What is interstitial nephritis

Interstitial nephritis is a kidney disorder in which the spaces between the kidney tubules become swollen (inflamed). This reduces the kidneys’ ability to filter properly. Your kidneys filter waste and extra fluid from your body.

Interstitial nephritis is a serious condition, but it can be treated. In rare cases, it may cause kidney failure. When the kidneys fail, waste and extra fluid build up in the body. This can cause problems with the heart, brain, lungs, and other organs.

Interstitial nephritis may be temporary (acute interstitial nephritis), or it may be long-lasting (chronic interstitial nephritis) and get worse over time.

The acute form of interstitial nephritis is most often caused by side effects of certain drugs.

Acute interstitial nephritis

Acute interstitial nephritis is an immune mediated condition that is characterized by an inflammatory infiltrate in the kidney interstitium and is a well-recognized cause of acute kidney injury ¹. Acute interstitial nephritis contributes 10-15% of all kidney diseases both in the US and around the world ². The incidence of acute interstitial nephritis is increasing worldwide and previous studies have ascribed this to a surge in drug induced acute interstitial nephritis in elderly patients ³. There has been a significant increase in the incidence of acute tubulo-interstitial nephritis (acute interstitial nephritis and acute pyelonephritis) in women less than 55 years of age with acute tubulo-interstitial nephritis now representing the most common cause of hospitalization from acute kidney injury in women in this age group ⁴.

Acute interstitial nephritis has many causes with the most common being drug-induced. One review of 128 patients with acute interstitial nephritis identified the following causes ⁵:

• Drugs: 71% (with one third caused by antibiotics);
• Infection: 15%;
• Idiopathic: 8%;
• Tubulointerstitial nephritis and uveitis (TINU) syndrome: 5%;
• Sarcoidosis: 1%.

The principle pathogenesis in drug-induced acute interstitial nephritis is hypersensitivity reaction to drugs, such as penicillin, nonsteroidal anti-inflammatory drugs (NSAIDs), and sulfa-containing drugs.

Acute interstitial nephritis has no racial predilections. Generally, sex does not have any influence on having the disease, except for analgesic nephropathy, which is 5-6 times more common in women. This is attributed to women taking more analgesics than men. The role of women’s physiology in pathogenesis of analgesic nephropathy is unknown.

Acute interstitial nephritis affects all ages, however, it must be remembered that renal toxicity is dependent on the cumulative effects of toxic substances. This means that the more the kidney is damaged due to toxic substances, the higher the risk of the kidney suffering from subsequent damage. Also, advanced age is a risk factor for acute interstitial nephritis because kidney function generally declines with age.

Acute interstitial nephritis symptoms

Acute interstitial nephritis usually presents with non-specific symptoms, such as:

• Nausea and vomiting;
• Generalized weakness;
• Lethargy.

However, it must be remembered that acute interstitial nephritis can be symptomless. It is important to establish if any new drugs have been started, particularly pain-killers and antibiotics. Also, the use of complementary or alternative medicines needs to be established. The patient should also be asked if they have had any recent infections, including viral illnesses.

Acute interstitial nephritis diagnosis

Clinical examination might not reveal any relevant findings as kidney disease does not usually present with any specific signs. However, patients with drug-induced acute interstitial nephritis might have signs of an allergic-type reaction. This includes:

• Rash: occurs in 15% of the patients.
• Fever: occurs in 27% of the patients.

General investigation

The patient usually needs a complete workup.

A routine set of general blood investigations will include:

• Full blood count: may show an increased white cell count;
• Liver function tests;
• Renal function tests: may show increased creatinine;
• Electrolytes: may show potassium abnormalities if in acute renal failure

Urinalysis will be done to examine the urine. Positive urinalysis findings include:

• Presence of white blood cells in the urine;
• Presence of red blood cells in the urine;
• Presence of protein in the urine.

However, it must be remembered that occasionally the patient’s urinalysis may come back normal – described as ‘bland urinalysis’. A relatively normal urinalysis does not exclude the diagnosis of acute interstitial nephritis.

Specific investigations

In order to diagnose the disease, some or all of the following tests may be done:

• Blood eosinophil count: eosinophils are a type of white blood cell involved in the allergic response; therefore, they may be elevated in acute interstitial nephritis. However, this is generally not the case in NSAID-induced acute interstitial nephritis.
• Urine microscopy: this involves taking a sample of the urine and examining it under the microscope. Typically, a collection of cells may be found in the urine, known as granular and epithelial cell casts. If blood cells are found, they are called red cell or white cell cast. By doing this test, other causes of acute renal failure can be ruled out.
• Renal biopsy: this involves taking a sample of the kidney and examining it under the microscope. Although this is the definitive diagnostic test for acute interstitial nephritis, it is an invasive procedure with potentially serious complications. Hence, this is only reserved in patients in which a definitive diagnosis is needed.

Another imaging study that can be done, albeit infrequently, is a gallium scan, which is a nuclear medicine imaging technique.

Acute interstitial nephritis treatment

The most important part of treatment is cessation of the offending agent. This includes a complete review of the patient’s current medications and stopping any drugs that may potentially be causing acute interstitial nephritis. If the patient does not show any symptoms and signs of improvement (in terms of clinical symptoms as well as blood results), corticosteroids can be administered to suppress inflammation. Evidence suggests that immunosuppressants (e.g., cyclophosphamide or mycophenolate mofetil) may be beneficial in acute interstitial nephritis that doesn’t respond to the cessation of the offending agent.

Acute interstitial nephritis prognosis

The overall prognosis for acute interstitial nephritis is excellent. Most patients’ renal function recovers upon cessation of the offending agent. The improvement occurs within 6-8 weeks. However, recovery may be incomplete leading to persistent elevation in plasma creatinine concentration.

Allergic interstitial nephritis

Allergic interstitial nephritis is the most common form of acute interstitial nephritis ⁶. Allergic interstitial nephritis is most often caused by exposure to a drug. Allergic interstitial nephritis is often associated with an acute decline in renal function and may be associated with permanent renal insufficiency. The hallmark pathologic finding of allergic interstitial nephritis is a marked inflammatory infiltrate of the renal interstitium. The classic clinical picture of allergic interstitial nephritis (i.e., fever, rash, eosinophilia) was well-described with the use of methicillin, which caused allergic interstitial nephritis in approximately 17% of cases. Identification and discontinuation of the offending medication have been the mainstays of treatment, with conflicting evidence regarding the benefit of steroid treatment ⁷.

Allergic interstitial nephritis causes

Allergic interstitial nephritis is most often caused by drug therapy (70% to 75% of cases), with antibiotics such as penicillins, cephalosporins, rifampin, sulfonamides, and ciprofloxacin accounting for about 30% to 49% of drug-induced cases. The most common class of medications causing allergic interstitial nephritis are nonsteroidal anti-inflammatory drugs (NSAIDs). Other commonly implicated drugs include indinavir, proton pump inhibitors (particularly lansoprazole and omeprazole), allopurinol, 5-aminosalicylates, diuretics, and cimetidine. Numerous case reports in the literature regarding other medication culprits demonstrate the need for ongoing consideration of allergic interstitial nephritis as a potential cause of worsening renal function after initiation of drug therapy. Polypharmacy, particularly in the elderly population, has made the identification of the causative agent challenging in many cases ⁸.

Allergic interstitial nephritis symptoms

Patients with allergic interstitial nephritis may present with the classic triad of rash, fever, and eosinophilia (in 10% of cases), but often present with mild worsening of renal function, prompting further investigation. Initial workup of the suspected condition should include a thorough history and physical examination with particular attention to over-the-counter medications such as NSAIDs and any recently introduced medications. The physical exam is only positive for rash, fever, and eosinophilia in 15%, 27%, and 23% of cases, respectively.

Worsening renal function, eosinophilia (about 30% of cases), eosinophiluria, white blood cells in the urine, proteinuria (typically non-nephrotic), and evidence of tubular injury (e.g., high fractional excretion of sodium, Fanconi syndrome) are common laboratory findings.

Allergic interstitial nephritis may occur as quickly as three days to several months after exposure to a drug. An earlier presentation is typically associated with the repeated exposure to offending drugs ⁹.

Allergic interstitial nephritis diagnosis

A thorough laboratory workup with a complete blood count with differential, comprehensive metabolic profile, urine eosinophils, and urinalysis with microscopy is indicated. If clinically warranted, a renal biopsy may be considered to make a definitive diagnosis. There is no imaging test to evaluate for allergic interstitial nephritis.

Allergic interstitial nephritis treatment

In patients with suspected or confirmed allergic interstitial nephritis, the mainstay of treatment is discontinuation of the offending agent. Immunosuppressive therapy has been used to treat allergic interstitial nephritis, but the paucity of randomized controlled trials has limited the evidence for this approach. Several small, uncontrolled studies have suggested improvement with the use of steroids, with the most improvement noted in patients receiving steroids within seven days of drug withdrawal. A wide variety of treatment regimens have been employed, with steroid therapy administered for one to 12 weeks. There is currently no preferred standard treatment regimen, although experts agree that a short course of steroids (less than 12 weeks) is likely sufficient. Steroids are generally considered if there has been no improvement in renal function within three to seven days after withdrawal of the offending drug.

There have been small case series evaluating mycophenolate mofetil and cyclosporine as options for therapy in glucocorticoid-dependent and resistant patients. Further study will need to be performed before this approach can be recommended ¹⁰.

Allergic interstitial nephritis prognosis

The prognosis of allergic interstitial nephritis is favorable in cases where a diagnosis has been made promptly. Predictors of decreased likelihood of recovery include interstitial fibrosis, interstitial granulomas, and tubular atrophy on renal biopsy. allergic interstitial nephritis with renal failure for greater than three weeks portends a worse prognosis, likely due to the development advanced fibrotic features on biopsy. NSAID-related allergic interstitial nephritis also is associated with a worse prognosis.

Acute hemodialysis has been required in as many as 30% to 69% of patients. One series revealed that 26% of patients with allergic interstitial nephritis ultimately returned to their baseline renal function, while 4% of patients required long-term renal replacement therapy. Another series noted a more favorable prognosis, with 74% of patients returning to their baseline renal function after six weeks of withdrawal of the offending drug.

Allergic interstitial nephritis due to proton-pump inhibitors has been noted to have less severe acute kidney injury but with less likelihood to recover by six months, which has been attributed to the likelihood of prolonged drug exposure.

Interstitial nephritis causes

The following can cause interstitial nephritis:

• Allergic reaction to a drug (acute allergic interstitial nephritis).
• Autoimmune disorders, such as antitubular basement membrane disease, Kawasaki disease, Sjögren syndrome, systemic lupus erythematosus, or granulomatosis with polyangiitis.
• Infections.
• Long-term use of medicines such as acetaminophen (Tylenol), aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs). This is called analgesic nephropathy.
• Side effect of certain antibiotics such as penicillin, ampicillin, methicillin, and sulfonamide medicines.
• Side effect of certain medicines such as diuretics (water pills) e.g., furosemide, thiazide diuretics, omeprazole, triamterene, and allopurinol.
• Too little potassium in your blood.
• Too much calcium or uric acid in your blood.

Interstitial nephritis may occur 2 or more weeks after you start a medicine. Talk to your doctor if you have any questions about a medicine you are taking.

Interstitial nephritis prevention

Often, interstitial nephritis can’t be prevented. Avoiding or reducing your use of medicines that can cause this condition can help reduce your risk. If needed, your provider will tell you which medicines to stop or reduce.

Interstitial nephritis 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.

The most common symptom of interstitial nephritis is a decrease in the amount of urine you produce. Other symptoms can include:

• Increased or decreased urine output.
• Blood in your urine or dark urine.
• Nausea or vomiting.
• Fever or rash.
• Elevated blood pressure.
• Changes in mental status, such as drowsiness, confusion or coma.
• Swelling of any area of your body.
• Sudden weight gain (this can be caused by extra fluid in the body).

Interstitial nephritis possible complications

Metabolic acidosis can occur because the kidneys aren’t able to remove enough acid. The disorder can lead to acute or chronic kidney failure or end-stage kidney disease.

Interstitial nephritis diagnosis

Your doctor will ask you about your medical history, including what medicines you take. Your doctor will listen to your heart and lungs for signs of excess fluid. This is a sign of kidney failure. Your doctor will check you for high blood pressure, which also is a sign of kidney problems.

This may reveal:

• Abnormal lung or heart sounds
• High blood pressure
• Fluid in the lungs (pulmonary edema)

Common tests include:

• Arterial blood gases
• Blood chemistry
• BUN and blood creatinine levels
• Complete blood count
• Kidney biopsy
• Kidney ultrasound
• Urinalysis

If you have one or more symptom, your doctor may test your urine (called a urinalysis) and your blood. He or she could also order imaging tests of your kidneys, such as an ultrasound. If something is found, they may order a biopsy.

Interstitial nephritis treatment

Interstitial nephritis is caused by an underlying problem. So treatment depends on what is causing the interstitial nephritis. If the interstitial nephritis is an infection, your doctor will treat the infection. If a medicine is causing interstitial nephritis, your doctor will probably have you stop taking the medicine. In some cases, corticosteroids or cyclophosphamide (medicines that reduce inflammation) may help. Dialysis, a treatment that uses a special machine to filter the blood, is sometimes necessary.

Limiting salt and fluid in the diet can improve swelling and high blood pressure. Limiting protein in the diet can help control the buildup of waste products in the blood (azotemia), which can lead to symptoms of acute kidney failure.

Living with interstitial nephritis

In most cases, interstitial nephritis is a short-term problem. Treatment of the underlying problem cures the condition. Rarely it can lead to long-term or permanent kidney damage, such as chronic kidney failure. This is more likely to happen in older adults.

Interstitial nephritis prognosis

Most often, interstitial nephritis is a short-term disorder. 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.

References

1. Wilson GJ, Kark AL, Francis LP, Hoy W, Healy HG, Mallett AJ. The increasing rates of acute interstitial nephritis in Australia: a single centre case series. BMC Nephrol. 2017;18(1):329. Published 2017 Oct 31. doi:10.1186/s12882-017-0747-7 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664794/
2. Tubulointerstitial Nephritis. https://emedicine.medscape.com/article/243597-overview
3. Praga M, Sevillano A, Auñón P, González E. Changes in the aetiology, clinical presentation and management of acute interstitial nephritis, an increasingly common cause of acute kidney injury. Nephrol Dial Transplant. 2015;30:1472–1479. doi: 10.1093/ndt/gfu326
4. Vu T, Hurst H. Acute kidney injury in Australia: a first national snapshot. Canberra, Australia: Australian Institute of Health and Welfare; 2015.
5. Baker RJ, Pusey CD. The changing profile of acute tubulointerstitial nephritis. Nephrol Dial Transplant. 2004;19(1):8-11
6. Finnigan NA, Bashir K. Allergic Interstitial Nephritis (AIN) [Updated 2019 Feb 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482323
7. Gaudreault-Tremblay MM, Litalien C, Patey N, Merouani A. Severe Acute Kidney Injury and Multiple Organ Failure in a 17-Day-Old Newborn: When Pathology Makes the Difference. Can J Kidney Health Dis. 2018;5:2054358118804834
8. Lomboy JR, Jose F. Allergic Interstitial Nephritis Masquerading as Pyelonephritis in a Pediatric Patient With Crohn Disease. J. Pediatr. Gastroenterol. Nutr. 2017 Jul;65(1):e18-e20
9. Moinuddin I, Bracamonte E, Thajudeen B, Sussman A, Madhrira M, Costello J. Allergic Interstitial Nephritis Manifesting as a Striated Nephrogram. Case Rep Med. 2015;2015:250530
10. Galesić K, Prkacin I, Tisljar M, Horvatić I, Ljubanović DG. [Drug induced allergic interstitial nephritis]. Lijec Vjesn. 2011 Jul-Aug;133(7-8):276-83