Chapter 526 Tubulointerstitial Nephritis
Tubulointerstitial nephritis (TIN, also called interstitial nephritis) is the term applied to conditions characterized by tubulointerstitial inflammation and damage with relative sparing of glomeruli and vessels. Both acute and chronic primary forms exist. Interstitial nephritis can also be present with primary glomerular diseases as well as systemic diseases affecting the kidney.
The hallmarks of acute TIN are lymphocytic infiltration of the tubulointerstitium, tubular edema, and varying degrees of tubular damage. Eosinophils may be present, especially in drug-induced TIN; occasionally, granulomas occur. The pathogenesis is not fully understood, but a T cell–mediated immune mechanism has been postulated. A large number of medications, especially antimicrobials, anticonvulsants, and analgesics, have been implicated as etiologic agents (Table 526-1). Other causes include infections, primary glomerular diseases, and systemic diseases such as systemic lupus erythematosus (SLE).
The classic presentation of acute TIN is fever, rash, and arthralgia in the setting of a rising serum creatinine. Although the full triad may be noted in drug-induced TIN, many patients with acute TIN do not have all the typical features. The rash can vary from maculopapular to urticarial and is often transient. Patients often have nonspecific constitutional symptoms of nausea, vomiting, fatigue, and weight loss. Flank pain may be present owing to stretching of the renal capsule from acute inflammatory enlargement of the kidney. If acute TIN is caused by a systemic disease such as SLE, the clinical presentation will be consistent with specific signs and symptoms of the underlying disease. Unlike the typical presentation of oliguric acute renal failure seen with glomerular diseases, 30-40% of patients with acute TIN are nonoliguric, and hypertension is less common. Peripheral eosinophilia can occur, especially with drug-induced TIN. Some degree of microscopic hematuria is invariably present, but significant hematuria or proteinuria >1.5 g/day is uncommon. One exception is patients whose TIN is caused by nonsteroidal anti-inflammatory drugs (NSAIDs), who can present with the nephrotic syndrome. Urinalysis can reveal white blood cells and granular or hyaline casts, but red blood cell casts, characteristic of glomerular disease, are not seen. The presence of urine eosinophils is neither sensitive nor specific.
The diagnosis is usually made based on clinical presentation and laboratory findings. A renal biopsy will establish the correct diagnosis in cases where the etiology or clinical course confounds the diagnosis. A careful history of the timing of disease onset in relation to drug exposure is essential in suspected drug-induced TIN. Because of the immune-mediated nature of TIN, signs or symptoms generally appear in 1-2 wk after exposure. In children, antimicrobials are a common inciting agent. NSAIDs are an important cause of acute TIN in children, and volume depletion or underlying chronic renal disease can increase the risk of occurrence. Urinalysis and serial measurements of serum creatinine and electrolytes should be monitored. Renal ultrasonography is not diagnostic but can demonstrate enlarged, echogenic kidneys. Removal of a suspected offending agent followed by spontaneous improvement in renal function is highly suggestive of the diagnosis, and additional testing is generally not performed. In more severe cases, in which the cause is unclear or the patient’s renal function deteriorates rapidly, a renal biopsy may be indicated.
Treatment includes supportive care directed at addressing complications of acute renal failure such as hyperkalemia or volume overload. Corticosteroid administration within 2 wk of the discontinuation of certain offending agents (e.g., NSAIDs or antibiotics) can hasten recovery and improve long-term prognosis. Whether these data apply to other inciting agents is not clear. For patients with prolonged renal insufficiency, the prognosis remains guarded, and severe acute TIN from any cause can progress to chronic TIN.
In children, chronic TIN most commonly occurs as the result of underlying congenital urologic renal disease, such as obstructive uropathy or vesicoureteral reflux, or an underlying metabolic disorder affecting the kidneys (see Table 526-1). Chronic TIN can occur as an idiopathic disease, although this is more common in adults.
The juvenile nephronophthisis (JN)–medullary cystic kidney disease complex (MCKD) is a group of inherited cystic renal diseases that share a common histologic phenotype of chronic TIN. JN is generally inherited as an autosomal recessive trait. Although rare in the USA, JN causes 10-20% of pediatric end-stage renal disease (ESRD) in Europe. Patients with JN typically present with polyuria, growth failure, “unexplained” anemia, and chronic renal failure in late childhood or adolescence. Variants of JN with extrarenal involvement include Senior-Løken syndrome (retinitis pigmentosa), Joubert syndrome, and oculomotor apraxia type Cogan. MCKD is an autosomal dominant disease that typically manifests in adulthood. Tubulointerstitial nephritis with uveitis is a rare autoimmune syndrome of chronic TIN with anterior uveitis and bone marrow granulomas that occurs primarily in adolescent girls. Chronic TIN is seen in all forms of progressive renal disease, regardless of the underlying cause, and the severity of interstitial disease is the single most important factor predicting progression to ESRD.
The pathophysiology of chronic TIN is undefined, but data suggest that it is immune-mediated. Cells making up the interstitial infiltrate appear to be a combination of native interstitial cells, inflammatory cells recruited from the circulation, and resident tubular cells that undergo epithelial-mesenchymal transformation. Grossly, kidneys can appear pale and small for age. Microscopically, tubular atrophy and “dropout” with interstitial fibrosis and a patchy lymphocytic interstitial inflammation are seen. Patients with JN often have characteristic small cysts in the corticomedullary region. In primary chronic TIN, glomeruli are relatively spared until late in the disease course. Patients with chronic TIN secondary to a primary glomerular disease have histologic evidence of the primary disease.
The clinical features of chronic TIN are often nonspecific and can reflect signs and symptoms of chronic renal insufficiency (Chapter 529). Fatigue, growth failure, polyuria, polydipsia, and enuresis are often present. Anemia that is seemingly disproportionate to the degree of renal insufficiency is common and is a particularly prominent feature of juvenile nephronophthisis. Because tubular damage often leads to renal salt wasting, significant hypertension is unusual. Fanconi syndrome, proximal renal tubular acidosis, distal renal tubular acidosis, and hyperkalemic distal renal tubular acidosis can occur.
The diagnosis is suggested by signs or symptoms of renal tubular damage such as polyuria and an elevated serum creatinine value, coupled with a history suggestive of a chronic disease, such as long-standing enuresis or the presence of anemia resistant to iron therapy. Radiographic studies, in particular ultrasonography, can give additional evidence of chronicity, such as small, echogenic kidneys, corticomedullary microcysts suggesting JN, or findings of obstructive uropathy. A vesicocystourethrogram can demonstrate the presence of vesicoureteral reflux or bladder abnormalities. If JN is suspected, molecular diagnosis is available. In instances in which the cause is unclear, a renal biopsy may be performed. In cases of advanced disease, a renal biopsy might not be diagnostic. Many end-stage kidney diseases display a common histologic appearance of tubular fibrosis and inflammation.
Therapy is directed at maintaining fluid and electrolyte balance and avoiding further exposure to nephrotoxic agents. Patients with obstructive uropathies can require salt supplementation and treatment with potassium-binding resin (Kayexalate). Prevention of infection by antibiotic prophylaxis can slow progression of renal damage in appropriate patients. Prognosis in patients with chronic TIN depends in large part on the nature of the underlying disease. Patients with obstructive uropathy or vesicoureteral reflux can have a variable degree of renal damage and thus a variable course. ESRD can develop over months to years. Patients with JN uniformly progress to ESRD by adolescence. Patients with metabolic disorders can benefit from treatment when available.
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