Article Update

Wednesday, June 24, 2020


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.

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.

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.

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.

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