Interstitial nephritis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

Two main diseases involve the renal tubules are: Acute tubular necrosis due to Ischemic or toxic injury .(for more about ATN click here), and tubulointerstitial nephritis with Inflammatory involvement of tubules and interstitium and its consequent reactions.

Since some cases of TIN are due  to bacterial infection, and the renal pelvis is deeply involved, therefore pyelonephritis is term describes this condition; and In general, the term interstitial nephritis is used for TIN that is owing to  nonbacterial causes of tubular injury such as  drugs, viral infections,autoimmune systemic diseases, in which these condition mechanism of damage is due to inflammatory responses not direct damage.

In 1938, Councilman was the first to discover the association between systemic infections and the development of TIN; in autopsy kidneys of children dying of diphtheria and scarlet fever. He described the findings as: cellular and fluid exudation in the interstitial tissue of kidneys, before the era of antibiotics.

The widespread use of renal biopsy and histological examination in TIN revealed a cellular infiltration, which is dominantly composed of T cells, together with somemacrophages and plasma cells, and led to the discovery of similar findings in association with drug-related renal failure and the same conditions.

There is no established system for the classification of TIN, however according to clinical manifestations and the inflammatory process, TIN, in spite of the etiologic agent, can be divided into acute and chronic categories.

It is thought that acute interstitial nephritis is mediated by hypersensitivity reaction to endogenous or exogenous antigens expressed by tubular cells. Numerous drugs such as antibiotics, NSAIDS, sulfa-containing drugs, etc, as well as systemic diseases, and Infections may lead injury to renal cells. the cascade activation owing to cellular injury toward inflammatory cell infiltration, and activation of cytokines causes an immunologic reaction in acute or chronic process.

In acute interstitial nephritis, this cascade activation can cause renal tubular dysfunction, whereas in chronic interstitial nephritis an insidious interstitial fibrosis,scarring, , and tubular atrophy spreads gradually and causes progressive chronic renal insufficiency.

Common causes of interstitial nephritis include drug side effects, particularly analgesics and antibiotics. Other common causes include associated nephrologic conditions, as well as microbial infections.

Interstitial nephritis accounts for 10-15% of kidney disease worldwide. Analgesic-induced nephritis is 5-6 times more common in women. The elderly have more severe disease and increased risk of permanent damage. Children exposed to lead poisoning are more likely to develop nephritis as young adult.

There are no established risk factors for TIN; Whereas according to etiologic causative factors, consumption of culprit drugs in causing TIN,previous history of hypersensitivity reactions to specific drug, presence of autoimmune systemic disease or some neoplasia or genetic condition, occupational or environmental exposure to heavy metals, and infection etiologies in association with obstructive uropathy, play role in in the development of TIN.

There is insufficient evidence to recommend routine screening for TIN.

In the majority of patients with TIN, recovery of renal function has been observed, and improvement immediately occurs upon stopping the offensive agent, nevertheless, about 12% of patients may progress to develop ESRD and its complications; and thus require dialysis or transplantation.

However there is no definite prognostic indicators for TIN, but renal failure lasts for >3 weeks, elderly patients and presence of tubular atrophy and interstitial fibrosis in the renal biopsy are associated with worse prognosis.

Renal biopsy is the gold standard and definitive test of establishing the diagnosis of TIN, however it is not needed in all patients and often considered to make a definitive diagnosis for patients who do not improve following withdrawal of offensive agent or in the presence of doubtful findings.

The majority of patients with interstitial nephritis are asymptomatic. However, nonspecific signs and symptoms may present depending upon underlying etiology and timing of presentation. Non specific symptoms include nausea, vomiting, malaise, and oliguria. Hematuria though not so common is also seen in some patients with tubulointerstitial nephritis. Other symptoms of interstitial nephritis include hypersensitivity reaction, such as rash, fever, and eosinophilia.

There are no physical examination findings specific to interstitial nephritis, and no characteristic findings exist. The presence of fever, rash in acute tubulointerstitial nephritis, livido reticularis, on physical examination may be suggestive of TIN, and provide clues to the diagnosis.

A variable combination of laboratory findings of TIN, such as rise in the plasma creatinine concentration, eosinophilia, eosinophiluria, changes of urine sediment, as well as evidences of tubulointerstitial damage based upon the culprit agent may present.

In some studies a variable amount of proteinuria among older patients and NSAID-induced AIN has been reported, although nephrotic-range proteinuria among patients with TIN is rare.

There are no ECG findings associated with TIN, however electrolyte imbalances due to complications of TIN may cause changes in ECG.

There are no x-ray findings associated with TIN.

There are no echocardiography/ultrasound findings associated with TIN.

There are no CT scan findings associated with TIN.

There are no MRI findings associated with TIN.

The mainstay of treatment for tubulointerstitial nephritis is discontinuation of potentially offending agen. The majority of patients due to drug-induced interstitial nephritis, improve spontaneously, however, renal function may not return to previous condition. No additional measures is needed among patients with minimal rise in the serum creatinine or those who demonstrate betterment after discontinuation of offending agent; otherwise if renal failure persists after removing the culprit drug, obtaining a renal biopsy and attempt glucocorticoids therapy for patients with biopsy-confirmed AIN must be considered.

There are no established measures for the primary prevention of tubulointerstitial nephritis.

The mainstay preventive action is to stay away from re-exposure to the offensive agents of the acute episode. Among patients with chronic inflammatory diseases such as Sjogren’s syndrome, sarcoidosis, or SLE, proper control of the underlying condition alongside with consideration of offensive agent is important and should be kept in mind.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. ; Associate Editor(s)-in-Chief:Mohsen Basiri M.D.

In 1938, Councilman was the first to discover the association between systemic infections and the development of TIN; In autopsy kidneys of children dying of diphtheria and scarlet fever.He described the findings as: cellular and fluid exudation in the interstitial tissue of kidneys, before the era of antibiotics.

In 1938, Councilman was the first to discover the association between systemic infections and the development of TIN; in autopsy kidneys of children dying of diphtheria and scarlet fever.^[1] He described the findings as: cellular and fluid exudation in the interstitial tissue of kidneys, before the era of antibiotics.

With development of renal biopsy led to find of similar characteristic in association with drug-related renal failure, histological examination in acute TIN reveals an infiltrate, which is largely composed of T cells, together with some macrophages and plasma cells. As there is some evidence for cutaneous delayed-type hypersensitivity and positive in vitrolymphocyte stimulation tests in response to suspected drugs, the etiology is presumed to be immune-mediated ^[2]. This is illustrated by the rapid recrudescence of disease upon inadvertent rechallenge in drug-related ATIN, a clear manifestation of an immunological memory response.^[3][4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:Mohsen Basiri M.D.

There is no established system for the classification of TIN; however according to clinical manifestations and the inflammatory process, TIN, in spite of the etiologic agent, can be divided into acute and chronic categories.

There is no established system for the classification of TIN. but most often it can be divided into acute or chronic categories; according to clinical manifestations and the inflammatory process, in spite of the etiologic agent.^[1]

• Acute tubulointerstitial nephritis (TIN): Commonly attributes an abrupt clinical onset with inflammatory responses of the kidney and involvement the interstitium and tubules. In this condition the glomeruli are intact or may affect in the late stage of disease.
• Chronic tubulointerstitial nephritis (TIN): The chronic manifestation of TIN results from interstitial fibrosis along with tubular atrophy. A process begins gradually and involves the kidneys insidiously.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

It is thought that acute interstitial nephritis is mediated by hypersensitivity reaction to endogenous or exogenous antigens expressed by tubular cells. Numerous drugs such as antibiotics, NSAIDS, sulfa-containing drugs, etc, as well as systemic diseases, and Infections may lead injury to renal cells. the cascade activation owing to cellular injury toward inflammatory cell infiltration, and activation of cytokines causes an immunologic reaction in acute or chronic process.

In acute interstitial nephritis, this cascade activation can cause renal tubular dysfunction, whereas in chronic interstitial nephritis an insidious interstitial fibrosis,scarring, and tubular atrophy spreads gradually and causes progressive chronic renal insufficiency.

In acute interstitial nephritis, espacially in acute drug-induced tubulointerstitial nephritis (TIN) an adverse reaction to any of an increasing number of drugs such as penicillins, rifampin, diuretics (thiazides), nonsteroidal anti-inflammatory agents, and numerous other drugs like phenindione, cimetidine occurs.^[1]

Many features of the disease suggest an immune mechanism. Clinical evidence of hypersensitivity includes latent period, eosinophilia and rash, the idiosyncratic drug reaction (i.e., the lack of dose dependency), and the recurrence of hypersensitivity after reexposure to the same drug or others that are similar in structure. Serum IgE levels are increased in some persons, suggesting type I hypersensitivity.

In other cases the nature of the inflammatory infiltrate and the presence of positive skin tests to drugs suggest a T cell–mediated (type IV) hypersensitivity reaction.^[2]

The most likely sequence of pathogenic events is as follows: The drugs act as haptens that, during secretion by tubules, covalently bind to some cytoplasmic or extracellular component of tubular cells and become immunogenic. The resultant tubulointerstitial injury is then caused by IgE- and cell mediated immune reactions to tubular cells or their basement membranes.

The development of drug-induced AIN is not dose-dependent, and recurrence or exacerbation can occur with a second exposure to the same or a related drug.^[3]

Since the majority cases of TIN are due to bacterial infection, and the renal pelvis is deeply involved, therefore pyelonephritis is term describes this condition. And In general, the term interstitial nephritis is used for TIN that are owing to nonbacterial causes of tubular injury.

bacterial infection in accompanied with obstruction or reflux such as Legionella, Leptospira, can primarily invade organs remote from the kidney and exerted an inflammatory response in the kidney without invading the kidney.^{[4] [5]}

However, more recent reports describe the identification of organism-specific antigens or DNA in kidney proximal tubule cells of patients with TIN, a histologic variant of TIN that is characterized by granuloma formation has been associated with Mycobacterium, fungi (histoplasmosis, coccidiomycosis), bacteria (Brucella, Chlamydia), spirochetes (Francisella, Treponema), and parasites (Leishmania, Toxoplasma).^[6]

Common conditions associated with interstitial nephritis include:

• SLE
• Sarcoidosis
• Sjogren’s syndrome

On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

The abnormalities in acute drug-induced nephritis are in the interstitium which shows pronounced edema and infiltration by mononuclear cells, principally lymphocytes and macrophages. Eosinophils and neutrophils may be present, often in large numbers. Interstitial non-necrotizing granulomas with giant cells may be seen with some Medications such as methicillin, thiazides, and rifampin. The glomeruli are normal except in some cases caused by nonsteroidal antiinflammatory agents, in which the hypersensitivity reaction also leads to podocyte foot process effacement and the nephrotic syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

Common causes of interstitial nephritis include drug side effects, particularly analgesics and antibiotics. Other common causes include associated nephrologic conditions, as well as microbial infections.

• 70 to 75 percent (with antibiotics responsible for 30 to 49 percent of these cases)^[1]

• Any drug has the potentiality to cause AIN, among case reports of many drugs causing AIN, but only a few have been reported with biopsy-proven AIN. The most common proven drugs cause of AIN includes:^{[2][3][4][5][6][7]}

• Nonsteroidal anti-inflammatory agents (NSAIDs)

• Penicillins and cephalosporins
• Antimicrobial sulfonamides, including trimethoprim-sulfamethoxazole
• Rifampin
• Diuretics, including loop diuretics such as furosemide and bumetanide, and
• Thiazide-type diuretics
• Ciprofloxacin and, perhaps to a lesser degree other quinolones
• Cimetidine
• Allopurinol
• Proton pump inhibitors such as omeprazole and lansoprazole
• Indinavir
• 5-aminosalicylates (eg, mesalamine)

Multiple organisms may cause TIN including bacterial viral fungal parasitic infections.^{[8][9][10][11][12][13]}

• Legionella,
• Leptospira,
• Streptococcus,
• Mycobacterium tuberculosis,
• Corynebacterium diphtheriae
• Yersinia,
• Enterococcus
• Escherichia coli

• Cytomegalovirus (CMV)
• Epstein-Barr virus (EBV),
• Aolyomavirus,
• Adenovirus,
• Candida

• Leishmania
• Toxoplasma

• Sarcoidosis

• SLE,

• Sjögren’s syndrome

Less common causes of TIN include:

• Heavy metals (eg, lead, cadmium, mercury)
• Obstructive uropathy, nephrolithiasis, reflux disease
• Neoplasia (eg, myeloma, leukemia, amyloidosis)
• Metabolic diseases (eg, hypercalcemia, cystinosis, potassium depletion, hyperoxaluria)

Cardiovascular	Granulomatosis with polyangiitis, Kawasaki’s disease
Chemical/Poisoning	Aristolochia, Quinine, Thiazide diuretics
Dental	No underlying causes
Dermatologic	Rubeola infection,
Drug Side Effect	Acetaminophen  , Acyclovir, Aldomet, Allopurinol, Alpha-interferon, Amlodipine, Ampicillin, Anitrim, Anti-tubular basement membrane antibodies  , Apo-sulfatrim, Aspirin, Azathioprine, Bactelan, Batrizol, Bumetanide, Captopril, Carbamazepine, Cefaclor, Cefotaxime sodium, Cefoxitin sodium, Cephalosporin, Chlorthalidone, Cimetidine  , Ciprofloxacin, Clofibrate, Cox-2 inhibitors, Creatine, Dabrafenib mesylate, Diazepam, Diclofenac, Diflunisal, Diltiazem, Diphenylhydantoin, Diuretics, Doxycycline, Ectaprim, Enterobacticel, Erythromycin, Esteprim, Ethambutol, Famotidine, Fenoprofen, Flurbiprofen, Furosemide, Griseofulvin, Hydralazine, Hydrochlorothiazide, Ibuprofen, Indinavir, Indomethacin, Isobac, Isoniazid, Kelfiprim, Ketoprofen, Lansoprazole, Macrolides, Mesalamine, Mesalazine, Methicillin, Metoxiprim, Minocycline hydrochloride, Naproxen, Novo-trimel, Nu-cotrimox, Olsalazine, Omeprazole, Oxacillin, Oxaprozin, Oxytetracycline, Pegylated interferon alfa-2b, Penicillin , Phenindione, Phenobarbital, Phenteramine, Phenylpropanolamine, Phenytoin, Piperacillin/tazobactam, Piroxicam, Polymyxin, Pranlukast, Propylthioruacil, Pro-trin, Rabeprazole, Ranitidine, Rifampin, Roubac, Streptomycin, Sulfatrim ds, Sulfinpyrazone, Sulfonamide, Sulfoxaprim, Sulindac, Syraprim, Tenofovir disoproxil fumarate, Tetracycline, Thiazide diuretics, Tolmetin, Treponema, Triamterene, Trimesuxol, Trimethoprim-sulfamethoxazole, Trimetoger, Trimetox, Trimzol, Trisulfa, Trisulfam, Uroplus ds, Uroplus ss, Vancomycin
Ear Nose Throat	Sjogren syndrome
Endocrine	No underlying causes
Environmental	No underlying causes
Gastroenterologic	Escherichia coli, Inflammatory bowel disease
Genetic	Alport syndrome, Bardet-biedl syndrome
Hematologic	Hypercalcemia, Hyperkalaemic distal renal tubular acidosis, Hyperuricemia, Hypokalemia, Sickle cell disease
Iatrogenic	No underlying causes
Infectious Disease	Adenovirus, Brucella, Candida, Chlamydia, Coccidioidomycosis, Corynebacterium diphtheriae, Cytomegalovirus, Diphtheria, Enterococcus, Epstein-barr virus  , Escherichia coli, Francisella, Hantaan virus, Histoplasmosis, Hiv infection, Legionellosis, Leishmaniasis, Leptospirosis, Mycobacterium tuberculosis, Mycoplasma infection, Polyomavirus, Rickettsia infection, Rubeola infection, Streptococcal infection, Syphilis, Toxoplasmosis, Uveitis, Yersinia
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	Creatine, Hyperuricemia, Hypokalemia
Obstetric/Gynecologic	No underlying causes
Oncologic	Myeloma
Ophthalmologic	Uveitis
Overdose/Toxicity	Cocaine
Psychiatric	No underlying causes
Pulmonary	Hantaan virus, Histoplasmosis, Sarcoidosis
Renal/Electrolyte	Alport syndrome, Granulomatosis with polyangiitis, Hyperkalaemic distal renal tubular acidosis, Reflux nephropathy, Renal failure, Sensenbrenner syndrome, Tubulointerstitial nephritis, Wegener’s granulomatosis
Rheumatology/Immunology/Allergy	Igg4-related disease, Kawasaki’s disease, Sarcoidosis, Sicca syndrome, Systemic lupus erythematosus
Sexual	Hiv infection, Syphilis
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

Interstitial nephritis accounts for 10-15% of kidney disease worldwide. Analgesic-induced nephritis is 5-6 times more common in women. The elderly have more severe disease and increased risk of permanent damage. Children exposed to lead poisoning are more likely to develop nephritis as young adult. TIN with uveitis is more common in adolescent female.

• In one study the incidence of TIN among asymptomatic patients, biopsied for either hematuria or proteinuria, was 0.7 per 100 000.^[1]
• However, in a series of 109 patients from a large centre, biopsied for unexplained renal impairment with normal sized kidneys, TIN accounted for 29 of 109 (27%) cases.^[2]
• Overally, tubulointerstitial nephritis accounts for 10-15% of kidney disease worldwide.

While the definitive diagnosis of TIN needs a kidney biopsy, then determination of prevalence of acute TIN are based on retrospective reviews of biopsy registries, with an overall average of 2.8%of the total biopsies. The incidence of acute TIN increases among biopsies done specifically to evaluate acute renal failure of unknown origin, with an overall average of 13.5%. ^[3]

• The prevalence of ATIN has increased in recent years, especially in patients aged >65 years. This could be due to an increase in drug-associated ATIN, which would justify early renal biopsy to identify ATIN and reduce the probability of progression to chronic kidney disease. ^[4]

• Patients of all age groups may develop TIN.The elderly have more severe disease and increased risk of permanent damage
• Children exposed to lead poisoning are more likely to develop nephritis as young adult.
• TIN with uveitis is more common in adolescent female
• Tubulointerstitial nephritis and uveitis (TINU) syndrome

• There is no racial predilection to TIN; whereas, lead nephropathy is more common in black people owing to socioeconomic factors.

• Analgesic-induced nephritis is 5-6 times more common in women, attributed to women taking more analgesics than men.

•  In certain regions, such as the Balkans (ie, Yugoslavia, Bosnia, Croatia, Romania, Bulgaria), where endemic nephropathy is common, interstitial diseases may be more prevalent.^[5]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

There are no established risk factors for TIN. Whereas according to etiologic causative factors, consumption of culprit drugs in causing TIN,previous history of hypersensitivity reactions to specific drug, presence of autoimmune systemic disease or some neoplasia or genetic condition, occupational or environmental exposure to heavy metals , and infection etiologies in association with obstructive uropathy, play role in in the development of TIN.

There are no established risk factors for TIN. Whereas according to etiologic causative factors the most potent risk factors in the development of TIN include:^[1]

• Consumption of culprit drugs in causing TIN
• Previous history of hypersensitivity reactions to a specific drug
• Presence of autoimmune systemic, neoplasia, metabolic or some genetic diseases
• Occupational or environmental exposure to heavy metals (eg, lead, cadmium, mercury )
• Infections in association with obstructive uropathy, reflux disease, nephrolithiasis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [[1]]; Associate Editor(s)-in-Chief:Mohsen Basiri M.D.

In the majority of patients with TIN, recovery of renal function has been observed, and improvement immediately occurs upon stopping the offensive agent.

Nevertheless, about 12% of patients may progress to develop ESRD and its complications; and thus require dialysis or transplantation.

However there is no definite prognostic indicators for TIN, but renal failure lasts for >3 weeks, older patients and presence of tubular atrophy and interstitial fibrosis in the renal biopsy are associated with worse prognosis.

• In the majority of patients with TIN, a full recovery or partial recovery occurs upon stopping the offensive agent. Meanwhile,about 12% of patients may progress to ESRD and its complications; and thus require dialysis or transplantation.^[1]

• Common complications of TIN include:
  • Hypertension
  • Hypokalemia
  • hypouricemia
  • hypophosphatemia
  • metabolic acidosis
  • Proteinuria
  • ESRD

In the majority of patients with TIN, a full recovery or partial recovery occurs upon stopping the offensive agent. Meanwhile,about 12% of patients may progress to ESRD and its complications; and thus require dialysis or transplantation.^[1]

• Renal failure lasts for >3 weeks.^[2][3] The opening <ref> tag is malformed or has a bad name
• Older patients^[4]
• Presence of tubular atrophy and interstitial fibrosis in the renal biopsy.The opening <ref> tag is malformed or has a bad name ^[5]

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