Transcript tubulointers 2014 - University of Yeditepe Faculty of Medicine, 2011

TUBULOINTERSTITIAL
DISEASE
Prof Dr.Gülçin Kantarcı
Yeditepe University Nephrology
Department
Aims & objectives


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State the definition of tubulointerstitial disease.
Identify clinical signs of tubulointerstitial disease.
Explain the pathophysiology of tubulointerstitial
disease.
Tubulointerstitial Nephrithis
The tubulointerstitial compartment is affected in all
the forms of renal disease. We can find the
pathology as tubular damage, tubular atrophy,
edema, interstitial inflammation or fibrosis.
Acute interstitial or tubular damage can produce
acute renal failure,
Chronic changes are a good indicator of
irreversible lesions primary injury to renal tubules
and interstitium resulting decreased renal function.
Acute Tubulointerstitial Nephrithis
The acute form is most often due
to allergic drug reactions or to
infections.
Diagnosis of ATIN
suggested by history and urine and blood tests and
confirmed by biopsy.
 Exclusion of glomerular disease
 Urinalysis: proteinuria<1 g/day (Proteinuria is usually
minimal but may reach nephrotic range with
combined ATIN-glomerular disease induced by
NSAIDs)
 WBC casts and granular casts
 Eosinophiluria
 Low molecular weight proteinuria (LMW-P)
( B2 micglobulin, Tamm-Horsfall gylcoprotein)

Tamm-Horsfall gylcoprotein
The most abundant protein of renal origin
 Synthesized by cells of the thick ascending limb of
the loop of Henle
 Excreted in the urine at a relatively constant rate
 Urinary excretion can increase following injury to
the distal tubule

Diagnosis of ATIN
Eosinophiluria has a positive predictive value of
50% and a negative predictive value of 90% for
ATIN; absence significantly excludes disease.
Blood test findings of tubular dysfunction include;
 hyperkalemia (defect in K excretion)
 metabolic acidosis (defect in acid excretion)

Ultrasound findings: The kidneys may be greatly
enlarged and echogenic by examination because of
interstitial inflammatory cells and edema.
Renal biopsy
not often performed for diagnostic purposes but
has helped characterize the nature and
progression of tubulointerstitial disease.
 Glomeruli are usually normal. The earliest finding is
interstitial edema, typically followed by interstitial
infiltration with lymphocytes, plasma cells,
eosinophils, and a few PMNs.
 The presence of granulomas suggests
sarcoidosis.

Acute Tubulointerstitial Nephritis
Acute tubulointerstitial nephritis (ATIN)

associated with an inflammatory infiltrate and
edema involving the renal interstitium (days to
months).
Over 95% of cases result from infection or an
allergic drug reaction;
 a syndrome of ATIN associated with uveitis
(renal-ocular syndrome-TINU) also occurs and
is idiopathic.

causes Acute Kidney Injury (AKI)
 severe cases, delayed therapy, or
continuance of an offending drug can lead
to permanent injury with Chronic Renal
Failure (CRF)

Symptoms and signs of ATIN
Fever
 urticarial rash

Onset may be as long as several weeks after a
1st toxic exposure or as soon as 3 to 5 days
after a 2nd exposure;
 extremes in latency range from 1 day with
rifampin to 18 mo with an NSAID.

Symptoms and signs of ATIN
• Abdominal pain, weight loss, and bilateral renal
masses (caused by interstitial edema) may also
occur and with fever may mistakenly suggest
renal malignancy or polycystic kidney disease.
• Many patients develop polyuria and nocturia
(defect in concentration and Na reabsorption).
• Peripheral edema and hypertension are
uncommon unless renal insufficiency or renal
failure occurs
Maculopapular rash in a patient with drug–induced acute interstitial nephritis
On light microscopy, interstitial infiltration with mononuclear cells, with normal glomeruli.
It is usually associated with interstitial edema, and with tubular lesions
prognosis

vary by the etiology and potential
reversibility of the disorder at the time of
diagnosis.
Prognosis
In drug-induced ATIN, renal function
usually recovers within 6 to 8 wk when the
offending drug is withdrawn, although
some residual scarring is common.
 Recovery may be incomplete, with
persistent azotemia above baseline
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histologic changes usually are reversible if
the cause is recognized and removed;
however, some severe cases progress to
fibrosis and renal failure.
Regardless of cause, diffuse rather than
patchy interstitial infiltrates, delayed
response to prednisone , and persistent acute
renal failure (> 3 wk) suggest irreversible
injury.
Chronic tubulointerstitial nephritis
The CTIN is irreversible and rather than allergic
condition, it is associated with
 genetic
metabolic
obstructive uropathy
chronic environmental toxins
drugs and herbs.
Chronic tubulointerstitial nephritis
(CTIN)
chronic tubular insults cause gradual
interstitial infiltration and fibrosis, tubular
atrophy and dysfunction, and a gradual
deterioration of renal function, usually over
years.
 Glomerular involvement (glomerulosclerosis)
is much more common in CTIN than in ATIN.

Causes of CTIN
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infections,
reflux or obstructive nephropathy,
drugs, and
other diseases.
toxins,
metabolic diseases,
hypertension
inherited disorders results in symmetric and
bilateral disease;
Diagnosis of CTIN

Findings of CTIN are generally similar to
those of ATIN, though urinary RBCs and
WBCs are uncommon. Because CTIN is
insidious in onset and is associated with
interstitial fibrosis, imaging tests may show
small kidneys with evidence of scarring
and asymmetry.
Pathogenesis of tubulointerstitial
fibrosis
Injury to the tubule and
peritubular capillary
leads to the

generation of
chemotactic and
adhesive factors that
result in macrophage
and T–cell
accumulation.

Local macrophage and
fibroblast activation ensues,
driven by growth factors
such as PDGF(platelet–
derived growth factor) and
TGF-β (transforming growth
factor- β), which results in
collagen production by
tubular cells and
fibroblasts,eventually
culminating in the fibrotic
lesion.
Renal biyopsy
In CTIN, glomeruli vary
from normal to
completely destroyed.
 The interstitium contains
varying degrees of
inflammatory cells and
fibrosis.

Tubular atrophy
Tubules may be
absent or atrophied
 Nonscarred areas
appear almost
normal. Grossly, the
kidneys are small
and atrophic


Tubular casts. Casts are
periodic acid–Schiff stain
(PAS) positive and usually
contain Tamm–Horsfall
protein. Some may contain
desquamated tubular cells
and macrophages.
(Periodic acid–Schiff
×400).
An intravenous urogram of a patient with
analgesic nephropathy

The pyelogram shows
evidence of a necrotic
papilla in the lateral
minor calyx producing a
'ring' sign
Prognosis of CTIN


depends on the cause and on the ability to
recognize and stop the process before
irreversible fibrosis occurs.
Many genetic (cystic kidney disease), metabolic
(cystinosis), and toxic (heavy metal) causes may
not be modifiable, in which case CTIN usually
evolves to end-stage renal disease
ANALGESIC ABUSE NEPHROPATHY
Analgesic abuse nephropathy (AAN) is CTIN
caused by cumulative lifetime use of large
amounts (eg, ≥ 2 kg) of certain analgesics.
 AAN predominates in women (peak incidence,
50 to 55 yr) and, in the US, is responsible for
3 to 5% of cases of end-stage renal disease
(13 to 20% in Australia and South Africa).


AAN was originally described in conjunction
with overuse of combination analgesics
containing phenacetin (typically with aspirin,
acetaminophen, codeine, or caffeine).
Patients present with;
renal insufficiency,
 a bland urinary sediment,
 non-nephrotic proteinuria.

Hypertension and
 impaired urinary concentration are
common.

Flank pain and hematuria are signs of
papillary necrosis that occur late in the
course of disease.
 Chronic complaints of musculoskeletal
pain, headache, malaise, and dyspepsia
may be precipitants of long-term
analgesic use rather than effects of AAN.
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Renal function stabilizes when analgesics are
stopped unless renal insufficiency is advanced,
in which case it may progress to renal failure.
Patients with AAN are at greater risk of
transitional cell carcinomas of the urinary tract.
METABOLIC NEPHROPATHIES
Acute urate nephropathy: This is not a true form
of ATIN but rather an intraluminal obstructive
uropathy caused by uric acid crystal
deposition within the lumen of renal tubules;
acute oliguric or anuric renal failure results.
 It most commonly occurs from tumor lysis
syndrome
Chronic urate nephropathy: This condition is
CTIN caused by deposition of Na urate
crystals in the medullary interstitium in the
setting of chronic hyperuricemia.
 Chronic urate nephropathy was once
common in patients with tophaceous gout
but is now rare because of treatment
Hyperoxaluria
a cause of both acute and chronic
tubulointerstitial nephritis.
 ATIN and AKI may develop in
susceptible patients who ingest highoxalate foods (eg, tea, chocolate,
spinach, star fruit) or who are exposed
to exogenous substances that are
metabolized into oxalate (eg, ethylene
glycol ingestion, methoxyflurane
anesthesia, large doses of ascorbic
acid).
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CTIN and progressive chronic renal
failure develop in patients with inherited
disorders of excessive oxalate
production (types I and II primary
hyperoxaluria) or acquired GI diseases
(eg, short bowel syndrome with
increased gut absorption).
Symptoms and signs
Differ by form of disease and include;
 hematuria
 renal colic from oxalate calculi,
 UTI and pyuria,
 hypertension,
 renal tubular acidosis
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HEAVY METAL NEPHROPATHY
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Lead: accumulates in proximal tubular cells.
Chronic lead exposure (5 to 30 yr) causes
progressive tubular atrophy, interstitial fibrosis,
hypertension, and gout.
Chronic low-level exposure may cause renal
insufficiency and hypertension independent of
tubulointerstitial disease.
Children exposed to lead paint dust or chips,
battery workers, and drinkers of moonshine alcohol
are most at risk.
Diagnosis

usually made by whole blood lead levels.
Alternatively, x-ray fluorescence
HEAVY METAL NEPHROPATHY
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
-
Cadmium: Cadmium from contaminated water,
food, and tobacco and from workplace
exposures can cause nephropathy.
Diagnosis
a history of occupational exposure,
increased levels of urinary β2-microglobulin,
increased urinary cadmium levels (> 7 μg/g
creatinine).
HEAVY METAL NEPHROPATHY
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Other heavy metals: Those that are nephrotoxic
include copper, gold, uranium, arsenic, iron, mercury,
bismuth, and chromium.
All cause tubular damage and dysfunction but
glomerulopathies may predominate with some
compounds (mercury, gold).
Treatment involves removal of the patient from
further exposure and chelating agents (copper,
arsenic, bismuth) or dialysis (chromium, arsenic,
bismuth).
REFLUX NEPHROPATHY
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Reflux nephropathy is renal scarring induced by
vesicoureteral reflux of infected urine into the renal
parenchyma.
Chronic pyelonephritis also may play a role, but
UTI without intrarenal reflux is unlikely to cause
nephropathy.
Vesicoureteral reflux (VUR)


VUR affects about 1% of newborns and 30 to 45%
of young children with a UTI
Few symptoms and signs are present in young
children, and the diagnosis is often overlooked until
adolescence, when patients present with
proteinuria, hypertension, and/or renal
insufficiency.
Diagnosis of VUR
voiding cystourethrogram (VCUG),
 radionuclide cystography
 (DMSA) 99m-technetium dimercaptosuccinic
acid (Renal scarring is diagnosed with radionuclide

scanning or with IVU, which is less sensitive)
voiding cystourethrogram (VCUG),
MYELOMA-RELATED KIDNEY DISEASE
Patients with multiple myeloma overproduce
monoclonal Ig light chains (Bence Jones
proteins); these light chains are filtered by
glomeruli, are nephrotoxic, and can damage
virtually all areas of the kidney parenchyma.
 The mechanisms of nephrotoxicity are
unknown. Tubulointerstitial and glomerular
damage are most common.

MYELOMA-RELATED KIDNEY DISEASE
Tubulointerstitial disease: Light chains saturate the
reabsorptive capacity of the proximal tubule, reach
the distal nephron, and combine with filtered proteins
and Tamm-Horsfall mucoprotein (secreted by the thick
ascending limb cells) to form obstructive casts.
Factors that predispose to cast formation:
 low urine flow,
 elevation of luminal NaCl concentration (eg, due to
a loop diuretic),
 radiocontrast agents,
 increased intratubular Ca (hypercalcemia frequently
occurring from bone lysis)
MYELOMA-RELATED KIDNEY DISEASE

Other types of tubulointerstitial lesions
associated with Bence Jones proteinuria include
proximal tubular transport dysfunction
producing Fanconi syndrome and light chain
interstitial deposition with inflammatory
infiltrates and active tubular damage.
Suggested readings:
•Current Medical Diagnosis and Treatment, Maxine A. Papadakis,
Stephen J. McPhee, Eds. Michael W. Rabow, Associate Ed.
•Andreoli and Carpenter's Cecil Essentials of Medicine 8th edition,
Andreoli and Carpenter, Elsevier
PART 11: RENAL AND GENITOURINARY DISEASES 123
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