CHRONIC
TUBULOINTERSTITIAL NEPHRITIS
Tubulointerstitial nephritis can be divided
into acute and chronic forms. Acute interstitial nephritis (AIN, see Plate4-28) is typically associated with more severe insults, which cause a rapid
decline in renal function and significant tubulointerstitial inflammation.
In contrast, primary chronic
tubulointerstitial nephritis (CTIN) results either from untreated AIN or more
commonly, a milder renal injury that takes a more indolent course. Instead of
inflammation, there is tubulointerstitial fibrosis and scarring, with a slow deterioration
of renal function. Although both acute and chronic forms have overlapping
causes, they can be considered separate renal diseases because of their unique
pathophysiologies.
Between 10% to 20% of cases of
end-stage renal disease (ESRD) worldwide result from primary CTIN, a number
that continues to grow as an increasing number of causes are
identified.
PATHOPHYSIOLOGY
CTIN can occur as either a primary
or secondary phenomenon. In primary CTIN, the initial injury affects the
tubulointerstitium without glomerular or vascular involvement. As the
tubulointerstitial damage progresses, however, glomerular sclerosis and
arteriolar thickening often develop. One possible mechanism to explain this
phenomenon is tubuloglomerular feedback. In tubuloglomerular feedback, tubular
damage results in decreased proximal reabsorption of electrolytes, which leads
to a high solute load at the macula densa and resultant vasoconstriction of the
afferent arteriole. This vasoconstriction causes glomerular ischemia that, if
persistent, can result in glomerulosclerosis. Another explanation of the
secondary glomerular damage seen in primary CTIN is “renal ablation
nephropathy,” a theory which speculates that glomerulosclerosis results from a
loss of renal mass caused by interstitial scarring.
In secondary CTIN, in contrast,
tubulointerstitial damage occurs in the setting of a primary glomerular or
vascular insult. The tubular disease is thought to occur because of a toxic
effect of filtered proteins on tubular cells. It is also thought that ischemia
distal to sclerotic glomeruli causes tubular injury. Once injured, these
tubular cells express adhesion molecules and elaborate cytokines and growth
factors that cause interstitial inflammation and fibrosis. Thus secondary CTIN is
a pathologic endpoint for many renal processes and is not considered a primary
renal disease.
There are numerous causes of
primary CTIN, and in general these are divided into seven major classes: toxic,
metabolic, autoimmune, infectious, neoplastic, hereditary, and miscellaneous.
Toxin-induced insults are the most common cause of CTIN, and the agents most
often implicated are analgesics, 5-ASA, lead, lithium, cadmium, and
aristolochic acid. Metabolic causes include abnormal uric acid metabolism,
hypokalemia, hypercalcemia, and hyperoxaluria. Autoimmune causes often include
Sjögren syndrome and sarcoidosis. The major infectious, neo-plastic,
hereditary, and miscellaneous causes include chronic pyelonephritis; multiple
myeloma (see Plate 4-53) and tubulointerstitial amyloidosis (see Plate 4-47);
polycystic kidney disease; and sickle cell disease, respectively.
Analgesic nephropathy is one of the
most significant causes of CTIN. It was first described in the 1950s, when a
series of 44 CTIN cases and 22 cases of papillary necrosis were found to be
associated with chronic analgesic use. At its peak, analgesic nephropathy was
estimated to cause approximately 1% of cases of ESRD in the United States and
as many as 20% of cases of ESRD in Europe and Australia.
The responsible analgesics often
included a mixture of different substances, including phenacetin, acetaminophen
(phenacetin’s major metabolite), and other agents such as NSAIDs, codeine,
aspirin, and caffeine. Although there was no direct evidence that phenacetin
was the main agent responsible for disease, multiple case series aroused enough
suspicion to cause this sub- stance to be banned in Europe in the 1970s and in
the
United States in 1983. Following
this ban, the incidence of analgesic nephropathy has been reported to have
decreased; however, variable reporting and difficulties in diagnosis have made
this hard to confirm. Moreover, experimental models and clinical case series
have illustrated the toxic potential of other analgesics, including
acetaminophen, NSAIDs, and aspirin.
Analgesic nephropathy (AN) can
serve as a model for the pathogenesis of CTIN. Although the exact mechanism
remains incompletely understood, it appears that toxic metabolites are
reabsorbed by tubular cells and accumulate. When there is an inadequate supply
of reducing agents, these metabolites cause oxidative injury. This injury is most
pronounced in the renal papilla, where blood flow and oxygen tension are low.
When analgesic combinations include an inhibitor of prostaglandin synthesis,
such as aspirin, the resulting renal vasoconstriction can predispose the
papilla to ischemia and ultimately necrosis. Although papillary necrosis is
characteristic of analgesic nephropathy it is not specific because it can also
occur in diabetes (see Plate 4-45), sickle cell anemia, urinary tract
obstruction (see Plate 6-1), and renal tuberculosis (see Plate 5-10). Indeed,
the tubular accumulation of toxic substances appears to be the major
pathogenetic mechanism by which many other substances cause CTIN. Other mechanisms,
however, may also be responsible. In chronic obstructive pyelonephritis, for
example, tubulointerstitial inflammation and scarring is caused by recurrent
infections superimposed on diffuse or localized obstructive lesions. In urate
nephropathy, deposition of monosodium urate crystals in the distal tubules and
collecting ducts induces formation of tophi, which are surrounded by foreign
body giant cells an other mononuclear cells that cause localized fibrosis.
PRESENTATION AND DIAGNOSIS
Because of its effects on glomeruli
described previously, CTIN is typically associated with a slow but progressive
decline of GFR. Early in the course of disease, however, there is mild (if any)
effect on blood pressure and minimal to absent edema on physical examination. Urinalysis
with microscopy shows no signs of inflammation and minimal proteinuria (often <1 g/day). In cases of analgesic nephropathy, patients may have flank pain
or hematuria associated with papillary necrosis. Other clinical features may be
extrarenal and reflect the underlying process.
If the tubular damage is more
advanced, patients may begin to exhibit evidence of renal tubular dysfunction,
including polyuria, renal tubular acidosis (see Plate 3-25), and even the renal
Fanconi syndrome (see Plate 4-64), which includes salt wasting, glucosuria,
aminoaciduria, phosphaturia, hypercalciuria, low molecular weight proteinuria,
and polyuria.
Imaging with renal ultrasound can
reveal evidence of cortical scarring, such as a bilateral reduction in kidney
size, irregular cortical borders, and hypoechoic segments; however, these
findings tend to occur late in the course of disease. Other imaging tests are
not routinely performed when diagnosing CTIN; however, if abdominal computed
tomography is performed, it may reveal renal papillary calcifications, which are
highly specific for analgesic-induced CTIN.
Because clinical and laboratory
findings are often ambiguous, the definitive diagnosis of CTIN often requires
renal biopsy. If there is evidence of cortical scarring on ultrasound, however,
a renal biopsy is often not performed because these patients have irreversible
kidney disease and are at higher risk for bleeding complications. If a biopsy
is performed, the major pathologic features of CTIN include atrophied, dilated
tubules with flattened epithelial cells and thickened basement membranes. The
interstitial compartment reveals fibrosis and scarring, with varying degrees of
leukocytic infiltration depending on the severity and persistence of the
disease. This infiltrate predominantly consists of lymphocytes, macrophages, or
B cells. Depending on the chronicity of renal injury, a variable degree
of glomerulosclerosis and/or arteriolar thickening may be seen.
Additional findings may be present
depending on the specific cause of disease, such as papillary necrosis in
analgesic nephropathy, distal tubular urate crystal deposition and tophi in
urate nephropathy, tubular (myeloma) casts in multiple myeloma, tubular
microcysts in lithium toxicity, and proximal tubular vacuolization in hypokalemic
nephropathy.
TREATMENT
The treatment of CTIN focuses on
identifying and addressing correctable risk factors, such as medication use,
metabolic abnormalities, and infections. Except in cases of neoplastic and
hereditary disease, renal dysfunction is often reversible if the inciting agent
is removed early enough. Patients with a significant amount of inflammation on
biopsy may be candidates for immunosuppression, although no randomized control
trials have supported its use. The two most important risk factors for
progression to end-stage renal disease are the serum creatinine concentration
at the time of diagnosis and the extent of tubulointerstitial scarring
at the time of biopsy.
