ANNALS of Internal Medicine APRIL 1975 • VOLUME 82 • NUMBER 4 Published Monthly by the American College of Physicians

Chronic Interstitial Nephritis: Etiologic Factors T. MURRAY, M.D., and M. GOLDBERG, M.D., F.A.C.P., Philadelphia,

Whether chronic interstitial nephritis (pyelonephritis) mainly results from kidney infection is widely debated. We studied 101 patients with interstitial nephritis, selected from 320 patients with newly diagnosed chronic renal disease, for frequency of etiological factors. Eleven had no etiologic factor(s) identified; 89 had clearcut factor(s): anatomic abnormalities 3 1 , analgesic abuse 20, hyperuricemia 11, nephrosclerosis 10, stones 9, sickle cell disease 1, tuberculosis 1, multiple causes 7. Bacterial infection (present in 2 7 % ) was found only with another preceding primary cause of renal damage. Analgesic abusers frequently denied drug ingestion; 1 5 % had urinary tract infection and 2 0 % classical papillary necrosis. Two had family histories of analgesic abuse with nephropathy. We conclude that interstitial nephritis is a common form of chronic renal disease, is seldom idiopathic, rarely results from bacterial infection alone in adults, and frequently results from analgesic abuse in the United States.

I T IS NOW WELL ESTABLISHED that chronic renal disease

commonly results from renal interstitial and tubular damage in the absence of primary glomerular disease. Although such disease has classically been termed chronic pyelonephritis, reflecting the feeling that infection serves as its primary cause, many other potential causes are presently known. Hence interstitial nephritis is probably a more appropriate name for the renal disease associated with such pathologic changes. The frequency with which various potential causes of interstitial damage are operative in patients with interstitial nephritis is not yet clearly defined. For instance, although infection has long been held to be the primary • From the Renal-Electrolyte Section, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.

Pennsylvania

cause in most patients, the question has been raised whether or not bacterial infection ever causes renal insufficiency in the adult in the absence of other primary causes of interstitial nephritis ( 1 , 2 ) . Furthermore, at least one known etiologic factor, analgesic abuse, has been considered an uncommon cause in the United States (3, 4 ) , although it is a common cause in other countries (5-7). In addition, there is the general impression that many patients with interstitial nephritis have no etiologic factor identifiable, but rather represent cases of "idiopathic" disease ( 8 ) . We designed this study to measure first the frequency with which various suspected causes were present in patients with a clinical diagnosis of interstitial nephritis, and then to assess the causal relation between these etiologic factors and the renal disease present in each patient. Our findings suggest that interstitial nephritis (as diagnosed clinically) is a common cause of chronic renal disease, that infection is rarely the primary cause of interstitial nephritis in the adult, that analgesic abuse nephropathy is as common a cause of interstitial nephritis in the United States as it is elsewhere, and that few patients have so-called "idiopathic" interstitial nephritis. Materials and Methods PATIENT POPULATION

The charts of all patients admitted to the Hospital of the University of Pennsylvania between January 1969 and December 1972, whose diagnoses included any form of chronic renal disease, were initially reviewed. From these 430 patients were first eliminated all who did not have firm evidence of renal insufficiency (serum creatinine, 1.3 mg/100 ml or less). Also eliminated were those in whom renal insufficiency had been documented at this hospital before January 1969. This latter exclusion was designed to eliminate patients whose etiologic evaluation had been carried out before the present spectrum of causes of interstitial damage was fully appreciated. Eliminated from the remaining group of 320 patients were

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any who had definitive evidence of primary glomerular disease. For purposes of this study such evidence included any of the following: biopsy-proved glomerulonephritis, erythrocyte casts in the urine sediment, a protein excretion of 4 g or more per day, or the presence of any systemic disease commonly associated with glomerulopathy (for example, diabetes mellitus or necrotizing vasculitis). After this latter exclusion, 101 patients remained in our final study group. All displayed one or more of the clinical or laboratory characteristics felt to be typical of interstitial nephritis. These included: a urinary sediment without cellular casts (except for leukocyte casts during acute episodes of kidney infection), a urinary protein excretion of less than 2 g per day, evidence of disproportionately severe tubular dysfunction (for example, hyperchloremic acidosis or massive salt wasting), or radiologic evidence of interstitial or calyceal abnormalities, (for example, asymmetrical scarred kidneys, calyceal distortion, or papillary necrosis (9, 1 0 ) ) . ETIOLOGIC FACTORS

In each of the 101 patients evidence for any factor which might have been a potential cause of interstitial nephritis was noted, then an assessment was made of the probable role that factor had played in causing the interstitial nephritis. Each factor was classified as either a primary or a secondary cause of the interstitial nephritis. To be considered the primary cause, a factor had either to have been the only potential cause present before the development of renal insufficiency, or to have preceded and resulted in the occurrence of all the other factors identified. On the other hand, all factors that followed and resulted from a primary cause were considered secondary causes. The criteria by which we evaluated the potential etiologic factors in our study group are summarized below. Anatomic Abnormalities: All patients with congenital or acquired abnormalities of the upper or lower urinary tract shown radiologically (either before or after the development of azotemia) were included in this group, that is, they were considered to have an "anatomic abnormality" as a possible (primary or secondary) cause of their interstitial nephritis. Analgesic Abuse: All patients who had ingested analgesic compounds that were estimated to contain 3 kg or more of either phenacetin or aspirin before the onset of their azotemia were included in this group. The requirement for a 3 kg ingestion is purposely higher than that required by others ( 1 1 ) , so that the existence of such abuse as a possible cause is unquestionable. Hyperuricemia: All patients who were known to have had hyperuricemia (uric acid greater than 9 mg/100 ml or clinical gout at any time before 1 January 1969 and who were known to have had normal renal function (normal blood urea nitrogen or normal serum creatinine) at the time of or after the initial documentation of hyperuricemia were included in this group. Also included were all patients who had hyperuricemia out of proportion to their level of renal functional impairment. A serum uric acid of greater than 9 mg/100 ml with a serum creatinine level of 1.5 mg/100 ml or less, of greater than 10 mg/100 ml with a serum creatinine between 1.5 and 2 mg/100 ml, or of greater than 12 mg/100 ml with a serum creatinine between 2.1 and 3 mg/100 ml was considered disproportionately elevated. Any patient in whom hyperuricemia was documented only after his serum creatinine was 3.1 m g / 100 ml or higher was not considered to have this as a possible cause of his interstitial nephritis. Nephrosclerosis: All patients with benign hypertension (that is, sustained diastolic blood pressure of 100 mm Hg or higher) whose onset preceded the development of azotemia were included in this group. Patients with the clinical-pathological syndrome of malignant or accelerated hypertension were excluded because this entity is known to be associated with significant glomerular abnormalities. Although it is recognized that, at least initially, the renal histopathologic findings of patients with benign nephrosclerosis differ from those of patients with interstitial nephritis, the clinical and 454

laboratory features of both groups are those of tubular or interstitial disease or both rather than primary glomerular disease. "Benign" essential hypertension was, therefore, considered to be a potential cause of clinical interstitial nephritis as defined by our study. Stones: All patients who had stones shown radiologically in both kidneys or in a solitary kidney, were included in this group. Sickle Cell Disease: All patients with documented hemozygous sickle cell disease were included in this group. Renal Tuberculosis: The one patient with renal tuberculosis confirmed by urine culture was included in this group. Infection: All patients with two or more positive urine cultures (greater than 100 000 organisms/ml), either before or after the onset of azotemia, were included in this group. Idiopathic or Indeterminate: All patients in whom no potential cause of interstitial nephritis could be identified were included in this group. This group, therefore, consisted of both those in whom no potential etiologic factor was identified despite an extensive evaluation and those in whom a complete evaluation was not carried out. Results GENERAL CHARACTERISTICS

In the 101 patients studied, s e r u m creatinine r a n g e d from 1.4 to 26 m g / 1 0 0 ml with a m e a n ± S E M of 7.7 ± 1 m g / 1 0 0 ml. T h e patients' ages r a n g e d from 10 to 81 years. F o r t y - n i n e were m e n a n d 5 2 w o m e n . All had, by definition, o n e or m o r e of the characteristics typical of interstitial nephritis (see M e t h o d s ) . A b n o r malities of the u r i n a r y sediment varied. N o n e h a d cellular casts except during bouts of acute pyelonephritis ( 7 p a t i e n t s ) , most h a d m o d e r a t e to m a r k e d p y u r i a ( 8 7 p a t i e n t s ) , m i n i m a l microscopic h e m a t u r i a ( 4 6 p a t i e n t s ) , and r a r e to m o d e r a t e l y frequent noncellular casts (hyaline, g r a n u l a r ) ( 7 1 p a t i e n t s ) . Seventy-six patients showed 1 + to 3 + proteinuria by qualitative examination, the urine being negative for protein by dipstick examination in the rem a i n i n g 25 patients. T w e n t y - f o u r h o u r protein excretion was less t h a n 2 g per day in all but one of the patients with qualitative proteinuria. ( O n e patient with gout excreted 2.3 g of protein per d a y . ) Intravenous Urographic Findings: T h e s e w e r e of four types. Specific abnormalities w e r e seen in those patients w h o h a d a n a t o m i c abnormalities or stones. T h e majority of patients, however, h a d only nonspecific changes suggestive of interstitial or calyceal disease ( 9 ) . Five patients h a d classical radiologic changes of papillary necrosis ( 1 0 ) . Six patients (with mild a z o t e m i a ) h a d n o r m a l intravenous pyelograms. Renal Histopathologic Material: This material was available in 37 patients. All of the etiologic factors identified in the total population of 101 patients except renal tuberculosis a n d sickle cell disease w e r e present in o n e or m o r e of these 37 patients. T h e histopathologic features w e r e evaluated in all cases by staff m e m b e r s of b o t h the R e n a l Section of the D e p a r t m e n t of M e d i c i n e and the P a t h o l o g y D e p a r t m e n t . T h e pathologists r e a d the slides in all 37 patients without specific knowledge of the clinical or l a b o r a t o r y characteristics of the patient. In all cases 15 or m o r e glomeruli were available for evaluation. T h e criteria used to diagnose interstitial nephritis were similar to those r e p o r t e d by others ( 1 2 ) . All 37 cases manifested changes typical of interstitial nephritis. T h e s e changes were

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characterized by tubular atrophy and dilatation, interstitial fibrosis and accompanying mononuclear cell infiltration, and periglomerular fibrosis. In addition, 24 patients showed changes compatible with arteriolar nephrosclerosis, although this was the predominant lesion only in 3 patients who had hypertension as the primary cause of their renal disease. PREVALENCE

OF

PRIMARY

AND SECONDARY

ETIOLOGIC

FACTORS

The frequency with which each potential etiologic factor was found in these 101 patients and an assessment of the contribution of each to the patients' renal disease is summarized in Table 1 and discussed below. Anatomic Abnormalities: This group contained 34 patients who ranged in age from 10 to 80 years. Seventeen were men and 17 women. Values of serum creatinine ranged from 1.6 to 25 mg/100 ml with a mean ± SEM of 7.7 ± 1 . 4 mg/100 ml. The anatomic abnormalities had resulted in varying degrees of obstruction in 32 cases, while 2 patients showed ureteral reflux without obstruction. In 31 patients the anatomic abnormality was assessed to be the primary cause of the renal disease. Although 12 of these 31 patients had other potential causes present, these developed after the initial demonstration of the primary anatomic abnormality (for example, infection or stonecomplicating obstruction). In three patients the anatomic abnormality was only one of various unrelated factors which could have served as primary causes. These three patients are included in the group designated as having multiple primary causes (Table 1). Analgesic Abuse: There were 20 patients who had abused analgesics. Their ages ranged from 32 to 62 years. Three were men and 17 women. Values for serum creatinine ranged from 1.7 to 26 mg/100 ml with a mean ± SEM of 7.9 ± 1.6 mg/100 ml. In all 20 patients the abuse of analgesic compounds was considered the primary cause of the renal disease. In 10 of these 20, other potential causes were present, but these were felt to have developed from the abuse of analgesics. Nine of these 10 had significant hypertension, but this had clearly occurred only after many years of extensive abuse of analgesics and only shortly (1 to 2 years) before the first observation of renal functional impairment. Infection (three separate positive urine cultures) was the additional factor present in the 10th patient and was also present (two positive cultures each) in 2 patients with hypertension. In all three patients the infections were noted only after renal insufficiency was present. Further details of our analgesic abuse population will be presented below. Hyperuricemia: The 17 patients in this group ranged in age from 23 to 83 years. Eleven were men and 6 women. Values for serum creatinine ranged from 1.5 to 26 mg/100 ml with a mean ± SEM of 5.8 ± 1.6 mg/100 ml. All 17 patients either had documented hyperuricemia at a time when their serum creatinine level was less than 1.5 mg/100 ml before 1 January 1969, or had hyperuricemia dysproportionate to their degree of azotemia {supra vida). In 11 patients the hyperuricemia was felt to be the primary cause of the renal disease. In nine of these it was the only

Table 1. Etiologic Factors of Interstitial Nephritis in 101 Patients

Factor

Primary Causes*

Secondary Factor f no.

Anatomic abnormalities Analgesic abuse Hyperuricemia Nephrosclerosis Stones Sickle cell disease (SS) Renal tuberculosis Bacterial urinary tract infection Multiple Idiopathic or indeterminate

31 20 11 10 9 1 1 0 7 11

0 0 0 7 3 1 0 27

* Only or initial etiologic factor present in indicated number of patients, f Occurred subsequent to primary cause {see text).

potential cause identified, while in two the only other potential causes identified were asymptomatic bacteriuria which first occurred after the development of azotemia. In the remaining six patients, an additional possible primary cause was also identified. Two of these had positive urine cultures documented after the hyperuricemia was first found but before azotemia developed. Three developed hypertension after the hyperuricemia was known to be present but before azotemia developed. The final two patients had unrelated anatomic abnormalities shown radiologically. These six latter patients were all classified as having multiple primary causes (Table 1). Nephrosclerosis: The 20 patients in this group ranged in age from 28 to 80 years. Seven were men and 13 women. Values for serum creatinine ranged from 1.8 to 23 mg/100 ml with a mean ± SEM of 6.6 ± 1.7 mg/100 ml. Although many of the 101 patients developed hypertension as their azotemia progressed, only those in whom the hypertension preceded the development of azotemia were included in this group (supra vida). In 10 patients hypertension was the only identifiable cause of renal disease. In the remaining 10 another potential cause of the interstitial nephritis was also identified. In 7 of these 10 the other potential cause was known to have been present before the onset of the hypertension and was also felt to have resulted in the development of the hypertension. In these seven, therefore, the hypertension was considered a secondary cause. In the remaining three patients, the hypertension developed after the initial documentation of hyperuricemia. These three are, therefore, considered to have multiple possible primary causes. Stones: The 12 patients in this group ranged in age from 24 to 70 years. Four were men and 8 women. Values for serum creatinine ranged from 1.5 to 10.0 mg/100 ml with a mean ± SEM of 3.0 ± 1.0 mg/100 ml. All 12 had pelviceal or calyceal stones in both kidneys or in a solitary kidney, all of which were radio-opaque. In 10 patients the stones were bilateral; while in 2 they were present in patients who had previously had unilateral nephrectomies. In nine patients the stones were felt to be the primary cause of the renal disease. Although four of these nine had another potential cause present, stones were felt to be responsible for the development of the other factors Murray and Goldberg • Chronic Interstitial Nephritis

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(for example, infection behind obstructing stones and hypertension complicating hydronephrosis). In three patients the stones were felt to be only secondary causes in that they were considered to have developed as a consequence of the obstructing anatomic abnormalities. Sickle Cell Disease: A 40-year-old man with a serum creatinine of 1.7 mg/100 ml and a 47-year-old woman with a serum creatinine of 2.1 mg/100 ml comprise this group. The man had sickle cell disease as the only shown potential cause of his renal disease. He had never suffered gross hematuria, but his intravenous urogram showed classical papillary necrosis. The woman had another primary cause of her renal impairment identified. Because she never manifested gross hematuria, her intravenous urogram showed no evidence of papillary necrosis, and she never had renal colic, her sickle cell disease was not considered to be a primary factor. Renal Tuberculosis: A 43-year-old man with a serum creatinine of 1.6 mg/100 ml had renal tuberculosis as the only identified cause of his interstitial nephritis. Bacterial Infection: Twenty-seven patients had at least two documented (by urine culture) urinary tract infections. Their ages ranged from 23 to 88 years; 11 were men and 16 women. Values for serum creatinine ranged from 1.5 to 23 mg/100 ml with a mean ± SEM of 5.7 ± 1.3 mg/100 ml. All 27 had other primary causes known to be present before the first documentation of bacteriuria. It was felt, therefore, that the infection was a consequence of the primary cause, and thus it was considered a secondary factor. The primary causes in these 27 patients were anatomic abnormalities in 14, stones in 7, gout in 2, nephrosclerosis in 1, and analgesic abuse nephropathy in 3. Multiple Causes: Seven patients, five men and two women, had multiple possible primary causes for their interstitial nephritis identified. No attempt was made to assign preeminence to any one of these potential causes. Idiopathic or Indeterminate: In 11 patients no potential cause of the interstitial nephritis was identified. These 11 ranged in age from 20 to 62 years. Four were men and seven women. Values for the serum creatinine ranged from 3.4 to 28 mg/100 ml with a mean ± SEM of 15.9 ± 2 . 7 mg/100 ml. In seven patients, designated as indeterminate, exhaustive evaluations were not undertaken in six because they had end-stage disease when first seen and in 1 because she refused evaluation. In the remaining four patients no known cause of interstitial nephritis was identified despite extensive diagnostic evaluations. Thus in summary, at least 89% of the patients studied here had a primary cause of their interstitial nephritis identified, while, at most, 11 % had "idiopathic" disease. Analgesic Abuse in Detail: The 20 patients with analgesic abuse nephropathy in this series share many features with previously reported cases. A comparison of these features is presented in Table 2. Most of our patients were middle-aged women who suffered recurrent headaches. Many were anemic, had gastrointestinal disturbances, and had mild hypertension of recent onset. A significant number had required psychiatric treatment in the past. Two differences between the findings in our patients and those previously reported by others are the low incidence of 456

Table 2. Clinical Features in 20 Cases of Analgesic Abuse Nephropathy

Age, yrs Female, % Headache, % Anemic, % Gastrointestinal disturbances, % Psychiatric treatment, % Hypertension, % Urinary infection, % Papillary necrosis, %

Our Patients

Published Cases*

32 to 62 85 80 65 40 10 50 15 20

30 to 65 >80 >70 >50 >35 5 to 15 >30 >30 >20

* References 7, 11, and 26.

urinary tract infections ( 1 5 % ) and of classical radiologic changes of papillary necrosis (20% ) in our patients. The analgesics abused by our patients included aspirin and phenacetin in all cases, although no patient took only these two compounds. Other commonly abused drugs included acetaminophen and, less often, codeine. A number of other features that have not been adequately emphasized by other studies were exemplified by the patients reported here. First, all 20 patients were from the United States, and yet they comprised 20% of the new cases of interstitial nephritis seen during the study period. Second, in many of these patients the diagnosis of analgesic abuse nephropathy was made only after a substantial delay. The referring physician made the correct diagnosis in none of our 20 patients. Furthermore, the correct diagnosis was made in only six patients ( 3 0 % ) by the primary physicians caring for the patient at the Hospital of the University of Pennsylvania (housestaff and attending staff). Part of this diagnostic difficulty was caused by the tendency of these patients to deny the abuse of analgesics. Seven of the 20 patients initially denied such abuse and its existence was only discovered after extensive questioning of either the patient or, more often, the patient's family. In these seven patients the primary physicians at the University Hospital made the correct diagnosis only once. More striking is the fact that in the remaining 13, although the patient readily admitted the abuse of analgesics, the primary physician made the correct diagnosis only five times. The final point shown by our patients is that the habit of analgesic abuse and the existence of analgesic nephropathy can often be discovered in family members of the index cases. Two of our 20 cases had such positive family histories. The pedigree of one is shown in Figure 1. In this family the abuse of analgesics spans four generations and has thus far resulted in renal disease in three of the four members of the third generation. The index case was a 48-year-old woman with recurrent headaches and analgesic abuse since her teenage years, a history of excretion of renal papillae, a serum creatinine of 3.0 mg/100 ml, and mild hypertension. It is interesting that her husband shares her habit of abuse. The second patient's family history includes extensive abuse of analgesics and the presence of mild renal impairment in his only two children.

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Discussion

This study was designed to provide more information on some of the controversial issues concerning the various etiologies of clinically diagnosed chronic tubulointerstitial renal disease. It is necessary, therefore, to be assured that the patients studied did indeed have interstitial nephritis and, further, that they did not represent a preselected subgroup of patients with this disease. A definite diagnosis of interstitial nephritis can only be made from examination of renal tissue. Restriction of the study group to patients from whom such tissue was available, however, would have resulted in the study of patients with either more severe or more diagnostically puzzling disease. To avoid this pitfall, we studied patients who were felt to have interstitial nephritis on the basis of clinical and laboratory features (that is, evidence of interstitial or tubular dysfunction). These features were selected so as to exclude from this study only those patients who had definitive evidence of a primary glomerular disease, but to include all patients who possibly had interstitial nephritis as their primary renal disease. The bias of the selection method, if any, might have resulted in inclusion in the study group of patients who had diseases other than interstitial nephritis—for example, chronic glomerulonephritis. Such patients should certainly have the various causes of interstitial nephritis present less often than do those with interstitial nephritis, and, thus, should have findings opposite to those shown in this study. To the extent that any patients without interstitial nephritis were included in our study group, therefore, our finding that a known cause of interstitial renal disease is present in 89% of the patients becomes more impressive. Although we studied patients who had clinical evidence of interstitial disease, there is evidence that our method of selecting patients also resulted in selection of those with histopathological evidence of interstitial nephritis. In all 37 patients from whom renal tissue was subsequently available, the diagnosis of chronic interstitial nephritis was confirmed histopathologically. It is certainly possible that some cases of glomerulonephritis, especially focal glomerulonephritis, would be incorrectly diagnosed both clinically and histopathologically as interstitial nephritis, especially on biopsy. It seems statistically unlikely, however, that at least 1 of these 37 cases histologically studied would not have shown evidence of such primary glomerular disease if this were a common disorder in our 101 patients. The group of 11 patients classified as having an idiopathic or indeterminate cause of their disease on clinical grounds would probably be the one most likely to include any patients with primary glomerular disease. Yet, in five of these patients histological examination of the kidneys failed to show evidence in glomerulopathy. Of course, to the extent that any of the patients in this group in fact had glomerulonephritis, our conclusion that few patients with clinical evidence of chronic interstitial nephritis have idiopathic disease would be strengthened further. It is also possible that the relative distribution of the various etiologies of interstitial nephritis in our study is reflective of the special interests of a University Hospital.

Figure 1 . Pedigree of a family with frequent headaches (H), analgesic abuse (AB) and azotemia (AZ). Propositus, indicated by arrow in the third generation, is a 48-year-old woman with more than 30 years of analgesic abuse for recurrent headaches, papillary necrosis, and a serum creatinine of 3.0 mg/100 ml. See text.

Although we cannot exclude this possible bias, we have no specific reason to believe that this is the case. During the period of our study (1969 through 1972) there was no member of our Renal Group or on the Staff of the University Hospital who had a known special investigative or teaching interest in any of the etiological types of interstitial renal disease which would have caused an unusual number of referrals for special study. We had not yet developed, for example, our special clinical investigative interests in analgesic abuse nephropathy or metabolic stone disease. A number of points concerning interstitial nephritis and its various etiologies are made by this study. First, interstitial nephritis comprised a significant proportion ( 3 3 % ) of all the chronic renal disease seen during the period of this study. The 101 patients with this entity were drawn from a population of 320 that consisted of all the patients with newly diagnosed chronic renal disease. It is difficult to compare this incidence to other reports that discuss the various etiologies of chronic renal disease. Previous studies have mainly concerned the etiologies in patients with "end-stage" disease. In addition, these studies have not employed the term interstitial nephritis but rather have only discussed "chronic pyelonephritis," and it is not clear how restrictive the definition of this term was in most of these. Raaschow (13) reported that 58% of patients dying of uremia before 1948 had "pyelonephritis." On the other hand, Barnes, Gergan, and Braun (14) suggest that 15% of patients undergoing transplantation in 1971 had "pyelonephritis," and Freeman (1) states that only 7% of 80 patients requiring dialysis or transplantation at his hospital between 1970 and 1973 had "pyelonephritis." In this last series, at least, it seems likely that a very restrictive definition of "chronic pyelonephritis" (that is, infection in the kidney) was employed, and thus that other cases with interstitial nephritis among the 80 patients would not be included in the 7% figure. Thus, although our suggestion that as much as one third of all chronic renal disease might be due to interstitial nephritis cannot be directly verified by other reports, it is not out of the range that these reports suggest might occur. Murray and Goldberg • Chronic Interstitial Nephritis

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The second conclusion of this study is that bacterial urinary tract infection is seldom the primary cause of chronic renal disease in the adult. Although 27 patients had documented infections, all had another etiologic factor as the primary cause of their renal disease. In all 27 it was felt that the infection had occurred as a consequence of this primary cause or as a consequence of the presence of chronic interstitial nephritis itself and thus served as only a secondary factor. Of course, it is possible that the superimposition of infection added to the extent of renal damage or to the rapidity with which this occurred. Chronic infection has been considered by many physicians the primary cause of the pathologic picture now best described as interstitial nephritis. Many other causes of this same picture are now recognized, however, so that a more up to date view is that many different factors can result in chronic interstitial scarring. It is still generally felt that chronic urinary tract infection is one of these factors (15). The evidence that infection in a child can result in functional renal impairment in the absence of any other predisposing factor is substantial (16), although the role that primary ureterovesical reflux alone plays in the pathogenesis of such disease is not yet clear (17). In the adult, on the other hand, the evidence that infection alone can cause renal insufficiency is less convincing. Freedman (18) suggested that there "was little to suggest that urinary infection played a significant role" in the renal disease of patients found at autopsy to have "pyelonephritis" while Pawlowski, Blosdoric, and Kimmelstiel (19) reached a similar conclusion about the majority of their patients. Prospective studies of chronic bacteriuria have likewise failed to document progression to chronic renal disease in adults unless there are other potentially damaging factors operative (20, 21). Our study thus supplies strong support for the contention that urinary tract infection does not directly cause chronic renal insufficiency in the adult. The third point made by this study is that analgesic abuse is a common cause of interstitial nephritis in the United States. At least in the area surrounding Philadelphia, during the period of this study, 20% of the newly diagnosed cases of interstitial nephritis were attributable to such abuse. Because the total number of patients available for review was 320, analgesic abuse caused 7% (20 of 320) of all the chronic renal disease seen. It must be recalled that none of these patients were referred here because of our interest in analgesic abuse. In fact, in none was the diagnosis even suggested before evaluation here. It has been suggested that analgesic abuse was an uncommon cause of renal disease in this country (2, 3 ) . During the past 10 years, however, more than 100 cases of analgesic nephropathy have been reported (22-26), although neither the incidence nor frequency has been defined. Our 20 patients were seen for the first time during a 4-year period. This incidence is similar to that reported by Gault and associates (11) from the Royal Victoria Hospital in Canada where 22 new cases were seen during a 4-year period. Most of the figures quoted concerning the frequency of analgesic nephropathy are based on studies of patients 458

with "end-stage" renal disease. For instance, analgesic abuse is said to be the cause of the renal disease of 17% of patients requiring dialysis or transplantation in Australia ( 6 ) , of 5.5% of patients on regular dialysis in Canada ( 7 ) , and in 3 % of patients undergoing transplantation in Europe ( 5 ) . Our suggestion that 7% of all chronic renal disease in the United States might be due to analgesic abuse is not strictly comparable because patients with all degrees of renal insufficiency, rather than just end-stage disease, were surveyed. Still, because analgesic nephropathy, if untreated, is likely to progress to end-stage disease in the majority of patients, the magnitude of the problem of analgesic nephropathy is probably as great in the United States as it is elsewhere. Our patients with analgesic nephropathy and most others reported from the United States exhibit most of the clinical and laboratory features reported as typical of this disease (11, 26). Two differences between the clinical features observed in this series and those previously reported were observed. Urinary tract infection occurred in only 15% of our patients while Linton (7) reported that 36% of 100 patients had "significant" bacteriuria and Fellner and Tuttle (26) state that 6 5 % of 35 patients had persistent, positive urine cultures. No definite explanation for the low incidence of infection found in this study is available, although our patients were studied while their renal impairment was relatively mild. In any case, since 64% of Linton's (7) and 8 5 % of our patients developed renal insufficiency without evidence of any previous infection, it seems clear that infection is not necessary for the development of analgesic nephropathy. Classical radiologic changes of papillary necrosis were documented in only 20% of our patients. It has been argued, however, that papillary necrosis is the primary lesion caused by abuse of analgesics (27, 28). Clinical studies have stated that radiologic changes are found in 90% of patients with this disease (11), but have included all changes, not only those of papillary necrosis. In our series all of the patients had some abnormalities shown radiographically thus agreeing with this latter observation. When definite radiologic evidence of papillary necrosis has been required before the diagnosis is made, figures higher than ours ( 5 8 % ) (29) and figures similar to ours (20% ) (26) have been reported. Because it has been shown that papillary necrosis can be demonstrated pathologically before it can be seen radiographically (30), the fact that all patients with analgesic nephropathy do not have radiologic changes of papillary necrosis does not prove that such necrosis is not an early lesion. In addition papillary necrosis can be involved in the pathogenesis of a patient's renal disease and yet classical radiologic evidence of such necrosis may not be evident. For instance in five of our patients the calyces could not be seen well enough after intravenous urography to comment upon the presence or absence of papillary necrosis. The fact that patients with analgesic nephropathy can have other family members who abuse analgesics and also have a similar type of renal disease has been noted previously (31, 32), but has not been adequately emphasized.

Apr/7 1975 • Annals of Internal Medicine • Volume 82 • N u m b e r 4

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Two of our patients had other family members who abused analgesics and who also had analgesic abuse nephropathy. The importance of careful review of the family history of all patients with analgesic nephropathy should thus be obvious. Also, our group of patients who abused analgesics points out the difficulty one often has in making the correct diagnosis. Others have commented upon the problem of patient denial (33), which was a feature in seven of our patients. In addition the correct diagnosis was not made by the referring physician in any of our cases and was only made by the primary physician caring for the patients at the University Hospital in 5 of the 13 patients who readily admitted the abuse of analgesics. We suggest, therefore, that analgesic nephropathy is a common disease in the United States and that the diagnosis would be made often if a detailed history of the ingestion of analgesics were obtained, if the possibility of the surreptitious use of analgesics were considered, and if the relation between the abuse of analgesics and the development of chronic renal disease were recalled by all physicians dealing with patients with any degree of chronic renal insufficiency. The final point shown by this study is that most patients ( 8 9 % ) with interstitial nephritis have an easily identified primary cause of their disease. Again there are few previous reports with which this finding can be compared. Freedman (18) in a review of patients in whom a diagnosis of "chronic pyelonephritis" was made at autopsy concluded that 13 of 14 patients had during life "some finding known to predispose towards renal disease." On the other hand, Angell, Relman, and Robbins (34) reported that 14 of 20 patients with "chronic pyelonephritis" at autopsy were without evidence of infection or any other disease known to cause renal disease. This latter study had, however, previously eliminated many patients with known causes of interstitial nephritis from consideration so that in fact only 14 of 80 patients with "chronic nonobstructive pyelonephritis" had idiopathic disease. Since our series included patients with obstructive abnormalities, the incidence of "idiopathic disease" in our series and in the two studies mentioned is probably comparable.

3. SCHREINER G : T h e nephrotoxicity of analgesic abuse. Ann Intern Med 57:1047-1052, 1962 4. SCHREINER G : Analgesic abuse a n d renal woes. Med World News 13:17-18, 1972 5. PARSONS F , CLARK P, SPOCK M : 1970 annual report o n renal transplantation in E u r o p e . Proc Eur Dialysis Transplant Assoc 7:15-24, 1970 6. S H I E L

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• Requests for reprints should be addressed to Martin Goldberg, M.D., F.A.C.P., 860 Gates Pavilion, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, P A 19104.

References 1. F R E E M A N R : Does bacteria lead t o renal failure? Clin Nephrol 1:61-62, 1973 2. FREEDMAN L : Urinary tract infection, in Diseases of the Kidney, edited by STRAUSS M , W E L T G, 2nd ed. Boston, Little, Brown and Co., 1971, p . 682

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A C K N O W L E D G M E N T S : Grant support: grants from the John A. Hartford Foundation, grant HL-00340 from the National Heart and Lung Institute, and training grant AM-05634 from the N a tional Institute of Arthritis, Metabolic and Digestive Diseases. Presented in part at the 55th Annual Session of the American College of Physicians in N e w York, N e w York, 3 April 1974. Received 3 July 1974; revision accepted 22 November 1974.

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and renal papillary necrosis: a syndrome in chronic non-obstructive pyelonephritis. Acta Med Scand 179:121-128, 1966 30. LALLI A : Renal papillary necrosis. Am J Roentgenol Radium Ther Nucl Med 114:741-745, 1972 31. NORDENFELT O : Deaths from renal failure in abusers of phenacetin containing drugs. Acta Med Scand 191:11-16, 1972 32. GRIMLAND K : Phenacetin and renal damage at a Swedish factory. Acta Med Scand 4 0 5 ( s u p p l ) : 1963 33. M U R R A Y

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Murray and Goldberg

• Chronic Interstitial Nephritis

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459

Chronic interstitial nephritis: etiologic factors.

Whether chronic interstitial nephritis (pyelonephritis) mainly results from kidney infection is widely debated. We studies 101 patients with interstit...
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