Tubulointerstitial nephritis

Involve structures in the kidney outside the glomerulus.

Involve tubules and/or the interstitium of the kidney and spares the glomeruli.

Primary glomerular diseases are often associated with prominent tubulointerstitial changes.

Associated with diverse etiologies.

Patients can present with acute or chronic disease.

Frequently involves exposure to drugs or other nephrotoxic agents such as heavy metals and, rarely, infection.

The most common form of tubulointerstitial inflammation is immunologic.

Acute tubulointerstitial nephritis includes hypersensitivity reactions from drugs, immunologic diseases, acute transplant rejection and infections.

Most cases of tubulointerstitial nephritis are caused by the use of medication such as antibiotics, NSAIDs, protein pump inhibitors and immune checkpoint Inhibitors.
Other causes of tubulointerstitial nephritis include systemic autoimmune diseases such as lupus, sarcoidosis, and Sjogren’s syndrome.
Chronic tubulointerstitial nephritis may be due to drugs, heavy metals, obstructive uropathy, nephrolithiasis and reflux disease, and immunologic diseases, vasculitis, antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides, chronic transplant nephropathy, neuropathy, atherosclerotic kidney disease, metabolic diseases and genetic diseases.

Clinical presentations are the result of the interation of renal cells and inflammatory cells and their products.

Injury to renal cells leads to expression of new local antigens, inflammatory cell infiltration, and activation of proinflammatory and chemoattractant cytokines.

Cytokines are produced by inflammatory cells and renal cells.

Acute interstitial nephritis is associated with tubular damage leading to renal tubular dysfunction, with or without renal failure.

Renal dysfunction is usually reversible, suggesting the regenerative capacity of tubules with preserved basement membrane.

Chronic tubulointerstitial nephritis is characterized by interstitial scarring, fibrosis, and tubule atrophy, with progressive chronic renal insufficiency.

Acute tubulointerstitial nephritis is hypersensitivity reaction to drugs such as penicillins, NSAIDs, and sulfa drugs.

Acute cellular injury can be caused by viral or bacterial infections.

Primary tubulointerstitial diseases constitute 10-15% of all kidney diseases.

May progress to end-stage renal disease.

Increased incidence of uroepithelial cancers is found among some patients.

Analgesic nephropathy is 5-6 times more common in women.

Acute tubulointerstitial nephritis (general features)

Acute tubulointerstitial nephritis manifests as acute renal failure.

Acute tubulointerstitial nephritis usually occurs within days of exposure to the offending drug.

In some instances, especially with NSAIDs, acute tubulointerstitial nephritis can begin after several months of exposure.

Acute tubulointerstitial nephritis commonly presents with rash, fever, eosinophilia, eosinophs in the urine, and elevated immunoglobulin levels.

Patients may present with rash and hematuria.

Proteinuria is usually absent or modest.

Urinalysis may show microscopic hematuria and/or sterile pyuria, with or without eosinophils.

Renal biopsy is required to make a definitive diagnosis.

Patients with acute tubulointerstitial nephritis caused by NSAIDs typically present with proteinuria.

Discontinuingof the offending drug usually results in complete recovery, but the rate of recovery is variable.

Almost all acute tubulointerstitial injuries are caused by hypersensitivity reactions to drugs and are not mediated by direct toxicity.

The most frequently implicated drugs are: penicillins, cephalosporins, sulfa drugs, quinolones, NSAIDs, diuretics, allopurinol, phenytoin, Rifampin, Interferon alfa, and proton pump inhibitors.

Allergic interstitial nephritis caused by NSAIDs may present with nephrotic syndrome.

Antibiotic-induced acute tubulointerstitial nephritis associated with rash, eosinophilia, and eosiniphils in the urine,, as well as pyuria, hematuria, and modest proteinuria are common.

Rifampin generally occurs when the antibiotic is reintroduced, and does not manifest with eosinophilia.

Hantavirus, CMV, and HIV are common among the infectious agents associated with acute interstitial nephritis.

Bacterial infection with renal parenchymal invasion is exceedingly rare in the absence of obstruction.

The chronic form of disease has an insidious onset and represents the response to a variety of insults.

Chronic tubulointerstitial nephritis is often diagnosed incidentally on routine laboratory screening or evaluation of hypertension.

Patients with chronic tubulointerstitial nephritis are usually asymptomatic.

Hypertension is common in chronic tubulointerstitial nephritis.

Analgesic nephropathy is the most common type of chronic interstitial nephritis worldwide.

Analgesic tubulointerstitial nephritis occurs with long-term ingestion of combinations of phenacetin, aspirin, and caffeine or phenacetin-acetaminophen or NSAIDs and acetaminophen.

Analgesic tubulointerstitial nephritis may be associated with papillary necrosis.

Analgesic nephropathy is most common in women in the sixth and seventh decades of life.

Patients with analgesic nephropathy present with renal insufficiency, modest proteinuria, sterile pyuria, and anemia.

Treatment for analgesic nephropathy includes discontinuation of analgesic use.

Increased incidence of uroepithelial cancers is also observed in patients with analgesic nephropathy.

Cyclosporin and tacrolimus can cause acute and chronic nephrotoxicity due to vasoconstrictive effects of these drugs.

Obstruction of urinary outflow can cause chronic tubulointerstitial disease.

Modest proteinuria and hyperkalemic renal tubular acidosis are common in tubulointerstitial nephritis.

Vesicoureteral reflux disease can result in focal glomerulosclerosis with nephrotic syndrome and a prominent tubulointerstitial component in adult life.

Recurrent urinary tract infection itself can cause ammonium magnesium phosphate stones, and aggravate tubulointerstitial disease.

Atherosclerotic kidney disease is a major category of chronic tubulointerstitial nephropathy.

Cholesterol microembolic disease may be accompanied by patchy tubulointerstitial nephritis with mild mononuclear cellular infiltration.

Chronic hypercalcemia, chronic potassium depletion, and cystinosis can lead to chronic tubulointerstitial nephritis.

Rash associated with acute allergic tubulointerstitial nephritis is highly variable.

Laboratory evaluation may reveal eosinophilia in approximately 50% of cases, but it is neither specific nor sensitive enough to establish the diagnosis.

The absence of eosinophiluria does not rule out the diagnosis.

Chemistries, including BUN and serum creatinine, provides information on whether renal insufficiency exists.

Urinalysis may reveal proteinuria, hematuria, and the presence of white cells.

Urine sediment may reveal casts, white cells, eosinophils, and crystals, but iin NSAID-induced AIN, eosinophils are usually absent.

Kidney biopsy is the definitive test for diagnosing acute allergic interstitial nephritis.

Kidney biopsy shows mononuclear and often eosinophilic cellular infiltration of the renal parenchyma with sparing of the glomeruli.

In most cases, stopping the offending agent results in recovery and resolution of the renal disorder, although some patients progress to chronic renal insufficiency.

If discontinuation of the offending agent does not result in rapid improvement steroid therapywith relatively high doses of prednisone is considered.

Treatment of chronic tubulointerstitial disease generally consists of supportive measures, such as adequate blood pressure control and management of anemia.

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