Kidney International, Vol. 54 (1998), pp. 313–327
PERSPECTIVES IN RENAL MEDICINE
The clinical spectrum of tubulointerstitial nephritis
ASGHAR RASTEGAR and MICHAEL KASHGARIAN
Department of Internal Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
Tubules and interstitium make up approximately 80% of
the renal volume, and occupy the compartment referred to
as the tubulointerstitium. The interstitium space takes up
13% of rat and up to 17% of dog and rabbit kidneys,
including 7 to 9% of renal cortex, 3 to 5% of outer medulla
and 30 to 40% of inner medulla and papillary tip [1, 2]. It
is made up of both cellular and matrix components. There
are two main cell types. (a) Type I interstitial cells are
fibroblast-like cells capable of producing and degrading
extracellular matrix. The lipid-rich interstitial cells in the
inner medulla, a possible source of prostaglandins, are also
considered to be a form of type I interstitial cells. (b) Type
II interstitial cells, found in all renal zones, include monocyte derived macrophages with capacity for phagocytosis
and dendritic antigen-presenting cells found primarily in
the cortex. The matrix is made up of a fibrillar net of
interstitial and basement membrane collagens and associated proteoglycans, glycoproteins, and interstitial fluid. The
interstitial compartment not only provides structural support for the individual nephrons, but also serves as a
conduit for solute transport [2]. It is also the site of
production of several hormones and cytokines such as
erythropoietin and prostaglandins.
Renal diseases can broadly be classified as glomerular,
vascular, tubulointerstitial or obstructive in origin. Diseases
of tubulointerstitial compartment may be the result of
primary injury to this compartment or secondary to injury
to other compartments. Several studies in patients with a
variety of renal diseases have shown that changes in the
tubulointerstitial compartment are a better predictor of the
severity of renal dysfunction and long-term outcome than
changes in other compartments [3–7]. Recent advances in
our understanding of the process of injury and repair in
general, and tubulointerstitial compartment in particular,
Key words: end-stage renal disease, analgesic-induced tubulointerstitial
nephritis, urinary tract obstruction, hyperuricemia, nephrocalcinosis, lead
nephropathy, sarcoid nephropathy, acute drug-induced tubulointerstitial
nephritis.
Received for publication September 15, 1997
and in revised form December 30, 1997
Accepted for publication January 1, 1998
© 1998 by the International Society of Nephrology
have helped elucidate some of the important pathogenic
events leading to tubulointerstitial nephritis (TIN). These
advances have been summarized in several excellent reviews [8 –12] and will only be discussed briefly here. This
review focuses primarily on clinical aspect of the diseases
where the tubulointerstitial compartment is the primary
target of the pathogenic process rather than being secondarily involved by damage to the glomerular, vascular compartment or collecting system.
The term acute interstitial nephritis was first used a
century ago in 1898 by Councilman in describing a group of
patients with systemic bacterial infection, primarily scarlet
fever and diphtheria. This term was applied to acute
inflammation of the kidney characterized by cellular and
fluid exudation in the interstitial tissue that was not dependent on the presence of bacteria [13]. For many decades,
the term chronic pyelonephritis was used to describe renal
diseases associated with chronic injury to interstitum, despite the lack of evidence for the presence of active
infection in a majority of the patients. Beginning in early
1950s, the work of Spuhler and Zollinger in Switzerland on
the role of analgesics [14, 15], and Henderson and colleagues in Australia on the role of lead in the development
of chronic tubulointerstitial nephritis (TIN) [16], provided
strong evidence that the so-called chronic pyelonephrits
was often not infectious in origin. It is now recognized that
TIN represents a group of diseases that are due to a variety
of etiologies and pathogenic mechanisms.
Given the tight structure-function relationship between
glomerular, vascular and tubulointerstitial compartments, a
significant overlap exists between the clinical presentation
of the diseases initiated in any compartment. In addition,
the clinical presentation of TIN depends both on its
etiology and the severity of renal dysfunction. Despite this
factor, certain findings are more common in these patients
than patients with glomerular disease. These include: (1) a
lack of significant proteinuria and hypoalbuminemia; (2)
the presence of sterile pyuria and white blood cell (WBC)
casts rather than hematuria and red blood cell (RBC) casts;
(3) the presence of a concentrating defect resulting in
polyuria and nocturia; and (4) the presence of other tubular
defects such as renal tubular acidosis, salt losing nephropathy and osteomalacia due to long-standing vitamin D
313
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Rastegar and Kashgarian: Tubulointerstitial nephritis
deficiency. These differences become increasingly blurred
with progression of renal failure.
TUBULOINTERSTITIAL NEPHRITIS
Epidemiology of tubulointerstitial nephritis
TIN is an important cause of renal failure and end-stage
renal disease (ESRD). The incidence of primary TIN varies
by geographical area, entry criteria, and mode of diagnosis
[17–22]. While renal biopsy remains the gold standard,
nephrologists are less likely to biopsy patients with clinical
signs and symptoms of TIN than patients with glomerular
disease. Therefore, the diagnosis of TIN is often based on
epidemiological, clinical and laboratory evaluations rather
than renal biopsy. In an autopsy series the incidence of TIN
was reported at 1.7% for acute and 0.2% for chronic TIN
[23]. In a Finnish study of 314,000 asymptomatic recruits,
174 with hematuria and/or proteinuria were biopsied. Two
patients had TIN for a prevalence of 0.7 per 100,000 in this
population [24]. Murray and Goldberg reported an incidence of 33% among 320 patients admitted to a teaching
hospital over a three year period (1969 to 1972) with a
diagnosis of CRF and serum creatinine of greater than 1.3
mg% [17]. The most common causes of TIN were urinary
tract obstruction, analgesic abuse, hyperuricemia and
nephrocalcinosis. In a similar study from a teaching hospital in North Carolina, TIN was also the most common
cause of CRF, accounting for 40.8% of the cases. The most
common etiologic diagnosis was analgesic-induced TIN
(AITIN), considered as definitive in 26.8% and probable in
14.6% of patients with TIN [25]. In both studies the
diagnosis of TIN was primarily based on clinicopathological
findings and less commonly on renal biopsy.
The incidence of TIN among ESRD patients varies from
42.2% in Scotland [26], 29% in Berlin [20], and 27.5% in
Delaware County, Pennsylvania [18] to 25.7% in North
Carolina, USA [25]. Rostand et al, in a study from Alabama
focusing on racial differences in ESRD, calculated an
annual incidence per 100,000 population of 2 for TIN, 2.3
for nephrosclerosis, 1.2 glomerulonephritis and 0.8 for
diabetes nephropathy [27]. In a renal biopsy study of 109
patients with unexplained renal failure (GFR , 60 ml/min)
and normal size kidney, TIN was the most common diagnosis, and was seen in 29 (27%) of patients [28]. The 1996
United States ESRD Registry Data, however, shows an
incidence of only 3% among all patients on dialysis [22]. If
obstructive disease and TIN associated with malignancy is
also included, the incidence approaches 7.5%, still significantly lower than the above quoted numbers. This difference may be due to several factors including lack of
diagnostic precision, the recent increase in the number of
patients with diabetes and other systemic diseases on
dialysis, and successful prevention and earlier treatment of
tubulointerstitial nephritis. Part of the difference is geo-
Table 1. WHO classification of tubulointerstitial diseaes
Infection
Acute infectious tubulointerstitial nephritis
Acute tubulointerstitial nephritis associated with systemic infection
Chronic infectious Tubulointerstitial nephritis (chronic
pyelonephritis)
Specific renal infection
Drug-induced tubulointerstitial nephritis
Acute drug-induced tubulotoxic injury
Drug-induced hypersensitivity tubulointerstitial nephritis
Chonic drug-induced tubulointerstitial nephritis
Tubulointerstitial nephritis associated with immune disorders
Induced by antibodies reacting with tubular antigens
Induced by autologous or exogenous antigen-antibody complexes
Induced by, or associated with, cell-mediated hypersensitivity
Induced by immediate (IgE-type) hypersensitvity
Obstructive uropathy
Vesicoureteral reflux associated nephropathy (reflux nephropathy)
Tubulointerstitial nephritis associated with papillary necrosis
Heavy metal-induced tubular and tubulointerstitial lesions
Acute tubular injury/necrosis
Toxic
Ischemic
Tubular and tubulointerstitial nephropathy caused by metabolic
disturbances
Hereditary renal tubulointerstitial disorders
Tubulointerstitial nephritis associated with neoplastic disorders
Tubulointerstitial lesions in glomerular and vascular diseases
Miscellaneous disorders
Balkan endemic nephropathy
graphic in nature, reflecting the role of environmental
factors in the development of TIN.
Classification of tubulointerstitial nephritis
There is no universally acceptable classification of TIN.
The most comprehensive is the WHO classification, which
uses a pathogenic and when possible an etiologic approach
to these diseases (Table 1) [29]. From a practical point of
view, we prefer a simpler classification initially dividing TIN
into primary and secondary forms, independent of acuity or
chronicity of the disease (Table 2). Primary TIN is comprised of diseases where the dominant pathogenic process
begins in the tubulointerstitial compartment, only secondarily affecting other compartments. Secondary TIN encompasses diseases where the primary pathogenic process
begins in vascular, glomerular or collecting system, followed by damage to the tubulointerstitial compartment.
This classification is by no mean all encompassing, and does
not recognize diseases that affect more than one compartment simultaneously such as systemic vasculitis, systemic
lupus erythematosus (SLE), or human immunodeficiency
virus (HIV) associated nephropathy.
Pathology of tubulointersitital nephritis
Although the tubulointerstitum can only respond in a
limited manner to a variety of insults, the pattern of
response can help define the acuity of the process, the
long-term prognosis and in some patients the pathogenesis
and/or etiology of the disorder. The initial division of the
Rastegar and Kashgarian: Tubulointerstitial nephritis
Table 2. Classification of tubulointerstitial nephritis (TIN)
I. Primary TIN
1. Infection (bacterial pyelonephritis, Hantavirus, Leptospirosis)
2. Immune-mediated (Sjögren syndrome, anti-tubular basement
membrane disease)
3. Drug-induced (AIN, analgesics-induced IN, lithium,
cyclosporine, Chinese herbs)
4. Toxins (lead)
5. Metabolic disorders (gouty nephropathy, hypercalcemic IN,
hypokalemoic)
5. Hereditary TIN (Wilson disease, cystinosis, hyperoxaluria)
6. Hematologic disorders (sickle cell disease, Light chain
nephropathy, cast nephropathy, light chain deposit diseases,
amyloidosis)
7. Miscellaneous (Balkan nephropathy)
II. Secondary TIN
1. Glomerular disease
2. Vascular disease
3. Structural disease
a. Cystic diseases
b. Obstructive disease
c. Reflux
histologic pattern of TIN is dependent on the presence or
absence of a significant inflammatory infiltrate in the
interstitium. In diseases where the infiltrate is predominant, the characteristics of the cellular components of the
infiltrate further assist in the differentiating types of TIN
with differing pathogenesis. The structural changes of
tubular injury include cytopathic changes from sublethal
injury to necrosis, alteration in growth including atrophy,
hypertrophy and simplification and the accumulation of
cast material in the tubular lumina. Interstitial changes
include edema, leukocytic infiltration and fibrosis.
In predominantly non-inflammatory lesions, the nature
of the tubular epithelial changes and the presence of renal
tubular pigments, cast material, crystals or other inclusions
assist in making these differentiations. Using histological
criteria, one can classify tubulointerstitial disease in such a
manner as to recognize the wide variety of potential
etiologic agents and different pathogenic mechanisms that
produce similar or identical morphologic patterns. In acute
or active forms of interstitial nephritis the interstitium is
edematous and there is a cellular infiltrate that may contain
lymphocytes, plasma cells or polymorphonuclear leukocytes, including eosinophils. Invasion of the tubules may be
seen to resemble the tubulitis of allograft rejection. In more
chronic forms, interstitial fibrosis and tubular atrophy is the
most prominent feature that may be accompanied by an
infiltrate comprised only of small lymphocytes. Marcussen
recently has brought attention to a sequence of events
where tubulitis eventually leads to tubular destruction and
the development of atubular glomeruli. This process contributes both to the histologic picture and the progressive
loss of function seen in chronic interstitial nephritis [30].
Pathogenesis of tubulointerstitial nephritis
The mechanisms by which various etiologic agents can
mediate renal tubulointerstitial injury can either be direct
315
through cytotoxicity or indirect by the induction of systemic
inflammatory or immunologic reactions. Direct cytotoxic
mechanisms are dose and exposure duration dependent,
such as what is seen in analgesic and lead nephropathy.
Indirect reactions are often idiosyncratic as occurs in the
acute interstitial nephritis associated with nonsteroidal
anti-inflamatory agents (NSAIDs). The nature of the injury
may be determined to some extent by factors unrelated to
the agent such as preexisting renal disease, or extrarenal
factors that can affect renal dosage such as abnormal liver
function. In addition, the differences in susceptibility of
different nephron segments can modify the renal response
to these agents, such as with heavy metal exposure. Studies
in experimental models and in human disease provide
compelling evidence for immune mechanisms of tubulointerstitial disease, and these have been reviewed extensively
[9, 31]. These mechanisms are in some instances analogous
to immune-mediated glomerular disease involving antibasement membrane antibodies or immune complex deposition. In other instances they are more specific to the
structures of the tubulointerstitium and involve antibodies
to cell surface antigens, or antigens processed and presented by tubular epithelial or interstitial dendritic cells to
the immune system, resulting in cell mediated reactions. In
addition, local activation of epithelial, endothelial and
interstitial fibroblastic cells results in expression of a variety
of cytokines and growth factors such as platelet-derived
growth factor (PDGF) and transforming growth factor-B
(TGF-B), which can contribute to inflamation and fibrogenesis in the tubulointerstitial compartment [10, 12, 32].
General approach to patients with tubulointerstitial
nephritis
Diagnosis of TIN should be considered in any patient
with unexplained renal failure and/or specific tubular dysfunction. As drugs and toxins are major causes of primary
TIN, a complete occupational history, history of drugs
ingestion (including over the counter drugs as well as
herbal medications) and toxin exposure should be sought.
In patients with systemic signs and symptoms known systemic disease, the renal disorder should be considered in
the context of a systemic illness.
The clinical presentation of TIN reflects the nature of
the underlying disease and severity of renal disorder.
Although there are significant overlaps between the clinical
presentation of glomerular and tubulointerstitial diseases,
several features may help differentiate between these two
entities. Patients with TIN tend to have less severe systemic
hypertension and edema and a slower rate of progression
[5, 33]. The initial presentation may be dominated by
clinical expression of the tubular defects such as polyuria,
nocturia, or abnormal biochemical parameters such as
metabolic acidosis and glycosuria [33]. Urinalysis may
provide strong evidence for the presence of tubular disorder with low specific gravity, high pH, and presence of
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glucose. Twenty-four-hour urine protein levels are rarely
greater than 2.5 g and are commonly below 1.0 g [5].
Urinary sediment varies from bland to active with WBCs
and WBC casts rather than RBC and RBC casts.
To establish a specific diagnosis, further workup is
necessary and should be guided by the clinical history and
initial findings. This workup may include specialized imaging, serological, biochemical and toxicological studies
and/or renal biopsy. The role of renal biopsy in the
diagnosis of TIN has not been systematically examined. In
certain circumistances the renal biopsy is carried out to
exclude glomerular pathology. In selected patients with
possible allergic or granulomatous interstitial nephritis and
interstitial nephritis associated with plasma cell dyscrasias,
it is often diagnostic. However, in many circumstances such
as lithium or lead nephropathy the findings are nonspecific.
In summary, the workup of patients suspected of TIN
should be guided heavily by the clinical and occupational
histories, epidemiology of known diseases, as well as clues
offered by the initial workup.
The WHO classification (Table 1) and our proposed
classification (Table 2) show that the list of disease categories under TIN is very long. This list includes disorders
associated with infection, drugs and toxins, metabolic,
hematologic and hereditary disorders. To provide an indepth review of the spectrum of TIN, we have chosen to
discuss four specific disorders that are either common, and
therefore clinically important, and/or exemplify a unique
type of injury to the tubulointerstitium. These diseases are
analgesic-induced TIN, granulomatous interstitial nephritis
of sarcoidosis, lead nephropathy, and drug-induced allergic
interstitial nephritis. Due to the limitation of space, several
other disorders such as lithium associated TIN, interstitial
nephritis due to hematologic disorders, and the recently
described interstitial nephritis due Chinese herbs are not
included in this review.
ANALGESIC-INDUCED TUBULOINTERSTITIAL
NEPHRITIS
Non-narcotic analgesics are among the most commonly
used medications in the world. These drugs, primarily
developed in the second half of the nineteenth century,
became very popular as single or mixed agents for control
of pain. They include salicylates such as aspirin, pyrazolones such as antipyrine, anilides such as phenacetin, and
acetoaminophen. Spuhler and Zollinger in the early to mid
1950s reported that 13 of 44 patients in Switzerland with
interstitial renal disease habitually consumed analgesics
[14, 15]. Although the importance of analgesic ingestion as
an etiologic factor was not initially clear, these and other
reports published from several other countries raised serious questions about a potential association between the use
of these medications and development of renal failure. This
association is supported by both epidemiological and ex-
perimental studies. In this review we will emphasize the
epidemiological data linking analgesic use to TIN.
Epidemiology of analgesic-induced tubulointerstitial
nephritis
The historical prevalence of analgesic-induced tubulointerstitial nephritis (AITIN) in different geographical areas
varies widely from 0% in Queenscliff, Australia, 10 to 35%
in Switzerland, 33 to 41% in Scandinavia and Wales, to
49% in Brisbane, Australia [34, 35]. The prevalence of
AITIN in ESRD patients varies from 1.7% in Philadelphia
[18], 10% in North Carolina [25] to 18% in Belgium [33, 36]
and 30% in Queensland, Australia [37]. In addition to great
variability among different countries and different regions
of the same country, there is a significant female preponderance in all series, with a female-to-male ratio as high as
6:1 [34]. Papillary necrosis is a well known component of
both clinical as well as experimental AITIN. Epidemiological data support this association with a close concordance
in the incidence of papillary necrosis and AATIN. For
example, the autopsy-based incidence of papillary necrosis
is only 0.2% in the US compared to 21% in Sydney and
Brisbane, Australia [32]. The marked variation in the
incidence of AITIN and papillary necrosis is best explained
by the overall consumption rate of analgesics, especially the
combination type containing phenacetin, in a given community [35]. This causal relationship is strengthen by the
effect of removal of phenacetin from formulary in many
countries beginning in early 1960s [38]. Follow-up reports
from Europe [39 – 41], Canada [42], and Australia [43]
documented a decrease in the prevalence of AITIN in
most, but not all, countries where analgesic mixtures often
containing phenacetin were banned.
The only prospective cohort study was carried out by
Dubach, Rosner and Pfister, who followed 623 female
workers with evidence of regular phenacetin use, and 621
age, parity, and in most cases, nationality, marital and work
matched controls [44]. Cross sectional data showed that a
history of renal disease, prevalence of proteinuria, and
abnormal concentrating ability, but not elevated serum
creatinine, was more frequent among consumers than
nonconsumers. After removal of the subjects with initial
renal abnormalities, other subjects were followed for 11
years and multiple indices of renal function and mortality
was evaluated. The frequency of low urinary specific gravity
and elevated serum creatinine was higher in phenacetin
users than controls; (23.2% vs. 6.7% and 6.7% vs. 0.9%,
respectively; P , 0.001). The relative risk (RR) for overall
mortality was 2.7, for death from renal and urogenital
disease 4.3, and for cardiovascular disease 4.5. However,
the RR for death from cancer of 2.0 did not achieve
significance [44].
In the past one and a half decades, six well designed,
case-controlled studies have been published evaluating the
Rastegar and Kashgarian: Tubulointerstitial nephritis
Table 3. Analgesic use and renal disease, summary of case-control
studies
Author
year/country
McCredie
82/Austratia
Murray
’83/USA
Sandler
’89/USA
Pommer
’89/Germany
Morlans
’90/Spain
Sandler
’91/USA
Perneger
’94/USA
Patient
Controls
N
129
223
533
1047
554
Analgesic outcome
RR/OR
Phen.
PN
17
All
ESRD
1.08 (NS)
516
AAP
Phen.
CRF
3.21
5.11
574
517
All
ESRD
2.44
340
673
Phen.
ASA
ESRD
19
2.54
544
516
All
CRF
716
361
AAP
NSAID
ESRD
2.1
2–2.4
8.8
Abbreviations are: RR, risk ratio; OR, odds ratio; PN, papillary
necrosis; AAP, acetaminophen; ASA, acetosalicylic acid; Phe, phenacetine containing. P value was significant unless indicated. (See text for
references and detail).
relationship between analgesics use and renal disease (Table 3).
These data are not strictly comparable. The definition of
regular or heavy use varies greatly and the amount of
ingestion is determined by recall. The end point varies from
papillary necrosis, TIN, renal failure, and most commonly
ESRD. Control groups were drawn from hospitalized patients [18], a normal population [21, 45, 46], outpatient
clinic patients [20], and both normal populations as well as
patients with renal failure without papillary necrosis [43]. In
addition, Sandler, Burr and Weinberg evaluated the role of
NSAIDs and found that renal failure was seen mostly
among the older men with heart failure [46]. This effect
probably reflects the hemodynamic rather than structural
effects of these drugs. Despite these differences, a comparison between these studies is helpful in understanding the
role of analgesics not only in the development of AITIN
but of renal failure.
McCredie et al, in a case control study of 91 patients with
definite and 38 patients with probable papillary necrosis
with appropriate controls, reported a risk ratio of 17 for
association between heavy analgesics use and papillary
necrosis [43]. The RR for analgesics not containing phenacetin could not be calculated because of small numbers.
Murray et al studied 527 patients from dialysis center in
Delaware County and 1047 controls [18]. This study did not
find any relationship between analgesics use and ESRD or
TIN. In contrast, a similar study from Berlin [20] found a
significant relationship between regular analgesic use and
ESRD with a RR of 2.44 (1.77 to 3.39) for regular intake of
any analgesics and 2.65 for the combination analgesics (the
majority containing phenacetin or phenazones). Although
317
the authors indicate that regular analgesic use was reported
most frequently in those with the diagnosis of AITIN (63
out of 577 patients), no specific RR is given for this group
or the group with nonanalgesic associated TIN. The study
by Sandler et al from North Carolina, where the use of
analgesics was significantly higher than Delaware county,
showed a RR of 1.71 for daily use of any analgesics and 6.06
for phenacetine containing analgesics [21]. This association
was strongest for TIN, but present for other renal diseases
including diabetic nephropathy as well as glomerulonephritis.
Regular analgesic use was much more common in Australia [43, 47], Germany [20], and North Carolina [21]
among both control and cases than Philadelphia. The
average amount of analgesics consumed by patients in
Australia with papillary necrosis was 25.3 kg, while the
average in all ESRD patients from Germany was 3.643 kg.
In study by Murray et al only 1.7% of cases and 1.9% of
control groups had total intake above 3.0 kg [18]. Interestingly, the two control groups in the Australian study had
average lifetime consumption of 13.7 and 7.2 kg, while in
the German study’s control group it was 0.756 kg. This
strongly supports the contention that the difference between the incidence in these four geographical areas reflects the overall incidence of regular analgesic (especially
combination analgesics) use in these populations. The
heaviest users develop the classical findings of AITIN with
clinically diagnosable papillary necrosis and renal failure. It
is possible that in areas with low to moderate consumption,
the lesion is subclinical and primarily present as progressive
renal failure in patients with or without known renal
disease. The pathologic lesion in this group of patients is
not defined and is presumed to be nonspecific interstitial
damage. In addition, the heavy use of analgesics among
controls in Australia and Berlin study indicates that either
some individuals are resistant to the effect of analgesics or
other factors are involved.
The studies by Sandler et al [46], Perneger et al [45] and
Morlan et al [48], while strengthening the association with
combination drugs containing phenacetine, raise questions
about the role of other analgesics including acetaminophen, NSAIDs and ASA. Perenger, Whelton and Klag
estimated that acetaminophen could account for 8 to 10%
of ESRD in the U.S. [45]. The odd ratio (OR) increased
from 1.4 (P 5 NS) for those who took up to one pill per day
to 2.1 (1.1 to 3.7) for those who took more than one pill per
day. The OR for the subgroup who had ingested a cumulative dose of greater than 5,000 pills was 8.8 [42]. The
findings in these reports are somewhat weakened by the
fact that the data are prone to recall bias, use of telephone
interviews as well lack of renal data in control patients.
These data, while open to methodological criticism, raise
important questions about the role of commonly used over
the counter drugs in the general population and patients
with underlying renal disease. Although phenacetine is
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Rastegar and Kashgarian: Tubulointerstitial nephritis
Fig. 1. (A) Low power view of the cortex of the kidney of a patient who died of renal failure secondary to analgesic induced tubulointerstitial nephritis.
There is extensive interstitial scarring (represented by the green staining of collagen) and tubular atrophy with no significant cellular infiltrate. This
cortical change was associated with medullary scars secondary to papillary necrosis (original magnification 350 Masson trichrome). (B) Low power view
of a renal biopsy of a patient with renal sarcoidosis. The interstitium contains several confluent non caseating granulomata (arrowhead) and a
nonspecific mononuclear infiltrate (original magnification 3100, hematoxylin and eosin stain). (C) High power view of the interstitial infiltrate of a renal
biopsy of a patient with acute allergic interstitial nephritis secondary to ingestion of a nonsteroidal anti inflammatory drug. There is interstitial edema
and a mixed cellular infiltrate which contains mononuclear cells, polymorhonuclear leukocytes and eosinophils (arrowheads). There is also evidence of
tubulitis (tubule identified by T) with foci of individual tubular epithelial cell necrosis (original magnification 3300, hematoxylin and eosin stain). (D)
Electron micrograph of the nucleus of a proximal tubular epithelial cell of a patient with lead nephropathy. There is an electron dense intranuclear
inclusion (arrowhead) that probably represents a lead metallothionein complex. These inclusions are characteristic of lead toxicity but are not uniformly
present in patients with lead nephropathy, especially in advanced disease (original magnification 313,600).
usually considered to be the main culprit, the role of other
analgesics cannot be ignored.
Histopathology of analgesic-induced tubulointerstitial
nephritis
The earliest lesion described in analgesic nephropathy is
capillary sclerosis of the urinary tract mucosa [49, 50]. A
similar lesion consisting of peritubular capillary sclerosis is
initially seen in the inner medulla and can be produced in
experimental animals [51]. This will eventually leads to
papillary necrosis followed by interstitial fibrosis. In the
cortex there is extensive interstitial scarring that is usually
bland with relatively few inflammatory cells, which if
present are generally small lymphocytes. Extensive tubular
atrophy is also seen (Fig. 1A). Glomerulosclerosis is also
present as a secondary change, but more commonly the
glomeruli are not damaged and become crowded because
of the tubular atrophy. Since renal biopsies rarely give a
significant sample of the inner medulla, it is often difficult
to assign the relatively nonspecific cortical changes of
interstitial fibrosis and tubular atrophy to this entity [52].
Similar lesions are produced in animal models using single
or combination analgesics [51, 53, 54]. Thus, the presence
of these cortical changes combined with radiologic and/or
clinical evidence of papillary necrosis are consistent with
the diagnosis of analgesic-induced nephropathy.
Pathogenesis of analgesic-induced tubulointerstitial
nephritis
The pathogenesis of analgesic nephropathy is incompletely understood and no single mechanism seems to
explain the findings. Prostaglandin inhibition, direct nephrotoxicity, and immunologic factors have all been suggested
as possibilities. For example, it has been suggested that
cyclooxygenase inhibition may lead to activation of
caspases and apoptosis of cells in the medullary environment with subsequent repair by fibrosis. The bulk of the
current evidence, however, points to a mechanism whereby
Rastegar and Kashgarian: Tubulointerstitial nephritis
a combination of analgesics may exert toxicity by the
generation of the metabolites of phenacetin, aspirin, paracetamol, and salicylic acid, which are then concentrated in
the medullary interstitium [54 –56]. Here they may be
oxidized by prostaglandin endoperoxidase synthase to form
even more toxic reactive metabolites that can injure either
one or all of the endothelial, tubular or interstitial cellular
components [57]. In addition, ASA and NSAIDs inhibit
prostaglandin production by inhibition of cyclooxyganase
enzymes. Renal blood flow is very dependent on systemic as
well as local production of vasodilatory prostoglandins.
This is especially true for renal medulla, which normally
lives at edge of hypoxia and therefore is more prone to
ischemic damage. The final injury is therefore due to both
hemodynamic as well as cytotoxic effects of these drugs
resulting in papillary necrosis and interestital fibrosis [58].
Clinical features and management of analgesic-induced
tubulointerstitial nephritis
As a component of analgesic syndrome AITIN presents
2 to 6 times more often in women than men. The major
components of this syndrome is headache and/or musculoskeletal pain, epigasteric pain, anemia and renal failure.
Abdominal pain is due to analgesic induced gastritis or
ulceration resulting in chronic blood loss and iron-deficiency anemia [59]. Urinary findings include sterile pyuria,
hematuria, and defects in urinary concentration and acidification. These findings are significantly more common than
in patients with glomerular disease [60]. The clinical presentation of the analgesic associated syndrome partly depends on the content of analgesic mixture. Dyspepsia and
iron deficiency anemia are more common in aspirin containing mixtures, while methemoglobinemia is a feature of
mixtures containing phenacetin or its derivatives. It is
estimated that approximately 10% of patients with analgesic syndrome develop ESRD [61]. On a long term basis the
clinical signs and symptoms of renal damage dominate,
including papillary necrosis, CRF and in a small subgroup,
uroepithelial tumors.
The diagnosis should be suspected in any individual with
unexplained renal failure, especially in the presence of
anemia out of proportion to the renal failure, a history of
papillary necrosis, or unexplained medullary or papillary
calcification. A history of analgesic use is often difficult to
get and should be sought initially indirectly by focusing on
reasons for taking analgesics [60]. Many of the signs and
symptoms associated with AITIN (such as hypertension,
anemia, sterile pyuria) do not have adequate specificity and
sensitivity to be helpful. Elseviers et al in a series of studies
have provided strong evidence that specific anatomic
changes, best seen by non-contrast computer tomography
(CT scan), has much greater sensitivity and specificity than
other clinical signs and symptoms in the diagnosis of ESRD
due to AITIN [62, 63]. These changes are: (1) decrease in
renal volume; (2) bumpy renal contours; and (3) papillary
319
calcification. In a more recent study these observations
were validated in a representative sample of patients with
analgesics abuse with ESRD and extended to patients with
moderate renal failure [64]. In patients with ESRD, decreased renal volume had the greatest sensitivity at 95%
while papillary calcification had the highest specificity at
97%. The combination of small kidneys and a bumpy renal
contour or papillary necrosis had a sensitivity and specificity of 90%. In patients with moderate renal failure papillary
calcification was most sensitive at 92% and specific at
100%. Combination of papillary necrosis with either a
bumpy renal contour or small kidneys did not improve
sensitivity or specificity [64]. In clinical practice, however, it
is important to remember that the predictive value of this
test, like any other diagnostic test, is very much dependent
on the prevalence of the disease in the population under
study. This test should therefore be utilized only in patients
with a reasonable risk for AITIN and not as a general
screening test.
The course of renal failure is often indolent, progressing
over years to decades. If the drug is discontinued early in
the course of renal injury, there is often stabilization or
improvement in renal function. However, many patients
continue to use the drug, despite advice to the contrary, and
eventually develop ESRD [65].
The full spectrum of analgesic-associated interstitial
damage includes patients who do not fit the classical
diagnosis of AITIN. These patients often have other underlying renal diseases and the habitual use of analgesics
accelerates the course of renal failure [45, 46, 48]. This
group probably represents the majority of patients in
countries with low to moderate analgesic use. No specific
diagnostic test exists to allow recognition of these patients.
We therefore feel that a careful history of analgesics use
should be obtained in all patients with renal disease. While
intermittent use of these drugs is safe in normal individuals
as well as individuals with renal failure, long term use of
these drugs (especially combination analgesics) should be
avoided as it could result in AITIN or accelerate the course
of the underlying renal disease [66, 67].
KIDNEY IN SARCOIDOSIS
Sarcoidosis is a systemic disease of unknown etiology
characterized by the presence of noncaseating granulomata
in affected organs. The clinical presentation is usually
dominated by pulmonary, dermal, and ocular involvement.
Renal involvement is due to infiltration of renal interstitum
by granulomata (Fig. 1B) and/or by granuloma-induced
disturbances in calcium homeostasis. Granulomatous interstitial nephritis (GIN) is, however, seen in other diseases
including allergic interstitial nephritis, Wegener’s granulomatosis, Berrylliosis, and tuberculosis [63, 68 –70]. The
glomeruli are usually normal, however, granulomata can
occasionally involve renal vessels. Other findings include
320
Rastegar and Kashgarian: Tubulointerstitial nephritis
interstitial fibrosis and tubular atrophy. Interstitial calcification is seen in patients with hypercalcemia and or hypercalciuria.
Granulomatous inflammation represents an intense immunologic response to a presumed antigen and consists of
a collection of monocyte-derived macrophages and lymphocytes. Activated macrophages, located primarily in the
center of the granuloma, are capable of antigen presentation to the lymphocytes and can coalesce into epithelioid or
multinuclear giant cells. Lymphocytes are primarily CD4positive helper cells with a small number of CD8-positive
suppresser cells forming a ring on the periphery of granuloma. The increase in number of activated macrophages
and lymphocytes represents both local proliferation as well
as recruitment from the circulating pool. These events are
triggered by release of multiple cytokines including interleukin (IL)-1, IL-2, interferon gamma, colony stimulating
factor, and chemotactic factor for monocytes. Tissue injury
is a byproduct of this intense immunologic activity and
involves recruitment of neutrophils capable of tissue necrosis through degranulation. Granulomata eventually undergo resolution by fibrosis. This process involves recruitment of fibroblast into granulomata by multiple cytokines
including TGF-B and PDGF. The fibroblast proliferate
locally and begin to lay down matrix protein resulting in
irreversible fibrosis [71].
Clinical features of sarcoid nephropathy
The incidence of renal involvement in sarcoidosis is
unknown. A prevalence of 7 and 37% is reported in two
autopsy series published over four to five decades ago [72,
73]. Renal involvement however is often clinically silent.
LaBecq, Verhaegen and Desmet studied 152 patients and
found 75 (49%) with a clinical renal abnormality that was
primarily proteinuria and/or abnormal urinary sediments;
21 patients (14%) had renal calculi at some time in the
course of the disease. Of the 25 patients who underwent
renal biopsy, 10 had epithelioid granulomata [74]. These
findings are supported by a smaller study of 42 patients by
Romer, 23 of whom had renal abnormalities. Renal biopsy
carried out in 15 patients showed GIN in five [75]. GIN
usually presents as renal failure progressing over weeks to
months. Kenouch and Mery noted that out of 75 reported
cases in literature all but three had renal failure at presentation [76]. Proteinuria is mild, however, many patients
have tubular defects including diabetes insipidus, renal
tubular acidosis, and glycosuria.
Macrophages in sarcoid granuloma contain a 1-alpha
hydroxylase enzyme capable of activating vitamin D to its
active form. The resultant increase in absorption of calcium
from the gut causes hypercalcemia and hypercalciuria
presenting as nephrolithiasis and/or nephrocalcinosis. The
incidence of hypercalciuria is reported to be from 10 to
60%, hypercalcemia at 10%, and nephrocalcinosis at 5%
[77]. In a highly selected referral group of 42 patients,
Romer noted calcium abnormalities in 19: 3 with hypercalcemia, 4 with hypercalciurias, and 12 with hypercalcemia
and hypercalciuria [75]. The macrophage alpha hydroxylase
enzyme is unique in that it is not accompanied by the
24-hydroxylase enzyme. It also lacks negative feedback
inhibition to its own product. It is, however, very sensitive
to inhibition by glucocorticoids [78].
Diagnosis and treatment of sarcoid nephropathy
Sarcoid nephropathy should be considered in any patient
with unexplained renal failure and hypercalcemia, nephrocalcinosis, renal tubular defect or increased immunoglobulins. These patients often have signs and symptoms of
pulmonary, ocular and/or dermal involvement with sarcoidosis. The initial workup should therefore attempt to establish this diagnosis through a standard workup. The presence of granulomata on renal biopsy, while not specific to
sarcoidosis, should strongly suggest this diagnosis in an
appropriate setting [68, 69]. In patients with known sarcoidosis, sarcoid nephropathy should be considered in the
presence of renal failure, hypercalcemia, nephrolithiasis,
nephrocalcinosis or renal tubular defects.
GIN can be treated effectively with glucocorticoids [75].
Patients often respond quickly with improvement in renal
function, however, this depends greatly on the extent and
severity of inflammation and fibrosis before treatment is
initiated. There are no data regarding the dose or length of
the treatment. We recommend the standard anti-inflammatory dose of 1 to 1.5 mg/kg initially continued for eight
weeks, followed by slow taper guided by recurrence of signs
and symptoms of disease activity.
The hypercalcemia/hypercalcuric syndrome also responds quickly to corticosteroid, but a recurrence may
occur if the treatment is discontinued rapidly. In general
the dose needed to treat this complication is significantly
lower than the dose needed to treat GIN, and can be as low
as 35 mg of prednisone daily [79]. Chloroquine, by decreasing the level of 1,25 dihydroxycholecalciferol, is an effective
therapy for the hypercalcemic/hypercalciuric syndrome
[80]. Ketoconazole, an inhibitor of steroidogenesis, has
been used in a single patient who could not tolerate
corticosteroids. It was effective in decreasing the level of
active vitamin D as well as serum and urinary calcium [81].
The length of any of the treatments is dependent on the
level of activity of the disease and may be lifelong in a small
number of patients.
LEAD NEPHROPATHY
An abundant heavy metal, lead has been a part of human
history for millennia. The major sources of exposure today
are through lead-based paints, lead leached into food and
beverages during processing and storing, and, increasingly,
through industrial and environmental exposure. Lead toxicity affects many organs resulting in encephalopathy, anemia, peripheral neuropathy, gout, and renal failure. Acute
Rastegar and Kashgarian: Tubulointerstitial nephritis
lead toxicity, often seen in children below six years of age,
is primarily due to paint chip pica, and results in severe
encephalopathy, seizures and proximal tubular damage
presenting as Fanconi syndrome [82]. The blood lead level
in these children is usually above 150 mg/dl and the
diagnosis is usually apparent. The pathology includes the
presence of proximal tubular intranuclear inclusion bodies
that resolve with chelation therapy (Fig. 1D). If exposure
continues, chronic tubulointerstitial nephritis may develop
decades later and present as progressive renal failure
and/or hypertension.
Epidemiology of lead nephropathy
The first case of lead-induced renal cortical atrophy and
interstitial fibrosis was reported by Lanceraux in 1863 and
1881. It was found in an artist who habitually had held his
painting brush in his teeth [83]. Although lead nephropathy
was accepted as a defined entity by the end of the 19th
century, it was the epidemic of lead nephropathy in
Queensland, Australia that provided the strongest link
between lead and chronic TIN. Lead exposure was due to
the lead based paints used between 1890 and 1930 [84].
Henderson, among others, noted the excess mortality due
to chronic interstitial nephritis to be present in Queensland
but not in other parts of Australia. The higher mortality
was observed first in the youngest age groups and then later
in the oldest age groups. It declined beginning in 1930s,
after lead-based paints were banned in 1922 [16]. Henderson traced 354 out of 401 cases of childhood plumbism
admitted to Brisbane Children’s Hospital between 1915 to
1935, and noted that of the 165 who had already died, 108
had died of renal or vascular disease and 20 of 187 living
individuals had proteinuria and/or hypertension. He then
correlated the incidence of granular contracted kidney
found at autopsy with the lead content of the skull in
Queensland and Sydney, and showed that the lead content
of the skull closely correlated with the incidence of renal
failure. In addition, 67% of patients with small contracted
kidneys in Queensland did not fit into a known renal
disease while all the patients in Sydney had a known
primary diagnosis. The bone lead content in patients with
small contracted kidneys from Queensland was significantly
higher than in other patients in either Sydney or Queensland (8 vs. 2 mg/100 g of bone) [85]. Emmerson showed a
significantly higher total body lead burden using EDTA
mobilization tests in subjects with CTIN of unknown etiology compared to chronic renal failure of known etiology
and normal subjects [86]. Chronic lead toxicity in the U.S.
is more commonly due to ingestion of illicit alcohol (socalled moonshine) where lead is leached into the product
during the distillation process [87, 88]. More recently the
major source of lead exposure has shifted from lead-based
paint and moonshine to industrial exposure. This type of
exposure is often insidious, occurring over very long periods [89 –91]. Weeden, Mallik and Batuman studied 140
321
asymptomatic lead workers, 113 of whom had increased
total body lead burden by the EDTA mobilization test.
Twenty-one of the 57 patients who had GFR measurements
by the iothalamate Na 125I test had values below 90
ml/min/1.73 m2. However, only 3 patients had a serum
creatinine above 1.5 mg%. Using stringent criteria, the
authors felt that at least 15 of the patients had lead
nephropathy [90]. Pinto de Almeida et al screened 52 lead
workers in Brazil with high lead exposure and compared
their renal function with 44 workers from a paper mill.
Renal dysfunction defined as serum creatinine above 1.5
mg% was seen in 17 (32.7%) of the lead workers and 1
(2.3%) of controls. In addition, the exposed group had
significantly higher uric acid level than control (6.6 6 1.7 vs.
4.4 6 1.2 mg%, P , 0.001) [91].
Two studies have shown an inverse relationship between
low level lead exposure and renal function in general
population [92, 93]. In the study of approximately 2,000
civil servants in England, Staessen noted a decrease in GFR
by 10 to 13 ml/min with a 10-fold increase in the serum lead
level [92]. In another retrospective cohort study of 459 men,
a similar rise in the serum lead level was associated with a
small but significant increase in serum creatinine equivalent
to the expected rise seen with 20 years of aging [93]. No
data on bone lead level was provided in either study and no
patient developed ESRD. The role of childhood lead
exposure in development of CRF remains controversial.
The Australian studies by Henderson et al established a
causal relationship in that population [16]. Two recent
studies evaluating renal function 17 to 50 years after an
episode of acute childhood plumbism, however, have failed
to show any effect on renal function [94, 95]. The difference
between these findings and the findings reported by Henderson and others from Australia probably reflects the
greater lead burden in the latter population. The Australian children were exposed to lead paint over a long period
of time when the danger of the exposure was unknown [16].
The American studies are a follow up of children diagnosed
with acute plumbism and who were probably removed from
continuous exposure. These studies are therefore not comparable to the Australian study.
Although ESRD is a feature of lead exposure in unique
populations [16], its contribution to overall ESRD incidence is not clear. In a study of 135 patients from Belgium,
France and Germany, 8 patients (5%) had an iliac bone
lead level equivalent to level seen in lead workers. Follow-up data in 6 of these patients verified a history of
significant lead exposure with no other renal disease. In this
population it is possible that exposure to lead played a
significant role in the development of renal failure [96]. In
summary, acute childhood plumbism is not associated with
renal failure decades later, and low level lead exposure in
general population is associated with mild but significant
depression of renal function. The role of such exposure in
the development of ESRD is at present unclear.
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Pathology of lead nephropathy
Renal biopsies have not been carried out systematically
in patients with lead nephropathy. Biopsies in 12 patients
with subclinical lead nephropathy and mild to moderate
decrease in GFR were normal in six and showed primarily
focal tubular atrophy and interstitial fibrosis with minimal
cellular infiltration in others. Electron microscopy showed
mitochondrial swelling, loss of cristae, loss of basal infoldings, and a lysosomal-like structure containing dense bodies
in the proximal tubules. Immunofluorescence microscopy
showed mild deposits of immunoglobulins and complement
in both glomeruli and proximal tubules [90]. The most
extensive pathological data are provided by Inglis, Henderson and Emmerson on patients who had died of severe lead
exposure in Australia [97]. Kidneys were fibrotic and
shrunken, often weighing less than 100 grams. The interstitum showed variable degree of fibrosis with tubular
dilation. The vessels had thickened muscular walls with
subintimal hyaline deposition in afferent arterioles. The
most specific and interesting finding was the disappearance
of glomeruli “without trace” noted in a majority of the
specimens [97]. It should be noted that these findings are in
autopsies of patients who had died of ESRD. Although
some of the findings are nonspecific and are seen in any
end-stage tubulointerstitial disease, the severity of renal
contraction as well and glomerular drop out favors this
diagnosis.
Clinical features of lead nephropathy
Epidemiological studies have firmly established the relationship between chronic lead toxicity and chronic TIN.
Renal failure becomes apparent years after the exposure
and is associated with gout in up to half of the cases [86].
Although hyperuricemia is common in renal failure, gout is
highly unusual and its presence should raise the possibility
of lead nephropathy [98, 99]. In addition, patients with
primary gout without lead toxicity rarely develop renal
failure [100, 101]. Bautman et al studied 44 patients with
gout, half with renal failure (serum creatinine . 1.5 mg%).
Three-day EDTA mobilization tests resulted in a significantly greater lead excretion in patients with rather than
without renal failure (806 6 90 vs. 470 6 52 mg/three days,
P , 0.005). Lead excretion in 10 patients with renal failure
of other etiologies was similar to patients with gout without
renal failure and normal subjects [102].
The diagnosis of lead nephropathy should be considered
in any patient with progressive renal failure, mild to
moderate proteinuria, significant hypertension, history of
gout and appropriate history of exposure. Ultrasonography
of the kidneys shows bilaterally small, echogenic kidneys
without focal scars. As the blood lead level only reflects
recent lead exposure and is usually normal in these patients, the diagnosis should be based on measurement of
body lead burden by EDTA mobilization test or measure-
ment of bone lead content by bone biopsy. The EDTA test
involves administration of 2 grams of EDTA intramuscularly in two divided doses 8 to 12 hours apart and collection
of three consecutive 24-hour urine samples. Individuals
with a high lead burden will have a cumulative excretion
rate of more than 0.6 mg. Renal failure in itself does not
increase body lead load but delays lead excretion [102]. The
three-day urinary collection, however, assures a complete
measurement of excreted lead in these patients. Recently, a
new technique using x-ray fluorescence has been utilized to
measure the bone lead level [103]. This technique is highly
accurate and reproducible and can provide a rapid, noninvasive measure of body lead stores [104].
In general the clinical course of lead nephropathy is
slowly progressive and is often dominated by recurrent
gouty attacks and hypertension. There is little experience in
the therapeutic use of EDTA in patients with chronic renal
disease. Weeden et al treated 8 patients with industrial
exposure with EDTA injection trice weekly for 6 to 50
months. Four patients improved with a 20% increase in
GFR. All these patients had mild renal failure with the
lowest GFR of 52 ml/min before treatment. EDTA has no
effect on patients with serum creatinine of greater than 3.0
mg% [90]. Hypertension and gout dominate the course,
which finally leads to ESRD in a small subgroup.
Lead and hypertension
Hypertension is a very common feature of lead nephropathy. Association between hypertension without renal failure and low level lead exposure has gained increasing
support over the past two decades. In a study of 21
hypertensive patients with no renal disease and 27 with
renal disease the three days EDTA mobilization test
showed a significantly higher excretion of lead in those with
renal failure (860 6 101) than those without renal failure
(340 6 39, P , 0.001) and patients with comparable renal
failure of known cause (440 6 50) [105, 106]. This relationship has been strengthened by a variety of epidemiological
studies done in the past decade [107–110].
In a recent case-control study of 1171 participants in the
Normative Aging Study, Hu et al [110] using K-x-ray
fluorescence showed that body lead burden was an an
independent risk factor along with body mass index and
family history of hypertension for the development of
hypertension. The link may be through activation of reninangiotensin system [111–113] or through an increase in
sodium-lithium countertransport [114].
ACUTE DRUG-INDUCED TUBULOINTERSTITIAL
NEPHRITIS
It is now widely recognized that a large variety of drugs
including b-lactam antibiotics, non-steroidal anti-inflammatory drugs, diuretics, anticonvulsants, and an increasingly diverse group of other drugs can be associated with an
allergic acute tubular interstitial nephritis [115–124]. In two
Rastegar and Kashgarian: Tubulointerstitial nephritis
large unselected renal biopsy series, the incidence of acute
interstitial nephritis (AIN) was estimated at 1.2 to 1.3%
[23, 125]. Richet et al, in a study of 976 patients with acute
renal failure, noted that 14% of 218 biopsies were compatible with this diagnosis for a minimum incidence of 3% in
this population [126]. The exact incidence is unknown, as
the reported series is small and highly selective and patients
with this diagnosis are often not biopsied.
Pathology and pathogenesis of acute interstitial nephritis
It is likely that this form of interstitial nephritis is
immunologically mediated and idiosyncratic in nature. The
clinical evidence is circumstantial and consists of the presence of a rash, fever and/or eosinophilia, the occurrence of
nephritis in only a minority of exposed individuals independent of the drug dose, the recurrence of the disease upon
re-exposure and the response to corticosteroid therapy
[127]. The exact immune mechanisms involved have not
been clearly defined, but it is likely that cell mediated
hypersensitivity is involved since the histologic lesion is very
similar to that seen in allograft rejection.
One of the most distinguishing features of acute druginduced tubulointerstitial nephritis is the nature of the
interstitial infiltrate. The interstitium is edematous, where
the tubules are separated by a palely stained interstitium
(in contrast to the dense staining of fibrosis) and infiltrated
with a significant number of eosinophils and mononuclear
cells (Fig. 1C). The infiltrate is characteristically focal, is
most prominent at the cortical medullary junction, and
often surrounds individual tubules. The mononuclear portion of the infiltrate is predominately lymphocytic with
some macrophages and plasma cells, and sometimes forms
granulomata. The eosinophils tend to concentrate in small
foci and may form the eosinophilic microabscesses. Neutrophils can be present but are uncommon. A second
distinguishing characteristic is the presence of tubulitis.
Particularly with PAS stains, lymphocytes can be seen
invading the tubules beneath the tubular basement membrane. Variable degrees of tubular epithelial cell damage
with evidence of regeneration as identified by the presence
of mitotically shaped and pleomorphic nuclei are almost
always found, but extensive necrosis of the epithelium is
rare. Additional evidence that the process is immune
mediated has been derived from immunohistochemical
analysis of biopsies of such patients. The infiltrate usually
has a predominance of T lymphocytes expressing the CD4
antigen, and in most cases there is an enhanced expression
of HLA Class II antigens on the tubular epithelium [120 –
130]. Immunofluorescence and electron microscopy of such
cases has not revealed the presence of immune deposits,
further suggesting that the immune process is cell mediated. The glomeruli are usually not affected and evidence
of vasculitis is generally not seen. Although drugs have
been implicated in most cases of allergic interstitial nephritis, a similar picture can be found in patients with lupus
323
nephritis [131–133] and rarely in association with antitubular basement membrane antibodies [120]. Biopsy
proven instances of acute oliguric tubulointerstitial nephritis with a similar histologic picture but without any known
drug exposure have also been reported [124, 134]. One
special group includes the association of acute interstitial
nephritis with uveitis and bone marrow and lymph node
granulomata [135–137]. This syndrome occurs predominately in adolescent girls and young women and with the
presence of granulomata in the kidney, and must be
distinguished from sarcoid involvement.
Clinical features and management of acute interstitial
nephritis
Although the clinical manifestations may be variable,
they are usually heralded by fever, hematuria and/or
azotemia. Eosinophilia occurs in a majority of cases. Urinalysis reveals hematuria, sterile pyuria and moderate
proteinuria. Eosinophils may be detected in the urinary
sediment [138, 139]. A variety of tubular defects including
hyporenenimic hypoaldosteronism, salt losing nephropathy
[122], and potassium and magnesium wasting [140] have
been reported. A skin rash is seen in some patients lending
support to the concept that the disease may be immunologically mediated. The azotemia may be severe and patients may present with acute renal failure leading to the
use of the renal biopsy as a diagnostic procedure. A unique
syndrome of renal failure and nephrotic syndrome is reported in association with NSAIDs [128, 141] and less
commonly other drugs [142]. Renal biopsy, in addition to
classical findings of allergic interstitial nephritis, shows
extensive foot process fusion compatible with nil disease.
The diagnosis of AIN is primarily clinical, and is often
considered in the setting of rising creatinine in a patient
with or without history of chronic renal failure. A minority
of patients have a classical triad of skin rash, fever, and
eosinophilia initially described with methicillin-induced
AIN [117]. Urinalysis shows variable degrees of proteinuria
in association with pyuria and hematuria. Using a special
stain, Nolan, Angers and Kelleher reported a sensitivity of
91% (10 of 11 patients) and specificity of 85% (69 of 81
controls) for eosinophiluria [139], for a positive predictive
value of 43%. Given the spectrum of the disease and lack of
standardization of the test, its value in management of
patients with AIN should be questioned [127, 138, 143]. In
a study of 97 patients, gallium scanning had a sensitivity of
100% and specificity of 91%, which decreased to 85% if the
data were limited to biopsy proven patients only [144].
These data have not been independently verified. Renal
biopsy remains the gold standard and should be strongly
considered in any patient where the exact diagnosis is
critical for appropriate management.
The course of AIN is highly variable and can lead to
irreversible renal failure if the offending agent is not
removed. In patients with mild to moderate renal failure,
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Rastegar and Kashgarian: Tubulointerstitial nephritis
discontinuation of the drug is often associated with a return
of renal function toward baseline. In two biopsy-proven
series with total of 44 patients, 2 developed ESRD, 17
returned to normal renal function, and the remainder
recovered significantly but remained with varying degree of
renal failure. The recovery rate is probably higher as the
preinjury creatinine was not available in all patients [120,
145]. The recovery often takes several weeks and may
continue up to a year after discontinuation of offending
agent [145]. These two series are too small to develop
reliable predictive parameters, however, the severity of
initial clinical course, degree of improvement in the initial
six to eight weeks and severity of pathological lesion
correlated with the final outcome [120, 145]. The role of
steroid therapy in the management of these patients is
highly controversial. Galpin et al in a study of methicillininduced AIN noted that 8 patients treated with prednisone
had greater and faster recovery of their renal function
compared to 14 untreated patients [120]. Pusey et al, in
another retrospective study, noted that 7 of 7 patients
treated with intravenous prednisone recovered, while two
untreated patients developed chronic renal failure and one
patient had slow recovery [146]. These uncontrolled retrospective studies in highly selected patients do not provide
adequate guidelines to clinicians in the management of
these patients. Given the suggestive data in literature and
until well-controlled prospective studies are done, we recommend a short course of high-dose steroid therapy (1
mg/kg body wt for 2 weeks with a rapid taper) in patients
with appropriate clinical and/or histological findings and
significant renal failure. In patients with mild renal failure
we prefer to discontinue the offending agent and follow the
patient closely.
CONCLUDING REMARKS
Tubulointerstitial diseases represent a group of heterogenous disorders with vaying etiology, pathogenesis and
clinical course, and make up a significant percentage of
patients with renal disease. Over the past three decades, we
have developed an better understanding of the basic mechanism of tubulointerstitial injury as well as epidemiology,
clinical presentation and course of specific disorders. As
the four disorders discussed in this report shows, many
tubulointerstitial disorders are either preventable and/or
treatable. In addition, new disorders involving this compartment, such as TIN due to Chinese herbs used for
weight loss [147], continue to be described. A better
understanding of the epidemiology, pathogenesis, clinical
presentation and course of the disease should help us
prevent and/or treat this group of disorders.
Reprint requests to Asghar Rastegar, M.D., Department of Internal Medicine, Yale University School of Medicine, 333 Cedar St., New Haven,
Connecticut 06520, USA.
APPENDIX
Abbreviations used in this article are: AIN, acute interstitial nephritis;
AITIN, analgesic-induced tubulointerstitial nephritis; ASA, acetosalicylic
acid; CRF, chronic renal failure; CT, computer tomography; CTIN,
chronic tubulointerstitial nephritis; ESRD, end-stage renal disease; GFR,
glomerular filtration rate; GIN, granulomatous interstitial nephropathy;
HIV, human immunodeficiency virus; IL, interleukin; NSAIDs, nonsteroidal anti-inflammatory drugs; OR, odds ratio; PDGF, platelet-derived
growth factor; RBC, red blood cells; RR, relative risk; SLE, systemic lupus
erythrematosus; TGF-B, transforming growth factor-B; TIN, tubulointerstitial nephritis; WBC, white blood cells.
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