C. M. Kunin
Natural History of "Lower" Urinary Tract Infections Summary: Our current knowledge of the long-term outcome of uncomplicated urinary tract infections in women is based on a re-evaluation of the criteria for defining pyelonephritis at autopsy, careful description of the causes of renal disease among patients entering dialysis and transplant programs, long term observation of patients, and epidemiologic studies which have attempted to determine the association of bacteriuria with mortality. The weight of the evidence favors the conclusion that although urinary tract infections can produce severe impairment of renal function, this is rare in the absence of a major predisposing factor such as obstruction, calculus, reflux, abnormalities of the voiding mechanism or diabetes. The predisposing lesions, however, may go undetected until heralded by episodes of acute pyelonephritis or by renal failure. Unfortunately, urinary tract infections are so common that it is difficult to distinguish the population at greatest risk. The possible role of renal damage produced by autoimmune mechanisms following infection needs continued study.
Zusammenfassung: Nati~rlicher Verlauf der ,,unteren" Harnwegsinfektionen. Unser derzeitiges Wissen fiber die Langzeitergebnisse bei unkomplizierten Harnwegsinfektionen der Frau basiert auf der kritischen Oberprfifung der Kriterien ffir die pathologisch-anatomische Definition der Pyelonephritis, der sorgffiltigen Dokumentation der Ursachen von Nierenerkrankungen bei Dialysepatienten und Transplantatempf/ingern, auf Langzeit-Uberwachungsstudien an Patienten sowie auf epidemiologischen Studien zur Kl~irung d e r Assoziation von Bakteriurie und Sterblichkeit. Obwohl Harnwegsinfektionen zu einer schweren Beeintr/ichtigung der Nierenfunktion fiihren k6nnen, sprechen die vorhandenen Daten daftir, dag es ohne gr613ere pr/idisponierende Faktoren wie Obstruktion, Konkrement, Reflux, Entleerungsst6rungen oder Diabetes nur selten zur Niereninsuffizienz kommt. Diese pr/idisponierenden Faktoren k6nnen jedoch unentdeckt bestehen, bis sie durch eine akute Pyelonephritis oder Nierenversagen zum Vorschein kommen. Bei der H~iufigkeit von Harnwegsinfektionen ist es schwer, die am st~irksten gef/ihrdete Gruppe abzugrenzen. Ein bedeutsamer Forschungsschwerpunkt fiir die Zukunft ist die Frage der durch Autoimmunmechanismen verursachten Nierensch/idigung nach Infektionen.
vide a middle ground where most can agree. We are rapidly approaching this point in understanding the clinical significance of urinary infections, A reasonable consensus has now developed concerning the risk factors for development of pyelonephritis and the long-term effects of this disease. This is due largely to improved criteria for bacteriologic and anatomical diagnosis, appreciation of the role of reflux nephropathy as the major cause of focal scars and data that have emerged from prospective studies of the natural history of patients with recurrent urinary tract infections. One issue that has created considerable debate is whether significant renal damage is produced in females by recurrent infection, and, if so, how frequently does this occur. Stated differently, are mechanical or physiologic alterations in the host prerequisites for renal damage? Are there special circumstances when virulent microorganisms produce infection in the otherwise normal host? The answers to these questions are critical since the justification for screening to detect infection, the need for urologic evaluation, assessment of therapeutic strategies and development of a vaccine depend on how likely it is that urinary tract infections will decrease renal function, or produce hypertension or shorten life. It must be kept in mind, however, that regardless of the answers to these questions we cannot dismiss lightly the considerable morbidity that is associated with urinary tract infections. We must also recognize that pyelonephritis is often focal and may involve only one kidney, Loss of the function of one kidney cannot be considered to be benign even though overall renal function is preserved.
Historical Perspective The role of urinary tract infections in causing end-stage renal failure and hypertension was first evaluated in the era before effective chemotherapeutic agents were available. The early investigators, therefore, were able to observe the expression of uncontrolled infection. Most of the observations were made in selected series of cases followed for long periods of time or studied at autopsy. The stage was set in the United States by the work of Longcope [1], and Weiss and Parker [2] who described young women with severe renal disease due to bilateral infection of the kidneys. Hypertension and end-stage renal failure were observed commonly in their series. They were particularly struck by sclerosis of the renal arterioles in the absence of generalized arteriosclerotic disease, and believed that this may have had a role in producing hypertension. Both Weiss and Parker as well as Longcope emphasiz-
Introduction As in every field o f medicine there are enthusiasts and iconoclasts. Only time and extensive experience will proS 44
C. M. Kunin, M.D., Department of Medicine,Ohio State UniversityCollege of Medicine, 410 West 10th Avenue, Columbus,Ohio 43210, USA.
Infection 18 (1990) Suppl. 2 © MMV Medizin Verlag GmbH Mfinchen, Miinchen 1990
C. M. Kunin: Natural History of Urinary Infections ed that hypertension was not seen in acute pyelonephritis, but only after renal insufficiency had developed as long as 10-15 years later. In reviewing their cases of acute interstitial and diffuse suppurative nephritis is is clear that Weiss and Parker appreciated the importance of pyelographic changes, the focal nature of the renal lesions and the histologic findings of acute interstitial inflammation and abscesses. These cases were real, and similar isolated cases of bilateral pyelonephritis have been described in the postantibiotic era by Bailey, Little andRolleston [3] and Davies, McLachlan and Asscher [4]. The major problem arises in the interpretation of what Weiss and Parker termed chronic or healed pyelonephritis. This entity accounted for many of their cases. They stated " . . . in the healed stage it is often difficult to determine whether one is dealing with a healed pyelonephritis.., or with a primary vascular kidney disease". Nevertheless they developed a series of morphologic criteria for chronic pyelonephritis from which they concluded that it was more frequent than glomerulonephritis as a cause of Bright's disease. These lesions included a) inflammatory reaction of the interstitial tissues; b) colloid casts in the tubules, which are lined with atrophic epithelium; c) periglomerular fibrosis; d) evidence of infection or inflammation within the tubules. Clinicians were also struck by what was termed as pyelonephritis lenta or silent pyelonephritis [5]. This was used to describe the insidious appearance mostly in young adult females of end-stage renal disease often accompanied by hypertension. Acute pyelonephritis in pregnancy was well described by Crabtree [6] working in the 1930s. He noted that the effect of pyelonephritis on renal function was not great during the acute and subacute phases of the disease. He explained this by the focal and irregular distribution of the lesions. There were several cases of acute pyelonephritis following pregnancy in the series described by Weiss and Parker, but none were fatal. Instead they were detected at autopsy in deaths form other causes. Crabtree and Reid [7] studied 45 women who had pyelonephritis of pregnancy ~ five to ten years previously. They found five with renal stones, three with significant decrease in renal function as determined by delayed excretion of phenolsulfonaphthalein and one with an increase in nonprotein nitrogen. Four patients showed poor visualization of one kidney on intravenous pyelogram. Hypertension was not common. Crabtree commented on the findings in these cases as follows. "There is not now sufficient evidence to permit accurate
estimation of the remote effects of pyelonephritis on duration of life, state of health during life, and relation to mortality". This statement presaged the current controversy. Studies of Urinary Infections in the Postantibiotic Era In recent years our understanding of the pathogenesis and natural history of urinary tract infection has been improved by: a) More strict definition of bacterial pyelonephritis as seen at autopsy and appreciatiOn of the similarity of the lesions produced by vascular disease, interstitial nephritis and papillary necrosis to those of pyelonephritis; b) Evidence that vesicoureteral reflux is the major cause of focal renal cortical scars and distortion of the renal calyces and that most renal damage occurs in the first five years of life; c) The elucidation of the role of analgesic drugs in producing interstitial nephritis and papillary necrosis that must be distinguished from bacterial pyelonephritis; e) Improved bacteriologic methods to diagnose urinary tract infections and to perform epidemiologic studies; f) Long-term prospective population studies and clinical trials to determine the outcome of infection. Autopsy Studies The frequency of pyelonephritis reported at autopsy varies considerably and ranges from 1.9-20%, T a b l o 1. This is due to differing interpretations by pathologists of the nonspecific nature of the inflammatory and vascular changes that Weiss and Parker described as "healed pyelonephritis". Pawlowski et al. [8] re-examined the old criteria for chronic pyelonephritis by comparing cultures of bladder urine and kidneys with autopsy findings. They were unable to correlate the data obtained by culture with the morphology of the renal lesions. They relied instead on the patchy distribution of the lesion and the importance of finding of a polymorphonuclear leukocyte infiltration to make the diagnosis. They emphasized the difficulty of establishing an etiology based on morphologic grounds alone. Using rather rigid criteria to define pyelonephritis, Kimmelstiel [9] could identify pyelonephritis in only 2.8% of autopsies. Only 18 of 97 cases thought to have pyelonephritis also had azotemia. In most of these the disease could be explained by obstruction or dysplasia or calcinosis. The male to female sex distribution was 1:1.3. This report is in marked contrast to that of Gall [10] who considered the severely shrunken kidney as the "stigma" of pye-
Table 1: Pyelonephritis described at autopsy, selected studies.
MacDonaM et al.* Gall Kimmelstiel et al. Freedman
1957 1961 1961 1967
(11) (10) (09) (12)
100 2991 3393 4686
17 360 97 64
17 12 2.8 1.4
13 140 18 15
81 49 18.6 23.4
* These were consecutive cases and did not exclude obstructive uropathy or acute terminal infections; ** Among those believed to have pyelonephritis.
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C. M. Kunin: Natural History of Urinary Infections lonephritis. He considered pyelonephritis to account for a third of all renal disorders found at autopsy and to account for half the patients who developed chronic uremia. Similarly MacDonald et al. [11] reported that 18% of their autopsy series had healed pyelonephritis. Freedman [12] has provided what I consider to be the most convincing of the modern autopsy studies. He combined effectively anatomical and clinical data and excluded patients with genitourinary abnormalities, serious infections or bacteremia during a terminal illness. Pyelonephritis was found in only 1.4% of autopsies. There was a slight preponderance of males (57%). Renal insufficiency was found in one fourth of the Cases of pyelonephritis. The anatomic findings in these patients were equally distributed in both kidneys and lacked the broad scars expected in pyelonephritis. These lesiOns could be explained by severe vascular disease, papillary necrosis or medullary cysts. Most importantly, his analysis of the cases revealed that the role of urinary infection was negligible based on the clinical course. Thus it appears that bilateral, nonobstructive pyelonephritis sufficient to produce end-stage renal disease must be quite rare in the absence of obstruction. Still left unsettled, however, is whether an initial bacterial infection may induce an immunologic response that produces the nonspecific lesions. This is intriguing, but will require a new approach to the problem such as a role for autoimmunity to Tamm-Horsfall protein currently being pursued by Andriole and co-workers [13]. Studies of Large Series of Patients with End-stage Renal Disease
A reasonable estimate of the contribution of pyelonephritis to renal damage can be obtained from various studies of end-stage or chronic renal failure. For example, of 15,921 cases in the 12th Report of the Human Transplant Registry 2,123 or 13.1% were considered to have pyelonephritis. The cause of pyelonephritis in this group can be surmized from a breakdown of 161 cases awaiting transplantation described by Huland and Busch [14]. Of these, 26.1% were considered to have pyelonephritis, but all had one or more of the following complicating factors (ex, pressed as % of the total): vesicoureteral reflux 66.7, analgesic abuse 14.3, nephrolithiasis 11.9 and obstruction 7.2. These results are similar to those of Murra and Goldberg [15] who found that all their cases of interstitial nephritis considered to be related to infection could be accounted for by the presence of structural abnormalities. Thus these studies support the concept that renal damage from pyelonephritis sufficient to cause end-stage renal disease does not occur in the absence of associated complicating factors. Significant Bacteriuria as a Marker of Urinary Tract Infection
The studies.of pyelonephritis conducted in the 1930 and 1940s generated considerable interest since they suggested S 46
an important role for infection in the pathogenesis of renal disease. It is not surprising, therefore, that the exploitation of the quantitative bacterial count by Kass in 1956 [16] as an aid to diagnosis led to a virtual explosion of activity in this field. The concept of asymptomatic bacteriuria developed by Kass promised to help explain many of the problems encountered in understanding pyelonephritis lenta and it was hoped that this could possibly lead to a new approach to prevention not only of renal disease but of some of the major complications such as hypertension, prematurity and infection stones. The situation, however, became much more complex as so commonly occurs when a true "breakthrough" is developed. First of all it soon became obvious that significant bacteriuria in females is very common and the epidemiologic dynamics are complex. This was compounded by the frequent occurrence of spontaneous cure and relapses. Symptomatic infection was already known to be a common problem in general practice. Development of end-stage renal disease or even hypertension in these populations was rarely observed and it was hard to believe that the "common garden variety 'cystitis'" was more than a nuisance. Although many studies demonstrated that asymptomatic bacteriuria early in pregnancy predisposed to overt pyelonephritis in the last trimester, only a small proportion of premature births could be explained by urinary tract infection. Thus it became apparent fairly soon that large scale prospective studies were needed to determine the long-term outcome of uncomplicated urinary tract infections in females. Long-Term Follow-up Studies in Adult Females
The results of several long term studies are summarized in Table 2. Although at first glance most of these studies appear to support the notion that natural history of urinary tract infections in females is benign, more detailed examination of the reports reveal the occurrence of considerable morbidity. For example, persistent bacteriuria and recurrent symptomatic infections were common in most of the series. About one-quarter of the patients followed after pregnancy had persistent bacteriuria in the series of Gower [17] and Zinner and Kass [18]. Urine concentrating ability, when studied by Zinner and Kass andA/wall [19] was often found to be depressed, but returned to normal following therapy. It is important to emphasize that hidden among any group of women with urinary tract infections are some with scars and renal atrophy produced most likely by vesico-ureteral reflux in childhood. For example, in a long term study reported by Gower [20] 33% of women with unilateral and 50% of those with bilateral pyelonephritis were found to have reflux. The estimated ten year survival for these patients was 100% and 86%, respectively. On the other hand, survival in those with papillary necrosis and infection was only 56% at ten years. In a long-term follow-up study reported by Parker and Kunin [21] of women who had been hospitalized for acute pyelonephritis 10-20 years
Infection 18 (1990) Suppl. 2 © MMV Medizin Verlag GmbH Miinchen, Mtinchen 1990
C. M. Kunin: Natural History of Urinary Infections Table 2: Long-term follow-up studies of urinary tract infections in adult females.
1960 1961 1965
(26) (27) (28)
111 50 16
0.5-3 5 0.25-2
Zinner and Kass**
1968 1970 1971
(17) (29) (18)
164 70 192
0.5-4 4--7 10-14
Freedman
1972
(30)
250
12
Asscher et al. Gower***
1973 1973 1976
(31) (21) (20)
107 74 85
4 10--20 0.5-11
Alwall*
1978
(19)
94
3-7
Freedman* Pinkerton et al.** Little et al.* Gower et al.** Bullen and Kincaid-Smith**
Parker and Kunin***
None Unilateral nephrectomy in 2 Decrease in renal size after infection No progression No progression 2 cases of necrotizing pyelonephritis No, nor development of hypertension No progression Renal failure in 4 No progression except with analgesic use No progression ? hypertension
Symptomatic infections in adult females; ** Following pregnancy; *** Known to have acute and chronic infection in past. earlier, clinical illness began in most patients in association with marriage, pregnancy or the post-partum period. Repeat episodes of infection still occurred within the three years of follow-up in 29 (40%) and within six months in 16 (23%), Twelve (17%) were bacteriuric at the time of follow-up. Twenty,one (28%) had had an operative urological procedure; 17 (23%) had a history of renal stone. Elevated blood pressure, however, was no more common than expected for this age group. One patient had died of the complications of pyelonephritis, one required a renal transplant for end-stage renal disease and two others had azotemia. Seven patients had undergone unilateral nephrectomy for pyelonephritis. Most of these were doing well at the time of follow-up. Thus the morbidity was considerable in women who had infection severe enough to require hospitalization. Alwall [19] selected 844 non-pregnant women, age 21-70 years who were detected in screening programs. He excluded those with obstructive uropathy, concretions, diabetes and glomerulonephritis. Bacteriuric women were compared to several control groups. These consisted of nonbacteriuric women who did or did not have a past history of infection. There were no differences among the groups in serum urea nitrogen or creatinine. Radiological abnormalities on intravenous pyelogram ranged from 8,1-9.3%, but did not differ significantly among cases and controls. The only detectable difference was less concentrating ability in the bacteriurics, but this cleared with therapy. At follow-up 36 to 80 months later there were significantly more patients who developed hypertension among the bacteriurics, and those with past history of infection or sterile pyuria than nonbacteriuric controls with
no previous history of infection. Unfortunately, there were no follow-up intravenous pyelograms, nor report of changes in renal function other than concentrating ability. Alwall also described a selected series of 33 women who were followed over a 30 year period. They initially had normal findings on intravenous pyelogram. Many developed contracted kidneys and uremia was described in four patients. It is difficult to assess the risk of occurrence of renal failure from pyelonephritis in the general population based on this selected group of patients.
Long-Term Follow-up in School Girls There has been considerable interest in the potential to discover urinary tract infections early in childhood in the hope that detection of urologic abnormalities and treatment of infection might prevent renal damage later in life. The results of several follow-up studies (Fable 8) may be summarized as follows. Urinary infections are readily detected by screening for significant bacteriuria. Among the population with infection will be found a small proportion (about 5%) with important correctable urologic abnormalities, mostly high grades of vesico-ureteral reflux. Renal scars are almost always associated with reflux. Most of the renal damage, however, appears to have occurred earlier in life and although some progression does occur this is not very significant. Treatment of infection is effective in eradicating bacteria for a short period of time, but recurrence of infection is common so that there are few long lasting effects of short courses of therapy. Decrease in renal function and occurrence of hypertension is rare in girls who do not have major structural abnormalities.
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C. M. Kunin: Natural History of Urinary Infections
Table 3: Long-term follow-up studies of urinary tract infections in girls.
Savage et al.* Welch et al. Lindberg et al.* Cardiff-Oxford* Gillenwater et al.**
1975 1976 1978 1978 1979
(32) (33) (34) (35) (22)
63 40 116 208 60
2 6.5 5 4 9-18
No progression No progression No progression No progression Nephrectomy in 2, azotemia in 1 (see text)
* Treatment trials; ** Compared with 38 matched controls.
The only case controlled study was reported by Gillenwater, Harrison and Kunin [22]. They followed patients found to have persistent significant bacteriuria up to 18 years previously. These were first detected in a screening program conducted by the author in communities in Virginia. Sixty girls (48 white and 12 black) from the original cohort (henceforth referred to as cases) were followed in comparison to 38 controls, randomly drawn from the same population that participated in the screening program. The controls had been shown not to have had significant bacteriuria during annual surveys. They were then matched for age with the cases. During the follow-up years urine cultures were performed on each group at six month intervals and intravenous pyelograms were obtained on two occasions. The following observations were made: One or more episodes of bacteriuria occurred in 70% of the cases and 39.5% of the controls. More than five episodes occurred in 21.7% of cases compared to 2.6% in controls. Bacteriuria of pregnancy was noted in 63.9% of cases and 26.7% of controls. Hospitalizations for complications of urinary tract infection (including five for acute pyelonephritis) was required in ten cases and only one control. One case required 19 admissions for control of infection and other complications. Open urologic surgery was required in nine cases and none of the controls. This included two patients who underwent nephrectomy because of diseased kidneys. Blood pressure, however, did not differ significantly between groups. Finally radiologic abnormalities on intravenous pyelograms were observed in 20% of cases and in only one control (2.6%). The lesions found in the cases included caliectasis in seven, renal scarring in two and stones in one. The serum creatinine was significantly higher among the cases, but all were within the normal range for all, except for one case with bilateral atrophic pyelonephritis. It is clear from this study that urinary tract infection detected in childhood is benign in most of the girls. Nevertheless it was a major cause of morbidity in many and accounted for significant loss of renal function in some.
Evidence of Increased Mortality Among Adults with Bacteriuria There are now three studies which provide suggestive evidence of increased mortality, unrelated, as far as can be
S 48
determined, to alteration in renal function. Two of these studies are reported in elderly individuals by Sourander et al. [23] and Dontas et al. [24] and one among women found to have bacteriuria during large surveys by Evans et al. [25]. The latter study will be described briefly since it is pertinent to the question of the significance of uncomplicated urinary tract infection in females. Three surveys each were conducted in women in Wales and Jamaica over a 13 year period. Bacteriuria was detected on one occasion in 94 women and on two occasions in 26. These cases were compared with 1,115 women who were not bacteriuric on either occasion. The mortality risk ratio, after adjustment for age and weight, was 1.5 for bacteriuric women. The ratio increased to 2.0 for women who were bacteriuric on both surveys. The cause of death as stated on death certificate did not reveal any single cause of excess mortality. The positive association between bacteriuria and mortality is unexplained and may represent an associated but not causally related factor. For example, bacteriuria may be more common in patients with debilitating diseases or it may indicate a population that were more frequently in the hospital and had acquired infection in that environment possibly from catheters.
Comment This review seeks to find a middle ground between those who view urinary tract infections in females as little more than a benign nuisance, and others who have sought to implicate it as a major cause of renal failure. The difficulty appears to be related to which end of the spectrum of disease one examines; that is whether one looks at the process from the starting with the very common phenomena of significant bacteriuria or symptomatic urinary infections or examines the end-stages of renal disease. One only rarely has the opportunity to follow the same individual for very long periods of time. Clearly only a small proportion of individuals with urinary tract infection are at risk of significant renal damage from infection and most of these will have a major underlying process such as vesico-ureteral reflux. It now appears that the focal renal scars, once believed to be so very characteristic of pyelonephritis, are actually the residual of reflux in childhood often with superimposed infection. I believe that it is important to point out that patients do not announce themselves as hav-
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C. M. K u n i n : Natural History of Urinary Infections
ing underlying lesions of the urinary tract when they present with their first few episodes of infection. On the other hand it is unproductive to submit patients with a low likelihood of having abnormalities to extensive studies. As I see it there are two major challenges for further research in this field. The first is to be able to develop inexpensive
noninvasive procedures that can detect important structural or neurological abnormalities of the urinary tract. The other is to be able to test the hypothesis that autoimmune or other responses to past bacterial infection can damage the kidney.
References 1. Longcope, W. T.: Chronic bilateral pyelonephritis: its origin and its association with hypertension. Ann. Intern. Med. 2 (1937) 149-163. 2. Weiss, S., Parker, F." Pyelonephritis: its relation to vascular lesions and to arterial hypertension. Medicine 18 (1939) 221-315. 3. Bailey, R. R., Little, P. J., Rolleston, G. L.: Renal damage after acute pyelonephritis. Br. Med. J. 1 (1969) 550-551. 4. Davies, A. F., Mclachlan, M. F., Asseher, A. W.: Progressive kidney damage after non-obstructive urinary tract infection. Br. Med. J. 4 (1972) 406-407. 5. MacGregor, M.: Pyelonephritis lenta~ Consideration of childhood urinary infection as the forerunner of renal insufficiencyin later life. Arch. Dis. Child. 45 (1970) 159-171. 6. Crabtree, E. F., Prather, G. C., Prien, E. L: End-results of urinary tract infections associated with pregnancy. Am. J. Obstet. 34 (1937) 405. 7. Crabtree, E. G., Reid, D. E.: Pregnancy pyelonephritis in relation to renal damage and hypertension. Am. J. Obstet. 40 (1940) 17. 8. Pawlowsld, J. M., Bloxdorf, J. W., Kimmelstiel, P.: Chronic pyelonephritis: a morphologic and bacteriologic study. N; Engl. J. Med. 268 (1963) 965-969. 9. Kimmelstiel, P., Kim, O. J., Beres, J. A., WeUmann, K.: Chronic pyelonephritis. Am. J. Med. 30 (1961) 589-607. 10. Gall, E. A.: Pyelonephritis. Bull. NY. Acad. Med. 37 (1961) 367-382. 11. MacDonald, R. A., Levitiu, H., Mallory, G. K., Kass, E. H.: Relation between pyelonephritis and bacterial counts in the urine. N. Engl. J. Med. 256 (1957) 915-922. 12. Freedman, L R.: Chronic pyelonephritis at autopsy. Ann. Intern. Med. 66 (1967) 697-710. 13. Mayrer, A. R., Miniter, P., Andriole, V. T.: Immunopathogenesis of chronic pyelonephritis. Am. J. Med. 75 (1983) 59-70. 14. Huland, H., Busch, R.: Chronic pyelonephritis as a cause of end stage renal disease. J. Urol. 127 (1982) 642--643. 15. Murray, T,, Goldberg, M.: Chronic interstitial nephritis: Etiologic factors. Ann. Intern. Med. 82 (1975) 453-459. 16. Kass, E. H.: Horatio at the orifice: The significance of bacteriuria. J. Infect. Dis. 138 (1978) 546-557. 17. Gower, P. E., Haswell, B., Sidaway, M. M. E.: Follow-up of 164 patients with bacteriuria of pregnancy. Lancet i (1968) 990-994. 18. Zinner, S. H., Kass, E. H.: Long-term (10-14 years) follow-up bacteriuria of pregnancy. N. Engl. J. Med. 285 (1971) 820-827. 19. Alwall, N.: On controversial and open questions about the course and complications of non-obstructive urinary tract infection in adult women. Acta. Med. Scand. 203 (1978) 369-377.
20. Gower, P. E.: A prospective study of patients with radiological pyelonephritis, papillary necrosis and obstructive atrophy. Quart. J. Med. 178 (1976) 315-349. 21. Parker, J., Kunin, C. M.: Pyelonephritis in young women. JAMA 224 (1973) 585-590. 22. Gillenwater, J. Y., Harrison, R. B., Kunin, C. M.: Natural history of bacteriuria in schoolgirls. N. EngL J. Med. 301 (1979) 396-399. 23. Sourander, L. B., Kasanen, A. A.: A 5-year follow-up of bacteriuria in the aged. Geront. Clin. 14 (1972) 274-281. 24. Dontas, A. S., Kasvidi-Charvati, P., Papanayiotou, D. C., Marketos, S. G.: Bacteriuria and survival in old age. N. Engl. J. Med. 304 (1981) 939-943. 25. Evans, D. A., Kass, E. H, Hennekens, C. H., Rosner, B., Miao, L., Kendrick, M. L, Miall, W. E., Stuart, ILL.: Bacteriuria and subsequent mortality in adult women. Lancet i (1982) 156-158. 26. Freedman, L. R.: Prolonged observations of a group of patients with acute urinary tract infections. In: Quinn, E. L., and Kass, E. 1-1.(eds.): Biology of Pyelonephritis. Little, Brown and Co., Boston 1960, pp. 345--353. 27. Pinkerton, J. H. M., Wood, C., Williams, E. R.: Sequelae of urinary infection in pregnancy. A five year follow-up. Br. Med. J. ii (1961) 539-542. 28. Little, P. J., McPherson, H. E., de Wardener, H. E.: The appearance of the intravenous pyelogram during and after acute pyelonephritis. Lancet i (1965) 1186-1191. 29. Bullen, M., Kineaid-Smith, P.: Asymptomatic pregnancy bacteriuria a follow-up study 4-7 years after delivery. In: Kincaid-Smith, P., Fairley, K (eds.): Renal Infection and Renal Scarring. Mercedes Publishing Service, Melbourne 1971, pp. 33-39. 30. Freedman, L 1L: Natural history of urinary infection in adults. Kidney Internation. Suppl. 4 (1975) 96. 31. Asscher, A. W.: The challenge of urinary tract infections. Grune and Stratton, New York 1980, p. 209. 32. Savage, D. L., Adler, K., Howie, G., Wilson, I. E.: Controlled trial of therapy in covert bacteriuria of childhood. Lancet i (1975) 358-361. 33. Welch, T. R., Forbes, P. A., Drummond, K. M., Nogrady, M. B.: Recurrent urinary tract infection in girls. Arch. Dis. Child. 51 (1976) 114-119. 34. Lindberg, U., Ciaesson, I., Hanson, L .~, Jodal, U.: Asymptomatic bacteriuria in schoolgirls. VIII. Clinical course during a 3 year follow-up. J. Pediatr. 92 (1978) 194-199. 35. Asscher, A. W., Fletcher, E. L, Johnston, H. H.: Sequelae of covert bacteriuria in school girls. Lancet i (1978) 889-894.
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Natural History of "Lower" Urinary Tract Infections Summary: Our current knowledge of the long-term outcome of uncomplicated urinary tract infections in women is based on a re-evaluation of the criteria for defining pyelonephritis at autopsy, careful description of the causes of renal disease among patients entering dialysis and transplant programs, long term observation of patients, and epidemiologic studies which have attempted to determine the association of bacteriuria with mortality. The weight of the evidence favors the conclusion that although urinary tract infections can produce severe impairment of renal function, this is rare in the absence of a major predisposing factor such as obstruction, calculus, reflux, abnormalities of the voiding mechanism or diabetes. The predisposing lesions, however, may go undetected until heralded by episodes of acute pyelonephritis or by renal failure. Unfortunately, urinary tract infections are so common that it is difficult to distinguish the population at greatest risk. The possible role of renal damage produced by autoimmune mechanisms following infection needs continued study.
Zusammenfassung: Nati~rlicher Verlauf der ,,unteren" Harnwegsinfektionen. Unser derzeitiges Wissen fiber die Langzeitergebnisse bei unkomplizierten Harnwegsinfektionen der Frau basiert auf der kritischen Oberprfifung der Kriterien ffir die pathologisch-anatomische Definition der Pyelonephritis, der sorgffiltigen Dokumentation der Ursachen von Nierenerkrankungen bei Dialysepatienten und Transplantatempf/ingern, auf Langzeit-Uberwachungsstudien an Patienten sowie auf epidemiologischen Studien zur Kl~irung d e r Assoziation von Bakteriurie und Sterblichkeit. Obwohl Harnwegsinfektionen zu einer schweren Beeintr/ichtigung der Nierenfunktion fiihren k6nnen, sprechen die vorhandenen Daten daftir, dag es ohne gr613ere pr/idisponierende Faktoren wie Obstruktion, Konkrement, Reflux, Entleerungsst6rungen oder Diabetes nur selten zur Niereninsuffizienz kommt. Diese pr/idisponierenden Faktoren k6nnen jedoch unentdeckt bestehen, bis sie durch eine akute Pyelonephritis oder Nierenversagen zum Vorschein kommen. Bei der H~iufigkeit von Harnwegsinfektionen ist es schwer, die am st~irksten gef/ihrdete Gruppe abzugrenzen. Ein bedeutsamer Forschungsschwerpunkt fiir die Zukunft ist die Frage der durch Autoimmunmechanismen verursachten Nierensch/idigung nach Infektionen.
vide a middle ground where most can agree. We are rapidly approaching this point in understanding the clinical significance of urinary infections, A reasonable consensus has now developed concerning the risk factors for development of pyelonephritis and the long-term effects of this disease. This is due largely to improved criteria for bacteriologic and anatomical diagnosis, appreciation of the role of reflux nephropathy as the major cause of focal scars and data that have emerged from prospective studies of the natural history of patients with recurrent urinary tract infections. One issue that has created considerable debate is whether significant renal damage is produced in females by recurrent infection, and, if so, how frequently does this occur. Stated differently, are mechanical or physiologic alterations in the host prerequisites for renal damage? Are there special circumstances when virulent microorganisms produce infection in the otherwise normal host? The answers to these questions are critical since the justification for screening to detect infection, the need for urologic evaluation, assessment of therapeutic strategies and development of a vaccine depend on how likely it is that urinary tract infections will decrease renal function, or produce hypertension or shorten life. It must be kept in mind, however, that regardless of the answers to these questions we cannot dismiss lightly the considerable morbidity that is associated with urinary tract infections. We must also recognize that pyelonephritis is often focal and may involve only one kidney, Loss of the function of one kidney cannot be considered to be benign even though overall renal function is preserved.
Historical Perspective The role of urinary tract infections in causing end-stage renal failure and hypertension was first evaluated in the era before effective chemotherapeutic agents were available. The early investigators, therefore, were able to observe the expression of uncontrolled infection. Most of the observations were made in selected series of cases followed for long periods of time or studied at autopsy. The stage was set in the United States by the work of Longcope [1], and Weiss and Parker [2] who described young women with severe renal disease due to bilateral infection of the kidneys. Hypertension and end-stage renal failure were observed commonly in their series. They were particularly struck by sclerosis of the renal arterioles in the absence of generalized arteriosclerotic disease, and believed that this may have had a role in producing hypertension. Both Weiss and Parker as well as Longcope emphasiz-
Introduction As in every field o f medicine there are enthusiasts and iconoclasts. Only time and extensive experience will proS 44
C. M. Kunin, M.D., Department of Medicine,Ohio State UniversityCollege of Medicine, 410 West 10th Avenue, Columbus,Ohio 43210, USA.
Infection 18 (1990) Suppl. 2 © MMV Medizin Verlag GmbH Mfinchen, Miinchen 1990
C. M. Kunin: Natural History of Urinary Infections ed that hypertension was not seen in acute pyelonephritis, but only after renal insufficiency had developed as long as 10-15 years later. In reviewing their cases of acute interstitial and diffuse suppurative nephritis is is clear that Weiss and Parker appreciated the importance of pyelographic changes, the focal nature of the renal lesions and the histologic findings of acute interstitial inflammation and abscesses. These cases were real, and similar isolated cases of bilateral pyelonephritis have been described in the postantibiotic era by Bailey, Little andRolleston [3] and Davies, McLachlan and Asscher [4]. The major problem arises in the interpretation of what Weiss and Parker termed chronic or healed pyelonephritis. This entity accounted for many of their cases. They stated " . . . in the healed stage it is often difficult to determine whether one is dealing with a healed pyelonephritis.., or with a primary vascular kidney disease". Nevertheless they developed a series of morphologic criteria for chronic pyelonephritis from which they concluded that it was more frequent than glomerulonephritis as a cause of Bright's disease. These lesions included a) inflammatory reaction of the interstitial tissues; b) colloid casts in the tubules, which are lined with atrophic epithelium; c) periglomerular fibrosis; d) evidence of infection or inflammation within the tubules. Clinicians were also struck by what was termed as pyelonephritis lenta or silent pyelonephritis [5]. This was used to describe the insidious appearance mostly in young adult females of end-stage renal disease often accompanied by hypertension. Acute pyelonephritis in pregnancy was well described by Crabtree [6] working in the 1930s. He noted that the effect of pyelonephritis on renal function was not great during the acute and subacute phases of the disease. He explained this by the focal and irregular distribution of the lesions. There were several cases of acute pyelonephritis following pregnancy in the series described by Weiss and Parker, but none were fatal. Instead they were detected at autopsy in deaths form other causes. Crabtree and Reid [7] studied 45 women who had pyelonephritis of pregnancy ~ five to ten years previously. They found five with renal stones, three with significant decrease in renal function as determined by delayed excretion of phenolsulfonaphthalein and one with an increase in nonprotein nitrogen. Four patients showed poor visualization of one kidney on intravenous pyelogram. Hypertension was not common. Crabtree commented on the findings in these cases as follows. "There is not now sufficient evidence to permit accurate
estimation of the remote effects of pyelonephritis on duration of life, state of health during life, and relation to mortality". This statement presaged the current controversy. Studies of Urinary Infections in the Postantibiotic Era In recent years our understanding of the pathogenesis and natural history of urinary tract infection has been improved by: a) More strict definition of bacterial pyelonephritis as seen at autopsy and appreciatiOn of the similarity of the lesions produced by vascular disease, interstitial nephritis and papillary necrosis to those of pyelonephritis; b) Evidence that vesicoureteral reflux is the major cause of focal renal cortical scars and distortion of the renal calyces and that most renal damage occurs in the first five years of life; c) The elucidation of the role of analgesic drugs in producing interstitial nephritis and papillary necrosis that must be distinguished from bacterial pyelonephritis; e) Improved bacteriologic methods to diagnose urinary tract infections and to perform epidemiologic studies; f) Long-term prospective population studies and clinical trials to determine the outcome of infection. Autopsy Studies The frequency of pyelonephritis reported at autopsy varies considerably and ranges from 1.9-20%, T a b l o 1. This is due to differing interpretations by pathologists of the nonspecific nature of the inflammatory and vascular changes that Weiss and Parker described as "healed pyelonephritis". Pawlowski et al. [8] re-examined the old criteria for chronic pyelonephritis by comparing cultures of bladder urine and kidneys with autopsy findings. They were unable to correlate the data obtained by culture with the morphology of the renal lesions. They relied instead on the patchy distribution of the lesion and the importance of finding of a polymorphonuclear leukocyte infiltration to make the diagnosis. They emphasized the difficulty of establishing an etiology based on morphologic grounds alone. Using rather rigid criteria to define pyelonephritis, Kimmelstiel [9] could identify pyelonephritis in only 2.8% of autopsies. Only 18 of 97 cases thought to have pyelonephritis also had azotemia. In most of these the disease could be explained by obstruction or dysplasia or calcinosis. The male to female sex distribution was 1:1.3. This report is in marked contrast to that of Gall [10] who considered the severely shrunken kidney as the "stigma" of pye-
Table 1: Pyelonephritis described at autopsy, selected studies.
MacDonaM et al.* Gall Kimmelstiel et al. Freedman
1957 1961 1961 1967
(11) (10) (09) (12)
100 2991 3393 4686
17 360 97 64
17 12 2.8 1.4
13 140 18 15
81 49 18.6 23.4
* These were consecutive cases and did not exclude obstructive uropathy or acute terminal infections; ** Among those believed to have pyelonephritis.
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C. M. Kunin: Natural History of Urinary Infections lonephritis. He considered pyelonephritis to account for a third of all renal disorders found at autopsy and to account for half the patients who developed chronic uremia. Similarly MacDonald et al. [11] reported that 18% of their autopsy series had healed pyelonephritis. Freedman [12] has provided what I consider to be the most convincing of the modern autopsy studies. He combined effectively anatomical and clinical data and excluded patients with genitourinary abnormalities, serious infections or bacteremia during a terminal illness. Pyelonephritis was found in only 1.4% of autopsies. There was a slight preponderance of males (57%). Renal insufficiency was found in one fourth of the Cases of pyelonephritis. The anatomic findings in these patients were equally distributed in both kidneys and lacked the broad scars expected in pyelonephritis. These lesiOns could be explained by severe vascular disease, papillary necrosis or medullary cysts. Most importantly, his analysis of the cases revealed that the role of urinary infection was negligible based on the clinical course. Thus it appears that bilateral, nonobstructive pyelonephritis sufficient to produce end-stage renal disease must be quite rare in the absence of obstruction. Still left unsettled, however, is whether an initial bacterial infection may induce an immunologic response that produces the nonspecific lesions. This is intriguing, but will require a new approach to the problem such as a role for autoimmunity to Tamm-Horsfall protein currently being pursued by Andriole and co-workers [13]. Studies of Large Series of Patients with End-stage Renal Disease
A reasonable estimate of the contribution of pyelonephritis to renal damage can be obtained from various studies of end-stage or chronic renal failure. For example, of 15,921 cases in the 12th Report of the Human Transplant Registry 2,123 or 13.1% were considered to have pyelonephritis. The cause of pyelonephritis in this group can be surmized from a breakdown of 161 cases awaiting transplantation described by Huland and Busch [14]. Of these, 26.1% were considered to have pyelonephritis, but all had one or more of the following complicating factors (ex, pressed as % of the total): vesicoureteral reflux 66.7, analgesic abuse 14.3, nephrolithiasis 11.9 and obstruction 7.2. These results are similar to those of Murra and Goldberg [15] who found that all their cases of interstitial nephritis considered to be related to infection could be accounted for by the presence of structural abnormalities. Thus these studies support the concept that renal damage from pyelonephritis sufficient to cause end-stage renal disease does not occur in the absence of associated complicating factors. Significant Bacteriuria as a Marker of Urinary Tract Infection
The studies.of pyelonephritis conducted in the 1930 and 1940s generated considerable interest since they suggested S 46
an important role for infection in the pathogenesis of renal disease. It is not surprising, therefore, that the exploitation of the quantitative bacterial count by Kass in 1956 [16] as an aid to diagnosis led to a virtual explosion of activity in this field. The concept of asymptomatic bacteriuria developed by Kass promised to help explain many of the problems encountered in understanding pyelonephritis lenta and it was hoped that this could possibly lead to a new approach to prevention not only of renal disease but of some of the major complications such as hypertension, prematurity and infection stones. The situation, however, became much more complex as so commonly occurs when a true "breakthrough" is developed. First of all it soon became obvious that significant bacteriuria in females is very common and the epidemiologic dynamics are complex. This was compounded by the frequent occurrence of spontaneous cure and relapses. Symptomatic infection was already known to be a common problem in general practice. Development of end-stage renal disease or even hypertension in these populations was rarely observed and it was hard to believe that the "common garden variety 'cystitis'" was more than a nuisance. Although many studies demonstrated that asymptomatic bacteriuria early in pregnancy predisposed to overt pyelonephritis in the last trimester, only a small proportion of premature births could be explained by urinary tract infection. Thus it became apparent fairly soon that large scale prospective studies were needed to determine the long-term outcome of uncomplicated urinary tract infections in females. Long-Term Follow-up Studies in Adult Females
The results of several long term studies are summarized in Table 2. Although at first glance most of these studies appear to support the notion that natural history of urinary tract infections in females is benign, more detailed examination of the reports reveal the occurrence of considerable morbidity. For example, persistent bacteriuria and recurrent symptomatic infections were common in most of the series. About one-quarter of the patients followed after pregnancy had persistent bacteriuria in the series of Gower [17] and Zinner and Kass [18]. Urine concentrating ability, when studied by Zinner and Kass andA/wall [19] was often found to be depressed, but returned to normal following therapy. It is important to emphasize that hidden among any group of women with urinary tract infections are some with scars and renal atrophy produced most likely by vesico-ureteral reflux in childhood. For example, in a long term study reported by Gower [20] 33% of women with unilateral and 50% of those with bilateral pyelonephritis were found to have reflux. The estimated ten year survival for these patients was 100% and 86%, respectively. On the other hand, survival in those with papillary necrosis and infection was only 56% at ten years. In a long-term follow-up study reported by Parker and Kunin [21] of women who had been hospitalized for acute pyelonephritis 10-20 years
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C. M. Kunin: Natural History of Urinary Infections Table 2: Long-term follow-up studies of urinary tract infections in adult females.
1960 1961 1965
(26) (27) (28)
111 50 16
0.5-3 5 0.25-2
Zinner and Kass**
1968 1970 1971
(17) (29) (18)
164 70 192
0.5-4 4--7 10-14
Freedman
1972
(30)
250
12
Asscher et al. Gower***
1973 1973 1976
(31) (21) (20)
107 74 85
4 10--20 0.5-11
Alwall*
1978
(19)
94
3-7
Freedman* Pinkerton et al.** Little et al.* Gower et al.** Bullen and Kincaid-Smith**
Parker and Kunin***
None Unilateral nephrectomy in 2 Decrease in renal size after infection No progression No progression 2 cases of necrotizing pyelonephritis No, nor development of hypertension No progression Renal failure in 4 No progression except with analgesic use No progression ? hypertension
Symptomatic infections in adult females; ** Following pregnancy; *** Known to have acute and chronic infection in past. earlier, clinical illness began in most patients in association with marriage, pregnancy or the post-partum period. Repeat episodes of infection still occurred within the three years of follow-up in 29 (40%) and within six months in 16 (23%), Twelve (17%) were bacteriuric at the time of follow-up. Twenty,one (28%) had had an operative urological procedure; 17 (23%) had a history of renal stone. Elevated blood pressure, however, was no more common than expected for this age group. One patient had died of the complications of pyelonephritis, one required a renal transplant for end-stage renal disease and two others had azotemia. Seven patients had undergone unilateral nephrectomy for pyelonephritis. Most of these were doing well at the time of follow-up. Thus the morbidity was considerable in women who had infection severe enough to require hospitalization. Alwall [19] selected 844 non-pregnant women, age 21-70 years who were detected in screening programs. He excluded those with obstructive uropathy, concretions, diabetes and glomerulonephritis. Bacteriuric women were compared to several control groups. These consisted of nonbacteriuric women who did or did not have a past history of infection. There were no differences among the groups in serum urea nitrogen or creatinine. Radiological abnormalities on intravenous pyelogram ranged from 8,1-9.3%, but did not differ significantly among cases and controls. The only detectable difference was less concentrating ability in the bacteriurics, but this cleared with therapy. At follow-up 36 to 80 months later there were significantly more patients who developed hypertension among the bacteriurics, and those with past history of infection or sterile pyuria than nonbacteriuric controls with
no previous history of infection. Unfortunately, there were no follow-up intravenous pyelograms, nor report of changes in renal function other than concentrating ability. Alwall also described a selected series of 33 women who were followed over a 30 year period. They initially had normal findings on intravenous pyelogram. Many developed contracted kidneys and uremia was described in four patients. It is difficult to assess the risk of occurrence of renal failure from pyelonephritis in the general population based on this selected group of patients.
Long-Term Follow-up in School Girls There has been considerable interest in the potential to discover urinary tract infections early in childhood in the hope that detection of urologic abnormalities and treatment of infection might prevent renal damage later in life. The results of several follow-up studies (Fable 8) may be summarized as follows. Urinary infections are readily detected by screening for significant bacteriuria. Among the population with infection will be found a small proportion (about 5%) with important correctable urologic abnormalities, mostly high grades of vesico-ureteral reflux. Renal scars are almost always associated with reflux. Most of the renal damage, however, appears to have occurred earlier in life and although some progression does occur this is not very significant. Treatment of infection is effective in eradicating bacteria for a short period of time, but recurrence of infection is common so that there are few long lasting effects of short courses of therapy. Decrease in renal function and occurrence of hypertension is rare in girls who do not have major structural abnormalities.
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C. M. Kunin: Natural History of Urinary Infections
Table 3: Long-term follow-up studies of urinary tract infections in girls.
Savage et al.* Welch et al. Lindberg et al.* Cardiff-Oxford* Gillenwater et al.**
1975 1976 1978 1978 1979
(32) (33) (34) (35) (22)
63 40 116 208 60
2 6.5 5 4 9-18
No progression No progression No progression No progression Nephrectomy in 2, azotemia in 1 (see text)
* Treatment trials; ** Compared with 38 matched controls.
The only case controlled study was reported by Gillenwater, Harrison and Kunin [22]. They followed patients found to have persistent significant bacteriuria up to 18 years previously. These were first detected in a screening program conducted by the author in communities in Virginia. Sixty girls (48 white and 12 black) from the original cohort (henceforth referred to as cases) were followed in comparison to 38 controls, randomly drawn from the same population that participated in the screening program. The controls had been shown not to have had significant bacteriuria during annual surveys. They were then matched for age with the cases. During the follow-up years urine cultures were performed on each group at six month intervals and intravenous pyelograms were obtained on two occasions. The following observations were made: One or more episodes of bacteriuria occurred in 70% of the cases and 39.5% of the controls. More than five episodes occurred in 21.7% of cases compared to 2.6% in controls. Bacteriuria of pregnancy was noted in 63.9% of cases and 26.7% of controls. Hospitalizations for complications of urinary tract infection (including five for acute pyelonephritis) was required in ten cases and only one control. One case required 19 admissions for control of infection and other complications. Open urologic surgery was required in nine cases and none of the controls. This included two patients who underwent nephrectomy because of diseased kidneys. Blood pressure, however, did not differ significantly between groups. Finally radiologic abnormalities on intravenous pyelograms were observed in 20% of cases and in only one control (2.6%). The lesions found in the cases included caliectasis in seven, renal scarring in two and stones in one. The serum creatinine was significantly higher among the cases, but all were within the normal range for all, except for one case with bilateral atrophic pyelonephritis. It is clear from this study that urinary tract infection detected in childhood is benign in most of the girls. Nevertheless it was a major cause of morbidity in many and accounted for significant loss of renal function in some.
Evidence of Increased Mortality Among Adults with Bacteriuria There are now three studies which provide suggestive evidence of increased mortality, unrelated, as far as can be
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determined, to alteration in renal function. Two of these studies are reported in elderly individuals by Sourander et al. [23] and Dontas et al. [24] and one among women found to have bacteriuria during large surveys by Evans et al. [25]. The latter study will be described briefly since it is pertinent to the question of the significance of uncomplicated urinary tract infection in females. Three surveys each were conducted in women in Wales and Jamaica over a 13 year period. Bacteriuria was detected on one occasion in 94 women and on two occasions in 26. These cases were compared with 1,115 women who were not bacteriuric on either occasion. The mortality risk ratio, after adjustment for age and weight, was 1.5 for bacteriuric women. The ratio increased to 2.0 for women who were bacteriuric on both surveys. The cause of death as stated on death certificate did not reveal any single cause of excess mortality. The positive association between bacteriuria and mortality is unexplained and may represent an associated but not causally related factor. For example, bacteriuria may be more common in patients with debilitating diseases or it may indicate a population that were more frequently in the hospital and had acquired infection in that environment possibly from catheters.
Comment This review seeks to find a middle ground between those who view urinary tract infections in females as little more than a benign nuisance, and others who have sought to implicate it as a major cause of renal failure. The difficulty appears to be related to which end of the spectrum of disease one examines; that is whether one looks at the process from the starting with the very common phenomena of significant bacteriuria or symptomatic urinary infections or examines the end-stages of renal disease. One only rarely has the opportunity to follow the same individual for very long periods of time. Clearly only a small proportion of individuals with urinary tract infection are at risk of significant renal damage from infection and most of these will have a major underlying process such as vesico-ureteral reflux. It now appears that the focal renal scars, once believed to be so very characteristic of pyelonephritis, are actually the residual of reflux in childhood often with superimposed infection. I believe that it is important to point out that patients do not announce themselves as hav-
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C. M. K u n i n : Natural History of Urinary Infections
ing underlying lesions of the urinary tract when they present with their first few episodes of infection. On the other hand it is unproductive to submit patients with a low likelihood of having abnormalities to extensive studies. As I see it there are two major challenges for further research in this field. The first is to be able to develop inexpensive
noninvasive procedures that can detect important structural or neurological abnormalities of the urinary tract. The other is to be able to test the hypothesis that autoimmune or other responses to past bacterial infection can damage the kidney.
References 1. Longcope, W. T.: Chronic bilateral pyelonephritis: its origin and its association with hypertension. Ann. Intern. Med. 2 (1937) 149-163. 2. Weiss, S., Parker, F." Pyelonephritis: its relation to vascular lesions and to arterial hypertension. Medicine 18 (1939) 221-315. 3. Bailey, R. R., Little, P. J., Rolleston, G. L.: Renal damage after acute pyelonephritis. Br. Med. J. 1 (1969) 550-551. 4. Davies, A. F., Mclachlan, M. F., Asseher, A. W.: Progressive kidney damage after non-obstructive urinary tract infection. Br. Med. J. 4 (1972) 406-407. 5. MacGregor, M.: Pyelonephritis lenta~ Consideration of childhood urinary infection as the forerunner of renal insufficiencyin later life. Arch. Dis. Child. 45 (1970) 159-171. 6. Crabtree, E. F., Prather, G. C., Prien, E. L: End-results of urinary tract infections associated with pregnancy. Am. J. Obstet. 34 (1937) 405. 7. Crabtree, E. G., Reid, D. E.: Pregnancy pyelonephritis in relation to renal damage and hypertension. Am. J. Obstet. 40 (1940) 17. 8. Pawlowsld, J. M., Bloxdorf, J. W., Kimmelstiel, P.: Chronic pyelonephritis: a morphologic and bacteriologic study. N; Engl. J. Med. 268 (1963) 965-969. 9. Kimmelstiel, P., Kim, O. J., Beres, J. A., WeUmann, K.: Chronic pyelonephritis. Am. J. Med. 30 (1961) 589-607. 10. Gall, E. A.: Pyelonephritis. Bull. NY. Acad. Med. 37 (1961) 367-382. 11. MacDonald, R. A., Levitiu, H., Mallory, G. K., Kass, E. H.: Relation between pyelonephritis and bacterial counts in the urine. N. Engl. J. Med. 256 (1957) 915-922. 12. Freedman, L R.: Chronic pyelonephritis at autopsy. Ann. Intern. Med. 66 (1967) 697-710. 13. Mayrer, A. R., Miniter, P., Andriole, V. T.: Immunopathogenesis of chronic pyelonephritis. Am. J. Med. 75 (1983) 59-70. 14. Huland, H., Busch, R.: Chronic pyelonephritis as a cause of end stage renal disease. J. Urol. 127 (1982) 642--643. 15. Murray, T,, Goldberg, M.: Chronic interstitial nephritis: Etiologic factors. Ann. Intern. Med. 82 (1975) 453-459. 16. Kass, E. H.: Horatio at the orifice: The significance of bacteriuria. J. Infect. Dis. 138 (1978) 546-557. 17. Gower, P. E., Haswell, B., Sidaway, M. M. E.: Follow-up of 164 patients with bacteriuria of pregnancy. Lancet i (1968) 990-994. 18. Zinner, S. H., Kass, E. H.: Long-term (10-14 years) follow-up bacteriuria of pregnancy. N. Engl. J. Med. 285 (1971) 820-827. 19. Alwall, N.: On controversial and open questions about the course and complications of non-obstructive urinary tract infection in adult women. Acta. Med. Scand. 203 (1978) 369-377.
20. Gower, P. E.: A prospective study of patients with radiological pyelonephritis, papillary necrosis and obstructive atrophy. Quart. J. Med. 178 (1976) 315-349. 21. Parker, J., Kunin, C. M.: Pyelonephritis in young women. JAMA 224 (1973) 585-590. 22. Gillenwater, J. Y., Harrison, R. B., Kunin, C. M.: Natural history of bacteriuria in schoolgirls. N. EngL J. Med. 301 (1979) 396-399. 23. Sourander, L. B., Kasanen, A. A.: A 5-year follow-up of bacteriuria in the aged. Geront. Clin. 14 (1972) 274-281. 24. Dontas, A. S., Kasvidi-Charvati, P., Papanayiotou, D. C., Marketos, S. G.: Bacteriuria and survival in old age. N. Engl. J. Med. 304 (1981) 939-943. 25. Evans, D. A., Kass, E. H, Hennekens, C. H., Rosner, B., Miao, L., Kendrick, M. L, Miall, W. E., Stuart, ILL.: Bacteriuria and subsequent mortality in adult women. Lancet i (1982) 156-158. 26. Freedman, L. R.: Prolonged observations of a group of patients with acute urinary tract infections. In: Quinn, E. L., and Kass, E. 1-1.(eds.): Biology of Pyelonephritis. Little, Brown and Co., Boston 1960, pp. 345--353. 27. Pinkerton, J. H. M., Wood, C., Williams, E. R.: Sequelae of urinary infection in pregnancy. A five year follow-up. Br. Med. J. ii (1961) 539-542. 28. Little, P. J., McPherson, H. E., de Wardener, H. E.: The appearance of the intravenous pyelogram during and after acute pyelonephritis. Lancet i (1965) 1186-1191. 29. Bullen, M., Kineaid-Smith, P.: Asymptomatic pregnancy bacteriuria a follow-up study 4-7 years after delivery. In: Kincaid-Smith, P., Fairley, K (eds.): Renal Infection and Renal Scarring. Mercedes Publishing Service, Melbourne 1971, pp. 33-39. 30. Freedman, L 1L: Natural history of urinary infection in adults. Kidney Internation. Suppl. 4 (1975) 96. 31. Asscher, A. W.: The challenge of urinary tract infections. Grune and Stratton, New York 1980, p. 209. 32. Savage, D. L., Adler, K., Howie, G., Wilson, I. E.: Controlled trial of therapy in covert bacteriuria of childhood. Lancet i (1975) 358-361. 33. Welch, T. R., Forbes, P. A., Drummond, K. M., Nogrady, M. B.: Recurrent urinary tract infection in girls. Arch. Dis. Child. 51 (1976) 114-119. 34. Lindberg, U., Ciaesson, I., Hanson, L .~, Jodal, U.: Asymptomatic bacteriuria in schoolgirls. VIII. Clinical course during a 3 year follow-up. J. Pediatr. 92 (1978) 194-199. 35. Asscher, A. W., Fletcher, E. L, Johnston, H. H.: Sequelae of covert bacteriuria in school girls. Lancet i (1978) 889-894.
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