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Interstitial Nephritis

Tubulo-Interstitial Nephritis

Interstitial nephritis is a renal condition resulting from a variety of causes such as immune-mediated injury, medications, infections, and other mechanisms. It is an important cause of renal failure.


Presentation

No characteristic symptoms are apparent in both acute and chronic interstitial nephritis. However, a careful medical history may elicit conditions frequently associated with the disease. Hypertension is common in many cases of interstitial nephritis but some patients may have normal or even low blood pressure. Suspicion should be high in patients with connective tissue disorders or other conditions that require long-term treatment with NSAIDs or analgesics. Occupational history may also provide a clue as to whether the patient is chronically exposed to environmental toxins, and the family history may reveal the presence of genetic disorders that predispose to the condition.

A previous medical history positive for atopy or allergy with a recent intake of medications may be important diagnostic clues for acute allergic interstitial nephritis. However, the chronic form of this condition is often insidious, with patients remaining asymptomatic for a long period of time. Often, chronic tubulointerstitial disease is diagnosed incidentally during routine laboratory testing.

A form of interstitial nephritis with associated uveitis (tubulointerstitial nephritis with uveitis) may present with systemic symptoms of fever, weight loss, fatigue, or malaise. Myalgia, flank or abdominal pain, arthralgia, and polyuria or nocturia may also be present.

Fatigue
  • METHODS: 59 patients 10 years of age with backache, feverish fatigue feeling, dysuria, joint pain, or dyspepsia, singly or in combination with elevated serum creatinine ( 116 and 98 µmol/L for male and females, respectively) were included in the study[ncbi.nlm.nih.gov]
  • Other general symptoms that occur with variable frequency include nausea, vomiting, fatigue, lack of appetite, and weight loss.[en.wikipedia.org]
  • Symptoms Swelling of the kidneys can lead to a number of symptoms that include: Fever Rash Body ache Feelings of Nausea or vomiting Loss of appetite Fatigue and weakness Problems in sleeping patterns Changes in the urinate quantity Muscle cramps Swelling[medanta.org]
  • Gradually renal failure, nausea, vomiting, weight loss, fatigue, and anemia develop. Acidosis and hyperkalemia may follow.[medical-dictionary.thefreedictionary.com]
  • Other symptoms of interstitial nephritis include: a fever blood in the urine exhaustion confusion fatigue nausea vomiting a rash water retention swelling weight gain from water retention feeling bloated elevated blood pressure Acute interstitial nephritis[healthline.com]
Cushingoid
  • He did not tolerate continued higher doses of prednisone because of mood swings and cushingoid features. Infliximab was initiated with improvement in renal function.[ncbi.nlm.nih.gov]
Recurrent Respiratory Infections
  • Herein, we report a case of KIN with atypical clinical presentation in a young patient with progressive kidney failure without proteinuria or hematuria or history of recurrent respiratory infections.[ncbi.nlm.nih.gov]
Laboratory Technician
  • The testing of urine for eosinophils was conducted by laboratory technicians using usual laboratory practices at the institution and reported in patients’ charts.[doi.org]
Burning Pain
  • Further, she complained about a burning pain in her left eye. Renal biopsy revealed acute TIN. Other conditions were excluded and TINU was diagnosed.[ncbi.nlm.nih.gov]
Nausea
  • Other general symptoms that occur with variable frequency include nausea, vomiting, fatigue, lack of appetite, and weight loss.[en.wikipedia.org]
  • Patient 2 In the same year, a 63-year-old man presented to the emergency department with a 3-week history of nausea, vomiting, weight loss and oliguria.[mja.com.au]
  • Symptoms Swelling of the kidneys can lead to a number of symptoms that include: Fever Rash Body ache Feelings of Nausea or vomiting Loss of appetite Fatigue and weakness Problems in sleeping patterns Changes in the urinate quantity Muscle cramps Swelling[medanta.org]
  • The presenting symptoms, which are associated with elevation of plasma creatinine, commonly include rash, arthralgia, malaise, fever, nausea, lethargy and weight loss.[medsafe.govt.nz]
  • Patients with AIN can present with features that indicate an immunological reaction (typically fever, rash and raised eosinophils) along with symptoms of acute renal failure, including oliguria, malaise, anorexia, nausea and vomiting.[pharmaceutical-journal.com]
Kidney Failure
  • In rare cases, it can cause permanent damage, including long-term (chronic) kidney failure. Acute interstitial nephritis may be more severe and more likely to lead to long-term or permanent kidney damage in older people.[nlm.nih.gov]
  • Herein, we report a case of KIN with atypical clinical presentation in a young patient with progressive kidney failure without proteinuria or hematuria or history of recurrent respiratory infections.[ncbi.nlm.nih.gov]
  • Symptoms Interstitial nephritis can cause mild to severe kidney problems, including acute kidney failure. In about half of cases, people will have decreased urine output and other signs of acute kidney failure.[mountsinai.org]
  • Laboratory findings revealed pancytopenia, elevated lactate dehydrogenase, and ferritin as well as liver and kidney failure.[ncbi.nlm.nih.gov]
  • In chronic tubulointerstitial nephritis, the most serious long-term effect is kidney failure.[en.wikipedia.org]
Oliguria
  • By the time oliguria has supervened, the need for renal replacement therapy is imminent.[doi.org]
  • Three patients presented with edema and two with oliguria, while none had frank hematuria, fever, arthralgia, skin rash or history of exposure to nonsteroidal antiinflamatory drugs, analgesics, antibiotics, allopurinol, or Chinese herb before presentation[ncbi.nlm.nih.gov]
  • Fractional Excretion of Sodium (FENa) may be useful if oliguria 7. CLOSE monitoring of DAILY AM weights and STRICT Intake and Output records each 24hrs Imaging Studies 1.[renalandurologynews.com]
  • Patients with AIN can present with features that indicate an immunological reaction (typically fever, rash and raised eosinophils) along with symptoms of acute renal failure, including oliguria, malaise, anorexia, nausea and vomiting.[pharmaceutical-journal.com]
  • […] only 5% of cases Nephrotic Syndrome (see Nephrotic Syndrome, [[Nephrotic Syndrome]]): occurs in However, in NSAID-associated acute interstitial nephritis cases, co-existing membranous nephropathy or minimal change disease may produce nephrotic syndrome Oliguria[mdnxs.com]

Workup

An elevated serum creatinine and the presence of white blood cells (WBC), WBC casts, or eosinophils in the urinalysis may suggest tubulointerstitial nephritis. These findings are generally different from other forms of acute kidney injury (AKI), such as red blood cells (RBC) and RBC casts in acute glomerulonephritis. Abnormal laboratory findings that appear shortly after intake of a new drug is suggestive of acute allergic tubulointerstitial disease, especially if the drug in question has been known to cause interstitial nephritis. However, the presence of normal urinalysis results does not exclude the diagnosis [9].

Imaging studies, namely ultrasound, should be done prior to biopsy and in order to rule out obstruction. A renal biopsy is performed to establish a definitive diagnosis, with typical histopathologic findings showing tubulointerstitial infiltrates composed of T lymphocytes and monocytes, with eosinophils, neutrophils, or plasma cells occasionally present. There is also marked interstitial edema, and inflammatory infiltration of the tubular basement membrane may be present. However, a renal biopsy may not be necessary in some cases, especially in patients whose renal function improves upon cessation of intake of offending agents.

The underlying etiology should be determined after a diagnosis of tubulointerstitial nephritis is made. This may involve several laboratory tests to rule out different etiologies associated with the condition. These tests may include autoimmune antibodies (ANCA, antinuclear antibody (ANA), anti-dsDNA, anti-Ro/SSA) to detect the presence of connective tissue disorders and vasculitides such as SLE, Sjogren's syndrome, or ANCA vasculitis, serological tests to identify viral, parasitic, or bacterial infections, and chest X-rays to rule out tuberculosis or sarcoidosis, among others.

Pyuria
  • When only patients with pyuria were considered, there were marginal changes in the values ( Table 3 ).[doi.org]
  • Risk factors In ATIN, active urinary sediment with sterile pyuria Sometimes renal biopsy Usually imaging to exclude other causes Few clinical and routine laboratory findings are specific for tubulointerstitial nephritis.[merck.com]
  • All patients had sterile pyuria and each of nine patients studied by Wright's stain of urine sediment had marked eosinophiluria.[ncbi.nlm.nih.gov]
  • (Leukocyturia) Pyuria should be checked PRIOR to testing for eosinophils May be associated with WBC casts CLINICAL PEARL: Pyuria is COMMON ( 80% Methicillin related cases of AIN and 50% in drugs OTHER than Methicillin) Absence of pyuria does NOT rule[renalandurologynews.com]
  • Clin Nephrol 2009;72:331 ) Fever, hematuria, azotemia and eosinophilia Variable skin rash May be associated with inactive cytochrome P450 polymorphisms ( Ren Fail 2009;31:749 ) Urinalysis: suggestive of infection (eosinophils, hematuria, proteinuria, pyuria[pathologyoutlines.com]
Hypertriglyceridemia
  • HPS could be diagnosed with the presence of six criteria: fever, splenomegaly, bicytopenia, high ferritin, hypertriglyceridemia, and high levels of soluble CD25.[ncbi.nlm.nih.gov]
Normocytic Anemia
  • Laboratory investigations showed normocytic anemia, azotemia, hematuria and proteinuria. Renal ultrasound was normal.[ncbi.nlm.nih.gov]
Gram-Positive Rods
  • Renal biopsy showed granulomatous interstitial nephritis with gram-positive rod-shaped organisms with a "belt-like stripe" in tubular epithelial cells.[ncbi.nlm.nih.gov]

Treatment

The primary treatment of both acute and chronic interstitial nephritis relies on the proper management of the underlying cause, such as removal of the offending agent in acute allergic nephritis. Corticosteroids are useful for acute forms such as immune-mediated causes of interstitial nephritis and some cases of drug-induced interstitial nephritis. Patients with acid-base disorders, electrolyte imbalances, proteinuria, and renal insufficiency may require co-management with a nephrologist.

Prednisone 1mg/kg orally once daily with dose tapering spread over 4 to 6 weeks may be given for immune-mediated and drug-induced interstitial nephritis in order to hasten recovery and potentially decrease the need for dialysis. For the latter case, corticosteroids are most effective when given within two weeks of removal of the offending cause. However, NSAID-induced interstitial nephritis is less responsive to corticosteroids than drug-induced interstitial nephritis.

Corticosteroids should only be started after a definitive diagnosis is obtained through biopsy, and if no improvement occurs after a few days of removing the offending agent. Treatment with corticosteroids may produce variable results, with some patients recovering full renal function after a few weeks and some progressing to chronic renal insufficiency.

Management of chronic interstitial nephritis requires supportive measures such as controlling the hypertension and anemia related to the disorder. Angiotensin-converting enzyme (ACE)-inihibitors or angiotensin II receptor blockers (ARBs) may delay disease progression in patients with chronic interstitial nephritis and progressive renal injury. Patients may also benefit from dietary measures such as sodium restriction.

Patients with acute or chronic interstitial nephritis should receive follow-up care in order to monitor the renal function. Long-term follow up care is important for chronic interstitial nephritis in order to optimize control of blood pressure.

Prognosis

The most severe complication associated with tubuointerstitial nephritis is end-stage renal disease (ESRD), a condition that requires dialysis or renal transplantation. Acid-base disorders are often present due to the resultant renal tubular dysfunction. Patients with analgesic, Balkan endemic, or aristolochic acid nephropathies are at an increased risk for urothelial cancers.

Removal of the offending agent in allergic interstitial nephritis is sufficient for the resumption of normal renal function. Spontaneous improvement in renal function may occur after a microembolic event in cholesterol kidney disease, though complete resolution of the renal dysfunction is not expected to happen. Hypertension may be also be a factor in tubulointerstitial nephritis, though not all cases are associated with hypertension (acute allergic interstitial nephritis or Balkan endemic nephropathy).

In terms of disease progression, most cases of chronic tubulointerstitial nephritis eventually progress to ESRD, though at a much slower rate compared to glomerular disorders.

Etiology

Many disease entities can cause injury to the renal interstitium and the renal tubules, as well as ingestion of substances harmful to the kidneys. Acute allergic interstitial nephritis is the most common form of interstitial nephritis and is caused by hypersensitivity reactions to certain drugs [3] [4]. Nephrotoxic medications, which are drugs that directly cause renal damage, are a major cause of interstitial nephritis. Other significant substances that cause direct renal injury include toxins and heavy metal such as lead or mercury. Factors that cause acute cases of nephritis differ from those that cause the chronic form of the condition. Infections from different pathogens are a major cause of acute interstitial nephritis. These include viruses such as hantavirus, cytomegalovirus (CMV), and human immunodeficiency virus (HIV). Parasitic infections including toxoplasmosis or leishmaniasis and fungal infections such as histoplasmosis are also an important cause of acute interstitial nephritis. Bacterial infections, however, do not cause acute interstitial nephritis unless accompanied by urinary obstruction or reflux

Chronic interstitial nephritis is a result of accumulated damage to the renal interstitium. Therefore, chronic exposure to heavy metals is an important cause of this condition, as well as long-term use of nephrotoxic drugs such as analgesics, tacrolimus, or cyclosporine. Cholesterol microembolism due to atherosclerotic ischemic renal disease can also cause chronic interstitial nephritis, as well as malignancies such as myelomas and leukemias. Disorders in metabolism that cause hyperoxaluria, hypercalcemia, or cystinosis lead to the development of this condition. Chronic interstitial nephritis may also be caused by a condition known as Balkan endemic nephropathy and exposure to aristolochic acid found in certain Chinese herbs [6].
Disorders that affect the immune system such as sarcoidosis, Wegener granulomatosissystemic lupus erythematosus and antineutrophil cytoplasmic antibody (ANCA) vasculitis can cause both acute [5] and chronic forms of this disease.

Epidemiology

Diseases that primarily affect the renal tubules and interstitium without involving the glomeruli (primary tubulointerstitial disease) account for 10-15% of all renal diseases worldwide and in the United States. This condition may even be more prevalent in Balkan countries where endemic nephropathy is common.

In terms of gender predilection, analgesic nephropathy is 5-6 times more common in women and is probably due to greater intake of these medications in this population. However, differences in analgesic metabolism or a higher sensitivity to analgesic toxic effects in females cannot be ruled out.

Although lead nephropathy may be more common in blacks due to environmental factors arising from socioeconomic status, tubulointerstitial nephritis does not demonstrate any racial predisposition.

The etiologies of tubulointerstitial nephritis may appear in different age groups. Atherosclerotic or ischemic kidney disease usually appear in the elderly population, whereas cystinosis, hyercalcemia, or oxalosis can appear in younger age groups. Renal injuries related to toxic agents such as lead may appear with advancing age since they are associated with the accumulation of the toxic substance.

Sex distribution
Age distribution

Pathophysiology

The primary pathology in both forms of interstitial nephritis is due to inflammation affecting the renal interstitium and the renal tubular cells. This is caused by either lethal or sublethal injury that triggers the initial inflammatory response, which eventually lead to the release of inflammatory cytokines and infiltration of the renal interstitium and renal tubules by inflammatory cells. These events eventually result in either acute or chronic inflammation [7][8].

The acute form of interstitial nephritis has a greater chance of reversibility, even in cases of severe interstitial injury, as long as the damage does not extend to the epithelial basement membranes. The reason for this reversibility is most probably due to the regenerative capacity of the renal epithelium. On the other hand, chronic interstitial nephritis tends to be less reversible since it represents a chronic accumulation of injuries in the interstitium, leading to progressive renal insufficiency accompanied by tubular atrophy, fibrosis, and interstitial scarring.

Other pathological mechanisms can trigger the inflammation seen in interstitial nephritis. Acute tubulointerstitial nephritis is the result of an exaggerated immune response (hypersensitivity) against certain drugs, whereas bacterial or viral infections can cause direct damage to the renal interstitium. However, bacterial infections in the absence of significant urinary obstruction or reflux are not enough to cause interstitial injury since the renal parenchyma is generally resistant to damage in the absence of these conditions.

Prevention

A thorough knowledge of the risk factors related to the development of interstitial nephritis is essential in the prevention of this condition. Careful monitoring of the clinical condition in patients at risk for interstitial nephritis and early intervention are equally important in preventing the development of this disease.

Summary

Many different forms of renal injuries may give rise to a condition called interstitial nephritis, characterized histologically by inflammation and edema of the renal interstitium accompanied by a sudden deterioration in renal function. Interstitial nephritis is a misnomer since this condition affects both the interstitium and the tubules of the kidney, and a more appropriate term would be tubulointerstitial nephritis. The characteristic renal histopathologic changes associated with this condition were first noted in 1898 during autopsies of patients with scarlet fever and diphtheria.

Interstitial nephritis may present as either an acute or chronic condition. The acute type is commonly caused by allergic drug reactions, whereas the chronic form of the disease is caused by a wide range of causes such as genetic diseases, disorders of metabolism, or obstruction in the urinary tract. Chronic exposure to heavy metals such as lead is also a causative agent, as well as ingestion of environmental toxins and certain herbs. Although a thorough medical history and urinalysis may suggest a diagnosis of interstitial nephritis, a biopsy is often required to form a definitive diagnosis. The prognosis and treatment of the condition varies, and will depend on the severity of the condition, the underlying etiology, and its potential reversibility [1] [2].

Patient Information

Interstitial nephritis is a disease causing inflammation (swelling) of the spaces between the kidney tubules. As a result, your kidneys will not be able to work properly. This disease may be temporary (acute) or long-lasting (chronic) and may even cause failure of the kidneys (renal failure) if not treated properly.

The following factors can cause interstitial nephritis:

  1. Long-term intake of drugs such as pain relievers (acetaminophen, aspirin, NSAIDs) or side effects of antibiotics such as penicillin and sulfonamides
  2. Allergic reaction to a drug
  3. Autoimmune disorders such Wegener granulomatosis or Sjogren’s syndrome
  4. Kidney infections
  5. Lead or heavy metal poisoning
  6. Too little potassium or too much uric acid or calcium in the blood

Patients with interstitial nephritis may experience symptoms such as fever, rash, nausea, vomiting, decreased urine output, swelling in any area of the body, water retention and weight gain, and changes in the mental status such as drowsiness or confusion.

A physical examination from your doctor may reveal high blood pressure, fluid in the lungs, or abnormal heart or lung sounds. In addition, your doctor may request for laboratory tests such as complete blood count, urinalysis, arterial blood gas analysis, blood chemistry, blood urea nitrogen, or serum creatinine. Additional diagnostic tests such as a kidney ultrasound or a kidney biopsy may also be necessary.

Treatment of interstitial nephritis will depend on the cause of the disease. Stopping intake of medications that can cause this disease is often necessary, and dietary measures such as limiting salt and fluid intake may also help. Keeping your blood pressure low (if you have hypertension) is also an important part of the treatment. Dialysis may also be done if needed, though this is usually temporary.

Interstitial nephritis is usually a short-term disease and recovery is likely. Possible complications of interstitial nephritis include chronic renal failure if the damage to the kidneys is severe. Acid can also build up in the body if the kidneys cannot excrete it, causing metabolic acidosis.

Interstitial nephritis may be prevented through limiting the intake of drugs known to cause the condition.

References

Article

  1. Perazella MA, Luciano RL Review of select causes of drug-induced AKI. Expert Rev Clin Pharmacol. 2015;8(4):367-71
  2. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, Saran R, Wang AY, Yang CW. Chronic kidney disease: global dimension and perspectives. Lancet. 2013;382(9888):260-72
  3. Markowitz GS, Bomback AS, Perazella MA. Drug-Induced Glomerular Disease: Direct Cellular Injury. Clin J Am Soc Nephrol. 2015;10(7):1291-9.
  4. Shirali AC, Perazella MA. Tubulointerstitial injury associated with chemotherapeutic agents. Adv Chronic Kidney Dis. 2014;21(1):56-63.
  5. Korsten P, Müller GA. Interstitial nephritis in rheumatic diseases. Z Rheumatol. 2015;74(4):290-9
  6. Wernerson A, Wijkström J, Elinder CG. Update on endemic nephropathies. Curr Opin Nephrol Hypertens. 2014;23(3):232-8.
  7. Zoja C, Abbate M, Remuzzi G. Progression of renal injury toward interstitial inflammation and glomerular sclerosis is dependent on abnormal protein filtration. Nephrol Dial Transplant. 2015;30(5):706-12.
  8. Haas M. Chronic allograft nephropathy or interstitial fibrosis and tubular atrophy: what is in a name? Curr Opin Nephrol Hypertens. 2014;23(3):245-50
  9. Perazella MA. Diagnosing drug-induced AIN in the hospitalized patient: a challenge for the clinician. Clin Nephrol. 2014;81(6):381-8.

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Last updated: 2019-07-11 20:52