering from chronic glomerulonephritis, hypertension or other non-renal disease. The present study was carried out in order to (1) reinvestigate this problem in another group of patients differing from these studied 10 years ago [7] and (2) to find out whether patients with chronic pyelonephritis and a history of phenacetin abuse can be distin guished from patients with chronic pyelone phritis and no such history.
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:04:55 AM
Abstract. A history of phenacetin abuse has been found almost three times more frequently among subjects diagnosed on clinical and functional grounds as suffering from chronic pyelo nephritis than among those suffering from other renal diseases or among non-renal controls. The chronic pyelonephritis in subjects admitting phenacetin abuse has been usually character ized by a more frequent intense bacteriuria and leucocyturia, by a slightly more frequent haematuria, history of renal colic, presence of stones and more rapid downhill course of glome rular filtration rate than in subjects without phenacetin abuse. A sterile lesion also without any past evidence of infection was observed only in subjects with the heaviest analgesic abuse. The discontinuation of the abuse in 5 subjects led to an improvement of the renal function.
312
Brod/Kuhn/Stender/Stolle
The functional pattern of chronic pyelone phritis consists of the following [8a-c]: (1) The urinary protein excretion is less than 1.5 g/ 24 h in 90% of the patients. (2) In the Addis count leucocytes are the predominating or exclusive element in 75% of patients. Erythrocytes may predominate if renal stones or some other bleeding conditions are the cause of pyelo nephritis. Casts are absent ore rare. (3) Counts of 100,000 microbes/ml are present in 80% of cases. (4) From the earliest stage of the disease the concentrating ability is reduced out of pro portion to the reduction of the glomerular fil tration rate (GFR). (5) In 75% of patients an asymmetry of the isotope renograms, of renal scans of the size of the kidneys and of the speed of excretion of the radio-opaque dye can be found. (6) The renal X-ray changes of chronic pyelonephritis, as described by Dedjar [13], consist in an irregular narrowing of the renal cortex with flattening of the papillae and dila tation of the calyces (‘clubbing’), in the de creased density and eventual disappearance of a pyelographic contrast and in the diminished size of the renal shadows (‘contracted kidneys’). The radiological signs of papillary necrosis are thought to be the penetration of the dye be tween the flattened tip of the papilla and the rest of the pyramid and/or a complete loss of the tip of the papilla with a convex rounding up of the shadow of the calyx. No single one of these signs is diagnostic. They must be considered in their entirety. If any of the above investigations is left out the diagnostic accu racy drops from 94.5 to 50% or less (8c). Methods Our retrospective study was carried out on 196 patients diagnosed as suffering from chronic inter
stitial nephritis, of whom more than 90% proved to have chronic pyelonephritis [7]. Other groups studied were 80 patients suffering from chronic glomerulo nephritis, 241 patients with essential hypertension, 125 patients with renal stones but no clinical evidence of chronic pyelonephritis, and a control group of 298 hospital patients without renal disease. The clinical diagnosis of the renal patients was based on a thorough history, examination and the following nephrological investigations were performed: (a) Qualitative and quantitative examination of urinary protein excretion, urinary deposit (Addis count) and urinary bacterial flora, (b) GFR (endogenous creatinine clearance) in two 12-hour urinary collections, (c) Maximum concentrating ability during a 24-hour water de pletion (except in those subjects with a GFR below 20 ml/min). (d) Infusion pyelography, (e) Isotope renography and renal scan, (f) Renal biopsy (in cases of doubt and in the majority of patients with glome rulonephritis). History of analgesic intake was obtained by ques tioning the subjects directly about the nature and num ber of any tablets they were taking and for how long. Abuse was considered when at least one analgesic tablet containing 0.12-0.25 g phenacetin a day for at least 1 year had been admitted by the subject. The total estimated phenacetin intake ranged from 0.5 to 15 kg over 1-40 years. The preparations taken and the phenacetin content are listed in table I. The statistical significance of the data was analysed by the y2-test.
Results Frequency o f Phenacetin Abuse Among Patients with Different Kidney Diseases From table II it is clear that in the 196 patients diagnosed as having chronic pyelo nephritis phenacetin abuse was encountered in 83 (42.3%), whereas in 80 glomerulonephritics this amounted to 11 (13.7%) and in the 241 subjects with essential hypertension to 35 (14.5%). Among 125 patients suffering from renal stones a history of phenacetin abuse was recorded in 20 (16.0%) and in the control group (298 subjects) in 45 (15.1%).
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Diagnosis of Chronic Pyelonephritis
313
Phenacetin Abuse and Chronic Pyelonephritis
In all the subgroups apart from chronic glomerulonephritis, phenacetin abuse was found more frequently among women, but not to a significant degree statistically. A phenace tin intake exceeding a total of 1 kg was en countered in 42 subjects labelled as suffering from chronic pyelonephritis (21.4%), in 6 (2.5%) of those with essential hypertension, in 9 (11.2%) glomerulonephritics, in 6 (4.8%) subjects with renal stones and in 22 controls (7.4%). A total exceeding 2 kg was recorded in 26 (13.2%) pyelonephritics, in none of the glomerulonephritics, in 3 (1.2%) of those with essential hypertension, in 2 (1.6%) patients
Table I. List of analgesic drugs used by the patients with their phenacetin and dérivâtes of acetylsalicylic acid and pyrazolone content per tablet (in mg) Drug
Phen acetin
Acetyl salicylic acid
Pyrazo lone
Dolviran® Gelonida® Migränc-Kranit® Octadon® Quadronal® Saridon® Spalt® (tili 1965) Thomapyrin®
200 250 120 170 150/300 250 280 200
200 250
— -
160 190 150/300 150 98 -
-
20 -
72 250
Table II. Frequency of phenacetin abuse among patients with various kidney diseases and among non-renal controls (the statistical significance of the differences is indicated below; only those differences which were significant are listed) Diagnosis
Total number
Males a
Females b
Total c
Abuse > 1 kg Abuse > 2 kg d e
Chronic 1 pyelonephritis
196
20/54 (37.0)
63/142 (44.3)
83/196 (42.3)
42/196 (21.4)
Chronic 2 glomerulonephritis
80
7/48 (14.5)
4/32 (12.5)
11/80 (13.7)
9/80 (11.2)
0
Essential hypertension 3
241
17/135 (12.55)
18/106 (16.9)
35/241 (14.5)
6/241 (2.5)
3/241 (1.2)
Nephrolithiasis 4
125
6/73 (8.2)
14/52 (26.9)
20/125 (16.0)
6/125 (4.8)
2/125 (1.6)
Controls 5
298
20/162 (12.3)
25/136 (18.3)
45/298 (15.1)
22/298 (7.4)
5/298 (1.6)
+ + + I a x 2a 1 a x 3a 1 a x 4a 1 a x 5a
++ + l b x 2b 1 b x 3b 1 b x 4b l b x 5b
+++ 1c 1c 1c 1c
++ + Id x 2d Id x 3d Id x 4d Id x 5d + 3d x 5 d
+ 1 e x 3e
Percentages are in parentheses.
2c 3c 4c 5c
+ + + 1 e x 4e 1 e x 5e Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:04:55 AM
+ p
Phenacetin Abuse and Chronic Pyelonephritis J. Brod, K. W. Kühn, H. S. Stender and E. Stolle Department of Medicine, Division of Nephrology, and Institute of Clinical Radiology, Medical School, Hannover
Key Words. Phenacetin abuse • Chronic pyelonephritis • Phenacetin kidney • Interstitial nephritis
In 1953, Spuhler and Zollinger [35] noted that almost one third of the patients, in whom chronic pyelonephritis had been found on post mortem, gave a history of phenacetin abuse. A long argument as to whether phenacetin (and perhaps also some other analgesic agents like aspirin) is causally related to interstitial inflammation of the kidneys seems at present to be answered positively by numerous clinical and pathological [4, 6, 10, 11, 15-18, 33, 34], epidemiological [14a, 14b, 19, 20] and experimental [1-3, 5, 12, 23, 26, 28, 31] studies. In a previous study one of us [7] found
phenacetin abuse nearly seven times more fre quently in patients diagnosed as having chron ic pyelonephritis on clinical and functional grounds, than in other patients suffering from chronic glomerulonephritis, hypertension or other non-renal disease. The present study was carried out in order to (1) reinvestigate this problem in another group of patients differing from these studied 10 years ago [7] and (2) to find out whether patients with chronic pyelonephritis and a history of phenacetin abuse can be distin guished from patients with chronic pyelone phritis and no such history.
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:04:55 AM
Abstract. A history of phenacetin abuse has been found almost three times more frequently among subjects diagnosed on clinical and functional grounds as suffering from chronic pyelo nephritis than among those suffering from other renal diseases or among non-renal controls. The chronic pyelonephritis in subjects admitting phenacetin abuse has been usually character ized by a more frequent intense bacteriuria and leucocyturia, by a slightly more frequent haematuria, history of renal colic, presence of stones and more rapid downhill course of glome rular filtration rate than in subjects without phenacetin abuse. A sterile lesion also without any past evidence of infection was observed only in subjects with the heaviest analgesic abuse. The discontinuation of the abuse in 5 subjects led to an improvement of the renal function.
312
Brod/Kuhn/Stender/Stolle
The functional pattern of chronic pyelone phritis consists of the following [8a-c]: (1) The urinary protein excretion is less than 1.5 g/ 24 h in 90% of the patients. (2) In the Addis count leucocytes are the predominating or exclusive element in 75% of patients. Erythrocytes may predominate if renal stones or some other bleeding conditions are the cause of pyelo nephritis. Casts are absent ore rare. (3) Counts of 100,000 microbes/ml are present in 80% of cases. (4) From the earliest stage of the disease the concentrating ability is reduced out of pro portion to the reduction of the glomerular fil tration rate (GFR). (5) In 75% of patients an asymmetry of the isotope renograms, of renal scans of the size of the kidneys and of the speed of excretion of the radio-opaque dye can be found. (6) The renal X-ray changes of chronic pyelonephritis, as described by Dedjar [13], consist in an irregular narrowing of the renal cortex with flattening of the papillae and dila tation of the calyces (‘clubbing’), in the de creased density and eventual disappearance of a pyelographic contrast and in the diminished size of the renal shadows (‘contracted kidneys’). The radiological signs of papillary necrosis are thought to be the penetration of the dye be tween the flattened tip of the papilla and the rest of the pyramid and/or a complete loss of the tip of the papilla with a convex rounding up of the shadow of the calyx. No single one of these signs is diagnostic. They must be considered in their entirety. If any of the above investigations is left out the diagnostic accu racy drops from 94.5 to 50% or less (8c). Methods Our retrospective study was carried out on 196 patients diagnosed as suffering from chronic inter
stitial nephritis, of whom more than 90% proved to have chronic pyelonephritis [7]. Other groups studied were 80 patients suffering from chronic glomerulo nephritis, 241 patients with essential hypertension, 125 patients with renal stones but no clinical evidence of chronic pyelonephritis, and a control group of 298 hospital patients without renal disease. The clinical diagnosis of the renal patients was based on a thorough history, examination and the following nephrological investigations were performed: (a) Qualitative and quantitative examination of urinary protein excretion, urinary deposit (Addis count) and urinary bacterial flora, (b) GFR (endogenous creatinine clearance) in two 12-hour urinary collections, (c) Maximum concentrating ability during a 24-hour water de pletion (except in those subjects with a GFR below 20 ml/min). (d) Infusion pyelography, (e) Isotope renography and renal scan, (f) Renal biopsy (in cases of doubt and in the majority of patients with glome rulonephritis). History of analgesic intake was obtained by ques tioning the subjects directly about the nature and num ber of any tablets they were taking and for how long. Abuse was considered when at least one analgesic tablet containing 0.12-0.25 g phenacetin a day for at least 1 year had been admitted by the subject. The total estimated phenacetin intake ranged from 0.5 to 15 kg over 1-40 years. The preparations taken and the phenacetin content are listed in table I. The statistical significance of the data was analysed by the y2-test.
Results Frequency o f Phenacetin Abuse Among Patients with Different Kidney Diseases From table II it is clear that in the 196 patients diagnosed as having chronic pyelo nephritis phenacetin abuse was encountered in 83 (42.3%), whereas in 80 glomerulonephritics this amounted to 11 (13.7%) and in the 241 subjects with essential hypertension to 35 (14.5%). Among 125 patients suffering from renal stones a history of phenacetin abuse was recorded in 20 (16.0%) and in the control group (298 subjects) in 45 (15.1%).
Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:04:55 AM
Diagnosis of Chronic Pyelonephritis
313
Phenacetin Abuse and Chronic Pyelonephritis
In all the subgroups apart from chronic glomerulonephritis, phenacetin abuse was found more frequently among women, but not to a significant degree statistically. A phenace tin intake exceeding a total of 1 kg was en countered in 42 subjects labelled as suffering from chronic pyelonephritis (21.4%), in 6 (2.5%) of those with essential hypertension, in 9 (11.2%) glomerulonephritics, in 6 (4.8%) subjects with renal stones and in 22 controls (7.4%). A total exceeding 2 kg was recorded in 26 (13.2%) pyelonephritics, in none of the glomerulonephritics, in 3 (1.2%) of those with essential hypertension, in 2 (1.6%) patients
Table I. List of analgesic drugs used by the patients with their phenacetin and dérivâtes of acetylsalicylic acid and pyrazolone content per tablet (in mg) Drug
Phen acetin
Acetyl salicylic acid
Pyrazo lone
Dolviran® Gelonida® Migränc-Kranit® Octadon® Quadronal® Saridon® Spalt® (tili 1965) Thomapyrin®
200 250 120 170 150/300 250 280 200
200 250
— -
160 190 150/300 150 98 -
-
20 -
72 250
Table II. Frequency of phenacetin abuse among patients with various kidney diseases and among non-renal controls (the statistical significance of the differences is indicated below; only those differences which were significant are listed) Diagnosis
Total number
Males a
Females b
Total c
Abuse > 1 kg Abuse > 2 kg d e
Chronic 1 pyelonephritis
196
20/54 (37.0)
63/142 (44.3)
83/196 (42.3)
42/196 (21.4)
Chronic 2 glomerulonephritis
80
7/48 (14.5)
4/32 (12.5)
11/80 (13.7)
9/80 (11.2)
0
Essential hypertension 3
241
17/135 (12.55)
18/106 (16.9)
35/241 (14.5)
6/241 (2.5)
3/241 (1.2)
Nephrolithiasis 4
125
6/73 (8.2)
14/52 (26.9)
20/125 (16.0)
6/125 (4.8)
2/125 (1.6)
Controls 5
298
20/162 (12.3)
25/136 (18.3)
45/298 (15.1)
22/298 (7.4)
5/298 (1.6)
+ + + I a x 2a 1 a x 3a 1 a x 4a 1 a x 5a
++ + l b x 2b 1 b x 3b 1 b x 4b l b x 5b
+++ 1c 1c 1c 1c
++ + Id x 2d Id x 3d Id x 4d Id x 5d + 3d x 5 d
+ 1 e x 3e
Percentages are in parentheses.
2c 3c 4c 5c
+ + + 1 e x 4e 1 e x 5e Downloaded by: King's College London 137.73.144.138 - 1/16/2019 4:04:55 AM
+ p
