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Pyelonephritis: A Historical Reappraisal

Samaya Anumudu1,2 and Garabed Eknoyan1,2

1Section of Nephrology, Selzman Institute of Kidney Health, Houston, Texas; and 2Department of Medicine, Baylor College of Medicine, Houston, Texas

JASN 30: ccc–ccc, 2019. doi: https://doi.org/10.1681/ASN.2019010017

There is no human knowledge which can- the patient at the site of the swelling, mak- with the publication of Reports of Medi- not lose its scientific character when we ing an especially deep cut over the kidney” cal Cases by Richard Bright7 (1789–1858) forget the conditions under which it origi- to drain the pus.4 in 1827 linking dropsy and proteinuria nated, the questions it answered and the A clearer description appears in the to kidney disease. Bright7 considered function it was created to serve.1 first book on renal diseases Diseases his disease an inflammatory process or As with most diseases of the kidney, of the Kidney and Bladder by Rufus of nephritis, a term denoting “inflamma- pyelonephritis is an old ailment, which Ephesus, which was published between tion of the kidnies” that dates back to as a diagnosis, is a relatively new entity; late first and early second centuries 1567.7 This was an important conceptual it entered medical nosology in 1837, AD. Rufus describes “Inflammation of evolution from the past when the kid- but it remained dormant until the the Kidneys” as “flank pain...at the begin- ney had been considered resistant to 1950swhenitwasrevived andforabrief ning the urine is thin and aqueous but as inflammation, a notion to which Bright interval, heralded as the leading cause the disease progresses it becomes more still ascribed as he states, “Inflammation of ESRD. reddish...it is then that suppuration of the of one or both kidneys, as a purely idio- For most of its history, the kidney was kidneys, which in most cases is the culmi- pathic disease is less frequently met than considered a parenchymatous organwith nation of the inflammation, becomes evi- with other phlegmasiae.”7 Although glandular features accounting for its se- dent...fever is not regular but intermittent some of the patients studied by Bright7 cretion of urine, in which the dense sub- and accompanied by chills.”5 The “thin and are consistent with pyelonephritis, it stance and tight capsule made it resistant aqueous” urine of Rufus may be taken as was his French contemporary in Paris to inflammation.2 Its principal afflictions what would be described in the 1950s Pierre Rayer (1793–1867) who first were considered calculous or obstructive as the reduced capacity to concentrate coined the term pyelonephritis (pyélo- diseases. That there may be some validity urine maximally in pyelonephritis.3 néphrite) in his Atlas des Maladies des to the ancient notion of renal resistance to Similar versions of renal inflamma- Reins published in 1837 (Figure 1).8 In infection was documented in the 1950s in tion appear in later texts, but for most it, he states, “I have designated as pyelo- experimental models of pyelonephritis in of medical history, it was inflammation nephritis the reunion of the inflamma- which chronic infection could not be pro- of specific urinary tract sites that attrac- tion of the renal pelvis and calyces with duced without inducing some form of re- ted attention (urethritis, cystitis, and inflammation of the two renal sub- nal injury, such as obstruction, massage, prostatitis), often to the exclusion of stances (cortex and medulla);...it is or trauma, to the kidney.3 the kidney. Their treatment was assigned rare for it to begin in the kidney and to surgeons specializing in the urogenital then extend to the urinary tract...in tract, a limitation that persisted well these complex cases one encounters PYELONEPHRITIS—AN OLD after pyelonephritis was defined in most of the changes in renal tissue pre- NAMELESS CLINICAL ENTITY 1837 but remained glowingly absent viously described and illustrated under from urologic dictionaries, classification It is within this context that renal infection of kidney diseases, and texts well into appears in the Hippocratic Corpus (circa the first decades of the 20th century.6 “ Published online ahead of print. Publication date fourth century BC) as Another disease available at www.jasn.org. of the kidney...violent pain present as in preceding disease (calculous)...the pains PYELONEPHRITIS—A NAMED Correspondence: Dr. Garabed Eknoyan, Department DIAGNOSTIC ENTITY of Medicine, Baylor College of Medicine, One increase greatly...when the kidney suppu- Baylor Plaza, Houston, TX 77030. Email: geknoyan@ rates, swelling appears beside the spine.”4 bcm.edu

What is described is likely pyonephrosis, Medical interest in pyelonephritis traces Copyright © 2019 by the American Society of for which the text recommends to “incise back to the beginnings of nephrology Nephrology

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PYELONEPHRITIS—AN and attempts at quantifying bacterial INFECTIOUS DISEASE counts in catheterized urine were first made in 1941; however, it was in 1956 That pyelonephritis may be due to in- that Edward Kass (1917–1990) at vading organisms was a result of concur- the Mallory Institute of Pathology rent progress in bacteriology (Figure 2). established the quantitative basis of The pioneering studies of Louis Pasteur bacterial counts for the diagnosis of sig- (1822–1895) in Paris and Robert Koch nificant urinary tract infection that (1843–1910) in Berlin had solved the could account for the development of mystery of contagious diseases and pyelonephritis.3,15 launched the study of bacteria in the Initially, renal infections were con- 1860s.10 Actually, Pasteur was the first sidered to be brought by way of the to report in 1862 that urine is normally bloodstream (i.e., “hematogenous” or sterile and an excellent culture medium “descending” in origin). This was due to for the study of microorganisms.11 Fur- the then prevalent clinical models of renal thermore, in studies done with Joaquin infection: bacterial endocarditis and tu- Albarrán (1860–1918), then his assistant berculosis. Experimental and clinical and later, Chief of Urology at Hôpital studies soon revealed that “ascending” in- Necker, they described an organism fection, as had been implied by Rayer, was (Bacillus pyogenes) responsible for urine the principal route of renal infection.3 infections.12 Later studies established Figure 1. First use of the term pyelone- that most cases of urinary bacteria were phritis. Plate XVI from P. Rayer. Reprinted “gram-negative rods,” notably that of PYELONEPHRITIS—THE FIRST 100 courtesy of BIU Santé-Paris from ref. 8, with “Bacterium coli commune,” which was YEARS permission. identified in 1885 by the German pedia- trician Theodor Escherich (1857–1911). Progress would come from efforts at ”8 nephritis and pyelitis. In his subse- In 1959, the organism studied by classifying Bright disease. Over time, quentthree-volumetextondiseasesof Escherich was termed Escherichia coli the initial classification on the basis of the kidneys, TraitédesMaladiesdesReins in his honor.13 Also, Koch first isolated gross appearance of the kidney (big white published between 1839 and 1841, his Tuberkelvirus,latertermedMycobacte- and little red) was refined by microscopic Rayer addresses the issue in greater de- rium tuberculosis, from the sputum and features (inflammatory, degenerative, or tail.9 Reflecting the pre-eminence of py- urine in 1882.14 sclerotic), localized to structural compo- elitis, to which he dedicates the first 240 The term “bacteriuria” was intro- nents (glomerular, tubular, interstitial, or pagesofvolume3,hedevotesonlyfour duced in 1881. Low concentrations of vascular), and linked to clinical correlates pages to that of pyelonephritis. bacteria were considered contaminants, (nephritis, nephrosis, or nephrosclerosis).

Figure 2. The ups and downs of reference to pyelonephritis in the literature. Graphic display of the relative frequency of the term “pyelonephritis” used in a corpus of books (vertical axis) over time (horizontal axis). The black boxes indicate the principal events in the history of pyelonephritis. The tapering after 1980 corresponds to the period when nephrology came of age and other causes of interstitial nephritis were identified.27

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It is within the inflammatory nephritides several folds greater than those patients had depended mainly on the presence of that the lesion of interstitial nephritis diagnosed clinically. Additionally, unlike significant bacteriuria. (3)Long-term was introduced in the 1880s and in the its acute form, chronic pyelonephritis evaluation of individuals with bacteri- prevailing notion of toxicity at the time, usually was a low-grade, relatively uria, especially women, revealed that oc- attributed to that of bacterial toxins.16 In asymptomatic infection with periods casional urinary tract infections were the process, the “pyelo” of pyelonephri- of remission and exacerbation, termed fairly benign and in the absence of uri- tis was forgotten, and the pathologic le- “inapparent” or “subclinical” pyelone- nary tract abnormalities, did not even- sions of interstitial nephritis were taken phritis, that eventuated in chronic tuate in renal failure. (4) Data accrued as indicative of chronic or healed pyelo- nephritis.3,20,21 from patients being initiated on dialysis nephritis (Figure 2). This led to the proposal that, whereas revealed a paucity of cases that could be It is within this context that the po- clinically evident acute pyelonephritis ascribed to pyelonephritis. (5)Epidemi- tential detrimental effects of chronic is encountered in isolated and unre- ologic studies on the basis of the refine- pyelonephritis emerged in the German lated events, chronic pyelonephritis is ments in the diagnosis of pyelonephritis literature between the 1860s and 1930s, actually a continuum that manifests revealed no difference in the prevalence principally as a subject of pathologic in- itself as acute pyelonephritis (with or of hypertension in those with bacteriuria terest.3 Their clinical features were ex- without recurrent episodes) in infancy compared with controls.22,24 These find- posed in 1933 by Warfield Longcope due to vesicoureteral reflux, in women ings coupled with the availability of (1877–1953), then professor of medicine due to “honeymoon cystitis” or “pyelitis antibiotics to control bacteriuria put an at Johns Hopkins Medical School, who of pregnancy,” and in men due to pros- end to the unjustified inflated role of described the course of progressive kid- tatitis. Between these episodic symp- chronic pyelonephritis as the principal ney failure with contracted kidneys due tomatic phases, the disease could persist cause of kidney failure that it had been to pyelonephritis.17 or smolder on as symptomless bacteri- pronounced. As a result, by the late These findings were confirmed and uria, eventually leading to chronic py- 1970s and early 1980s, it was established expanded by the subsequent 1939 mile- elonephritis: a disease that was then that, although urinary tract infections can stone report of Soma Weiss (1898–1942) promulgated as the most common cause impair kidney function, it is a rare out- at Harvard and Frederic Parker (1890– of kidney failure.3,20,21 Hence, the tan- come in the absence of major predisposing 1969) at the Mallory Institute of Pathol- talizing possibility that CKD may be factors, such as obstruction, calculus, ogy.18 In their account of 100 patients, prevented by early detection and treat- reflux, neurogenic bladder dysfunction, they described the variable clinical and ment of urinary tract infections prevailed or diabetes.24 structural correlates of pyelonephritis as in the late 1950s and early 1960s, just as Relevant to the story of pyelonephri- an acute, chronic active, healed, and nephrology was a budding specialty and tis are the colloid casts of so-called healed but recurrent disease. Addition- kidney failure was identified as a treatable thyroidization of the kidney that had ally, they highlighted the vascular lesions disease with RRT (Figure 2). been considered diagnostic of chronic of pyelonephritis and their relation The virtual explosion of studies pyelonephritis but are nonspecific, and to coexistent hypertension that had on pyelonephritis that followed in the they can occur with reflux of sterile urine not been emphasized previously. This 1960s and 1970s during the maturation as well as most other causes of chronic initiated a wave of nephrectomies of uni- of nephrology led to a re-evaluation of interstitial nephritis.3,23,24 They were laterally contracted kidneys for the relief the facile conclusions about chronic py- shown to contain Tamm–Horsfall glyco- of hypertension, the futility of which was elonephritis that had been derived there- protein, which in 1987, was identified as exposed in 1956 to its proponents in the tofore from episodic bacteriuria and uromodulin, a protein with a protective Journal of Urology by the renal physiol- postmortem studies.22–24 The accruing role against infection and antigenic po- ogist Homer W. Smith (1895–1962), evidence derived from experimental tential in the immunopathogenesis of whose numerous seminal contributions and clinical studies revealed the follow- renal scarring in which genetic variants to kidney function in health and disease ing. (1) The tubular and interstitial mor- have been associated with increased were fundamental to the foundation of phologic changes that had been taken as risk of CKD.25 nephrology.19 diagnostic of chronic pyelonephritis could be due to a host of other causes that were being identified, such as anal- CONCLUSIONS PYELONEPHRITIS—NEPHROLOGY gesic nephropathy, Balkan nephritis, COMES OF AGE drug toxicity, sickle cell disease, and is- The history of pyelonephritis has been chemia. (2) Technical developments, one of perceptive descriptions inter- Additional studies revealed that pyelone- such as pyelograms, voiding cystograms, spersed between periods of relative neglect phritis was more common than it had kidney biopsy, and functional tests, (Figure 2). It began as an enigmatic in- been considered theretofore, with the added considerable refinement to the flammatory renal lesion, which centuries number of cases detected at postmortem clinical diagnosis of pyelonephritis that later, was attributed to bacterial infection

JASN 30: ccc–ccc,2019 Pyelonephritis 3 PERSPECTIVE www.jasn.org and then, to organisms with pathogenicity 4. Hippocrates: Loeb Classical Library,Vol.6, 15. Kass EH, Zinner SH: Bacteriuria and renal – and antibiotic sensitivity that could be as- Cambridge, United Kingdom, Harvard Uni- disease. J Infect Dis 120: 27 46, 1969 versity Press, 1988, pp 121–123 16. Weening JJ, Jennette JC: Historical milestones in sessed and treated. The brief claim that py- 5. Eknoyan G: Rufus of Ephesus and his renal pathology. Virchows Arch 461: 3–11, 2012 elonephritis may be the leading cause of “Diseases of the Kidneys.” Nephron 91: 17. Longcope WT, Winkenwerden WL: Clinical kidney failure in the early 1960s was put 383–390, 2002 features of the contracted kidney due to py- to rest with the advent of nephrology as an 6. Ballenger EG, Frontz WA, Homer HG, Lewis elonephritis. Bull Johns Hopkins Hosp 53: – investigative scientific discipline. Interest B, editors: History of Urology, Vols. 1 and 2, 255 287, 1933 Baltimore, MD, The Williams and Wilkins 18. Weiss S, Parker F: Pyelonephritis: Its relation in pyelonephritis seems to be undergoing Company, 1933 to vascular lesions and to arterial hyperten- a revival, with new evidence on the role 7. Bright R: Reports of Medical Cases,London, sion. Medicine 18: 221–315, 1939 uromodulin in CKD25 and its occurrence Longman, Rees, Orme, Brown and Greer, 1827 19. Smith HW: Unilateral nephrectomy in hy- in transplant recipients, in whom it is a 8. Rayer P: Atlas des Maladies des Reins, Paris, pertensive disease. JUrol76: 685–701, 1956 risk factor for graft loss and death.26 J.B. Baillière, 1837 20. Sanford JP: Inapparent pyelonephritis; the miss- 9. Rayer P: Traite´ des Maladies des Reins, Paris, ing link. JAmMedAssoc169: 1711–1714, 1959 J.B. Baillière, 1841 21. Gall EA: Pyelonephritis. Bull N Y Acad Med 10. Evans AS: Causation and disease: The Henle- 37: 367–382, 1961 DISCLOSURES Koch postulates revisited. Yale J Biol Med 22. Heptinstall RH: The enigma of chronic py- 49: 175–195, 1976 elonephritis. JInfectDis120: 104–108, 1969 None. 11. Vallery-Radot R: Louis Pasteur. His Life and 23. Kunin CM: Does kidney infection cause renal Labours, London, Longmans, Green & Co., failure? Annu Rev Med 36: 165–176, 1985 1865 24. Hodson J: Reflux nephropathy. Med Clin – REFERENCES 12. Casey RG, Thornhill JA: Joaquin Maria North Am 62: 1201 1221, 1978 Albarran Y Dominguez: Microbiologist, his- 25. Devuyst O, Olinger E, Rampoldi L: Uromodulin: tologist, and urologist--a lifetime from or- From physiology to rare and complex kidney 1. Farrington B: Greek Science: Its Meaning for phan in Cuba to Nobel nominee. Int J Urol disorders. Nat Rev Nephrol 13: 525–544, 2017 Us, Baltimore, MD, Penguin Books, 1969 13: 1159–1161, 2006 26. Graversen ME, Dalgaard LS, Jensen-Fangel 2. Eknoyan G: The early modern kidney— 13. Hacker J, Blum-Oehler G: In appreciation of S, Jespersen B, Østergaard L, Søgaard OS: nephrology in and about the nineteenth Theodor Escherich. Nat Rev Microbiol 5: Risk and outcome of pyelonephritis among century. Part 1. Semin Dial 26: 73–84, 2013 902, 2007 renal transplant recipients. BMC Infect Dis 3. Kass EH: The role of asymptomatic bacteriuria 14. Cambau E, Drancourt M: Steps towards the 16: 264, 2016 in the pathogenesis of pyelonephritis. In: Biology discovery of Mycobacterium tuberculosis by 27. Google Ngram viewer. Available at https:// of Pyelonephritis,editedbyQuinnEL,HassEH, Robert Koch, 1882. Clin Microbiol Infect 20: books.google.com/ngrams. Accessed April Boston, Little Brown and Company, 1960 196–201, 2014 17, 2019

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