Artıcle

Interstitial Nephritis: Wherefrom, Wherein, and Whereto

Garabed Eknoyan

considered, the “whereto” is not within the bounds

of history and will only be alluded to.
Abstract

To appreciate how this history began, it is useful

to recall the evolution of the kidney traced by Homer
Abnormalities of the renal interstitium were noted

Smith in his erudite 1953 book “From Fish to

early while identifying chronic kidney disease in 1827;

Philosopher.”1 The complex vital organ that the kidney

however, interest in glomerular and vascular lesions

would ultimately become originated as a secretory

was then distracted from their further study. As a

tubule some 600 million years ago. It was only when

complication of scarlet fever, interstitial lesions
attracted attention in 1859 and came to be defined as
predatory fish emerged some 200 million years later
acute interstitial nephritis in 1898. The chronic form of
that the vestigial vascular tufts of the glomerulus first
interstitial nephritis was traditionally attributed to
appeared for the excretion of nitrogenous products
pyelonephritis until the advent of kidney biopsy

by filtration.
in the 1950s, when interstitial lesions were recognized
as an independent primary cause of chronic kidney
disease from studies of analgesic nephropathy and
vesico-ureteral reflux. The term tubulointerstitial Origins

For most of its recorded medical history, the kidney

nephritis was introduced in 1963 and promoted to

was considered an undifferentiated “parenchymatous”

denote the role of the tubules in the pathogenesis and

excretory organ as defined by Erasistratus (304-250 BC)

the clinical presentation of interstitial nephritis as

to which Galen (129-216 AD) then endowed attractive

tubular dysfunction. Studies since then have

powers to serve the nutritional needs of the body in

established that fibrotic tubulointerstitial nephritis
lesions correlate best with the severity and
attracting and then eliminating excess fluidities. This
progression of kidney diseases independent of their
notion of a “non-differentiated” parenchymatous,
etiology.
“sponge-like” emunctory organ prevailed until the
Scientific Revolution, when Bartolomeo Eustachio
Key words: Interstitial fibrosis, Parenchymatous nephritis,

(1510-1574) first referred to the vertical lines that

Transplant rejection, Tubulointerstitial nephritis

appear to constitute the kidney as canaliculi,

vessels, and tubules; in 1662, Lorenzo Bellini
Introduction

Its ambitious title notwithstanding, this report is a (1643-1704) then clearly characterized the tubular
historical inquiry into the “wherefrom” of interstitial composition of the kidney. Shortly thereafter,
nephritis and its conceptual evolution from a using a microscope, Marcello Malpighi (1628-1694)
descriptive structural renal lesion into a clinical identified his eponymous renal corpuscles in 1666
diagnostic entity. Although the “wherein” will be (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
From the Selzman Institute of Kidney Health, Section of Nephrology, Department of Medicine,
Baylor College of Medicine, Houston, Texas, USA

ultrafiltration driven by physical forces. The

Acknowledgements: The author has not received any funding or grants in support of the

functional studies that followed then established

presented research or for the preparation of this work and has no declarations of potential conflicts
of interest.

the central role of the kidney in maintaining

Corresponding author: Garabed Eknoyan, Baylor College of Medicine, One Baylor Plaza,

homeostasis postulated by Claude Bernard

Houston, TX 77030, USA
Phone: +1 713 798 4748 E-mail: geknoyan@[Link]

Experimental and Clinical Transplantation (2023) Suppl 2: 42-45 (1818-1878) in 1878.2-4

Copyright © Başkent University 2023 10.6002/ect.ıAHNcongress.10

Printed in Turkey. All Rights Reserved.
 Garabed Eknoyan /Experimental and Clinical Transplantation (2023) Suppl 2: 42-45 43

entered the medical lexicon and gradually replaced

the “interstitial nephritis” of Rudolf Virchow by the
Wherefrom of ınterstitial Nephritis

It was within this unfolding of the structural and closing years of the 19th century. About 20 years later,
functional features of the kidney that the foundations the term “nephrosis” came to replace the noninflam-
of clinical nephrology were laid by Richard Bright matory degenerative tubular lesions of Virchow’s
(1789-1858) in his 1827 landmark study, “Report of “parenchymatous nephritis.”3,6 In the process, the
Medical Cases.”5 In the conceptual evolution of interstitial fibrous lesions of the now orphaned term
Bright’s disease, the structural lesions of interstitial interstitial nephritis were attributed to an increasing
nephritis would be identified.3,6 Bright characterized pathogenetic role in the progression of kidney
the renal lesions of his eponymous disease as disease; as a result, the term interstitial nephritis
“decidedly inflammatory” and used the term reentered the nosology of kidney disease late in the
“nephritis” in his writings; however, it was Rudolf 19th century, as a new clinical entity of acute kidney
Virchow (1821-1902) who formalized the use of the injury (Figure 1).
term nephritis. Bright classified the diseased kidneys The existence of a nondescript supportive renal
based on their gross appearance into (1) a large soft matrix that William Bowman had mentioned
white kidney, (2) a red hard granular kidney, and (3) received increased attention by one of the early
a contracted scirrhous small kidney. Their respective authorities on Bright’s disease, George Johnson
microscopic features were then classified in 1858 by (1818-1896), who, beginning in 1846, highlighted the
Rudolf Virchow (1821-1902) as (1) a degenerative presence of intertubular fibrous tissue in cases of
process of the tubules or “parenchymatous nephritis” acute glomerulonephritis whose progression led to
of the white kidney, (2) an inflammatory process of the shrunken cirrhotic end-stage kidney of Bright’s
the nonparenchymatous renal tissue or “interstitial disease.7 The interstitial lesions of acute kidney
nephritis” of the red kidney, both of which could disease were described in 1859 by a student of
coexist in the same kidney and either could Virchow, Arnold Beer (1835-1881) as “intertitielle
eventuate in (3) a small cirrhotic end-stage kidney.6 Nierenaffection” (interstitial kidney affection) in the
Of further credit to Virchow, his trainees case of a 5.5-year-old boy with scarlet fever.8 These
determined the microscopic details of the lesions of lesions were further investigated in 1878 by Bryan
Bright’s disease. Axel Key (1832-1901) identified the Charles Waller (1853-1932) in his medical thesis, titled
mesangial and epithelial cells of the glomerulus in “An investigation into the microscopic anatomy of
1865, and Edwin Klebs (1834-1913) described interstitial nephritis,” who classified the lesions into
their proliferation in what he termed “glomerulo- an initial phase of lymphoid cellular infiltration
nephritis” in 1869. That is when glomerular nephritis followed by one of gradual fibrous metamorphosis.9

Figure 1. Timeline of the Conceptual Evolution of Interstitial Nephritis

The names of the principal contributing authors are shown in capital, bold letters, and their contributions to the nosology and epistemology of
interstitial nephritis are in italics.
44 Garabed Eknoyan /Experimental and Clinical Transplantation (2023) Suppl 2: 42-45 Exp Clin Transplant

Waller is better known for sponsoring and mentoring glomeruli and vasculature of the kidneys. Lesions of
the medical education of Arthur Conan Doyle interstitial nephritis were traditionally attributed to
(1859-1930) and for inspiring him with the pyelonephritis. That this is not the actual case became
observational and analytic aptitudes used in creating evident after the availability of kidney biopsy. The 2
the fictional character of Sherlock Holmes.10 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
emergence of Acute ınterstitial Nephritis

The glomeruli were noted to be normal in some the 1960s.17,18 Since then, a growing number of
reports of interstitial nephritis, as highlighted in 1860 disparate kidney diseases have been attributed to
by another student of Rudolf Virchow, Arthur chronic interstitial nephritis (Figure 1). Most recent on
Biermer (1827-1892), in his report of a case of scarlet this expanding list are those of “aristolochic acid
fever in which the kidneys at autopsy were grossly nephropathy,” which is now recognized as the
enlarged due to interstitial infiltration with lymphoid etiology of what had been reported as Balkan
cells.11 Subsequent reports of similar cases led to their nephropathy and Chinese herbal nephropathy and of
being labeled “acute lymphomatous nephritis” in the what was initially considered Mesoamerican nephro-
1880s, which William Councilman (1854-1933), a pathy but is now more appropriately referred to as
pathologist at Harvard with interest in infectious CKD of unknown etiology and that of chronic
diseases, termed “acute interstitial nephritis” (AIN) as allograft nephropathy.13-16,19
a distinct entity in 1898.12 In his review of 42 cases of The broader descriptive term “tubulointerstitial”
“non-suppurative inflammatory interstitial lesions” entered the parlance of nephrology in the early 1960s
predominantly in cases of diphtheria, scarlet fever, and as “néphropathie tubulo-interstitielle” (tubulo-intersti-
measles, Councilman identified the infiltrating cells as tial nephropathy) in the report of an inherited tubular
mononuclear plasma cells that had migrated from the form of CKD in children.20 It soon became evident that
circulation and multiplied locally, confirming the variable degrees of tubular injury was usually present
original report of Bryan Waller. He localized the in AIN, that the tubules had an important role in the
inflammatory foci to the boundary zones of the pathogenesis of the interstitial lesions, and that tubular
pyramids and the cortical peritubular interstitium dysfunction preceded the fall in glomerular filtration
surrounding the subcapsular glomeruli. rate AIN and was usually clinically detectable well
With the eradication of infections and increasing before the onset of azotemia and oliguria, which led to
interest in acute tubular necrosis as a cause of acute the preferential use of the terms of acute and chronic
renal failure, the rather limited interest in AIN as a tubulointerstitial nephritis.13
diagnostic consideration literally faded away by the What then increased interest and contributed to
end of the 1940s. Ironically, the entity was resurrected the understanding of tubulointerstitial lesions was
in the late 1950s because of its dramatic increased the appreciation of their role in the progression of
occurrence due the very chemotherapeutic antibiotics CKD of any etiology. Tubulointerstitial changes had
that had eradicated infections. Since then, antibiotics been observed early in cases of Bright’s disease, but
and drugs continue to lead as causes of AIN.13-15 The interest in the glomeruli and vasculature detracted
most recent addition to this increasing list are drugs from their further consideration. With the advent of
used in treatment of COVID-19 and even its kidney biopsy, tubular injury and interstitial fibrosis
messenger RNA-based vaccine.16 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
emergence of chronic ınterstitial Nephritis

What led to improved accuracy in diagnosing AIN filtration rate in 1970.21

and the subsequent demonstration of the role of
interstitial fibrosis in progressive kidney disease was
the availability of kidney biopsy that was introduced
Wherein of ınterstitial Nephritis

in 1951. Much of the early and continued interest in Since then, the interstitium has been precisely
chronic kidney disease (CKD) centered around the delineated and its residual cellular and fibrillar
 Garabed Eknoyan /Experimental and Clinical Transplantation (2023) Suppl 2: 42-45 45

components identified.22 Moreover, the interstitium

has become the source of exponentially increasing
10. Reed J. Arthur Conan Doyle. The many faces of Sherlock Holmes.
Adv Psych Treat. 2012;18(4):289-291. doi:10.1192/[Link].111.009258

studies that have determined its function in the

11. Biermer A. Ein ungewöhlicher fall von Scharlach. Virchow Arch

generation of renin-angiotensin and erythropoietin

Pathol Physiol. 1860;19:537-545.

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12. Councilman WT. Acute interstitial nephritis. J Exp Med. 1898;3(4-
5):393-420. doi:10.1084/jem.3.4-5.393

interstitial fibrosis as a principal determinant of

13. Raghavan R, Eknoyan G. Acute interstitial nephritis – a reappraisal

progressive kidney failure.21,22 Advances in the

and update. Clin Nephrol. 2014;82(3):149-162. doi:10.5414/cn108386
14. Jonson RJ, Wesseling C, Newman LS. Chronic kidney disease of

understanding of the mechanisms of interstitial

unknown cause in agricultural communities. N Engl J Med.

fibrosis in CKD notwithstanding, the function of the

2019;380(19):1843-1852. doi:10.1056/NEJMra1813869
15. Perazella MA, Rosner MH. Drug-induced acute kidney injury. Clin J

normal renal interstitium in health and its changes in

Am Soc Nephrol. 2022;17(8):1220-1233. doi:10.2215/CJN.11290821

renal disease remain to be better elucidated.23,24

16. Ng JH, Zaidan M, Jhaveri KD, Izzedine H. Acute tubulointerstitial
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doi:10.1093/CKJ/sfab107
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