EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Interstitial fibrosis, Parenchymatous nephritis, Transplant rejection, Tubulointerstitial nephritis

Its ambitious title notwithstanding, this report is a historical inquiry into the “wherefrom” of interstitial nephritis and its conceptual evolution from a descriptive structural renal lesion into a clinical diagnostic entity. Although the “wherein” will be considered, the “whereto” is not within the bounds of history and will only be alluded to.

To appreciate how this history began, it is useful to recall the evolution of the kidney traced by Homer Smith in his erudite 1953 book “From Fish to Philosopher.”¹ The complex vital organ that the kidney would ultimately become originated as a secretory tubule some 600 million years ago. It was only when predatory fish emerged some 200 million years later that the vestigial vascular tufts of the glomerulus first appeared for the excretion of nitrogenous products by filtration.

For most of its recorded medical history, the kidney was considered an undifferentiated “parenchymatous” excretory organ as defined by Erasistratus (304-250 BC) to which Galen (129-216 AD) then endowed attractive powers to serve the nutritional needs of the body in attracting and then eliminating excess fluidities. This notion of a “non-differentiated” parenchymatous, “sponge-like” emunctory organ prevailed until the Scientific Revolution, when Bartolomeo Eustachio (1510-1574) first referred to the vertical lines that appear to constitute the kidney as canaliculi, vessels, and tubules; in 1662, Lorenzo Bellini (1643-1704) then clearly characterized the tubular composition of the kidney. Shortly thereafter, using a microscope, Marcello Malpighi (1628-1694) identified his eponymous renal corpuscles in 1666 (Figure 1). It was about 2 centuries later that, in 1842, William Bowman (1816-1892) established the glomerular-tubular connection and Carl Ludwig (1816-1895) presented the principle of glomerular ultrafiltration driven by physical forces. The functional studies that followed then established the central role of the kidney in maintaining homeostasis postulated by Claude Bernard (1818-1878) in 1878.^2-4

Wherefrom of Interstitial Nephritis

It was within this unfolding of the structural and functional features of the kidney that the foundations of clinical nephrology were laid by Richard Bright (1789-1858) in his 1827 landmark study, “Report of Medical Cases.”⁵ In the conceptual evolution of Bright’s disease, the structural lesions of interstitial nephritis would be identified.^3,6 Bright characterized the renal lesions of his eponymous disease as “decidedly inflammatory” and used the term “nephritis” in his writings; however, it was Rudolf Virchow (1821-1902) who formalized the use of the term nephritis. Bright classified the diseased kidneys based on their gross appearance into (1) a large soft white kidney, (2) a red hard granular kidney, and (3) a contracted scirrhous small kidney. Their respective microscopic features were then classified in 1858 by Rudolf Virchow (1821-1902) as (1) a degenerative process of the tubules or “parenchymatous nephritis” of the white kidney, (2) an inflammatory process of the nonparenchymatous renal tissue or “interstitial nephritis” of the red kidney, both of which could coexist in the same kidney and either could eventuate in (3) a small cirrhotic end-stage kidney.⁶

Of further credit to Virchow, his trainees determined the microscopic details of the lesions of Bright’s disease. Axel Key (1832-1901) identified the mesangial and epithelial cells of the glomerulus in 1865, and Edwin Klebs (1834-1913) described their proliferation in what he termed “glomerulo-nephritis” in 1869. That is when glomerular nephritis entered the medical lexicon and gradually replaced the “interstitial nephritis” of Rudolf Virchow by the closing years of the 19th century. About 20 years later, the term “nephrosis” came to replace the noninflam-matory degenerative tubular lesions of Virchow’s “parenchymatous nephritis.”^3,6 In the process, the interstitial fibrous lesions of the now orphaned term interstitial nephritis were attributed to an increasing pathogenetic role in the progression of kidney disease; as a result, the term interstitial nephritis reentered the nosology of kidney disease late in the 19th century, as a new clinical entity of acute kidney injury (Figure 1).

The existence of a nondescript supportive renal matrix that William Bowman had mentioned received increased attention by one of the early authorities on Bright’s disease, George Johnson (1818-1896), who, beginning in 1846, highlighted the presence of intertubular fibrous tissue in cases of acute glomerulonephritis whose progression led to the shrunken cirrhotic end-stage kidney of Bright’s disease.⁷ The interstitial lesions of acute kidney disease were described in 1859 by a student of Virchow, Arnold Beer (1835-1881) as “intertitielle Nierenaffection” (interstitial kidney affection) in the case of a 5.5-year-old boy with scarlet fever.⁸ These lesions were further investigated in 1878 by Bryan Charles Waller (1853-1932) in his medical thesis, titled “An investigation into the microscopic anatomy of interstitial nephritis,” who classified the lesions into an initial phase of lymphoid cellular infiltration followed by one of gradual fibrous metamorphosis.⁹ Waller is better known for sponsoring and mentoring the medical education of Arthur Conan Doyle (1859-1930) and for inspiring him with the observational and analytic aptitudes used in creating the fictional character of Sherlock Holmes.¹⁰

Emergence of Acute Interstitial Nephritis

The glomeruli were noted to be normal in some reports of interstitial nephritis, as highlighted in 1860 by another student of Rudolf Virchow, Arthur Biermer (1827-1892), in his report of a case of scarlet fever in which the kidneys at autopsy were grossly enlarged due to interstitial infiltration with lymphoid cells.¹¹ Subsequent reports of similar cases led to their being labeled “acute lymphomatous nephritis” in the 1880s, which William Councilman (1854-1933), a pathologist at Harvard with interest in infectious diseases, termed “acute interstitial nephritis” (AIN) as a distinct entity in 1898.¹² In his review of 42 cases of “non-suppurative inflammatory interstitial lesions” predominantly in cases of diphtheria, scarlet fever, and measles, Councilman identified the infiltrating cells as mononuclear plasma cells that had migrated from the circulation and multiplied locally, confirming the original report of Bryan Waller. He localized the inflammatory foci to the boundary zones of the pyramids and the cortical peritubular interstitium surrounding the subcapsular glomeruli.

With the eradication of infections and increasing interest in acute tubular necrosis as a cause of acute renal failure, the rather limited interest in AIN as a diagnostic consideration literally faded away by the end of the 1940s. Ironically, the entity was resurrected in the late 1950s because of its dramatic increased occurrence due the very chemotherapeutic antibiotics that had eradicated infections. Since then, antibiotics and drugs continue to lead as causes of AIN.^13-15 The most recent addition to this increasing list are drugs used in treatment of COVID-19 and even its messenger RNA-based vaccine.¹⁶

Emergence of Chronic Interstitial Nephritis

What led to improved accuracy in diagnosing AIN and the subsequent demonstration of the role of interstitial fibrosis in progressive kidney disease was the availability of kidney biopsy that was introduced in 1951. Much of the early and continued interest in chronic kidney disease (CKD) centered around the glomeruli and vasculature of the kidneys. Lesions of interstitial nephritis were traditionally attributed to pyelonephritis. That this is not the actual case became evident after the availability of kidney biopsy. The 2 diseases to attract attention to interstitial nephritis as a primary cause of CKD, in which the glomeruli and vasculature are initially spared, were analgesic nephropathy in the 1950s and vesico-ureteral reflux in the 1960s.^17,18 Since then, a growing number of disparate kidney diseases have been attributed to chronic interstitial nephritis (Figure 1). Most recent on this expanding list are those of “aristolochic acid nephropathy,” which is now recognized as the etiology of what had been reported as Balkan nephropathy and Chinese herbal nephropathy and of what was initially considered Mesoamerican nephro-pathy but is now more appropriately referred to as CKD of unknown etiology and that of chronic allograft nephropathy.^13-16,19

The broader descriptive term “tubulointerstitial” entered the parlance of nephrology in the early 1960s as “néphropathie tubulo-interstitielle” (tubulo-intersti-tial nephropathy) in the report of an inherited tubular form of CKD in children.²⁰ It soon became evident that variable degrees of tubular injury was usually present in AIN, that the tubules had an important role in the pathogenesis of the interstitial lesions, and that tubular dysfunction preceded the fall in glomerular filtration rate AIN and was usually clinically detectable well before the onset of azotemia and oliguria, which led to the preferential use of the terms of acute and chronic tubulointerstitial nephritis.¹³

What then increased interest and contributed to the understanding of tubulointerstitial lesions was the appreciation of their role in the progression of CKD of any etiology. Tubulointerstitial changes had been observed early in cases of Bright’s disease, but interest in the glomeruli and vasculature detracted from their further consideration. With the advent of kidney biopsy, tubular injury and interstitial fibrosis were noted to be the best correlates of the severity and progression to kidney failure in cases of glomerulonephritis and documented by morphomet-ric studies, correlating them to measured glomerular filtration rate in 1970.²¹

Wherein of Interstitial Nephritis

Since then, the interstitium has been precisely delineated and its residual cellular and fibrillar components identified.²² Moreover, the interstitium has become the source of exponentially increasing studies that have determined its function in the generation of renin-angiotensin and erythropoietin and have elucidated its role in the pathogenesis of interstitial fibrosis as a principal determinant of progressive kidney failure.^21,22 Advances in the understanding of the mechanisms of interstitial fibrosis in CKD notwithstanding, the function of the normal renal interstitium in health and its changes in renal disease remain to be better elucidated.^23,24

Volume: 21 Issue: 6 June 2023 - Supplement - 2

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