A PowerPoint presentation for the pediatric residents and pediatric nephrology fellows

1. S L I D E 0
Tubulo-interstitial Nephritis
Ibrahim Sandokji

2. S L I D E 1
Questions
Which of the following is true regarding drug-induced ATIN?
a. ATIN secondary to NSAIDs can present as nephrotic syndrome.
b. The triad of fever, rash, and arthralgia is present in the majority
of patients with drug-induced ATIN.
c. Eosinophiluria is pathognomonic for ATIN.
d. Renal injury always develops soon after starting the offending
drug.
e. Drug-induced ATIN is dose-dependent.

3. S L I D E 2
Questions
A 5-year-old girl presents with fever, fatigue, and abdominal pain
and is admitted to the hospital because of AKI with a creatinine
value of 1.3. According to history obtained, she had been taking
amoxicillin for 4 days for strep throat. Her physical examination is
normal; her urinalysis reveals a specific gravity of 1.009, negative
findings for blood and protein, 10 to 20 white blood cells, and no
casts. You suspect ATIN secondary to amoxicillin. Which of the
following is the next best step in her management?
a. Schedule her for a renal biopsy.
b. Discontinue amoxicillin and follow creatinine trend.
c. Administer pulse corticosteroids followed by oral prednisone.
d. Check eosinophils in the urine, if negative, continue workup
looking for other causes of AKI.
e. Change amoxicillin to a cephalosporin.

4. S L I D E 3
Questions
A 10-year-old boy presents with nonoliguric AKI. He has a renal
biopsy performed that shows severe interstitial inflammation with
predominant mononuclear cell infiltrate and no granulomas;
immunofluorescence is negative. There is no history of medication
use or evidence of any viral or bacterial infection. The patient
receives corticosteroids and his renal function returns to normal.
Regarding further evaluation and follow-up, which of the following
is the most accurate statement?
a. He will need follow-up with a nephrologist for at least 1 year.
b. He can follow up with his primary care physician for yearly
checkups only and does not need specialty care.
c. He needs an ophthalmology evaluation now, in addition to
follow-up with a nephrologist.
d. He needs follow-up with a rheumatologist because of the
possibility of underlying autoimmune disease.

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Content Specifications

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Definition and Classifications
• TIN is characterized by inflammatory infiltrate, edema, and fibrosis
affecting renal tubules and the interstitium.
Classification
Primary TIN
Inflammation starts in tubules & interstitium
Secondary TIN
Inflammation starts in glomeruli & vessels
The clinical spectrum of tubulointerstitial nephritis. Rastegar (1998) Kidney International

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Classification
Clinicopathologically
Acute TIN
Acute inflammatory cell-
mediated
Rapid decline in renal
function
Chronic TIN
Protracted onset
Slow decline in renal
function

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ATIN
• Epidemiology
– It accounts for 8% to 27% of the reported cases of acute kidney injury
(AKI) in adults and up to 7% in children
• Etiology
Singh AK, Colvin RB. N Engl J Med 2003;349:2055-2063.

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Etiologic Classification of ATIN
Kher et al (2016). Clinical Pediatric Nephrology, 3rd Edition

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Kher et al (2016). Clinical Pediatric Nephrology, 3rd Edition
Drugs-induced ATIN
• Most commonly
– Penicillins
– NSAIDs
– Rifampin
– Sulfonamide

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Pathophysiology
Kher et al (2016). Clinical Pediatric Nephrology, 3rd Edition

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Kher et al (2016). Clinical Pediatric Nephrology, 3rd Edition

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Low power view of severe acute interstitial nephritis
showing diffuse interstitial inflammatory infiltrate
Inflammatory process predominantly in the interstitium.
Insert shows a higher magnification, with arrows
pointing to eosinophils in the interstitium
Pathology

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Pathology
Light microscopy showing acute interstitial
inflammatory infiltrate consisting of mononuclear
cells in a patient with acute interstitial nephritis.
The patient presented with acute kidney injury
and proteinuria.
Inflammatory cell infiltration into +the tubules
resulting in tubulitis
Kher et al (2016). Clinical Pediatric Nephrology, 3rd Edition

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Pathology

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Pathology
Granuloma in the renal interstitium in a patient
with sarcoidosis
Kher et al (2016). Clinical Pediatric
Nephrology

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Pathology
Immunofluorescence
Classification
Pauciimmune
No antibodies or
immune deposits
Immune complex
deposits
Granular deposits
along the basement
membrane
Anti–TBM disease
Linear
immunofluorescence
staining for IgG and
complement along the
TBM

18. S L I D E 17
Pathology
• Immune complex deposits present along the basement membrane
Immunofluorescence microscopy showing intense staining of the
tubular basement membranes (TBMs) and Bowman capsule with
IgG in a finely granular pattern. The glomerular tufts (G) are
negative for immunofluorescence staining. Inset shows the TBMs
with finely granular staining pattern at 400x magnification.

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Pathology
• Anti–tubular basement membrane disease
– Linear immunofluorescence staining for IgG and complement along the TBM
Immunofluorescence microscopy showing linear immunoglobulin
G deposits in a patient with acute interstitial nephritis

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Clinical Features of ATIN
• Usually present with rise in sCr and non-specific symptoms
• Nausea, vomiting, malaise, back/flank pain, or asymptomatic
• Allergic-type symptoms like fevers, rash, peripheral eosinophilia
• 30% to 40% of patients with ATIN have nonoliguric AKI
• Classic triad of fever, arthralgia, and rash occurs only in <10%
• Tubular dysfunction and even Fanconi syndrome
• In drug-induced ATIN, renal manifestations develop on average 10
days after starting the medication; however, they can occur as early
as one day and as late as months after the inciting medication is
started

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Laboratory Findings in ATIN
• Urinalysis
– Hematuria (micro/macro)
– Proteinuria (UPC usually <1)
– Sterile pyuria
– White blood cell casts
– Eosinophiluria
– Or bland urine
• Blood tests
– Increased creatinine
– Tubular defects
• Proximal: proximal RTA, Fanconi syndrome
• Distal: hyperkalemia, Na wasting, distal RTA
• Medullary: concentration defect
– Eosinophilia
– Increased ESR

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• Urinary biomarkers:
– Monocyte chemotactic pep-tide-1 (MCP-1) might correlate with
interstitial edema and inflammatory infiltration
– N-acetyl-β-D-glucosaminidase (NAG) might correlate with more rapid
progression of renal dysfunction in patients with CTIN
– Ongoing studies for novel biomarkers

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White Blood Cell Casts Red Blood Cell Casts
Hyaline Casts Muddy Brown Granular Casts
Waxy Casts
Fatty Casts

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Eosinophiluria
• It is neither sensitive nor specific
• Seen only in ~20-60% of patients
• Present in UTIs, ATN and RPGN
Unstained urine sediment showing
leukocyturia (▴) with cellular casts (↑)
Hansel's stain of urine sediment showing both
free eosinophils (▴) and eosinophils in casts (↑)

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Renal US in ATIN
Diffusely enlarged, echogenic kidney in a patient with acute interstitial nephritis. However, the appearances are
nonspecific and are similar to those seen in several other acute disorders of the renal parenchyma

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Treatment
• Discontinuation of offending agent
• Supportive therapy
• Rarely might need a biopsy if:
– Unclear diagnosis
– When considering steroid therapy
– Or, if started steroids but no response in one week

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Corticosteroids Therapy
• Corticosteroids are the mainstay of treatment
• Although
– No randomized, controlled, prospective studies
– Conflicting studies, some revealed no benefit with corticosteroids and
others showed improvement of serum creatinine and decreased need
for dialysis
• A retrospective study of 60 adults with ATIN 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
Clarkson et al, Nephrol Dial Transplant (2004)

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Corticosteroids Therapy
– A prospective pediatric study showed that corticosteroids sped up
recovery of TIN (especially in patients with severe nephritis). But the
renal function did not differ significantly at 6-month follow-up.
– They suggested that because TIN may be self-limited, treatment may
be delayed by two weeks in uncomplicated cases
(a) Plasma creatinine (PCr) concentration and (b) urine low molecular weight (LMW) protein/creatinine
ratio at baseline and during follow-up visits in the non-treatment group (circles), in the low creatinine
group (squares), and in the high creatinine group (diamonds).
Jahnukainen et al, Pediatr Nephrol (2013)

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Corticosteroids Therapy
• Corticosteroids use is primarily guided by underlying
pathophysiology and severity of kidney damage
– Drug-induced TIN with mild AKI may recover spontaneously, so a trial
of drug cessation can be done first
– Severe AKI or systemic rheumatologic and inflammatory conditions
associated with TIN are usually treated with corticosteroids

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Mycophenolate mofetil (MMF)
• Mycophenolate mofetil (MMF) has been used in few case reports
and small studies when corticosteroids alone were not effective
– A retrospective study of eight adults with steroid-resistant, biopsy-
proven AIN, treated with MMF
– Mean decline in serum creatinine from 2.3 to 1.6 mg/dl over a mean of
24.3 mo of treatment.
Preddie et al. Clin J Am Soc Nephrol (2006)

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Chronic TIN
• Slowly progressive
• Renal tubular atrophy and
interstitial fibrosis
• Thickened and wrinkled TBM
• Glomeruli often show ischemic
changes with shrinking of the
glomerular tuft and wrinkling of
the Bowman capsule
• Eventually, leading to small and
shrunken kidneys with prominent
parenchymal scarring and
pelvicalyceal dilatation.
Glomerulus in a patient with chronic tubulointerstitial
nephritis showing periglomerular fibrosis and ischemic
glomeruli with collapsed capillary lumens.
Kher et al (2016). Clinical Pediatric Nephrology, 3rd Edition

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Etiology

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Clinical Features
• Asymptomatic proteinuria, or first presentation of CKD
• Nonspecific symptoms:
– Weight loss, growth failure, fatigue, anorexia, vomiting, and
polyuria/polydipsia
• Laboratory evaluation:
– Elevated serum creatinine
– Signs of tubular dysfunction
• Renal ultrasound
– Small, hyperechogenic kidneys
• A kidney biopsy is often needed to confirm the diagnosis

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Treatment
• Discontinuation of offending agent
• Supportive therapy
• No evidence of corticosteroids or immunosuppressive therpaies

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Tubulointerstitial Nephritis & Uveitis (TINU) syndrome
• The pathogenesis is unknown, but evidence suggests
– Autoantigen to modified C-reactive protein (mCRP)
– Delayed-type hypersensitivity
• Presentation
– Bilateral anterior uveitis (ocular pain, redness, photophobia, itching,
and visual impairment)
– Present before, simultaneous with, or up to several months after renal
disease
– Asymptomatic in ~50% of patients
• Laboratory findings
– Markedly elevated ESR +/- autoantibodies (ANA, RF & c-ANCA)
• Treatment
– Early referral to an ophthalmologist
– Uveitis requires topical or systemic corticosteroids
– Recurrences and relapses of uveitis are common

36. S L I D E 35
Questions
Which of the following is true regarding drug-induced ATIN?
a. ATIN secondary to NSAIDs can present as nephrotic syndrome.
b. The triad of fever, rash, and arthralgia is present in the majority
of patients with drug-induced ATIN.
c. Eosinophiluria is pathognomonic for ATIN.
d. Renal injury always develops soon after starting the offending
drug.
e. Drug-induced ATIN is dose-dependent.

37. S L I D E 36
Questions
A 5-year-old girl presents with fever, fatigue, and abdominal pain
and is admitted to the hospital because of AKI with a creatinine
value of 1.3. According to history obtained, she had been taking
amoxicillin for 4 days for strep throat. Her physical examination is
normal; her urinalysis reveals a specific gravity of 1.009, negative
findings for blood and protein, 10 to 20 white blood cells, and no
casts. You suspect ATIN secondary to amoxicillin. Which of the
following is the next best step in her management?
a. Schedule her for a renal biopsy.
b. Discontinue amoxicillin and follow creatinine trend.
c. Administer pulse corticosteroids followed by oral prednisone.
d. Check eosinophils in the urine, if negative, continue workup
looking for other causes of AKI.
e. Change amoxicillin to a cephalosporin.

38. S L I D E 37
Questions
A 10-year-old boy presents with nonoliguric AKI. He has a renal
biopsy performed that shows severe interstitial inflammation with
predominant mononuclear cell infiltrate and no granulomas;
immunofluorescence is negative. There is no history of medication
use or evidence of any viral or bacterial infection. The patient
receives corticosteroids and his renal function returns to normal.
Regarding further evaluation and follow-up, which of the following
is the most accurate statement?
a. He will need follow-up with a nephrologist for at least 1 year.
b. He can follow up with his primary care physician for yearly
checkups only and does not need specialty care.
c. He needs an ophthalmology evaluation now, in addition to
follow-up with a nephrologist.
d. He needs follow-up with a rheumatologist because of the
possibility of underlying autoimmune disease.

39. S L I D E 38
Thank you