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  • Kidney size is small and contracted.

  • Decreased urinary concentrating ability.

  • Hyperchloremic metabolic acidosis.

  • Reduced GFR.


The most common cause of chronic tubulointerstitial disease is obstructive uropathy, which may result from prolonged or recurrent obstruction. The major causes are prostate disease in men; ureteral calculus in a single functioning kidney; bilateral ureteral calculi; carcinoma of the cervix, colon, or bladder; and retroperitoneal tumors or fibrosis.

Reflux nephropathy from vesicoureteral reflux is primarily a disorder of childhood and occurs when urine passes retrograde from the bladder to the kidneys during voiding. It is the second most common cause of chronic tubulointerstitial disease. It occurs as a result of an incompetent vesicoureteral sphincter. Urine can extravasate into the interstitium, triggering an inflammatory response that leads to fibrosis over time. The inflammatory response is due to either bacteria or normal urinary components.

Analgesic nephropathy is most commonly seen in patients who ingest large quantities of pain medication. The drugs of concern are phenacetin, paracetamol, aspirin, and other NSAIDs; acetaminophen is a possible but less certain culprit. Ingestion of at least 1 g/day for 3 years of these analgesics is considered necessary for kidney dysfunction to develop, and most patients grossly underestimate their analgesic use. This disorder occurs most frequently in individuals who are using analgesics for chronic headaches, muscular pains, and arthritis; female sex, older age, and malnutrition are risk factors for analgesic nephropathy. Tubulointerstitial inflammation and papillary necrosis are seen on pathologic examination. Papillary tip and inner medullary concentrations of some analgesics are tenfold higher than in the renal cortex. Phenacetin was once a common cause of this disorder but is now rarely available. It is metabolized in the papillae by the prostaglandin hydroperoxidase pathway to reactive intermediates that bind covalently to interstitial cell macromolecules, causing necrosis. Aspirin and other NSAIDs can cause damage through intermediate metabolites, which can lead to cell necrosis. These drugs also decrease medullary blood flow (via inhibition of prostaglandin synthesis) and decrease glutathione levels, which are necessary for detoxification.

Environmental exposure to heavy metals—such as lead, cadmium, mercury, and bismuth—occurs infrequently now in the United States but can cause tubulointerstitial disease. Individuals at risk for lead-induced tubulointerstitial disease are those with occupational exposure (eg, welders who work with lead-based paint) and drinkers of alcohol distilled in automobile radiators (“moonshine” whiskey users). Lead is filtered by the glomerulus and is transported across the proximal convoluted tubule, where it accumulates and causes cell damage. Fibrosed arterioles and cortical scarring also lead to damaged kidneys.

A form of chronic tubulointerstitial disease disproportionately affecting male agricultural workers in Central America is an important cause of ESKD. While the exact pathophysiology is still unknown, the term Mesoamerican nephropathy is applied to reflect the geographic region in which this disease occurs. Affected individuals tend to be 30–50 years of age without diabetes, hypertension, or ...

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