Abstract

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Introduction
Tubulointerstitial nephritis (TIN) is a well-described entity, although often has a delayed
diagnosis given non-specific presenting signs and symptoms. TIN can be categorized based on
underlying etiology, histology, or duration (acute versus chronic). This review will focus on
common etiologies of TIN as well as developments in genetic discoveries and novel biomarkers
to aid in the diagnosis, prognosis, and treatment of the disease.

Definition
TIN is characterized by an immune-mediated infiltration of the kidney interstitium by
inflammatory cells, leading to non-oliguric or oliguric acute kidney injury (AKI) [1-4]. Less
frequently, the interstitial inflammation can lead to chronic changes with subsequent
development of chronic kidney disease (CKD) [5]. Numerous genetic and environmental factors
can cause or contribute to development of TIN. Particular aspects of histologic diagnosis (i.e.
granulomas) or associated systemic disease can aid in identification of underlying etiology. TIN
accounts for 2 % of native renal biopsies [6] and up to 27 % of cases of unexplained kidney
disease in adult patients [3]. In children, TIN (both acute and chronic) accounts for 1-7 % of the
histological diagnoses in renal biopsies [7, 8].

Etiology
TIN has multiple etiologies, including drug-related, infectious, systemic, autoimmune, genetic,
and idiopathic (Table 1). The most common cause of TIN is related to a medication or drug
exposure [2-4, 9]. Many medications have been implicated, with beta-lactam antibiotics and non-
steroidal anti-inflammatory (NSAID) drugs being the most common, and presenting with classic
TIN (Table 2). The presentation related to rifampin use is unique and can be accompanied by
sudden onset of symptoms and renal biopsy findings ranging from classic acute TIN to acute
tubular necrosis [10-12]. Overall, drug-induced TIN has been noted in 7-27 % of adult patients
with unexplained non-oliguric or oliguric AKI [13]. Infectious causes of TIN include viral,
bacterial, fungal or parasitic [14-16]. TIN has been reported as the third leading cause of graft
dysfunction in renal transplant patients [17]. TIN in immunosuppressed renal transplant
recipients is primarily related to infectious causes, including polyoma virus or cytomegalovirus,
and unfortunately can lead to increased risk of subsequent rejection [17-20]. TIN associated with
polyoma virus infection has been reported in association with primary immunodeficiency [21].
Bone marrow transplant recipients are at risk for necrotizing TIN caused by adenovirus [22-24]
and patients with HIV-associated nephropathy can have a component of TIN [25]. Epstein-Barr
infections have been associated with TIN with uveitis (TINU) syndrome in children and adults
[26, 27]. Among other infections associated with TIN are Mycoplasma pneumoniae, Yersinia
pseudotuberculosis and Leptospira shermani [28-31]. TIN has been described in association with
systemic inflammatory conditions such as inflammatory bowel disease, TINU syndrome,
sarcoidosis, systemic lupus erythematosus (SLE), and Sjögren's disease. IgG4-associated
immune complex multiorgan autoimmune disease (MAD) has also been linked with
development of TIN with IgG4 positive plasma cell interstitial infiltrates and C3 deposition [32].
Autoimmune pancreatitis is in the spectrum of IgG4-associated MAD where TIN is part of the
disease manifestation [33-35]. In the IgG4-associated conditions, hypocomplementemia and C3
interstitial deposition are frequently observed in addition to elevated serum levels of IgG and
IgE. By contrast, hypocomplementemic immune-complex-mediated TIN described in the setting
of advanced renal failure, eosinophilia, eosinophiluria and lymphopenia and characterized by
near-pure plasma cell interstitial infiltrates was unaccompanied by any extrarenal manifestations
[36]. Despite severe hypocomplementemia, C3, C4 or C1q complement was absent from
tubulointerstitial immune complex deposits [36]. TIN has also been described in patients with
anti-tubular basement membrane antibodies [37]. Often, TIN is under-recognized in these
inflammatory conditions and diagnosed later in the disease course.
Table 1
Etiology of TIN [1, 3, 44, 46]

Drug-Related

Antimicrobials

NSAID's

Other

Infectious

Viral:

Cytomegalovirus, Hepatitis, HIV, Epstein - Barr virus, Hantavirus, Polyomavirus

 Bacterial:

Salmonella, Streptococcus, Yersinia, Brucella, Leptospirosis

Fungal:

Histoplasmosis

Parasitic:

Leishmania, Toxoplasma

Localized TIN with acute pyelonephritis

Immune-Mediated

Sarcoidosis

Systemic Lupus Erythematosus

Sjögren's Disease
 Inflammatory Bowel Disease

Idiopathic

TINU

Granulomatous TIN

Medications

Sarcoidosis

Tuberculosis

Bacterial/Fungal infections

TINU

Granulomatosis with polyangiitis

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*NSAID's: Non-steroidal anti-inflammatories, TIN: Tubulointerstitial Nephritis, TINU: Tubulointerstitial Nephritis
and Uveitis Syndrome

Table 2
Medications implicated in tubulointerstitial nephritis (TIN) [1, 3, 44, 46]

Antimicrobials NSAIDs Diuretics Neuropsychiatric Other

Beta-lactams Ibuprofen Furosemide Carbamezepine Allopurinol

Cephalosporins Ketorolac Thiazide diuretics Lamotrigine Azathioprine

Sulfonamides Levetiracetam Antiepileptics

Macrolides Triamterene Phenytoin Proton-pump inhibitors

Gentamicin Amiloride Lithium

Nitrofurantoin Tienlinic acid Alendronate

Clotrimazole Chlorpropamide

Doxycycline Captopril
 Antimicrobials NSAIDs Diuretics Neuropsychiatric Other

Rifampin Sulfasalazine

Ethambutol

Isoniazid

Vancomycin

Ciprofloxacin

Acyclovir

Indinavir

*NSAID's: Non-steroidal anti-inflammatories

Several genetic factors have been associated with development of TIN. TIN antigen (TIN-ag) is
an extracellular matrix basement membrane protein and a target antigen in anti-tubular basement
membrane antibody-mediated TIN [38]. Deletion of the TIN-ag gene hTIN-ag localized on
chromosome 6 leads to disruption of the structure and function of tubulointerstitial epithelium
and basement membrane [39]. Additionally, Kidney Disease Improving Global Outcomes
(KDIGO) released a consensus report describing autosomal dominant tubulointerstitial kidney
disease [14]. Thus far, four causal genes, Uromodulin, Renin, Hepatocyte nuclear factor 1B,
and Mucin-1 have been identified [40]. These are a group of disorders that lead to progressive
tubulointerstitial fibrosis, a chronic form of TIN which inevitably leads to end-stage renal
disease.

Pathophysiology
Acute interstitial inflammatory reactions are associated with damage to the tubulointerstitium,
leading to AKI associated with TIN [4]. The high metabolic demand of the tubulointerstitium
makes it particularly susceptible to injury because the inflammation and associated edema
compromise renal blood flow, causing a decrease in glomerular filtration rate (GFR) [5]. In some
situations, damage may lead to fibrosis (see below).
Interstitial edema and infiltration of lymphocytes and plasma cells, as well as poor tubular
function in acute TIN, causes a decrease in GFR. In chronic TIN, fibrosis of the interstitium (as
opposed to edema) causes the decrease in GFR [5, 41]. If prolonged, acute interstitial
inflammatory reactions can lead to accumulation of extracellular matrix that causes irreversible
impairment of renal function with interstitial fibrosis and tubular atrophy [4, 13]. Initially
macrophages may help repair acute injury, but eventually can contribute to inflammation and
production of fibrogenic cytokines [5]. Studies have shown that the cytokine transforming
growth factor-beta (TGF-β) may mediate profibrotic responses in the tubulointerstitium [5, 42].
Tubular damage can decrease the number of functional nephrons, eventually resulting in
hyperfiltration and burnout of the remaining nephrons leading to CKD [5].
The pathophysiology of drug-induced TIN is thought to be immune-mediated and related to an
allergic reaction. There are five concepts that support this view: (1) TIN only occurs in a small
proportion of individuals taking a certain medication; (2) There is no dose-dependence; (3)
Patients develop systemic manifestations of a hypersensitivity reaction; (4) TIN can recur after
re-exposure to the drug; and (5) Eosinophils are often present on renal biopsy [4, 9]. This process
likely involves cellular immunity, as there are seldom immune deposits noted by
immunofluorescence on renal biopsies in patients with TIN [4].

Pathology
Regardless of underlying etiology, TIN is characterized histopathologically by tubulointerstitial
inflammatory cell infiltrate (primarily lymphocytic and eosinophilic) and interstitial edema [6]
(Fig. 1). When a significant number of eosinophils are present, drug-induced TIN needs to be
considered, but neither the presence nor absence of eosinophils is absolutely diagnostic [13].
NSAID-induced TIN is less likely to be associated with eosinophils on renal biopsy, likely due to
the anti-inflammatory properties of NSAIDs. A higher density of neutrophils and plasma cells
are suggestive of bacterial etiology [13].
Figure 1
Renal Histopathology in tubulointerstitial nephritis (TIN)
A. TIN with predominantly lymphocytic infiltrate associated with tubular damage and tubulitis (arrow).
Periodic acid Schiff stain, original magnification × 400. B. Acute drug-induced tubular injury, in this case
secondary to cidofovir. There is interstitial infiltrate (*), edema (#) and marked tubular regenerative
changes (arrows). Glomeruli show little change. Hematoxylin and eosin stain, original magnification ×
200. C. Granulomatous tubulointerstitial nephritis (arrow), in this case likely secondary to lamotrigine.
Hematoxylin and eosin stain, original magnification × 200.

Granulomatous TIN
Inflammatory cells infiltrating the tubulointerstitium can form granulomas, which are usually
scarce, and non-necrotic with few multinucleate giant cells [4, 43] (Fig. 1c). By contrast, necrotic
granulomas are commonly seen in TIN associated with bacterial (tuberculosis) or fungal
infections [44]. The presence of granulomas on renal biopsy defines granulomatous TIN, which
is relatively rare, with renal biopsy incidence of 0.5 % [9]. With time, the granulomas are often
replaced by fibrosis, but despite varying histopathology, a diagnosis of granulomatous TIN does
not necessarily correlate with poor prognosis [43, 45]. The underlying etiology for
granulomatous TIN is similar to TIN, although sarcoidosis, TINU syndrome, and certain drug-
related cases are more common (Table 1). Systemic diseases such as Crohn's disease have also
been implicated, though rare [46]. One study reported that the underlying etiology of
granulomatous TIN is not found in 50 % of patients [45]. Interestingly, granulomatous TIN has
been described in renal transplant recipients and was hypothesized to result from infections,
which are more common in this patient population because of the use of immunosuppressive
agents [44, 47].

Clinical presentation
A challenging feature of TIN is the non-specific symptomatic presentation, which often leads to
delayed diagnosis that may portend worse outcomes. Classically, presentation is thought to be
associated with a hypersensitivity reaction including rash, arthralgia and fever, but as few as 5-10
% of patients present with all of these findings [3, 9]. In a comprehensive study of acute TIN, at
presentation 15 % of patients had rash, 27.3 % had fever, 23 % had eosinophilia and only 10 %
had all three findings [3]. The tubulointerstitial infiltrate of inflammatory cells can cause edema
and painful stretching of the renal capsule, leading to abdominal, flank or loin pain [6]. Thus, the
kidneys in TIN are typically found to be normal sized or enlarged with increased cortical
echogenicity by ultrasound. If drug-related, TIN can manifest between 1 and 3 weeks after
exposure to the medication in most cases [44], with an average presentation of about 10 days
after exposure [4], except for rifampin exposure when the presentation may be much faster, as
described above. Presence of extrarenal manifestations may be helpful in identifying a risk for
TIN. A renal biopsy is the only definitive diagnostic modality that can confirm TIN suspected on
clinical grounds. A renal biopsy should be considered with severe renal dysfunction, lack of an
identifiable offending agent, lack of renal recovery, uncommon features of TIN or prior to
initiation of treatment [1], but otherwise TIN remains a clinical diagnosis. Tubulointerstitial
dysfunction should be suspected in patients who develop hyperkalemic, hyperchloremic
metabolic acidosis that is out of proportion to renal dysfunction [9]. Most patients are initially
noted to have AKI (elevated BUN and/or creatinine) with further workup revealing TIN. Other
presenting signs and symptoms are noted in Table 3. Tubular dysfunction can manifest as
Fanconi's syndrome, so patients may present with electrolyte abnormalities (as above), metabolic
acidosis, elevated fractional excretion of sodium, glycosuria, and aminoaciduria. Additionally,
eosinophilia, pyuria, hematuria, eosinophiluria, and mild proteinuria are present in a variable
number of cases [2, 6].
Table 3
Clinical Presentation of tubulointerstitial nephritis (TIN) [9, 89]

Symptoms

Fatigue

Anorexia, Weight Loss

Headache

Flank pain

Arthralgias
 Myalgias

Signs

Fever

Skin rash

Costovertebral Angle tenderness

Laboratory Findings

Blood studies: Renal Failure, Anemia, Eosinophilia

Urine studies: Sterile Pyuria, Proteinuria, Eosinophiluria, White Blood Cell Casts, Micro/Macroscopic
Hematuria (rare)

The differential diagnosis of both acute and chronic TIN is broad. Chronic TIN may manifest
similarly to obstructive nephropathy, chronic pyelonephritis, papillary necrosis, tubulopathies
including Fanconi syndrome, progressive interstitial fibrosis or Balkan endemic nephropathy
(BEN), Chinese herb nephropathy, and radiation nephritis [41, 48, 49]. Acute TIN has a
differential diagnosis that could include acute glomerulonephritis, pyelonephritis, atheroembolic
disease, or any cause of AKI (acute tubular necrosis, prerenal azotemia, urinary obstruction or
drug-induced AKI).
While eosinophiluria can be helpful in the diagnosis of TIN, it is neither sensitive nor specific.
Eosinophiluria can also be seen with cystitis, prostatitis, pyelonephritis, atheroembolic renal
disease, acute tubular necrosis and rapidly progressive glomerulonephritis [9]. In a study
evaluating drug-induced TIN, of the patients with biopsy-confirmed TIN, 67 % had
eosinophiluria whereas 33 % did not. Additionally, 13 % of patients without TIN had
eosinophiluria [4].

Tubulointerstitial Nephritis and Uveitis Syndrome (TINU) Syndrome

TINU is a rare disorder with only 133 cases reported in the literature by 2001 [50]. TINU
accounts for less than 2 % of cases of uveitis [1, 51, 52]. The median age at presentation is 15
years and the female to male ratio is 3:1 [52, 53]. Diagnosis requires the presence of both TIN
and uveitis, and is suggested by abnormal renal function, abnormal urinalysis, photophobia, eye
pain and redness, eyelid edema, rapidly progressive loss of vision, as well as symptoms of
systemic illness, including weight loss, fever, and fatigue [3, 50, 52]. In addition to the
aforementioned eye symptoms, conjunctival and perilimbal injection are present and pupils can
be small with sluggish or no light reaction. The ophthalmologic examination reveals anterior
chamber cells and flare, hypopyon, keratic nongranulomatous precipitates, vitreous humor cells,
intraretinal hemorrhages or retinal vascular sheathing, cotton wool spots, dilated retinal vessels
and retinal edema (Fig. 2). If there is a prolonged inflammatory process, anterior (iridocorneal)
or posterior (irido-lenticular) synechiae may develop. Anterior uveitis (Fig. 2a) is present in 80
% of cases of TINU while posterior and panuveitis (Fig. 2b and 2c) are less common [50, 54].
The ocular changes are bilateral in about 80 % of cases [55]. Uveitis generally occurs after onset
of TIN (60 % of cases), but may be present between one month before and three months after the
onset of TIN [3, 52]. In general the course and severity of uveitis does not correlate with that of
TIN [52, 53, 56-59].

Figure 2
Ophthalmologic findings in tubulointerstitial nephritis with uveitis (TINU)
A. Anterior uveitis complicated by posterior (irido-lenticular) synechiae (arrows). B. Panuveitis with
endothelial precipitates and chronic anterior synechiae (arrows). C. Fundus photograph of a patient with
panuveitis demonstrating retinal infiltrates.
Recurrence of uveitis occurs in about 40 % of patients with TINU and relapses tend to be more
severe than the initial episode. Younger patients are more likely to develop a chronic course of
uveitis lasting more than 3 months [52, 53, 57, 58, 60, 61]. Intraocular complications occur in
about 20 % of TINU patients and include posterior synechiae, optic disc swelling, cataracts,
elevated intraocular pressure or chorioretinal scarring (Fig. 2). Importantly some complications,
particularly cataracts and elevated intraocular pressure, are strongly associated with the use of
systemic corticosteroids (see below). TINU syndrome remains a diagnosis of exclusion
[53, 60, 62, 63]. Sarcoidosis and Sjögren's disease are in the differential diagnosis of TINU,
although, the median age and the type of nephritis and uveitis differ.
In general, the renal prognosis is good in the majority of treated patients with TINU [50]. While
the uveitis is more difficult to control, it carries a fairly good prognosis for visual acuity that
rarely decreases below 20/40, with no reported cases of permanent vision loss [3, 54, 64]. Up to
50 % of TINU patients present with no ocular symptoms [54], emphasizing the critical need for
uveitis screening in patients with TIN. This is particularly important in those patients who do not
have medication-induced or systemic disease-associated TIN. Conversely, TINU may be
underdiagnosed in patients presenting with idiopathic uveitis [50], also highlighting the
importance of screening uveitis patients for TIN. Recently, HLA-DR and –DQ alleles have been
identified and associated with TINU and are considered “risk alleles” [64]. DNA typing for these
alleles may be particularly useful in screening pediatric patients with idiopathic panuveitis (as
opposed to anterior uveitis), which can aid in the diagnosis of TINU [64].

TIN Associated with Inflammatory Bowel Disease (IBD)

IBD has been associated with a variety of renal and urologic complications that occur in up to 23
% of patients [46]. TIN has a strong association with IBD [65]. Other renal conditions in IBD
patients include nephrolithiasis/urolithiasis, fistulas, glomerulonephritis, and renal amyloidosis
[46, 66]. These manifestations may be secondary to systemic inflammation, susceptibility to
autoimmunity, nutritional deficits, medication use, genetic predisposition, and infectious agents
[65, 67]. One study reviewing renal biopsies in adults with IBD showed that TIN was present in
19 % of kidney biopsies [65]. Of those, 44 % were acute TIN, 25 % were chronic TIN, and 31 %
were granulomatous TIN [65]. Mesalamine, used in the treatment of IBD, is a well-known
medication associated with TIN [9, 46, 66, 67], but it has been clearly demonstrated that TIN can
occur independently of medication use in IBD.
Inflammation and disease activity in IBD has been associated with low-molecular-weight
proteinuria [46, 66], adding to the utility of urinary biomarkers for monitoring disease activity
and screening for TIN in IBD patients. Studies have shown an association between IBD activity
and elevated urinary beta2-microglobulin (B2M) [68], alpha1-microglobulin (A1M) [69], or N-
acetyl-beta-D-glucosaminidase (NAG) [70]. By contrast, other studies have found no such
correlation [71, 72]. One study showed that elevated urinary A1M was associated with TIN and
tubular damage, but this was independent of IBD activity [73]. A possible explanation for such
discrepancy in correlating urinary biomarkers with disease activity is the timing of TIN
diagnosis. For example, in those IBD patients who do not have routine urinary studies TIN may
be diagnosed late when irreversible renal damage might have already occurred leading to CKD
[67, 74]. The above studies indicate that routine screening for TIN should be implemented in
patients with IBD. This may be particularly important in patients receiving mesalamine, given
that associated TIN may be severe, chronic, and progressive if not detected early [65].

Treatment
Treatment for TIN remains influenced by clinicians’ prior experience with the disease and is
only supported by several small studies and case reports with conflicting results. There are no
randomized, controlled, prospective studies, and corticosteroids are the mainstay of treatment
although no consensus has been established regarding therapy duration or dose. It has been
theorized that early steroid treatment could prevent fibrosis by decreasing inflammatory
infiltrates [75], but has not yet been proven. Treatment is primarily guided by underlying
pathophysiology, if it can be determined. For example, drug-induced TIN may recover
spontaneously with cessation of the offending medication, particularly if identified early [2].
Aside from treating obvious sources of infection, other treatment options for infection-related
TIN have not been well-described, although in transplant patients immunosuppressive
medication can be decreased [14] or Cidofovir used in polyoma virus-associated infections [76].
Since medication-related acute TIN usually resolves after discontinuation of the offending drug,
we recommend that the first line of treatment for antibiotic-related acute TIN is its
discontinuation while the infection is treated with an alternative agent. The need for additional
medications such as corticosteroids should be assessed based on the subsequent clinical course.
On the opposite end of the spectrum, systemic rheumatologic and inflammatory conditions
associated with TIN (including TINU) are more often treated with corticosteroids or with other
agents based on the systemic disease [34, 36, 77].
A retrospective study of 60 adults with acute TIN with a variety of underlying etiologies showed
no difference in outcome when comparing treatment with corticosteroids to supportive care alone
when assessing serum creatinine at 1, 6, and 12 months follow-up or dialysis independence [6].
Conversely, a more recent prospective study assessing pediatric patients with idiopathic TIN or
TINU showed that corticosteroids sped up recovery of TIN, particularly in patients with more
severe disease [78]. Notably though, the renal function did not differ significantly at 6-month
follow-up. The study suggested that because TIN may be self-limited, treatment may be delayed
by two weeks in uncomplicated cases [78]. One multicenter retrospective study in adult patients
with drug-induced TIN showed that steroid treatment, particularly if started early, may decrease
the risk of incomplete renal recovery [75]. Results demonstrated that patients not treated with
corticosteroids were more likely to have a higher final serum creatinine and had a higher
likelihood of needing chronic dialysis. The most prominent difference between patients who
regained renal function and those who didn't was the time between removal of the offending
medication and initiation of corticosteroid treatment [75].
In granulomatous TIN, one small retrospective study suggested that treatment with
corticosteroids is associated with a better prognosis, irrespective of degree of tubulointerstitial
fibrosis or inflammation on biopsy [45]. Another report stated that findings of mild
tubulointerstitial fibrosis were associated with a better response to steroid therapy in
granulomatous TIN [44]. The IgG4-associated TIN is characterized by good response to
corticosteroids [34].
Aside from steroid therapy, mycophenolate mofetil has been proposed as a possible treatment
option in TIN. A retrospective chart review assessing a small group of adult patients with acute
TIN showed that mycophenolate mofetil was well-tolerated and may be a useful therapy for
steroid-resistant TIN or in patients with contraindications to steroid therapy [77].
In TINU, the treatment of anterior uveitis includes topical corticosteroids and cycloplegic agents
and is effective in about 50 % of patients [53, 61, 78, 79]. However, most patients (80 %) are
treated with systemic corticosteroids because of TIN. In patients who do not respond to systemic
corticosteroids or who demonstrate ocular or systemic toxicity from these medications,
immunomodulatory agents such as methotrexate, cyclosporine A, azathioprine, and
mycophenolate mofetil have been used to treat the uveitis [53, 58, 61]. While the interstitial
nephritis in TINU may resolve, uveitis requires long-term ophthalmologic care.

Monitoring
Aside from following renal function and electrolytes, clinicians often have a difficult time
monitoring TIN, particularly in chronic cases. Serum C3 and C4 complement, IgG isotypes and
IgE levels can help identify patients with IgG4-associated immune complex mediated TIN
variants. Urinary biomarkers have been proposed as a way of identifying and prognosticating
TIN. BEN provides an example of a chronic, progressive TIN that predominantly affects the
proximal tubule and serves as a useful model for testing biomarkers [80]. Low-molecular-weight
(LMW) proteinuria is suggestive of tubulointerstitial disease and possible fibrosis [78]. Beta-2
microglobulin (B2M) and alpha-1 microglobulin (A1M) are both LMW proteins that are
normally freely filtered through the glomerulus and reabsorbed by cells in the proximal tubule
[78, 81]. When renal tubules are damaged or dysfunctional, there is increased urinary excretion
of LMW proteins. One study of urinary biomarkers in patients with BEN concluded that B2M
had higher sensitivity and specificity than A1M in differentiating healthy controls from patients
with BEN [81]. A study assessing the utility of A1M as a marker for chronic TIN showed that
increased urinary ratios of A1M/albumin or A1M/protein in a 24-hour urine collection showed
an appropriate relationship with chronic TIN, and helped to differentiate it from healthy control
subjects and those with glomerulonephritis [41]. Another study analyzed 61 urinary proteins
present in patients with BEN, and found that A1M and B2M were consistently found in larger
amounts in patients with BEN compared to healthy controls and patients with pre-renal AKI
[80]. Additionally, in comparing BEN with glomerulonephritis, elevated B2M was the most
accurate biomarker for identifying BEN as opposed to glomerulonephritis [80]. Urinary B2M has
also been proposed as a screening measure for individuals with uveitis to help detect TINU
syndrome [50]. One study revealed that when using both serum creatinine and urinary B2M
levels in patients with uveitis, there is a positive predictive value of 100 % and negative
predictive value of 97 % when assessing for associated TIN [82]. At this time, compared to other
urinary biomarkers, B2M and A1M are most commonly used for testing for tubular damage.
B2M is degraded in urine when pH falls below 6, while A1M remains stable [81]. A Finnish
study of pediatric patients with TIN showed that patients with elevated and prolonged urinary
LMW protein excretion (B2M and A1M) had an associated decrease in measured GFR when
compared to those with normal urinary LMW protein excretion [78]. Another group studying
urinary biomarkers concluded that urinary monocyte chemotactic peptide-1 (MCP-1) levels
showed a close correlation with interstitial inflammation and edema in patients with drug-
induced TIN [83]. Eventually, MCP-1 may be used to help differentiate TIN from ATN, but is
not yet commercially available. Taken together, the above studies demonstrate that measurement
of urinary LMW protein excretion may be a feasible tool to monitor progression of
tubulointerstitial disease in patients with TIN.

Chronic TIN
While some episodes of acute TIN are reversible (particularly if an offending medication is
discontinued), others may progress into chronic TIN. The likelihood is increased with systemic
inflammatory or rheumatologic diseases as well as delayed removal of the medication in drug-
induced TIN [9], including analgesic and lithium nephropathy [84]. In one retrospective study of
biopsies from adult patients with TIN, the median percentage of interstitial fibrosis was 30 % and
median glomerulosclerosis was 8 % [6], which indicate chronic change. In an Italian registry of
renal biopsies, children with CKD most frequently had chronic interstitial diseases which
included juvenile nephronophthisis, chronic TIN or reflux nephropathy [7]. Rarer causes of
chronic TIN in children include heavy metal exposure [85] and neoplasia [86, 87]. As mentioned
previously, TIN-ag is an integral component of the renal tubular basement membrane. Defects in
the tubular basement membrane observed in juvenile nephronophthisis have been associated with
abnormalities in TIN-ag synthesis which can eventually lead to renal failure [39]. Ongoing
detection of LMW proteins in the urine may be signs of ongoing renal tubulointerstitial
inflammation or fibrosis, or both, which again supports the use of these biomarkers in follow-up
of patients with TIN [78]. Chronic TIN rarely results from bacterial infections alone [88].

Prognosis
Prognosis primarily depends upon the cause of TIN, in combination with therapy for systemic
diseases, timing of therapy, previous renal function, and removal of any known offending agents.
Chronicity portends a worse outcome, and detection of fibrosis on renal biopsy is a marker of
irreversible change. Early identification of TIN can often improve renal outcomes. Prolonged
LMW proteinuria is a marker for poorer prognosis and decreased GFR [78]. In a review of adults
with TIN, 64 % made a full recovery, while 23 % had partial recovery and 13 % remained on
renal replacement therapy [3].
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Conclusion
In summary, tubulointerstitial nephritis is an under-recognized disease that often presents with
non-specific symptoms. A high clinical suspicion and particular attention to extrarenal
manifestations and thorough review of potential risk factors are needed for accurate
identification and diagnosis. It is most important to remove any potential offending agent and
treat associated systemic disease to help preserve or recover renal function. Monitoring for TIN
in patients with uveitis or IBD could be a useful tool for early diagnosis and treatment. While
there are promising urinary biomarkers to diagnose and prognosticate TIN, A1M and B2M are
most promising for clinical use. Treatment is based on underlying pathophysiology, and use of
corticosteroids remains poorly supported by clinical trials. Randomized controlled prospective
trials are needed to best assess prognosis and therapy.