Tubulointerstitial Diseases, Chronic

Essentials of Diagnosis

• Kidney size is small and contracted

• Decreased urinary concentrating ability

• Hyperchloremic metabolic acidosis

• Reduced glomerular filtration rate (GFR)

General Considerations

• Obstructive uropathy may result from prolonged or recurrent obstruction; causes of obstructive uropathy include

  • Prostate disease in men

  • Ureteral calculus in a single functioning kidney

  • Bilateral ureteral calculi

  • Carcinoma of the cervix, colon, or bladder

  • Retroperitoneal tumors or fibrosis

• Reflux nephropathy from vesicoureteral reflux

  • Second most common cause of chronic tubulointerstitial disease

  • Occurs when urine passes retrograde from the bladder to the kidneys during voiding

  • 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

  • Most commonly seen in patients who ingest large quantities of pain medications

  • Medications of concern are phenacetin, paracetamol, aspirin, and other nonsteroidal anti-inflammatory drugs (NSAIDs); acetaminophen is a possible but less certain culprit

• Heavy metals

  • Environmental exposure to lead, cadmium, mercury, and bismuth can cause tubulointerstitial disease but occurs infrequently in the United States

  • 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)

• Mesoamerican nephropathy

  • A form of chronic tubulointerstitial disease disproportionately affecting male agricultural workers in Central America is increasingly recognized as an important cause of end-stage renal disease (ESRD)

  • Exact pathophysiology is still unknown

  • Affected individuals tend to be age 30–50 years without diabetes mellitus, hypertension or other causes of kidney disease who work under hot conditions, particularly in sugar cane or cotton fields, and thus are susceptible to dehydration

Symptoms and Signs

• Polyuria is common in chronic tubulointerstitial disease because tubular damage leads to nephrogenic diabetes insipidus, possibly from vasopressin insensitivity

• Volume depletion can occur as a result of a salt-wasting nephropathy in some individuals

• Obstructive uropathy

  • In partial obstruction, patients can exhibit

    • Polyuria (from tubular damage) or

    • Oliguria (due to decreased GFR)

  • Azotemia and hypertension (due to increased renin-angiotensin production) are usually present

• Vesicoureteral reflux

  • Hypertension

  • Substantial proteinuria

• Analgesics

  • Hematuria

  • Mild proteinuria

  • Polyuria (from tubular damage)

  • Anemia (from gastrointestinal bleeding or erythropoietin deficiency)

  • Sterile pyuria

• Heavy metals

  • Decreased secretion of uric acid, resulting in hyperuricemia and saturnine gout

  • Hypertension

  • The proximal tubular dysfunction from cadmium can cause hypercalciuria and nephrolithiasis

• Mesoamerican nephropathy

  • Affected individuals tend to be 30–50 years of age without diabetes, hypertension or other causes of kidney disease who work under hot conditions, particularly in sugar cane or cotton fields, and thus are susceptible to dehydration

• Obstructive uropathy

  • Abdominal, rectal, and genitourinary examinations are helpful

  • Urinalysis can show hematuria, pyuria, and bacteriuria but is often bland

  • Abdominal ultrasound may detect mass lesions, hydroureter, and hydronephrosis

  • CT scanning and MRI provide more detailed information

• Vesicoureteral reflux

  • Can be detected before birth via screening fetal ultrasonography

  • After birth, a voiding cystourethrogram can be done

  • Renal ultrasound or intravenous pyelogram (IVP) can show renal scarring and hydronephrosis in adolescents and young adults

  • Can develop after kidney transplantation

  • IVP is relatively contraindicated in patients with kidney dysfunction who are at higher risk for contrast nephropathy

  • On kidney biopsy, focal glomerulosclerosis can be seen in those with kidney damage

• Analgesics

  • An IVP may be helpful

  • However, IVP is rarely used in patients with significant kidney dysfunction, given the need for dye and associated risk of acute kidney injury

• Heavy metals

  • Calcium disodium edetate (EDTA) chelation test is most reliable for diagnosis

  • Urinary excretion of > 600 mg of lead in 24 hours following 1 g of EDTA indicates excessive lead exposure

• Mesoamerican nephropathy

  • In addition to low grade proteinuria, hyperuricemia and hypokalemia are consistently (but not universally) identified

  • On kidney biopsy, chronic tubulointerstitial injury may be accompanied by areas of glomerular ischemia despite very mild vascular changes

• Treatment depends on identifying the underlying disorder

• The degree of interstitial fibrosis that has developed helps predict recovery of kidney function

• Once there is evidence for loss of parenchyma (small shrunken kidneys or interstitial fibrosis on biopsy), little can prevent the progression toward ESRD

• Treatment is then directed at medical management

• Tubular dysfunction may require

  • Potassium and phosphorus restriction

  • Sodium, calcium, or bicarbonate supplementation

• If hydronephrosis is present, relief of obstruction should be accomplished promptly; prolonged obstruction leads to further tubular damage—particularly in the distal nephron—which may be irreversible despite relief of obstruction

• Neither surgical correction of reflux nor antibiotic therapy can prevent deterioration toward ESRD once renal scarring has occurred

• Patients with suspected lead nephropathy should continue EDTA chelation therapy if there is no evidence of irreversible renal damage (eg, renal scarring or small kidneys)

• Analgesic nephropathy

  • Requires withdrawal of all analgesics

  • Stabilization or improvement of kidney function may occur if significant interstitial fibrosis is not present

  • Ensuring volume repletion during exposure to analgesics may also have some beneficial effects

• Mesoamerican nephropathy

  • Patients should be counseled to remain adequately hydrated and, if possible, to minimize heat exposure

  • NSAIDs should be avoided due to their hemodynamic effects (reduced renal blood flow and glomerular filtration), which may exacerbate renal injury in states of volume depletion and hot climates

When to Refer

• Patients with stage 3–5 CKD should be referred to a nephrologist when tubulointerstitial diseases are suspected. Other select cases of stage 1–2 CKD should also be referred.

• Patients with urologic abnormalities (eg, reflux) should be referred to a urologist