Tubulointerstitial diseases are a group of renal disorders characterized by primary abnormalities in the renal tubules or interstitium. There are four principal causes: infectious, toxic, metabolic, and immunologic.
The morphologic changes in tubulointerstitial disease include the following.
Acute pyelonephritis is extremely common—1more so in females than in males (10:1). Acute pyelonephritis occurs at all ages, with highest frequency during early sexual activity and during pregnancy.
Acute pyelonephritis is a bacterial infection, usually ascending from the lower urinary tract. Ascent of infection from the bladder is facilitated when vesicoureteral reflux is present. This is more important in children but occurs also in adults. Bacteria spread from the renal pelvis to the tubules by intrarenal reflux. Reflux from the pelvis into the tubules is common: Over 60% of normal kidneys have reflux into at least one papilla. Hematogenous infection of the kidney is uncommon. Factors important in etiology are as follows (Figure 49-1):
Etiologic factors associated with acute pyelonephritis.
A short urethra, as in females.
Stasis of urine from any cause. The high incidence of urinary infections during pregnancy is believed to be the result of increased serum levels of progesterone, which decreases activity of the urinary tract smooth muscle, promoting stasis of urine.
Structural abnormalities in the urinary tract that promote stasis of urine or establish a communication between the urinary tract and an infected site, such as fistulous tracts between the urinary tract and intestine, skin, or vagina.
Vesicoureteral reflux of urine. Fifty percent of infants and young children with pyelonephritis show evidence of reflux, which is often familial and is due to an abnormality in the way the ureters enter the bladder.
Catheterization of the bladder. Strict aseptic precautions must be taken, and even then an indwelling urinary catheter is almost invariably associated with infection.
Seventy-five percent of cases of acute pyelo-nephritis are caused by Escherichia coli. When infections occur secondary to obstruction or catheterization, other organisms occur more often: Klebsiella, Proteus, Enterococcus faecalis, and Pseudomonas aeruginosa.
Postpubertal females have a significant incidence (5%) of asymptomatic bacteriuria (usually E coli), increasing to nearly 20% in pregnancy. The relationship of asymptomatic bacteriuria to acute pyelo-nephritis is not clearly established.
Grossly, acute pyelonephritis may be unilateral or bilateral. The kidney is enlarged and shows areas of suppuration (abscesses) in the cortex with radial yellow streaks traversing the medulla (Figure 49-2). The renal pelvis is erythematous and frequently covered with exudate. Extension to the perinephric space with formation of a perinephric abscess is not uncommon.
Acute pyelonephritis, showing diffuse hyperemia of the parenchyma and opened renal pelvis and multiple radially oriented suppurative streaks.
Microscopically, there is an acute suppurative inflammation beginning in the renal tubules, which show infiltration by neutrophils and hyperemia (Figure 49-3). Liquefactive necrosis of the tubules (suppuration) follows. Involvement is characteristically patchy.
Acute pyelonephritis, showing replacement of renal tubules by acute inflammatory cells in the large part of the picture. An exudate with neutrophils is present in the lumens of some of the residual tubules.
Onset is with high fever, chills, rigors, and flank pain. Dysuria and increased frequency are present in most cases.
The urine shows mild proteinuria, with neutrophils, white cell casts, and bacteria in the sediment. The diagnosis is made by quantitative urine culture (colony count). A positive culture with over 100,000 organisms/mL is diagnostic.
Treatment with antibiotics is effective. In an uncomplicated case, an antibiotic is selected that has activity against E coli (eg, ampicillin or trimethoprim-sulfamethoxazole). When culture and antibiotic sensitivity results are available, the antibiotic may be changed accordingly.
The prognosis is excellent. Most patients recover completely, and there are no long-term sequelae from a single episode. Recurrent attacks are associated with increasing fibrosis and may lead to chronic pyelonephritis.
Gram-Negative Sepsis with Shock
Blood culture is frequently positive in patients with acute pyelonephritis. In a few cases, bacteremia is severe and causes gram-negative shock. The mortality rate is then high.
When infection supervenes in an obstructed, hydronephrotic kidney, the dilated pelvicaliceal system becomes filled with pus. This is called pyonephrosis.
Extension of infection through the renal capsule leads to abscess formation in the perinephric fat.
Patients with diabetes mellitus who develop acute pyelonephritis tend to have more severe disease characterized by renal papillary necrosis (extreme inflammation of the papillae, which become necrotic and slough into the calices).
This disorder, characterized by anaerobic bacterial fermentation of glucose with gas formation in the renal parenchyma, occurs rarely in diabetic patients. Radiologic visualization of gas in the renal parenchyma is the basis for clinical diagnosis. Emphysematous pyelonephritis is a severe infection, often complicated by gram-negative shock and death. It is an indication for emergency nephrectomy.
Infectious chronic pyelonephritis accounts for 15–20% of cases of chronic renal failure. Several different etiologic factors are recognized (Figure 49-4).
Pathologic features of chronic pyelonephritis.
Chronic Obstructive Pyelonephritis
Chronic obstructive pyelonephritis is common and occurs at all ages in both sexes. Obstruction may be mechanical (eg, calculi, prostatic hyperplasia, tumors, congenital anomalies, retroperitoneal fibrosis) or paralytic (neurogenic [neuropathic] bladder). About 50% of patients give a history of a previous episode of acute pyelonephritis.
Chronic Pyelonephritis Associated with Vesicoureteral Reflux
About 50% of children with vesicoureteral reflux develop chronic pyelonephritis; regurgitation of urine from the renal pelvis into the collecting tubules may be etiologically important. Early diagnosis of childhood vesicoureteral reflux (by voiding cystography) permits treatment to prevent chronic pyelonephritis.
Kidneys involved by chronic pyelonephritis usually show asymmetric involvement, with irregular scarring and contraction. Deep cortical pits due to scarring over a deformed calix are typical. Deformity of the pelvicaliceal system is common. Hydronephrosis and suppuration may be present in cases due to obstruction (chronic suppurative pyelonephritis).
Chronic pyelonephritis may be distinguished grossly from chronic glomerulonephritis by the asymmetry of renal involvement and the larger size of the cortical scars (pitted scarred kidney) in the former.
Microscopically, there is marked patchy inflammation and fibrosis of the interstitium. The inflammatory cells are lymphocytes and plasma cells with scattered neutrophils. Periglomerular fibrosis later progresses to global sclerosis. Hypertrophy and dilation of surviving tubules may be present (called thyroidization because the numerous packed, dilated tubules superficially resemble thyroid follicles). Immunofluorescence and electron microscopy do not show immune complex deposition in the glomeruli.
Cases in which lipid-laden foamy histiocytes are conspicuous are sometimes classified as xanthogranulomatous pyelonephritis. Xanthogranulomatous inflammation is associated with enlargement of the kidney and the presence of caliceal staghorn calculi. The inflammatory process frequently extends into the perinephric tissues and may involve adjacent organs (eg, colon, skin of the back, diaphragm, and pleura). Rarely, fistulas form between the renal pelvis and these organs.
Chronic pyelonephritis usually manifests as hypertension or chronic renal failure. Pyuria (neutrophils in urine), mild proteinuria, and bacteriuria are present. In end-stage pyelonephritis, bacteriuria may be absent, and differentiation from chronic glomerulonephritis then becomes difficult.
Renal tuberculosis is uncommon in the United States and Western Europe but still occurs frequently in parts of the world where tuberculosis is endemic.
The kidneys are initially infected in the primary pulmonary stage by hematogenous dissemination (see Chapter 34: The Lung: I. Structure & Function; Infections). The bacilli remain dormant and become reactivated much later. Renal tuberculosis is most common in patients 20–50 years of age. Approximately half of the patients with renal tuberculosis have a normal chest x-ray because the original infection has long since healed.
The lesion usually begins in the corticomedullary region as a caseous granuloma (tuberculoma). Multiple granulomas are common. The kidney is grossly enlarged, and cut section shows several yellow crumbling foci. With progression, the granulomas open into the pelvicaliceal system, leading to discharge of the caseous material in the urine and cavitation of the lesion. Microscopically, there is central caseous necrosis surrounded by epithelioid cells, lymphocytes, and fibroblasts. Marked fibrosis is usually present. Acid-fast bacilli can be demonstrated in most cases.
Clinically, patients have a combination of chronic inflammatory and urinary symptoms: low-grade fever, weight loss, hematuria, frequency, and mild lumbar pain. The urine shows numerous neutrophils. Ordinary urine culture is sterile (leading to the misnomer “sterile pyuria”); however, culture for mycobacteria is positive and diagnostic.
Toxic Tubulointerstitial Disease
Radiation nephritis occurs when the kidneys are in the field of radiation during treatment of malignant neoplasms. The dose required to produce radiation nephritis is about 23 Gy—lower in children or when radiation is given in combination with cytotoxic drugs.
Pathologically, the main changes are in the small arteries, which show fibrinoid necrosis. Tubular atrophy and interstitial fibrosis follow.
Excessive use of analgesics is a relatively common cause of chronic renal disease in Australia and Europe but is rare in the United States. Analgesic nephropathy was first described following the use of analgesic powders containing phenacetin, aspirin, and caffeine. Phenacetin is believed to be the main offender.
Pathologically, analgesic nephropathy is characterized by necrosis of the apices of the renal papillae (renal papillary necrosis), which may be shed in the urine, causing ureteral colic. Interstitial medullary fibrosis and calcification may also occur. The mechanism of necrosis of renal papillae is unknown.
Clinically, there is hematuria, ureteral colic, hypertension, and progressive renal failure. The diagnosis may be suspected radiologically by the presence of calcification in the renal papillary region. In some cases, the shed necrotic renal papillary tissue may be identified in a sample of urine.
Acute Interstitial Nephritis
Several drugs cause acute interstitial nephritis. Methicillin, other penicillin derivatives, sulfonamides, and various diuretics have been incriminated. Many cases show features of an immune hypersensitivity reaction. Immunofluorescence shows linear deposition of IgG, C3, and part of the methicillin molecule in the tubular basement membrane in methicillin-induced cases.
Pathologically, there is tubular degeneration and necrosis and marked inflammation of the interstitium with lymphocytes, plasma cells, and eosinophils.
Clinically, patients develop renal symptoms about 2 weeks after exposure to the drug. Fever, hematuria, proteinuria, skin rash, and eosinophilia are common. Acute renal failure develops in 50% of cases.
Recovery usually occurs when the drug is withdrawn.
Acute Renal Tubular Necrosis
Drug-induced acute renal tubular necrosis has been reported as a result of exposure to (1) aminoglycosides (gentamicin, kanamycin); (2) amphotericin B, an antifungal agent; (c) cephaloridine; and (4) methoxyflurane, an anesthetic agent.
Nephrotic syndrome may be caused by (1) mercurial compounds used as skin ointments and diuretics; (2) trimethadione, an antiepileptic drug; and (3) gold, used in the treatment of rheumatoid arthritis.
Mercury and lead poisoning result in renal damage. Mercurial compounds cause proximal convoluted tubule damage. Lead poisoning damages the entire tubule. The presence of eosinophilic intranuclear inclusions is characteristic of lead poisoning. Both mercury and lead may cause acute or chronic renal failure.
Metabolic Tubulointerstitial Diseases
Acute urate nephropathy occurs with very high serum uric acid levels; urate crystals deposited in the tubules cause obstruction. Chronic urate nephropathy occurs with protracted hyperuricemia, resulting in tubulointerstitial inflammation and fibrosis. Clinically, the manifestations are mild and progression slow.
Hypokalemia causes tubular epithelial cell injury, leading to inability to concentrate urine, polyuria, loss of sodium in urine, and failure to excrete acid (renal tubular acidosis). Histologically, there is vacuolization of tubular epithelial cells, most prominently in the proximal tubule.
Acute hypercalcemia damages the distal convoluted tubular epithelium, resulting in failure to concentrate urine—manifested clinically as polyuria. With prolonged hypercalcemia, metastatic calcification occurs in the renal interstitium (nephrocalcinosis) and may lead to chronic renal failure.
Increased calcium excretion in the urine increases the risk of urinary calculi.
Immunologic Tubulointerstitial Disease
Immunologic mechanisms involving the renal tubules include transplant rejection (see Chapter 8: Immunologic Injury) and some cases of drug-induced acute interstitial nephritis. The latter is discussed under drug-induced nephrotoxicity (see above).