Researchers finds two protein biomarkers to diagnose acute interstitial nephritis (AIN)

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A team led by Johns Hopkins Medicine researchers says it has identified two protein biomarkers in urine that may one day be used to better diagnose acute interstitial nephritis (AIN), an underdiagnosed but treatable kidney disorder that impairs renal function in the short term and can lead to chronic kidney disease, permanent damage or renal failure if left unchecked.

The finding is reported in the May 16, 2019, issue of the Journal of Clinical Investigation Insight.

Acute interstitial nephritis is a condition marked by inflammation and swelling of the renal tubules, the tiny portals in the kidneys where blood is filtered.

As a result, the tubules cannot properly reabsorb water and useful organic substances, such as glucose and amino acids, or secrete waste products such as urea and creatinine into urine.

AIN is commonly the result of autoimmune diseases or allergic reactions to more than 100 medications, including antibiotics, pain relievers and antacids.

The disease is estimated to cause 15 to 20% of all hospitalizations for acute kidney injury.

Currently, the only method of diagnosing AIN is by examining renal tissue obtained with a biopsy, putting patients at some risk from complications.

Additionally, samples can sometimes be misinterpreted or yield inconclusive results.


Tubulointerstitial nephritis (TIN) is a frequent cause of acute kidney injury (AKI) that can lead to chronic kidney disease (CKD).

TIN is associated with an immune-mediated infiltration of the kidney interstitium by inflammatory cells, which may progress to fibrosis.

Patients often present with non-specific symptoms, which can lead to delayed diagnosis and treatment of the disease.

Etiology of TIN can be drug-induced, infectious, idiopathic, genetic, or related to a systemic inflammatory condition such as tubulointerstitial nephritis and uveitis (TINU) syndrome, inflammatory bowel disease, or IgG4-associated immune complex multiorgan autoimmune disease (MAD).

It is imperative to have a high clinical suspicion for TIN in order to remove potential offending agents and treat any associated systemic diseases.

Treatment is ultimately dependent on underlying etiology. While there are no randomized controlled clinical trials to assess treatment choice and efficacy in TIN, corticosteroids have been a mainstay of therapy and recent studies have suggested a possible role for mycophenolate mofetil.

Urinary biomarkers such as alpha1-microglobulin and beta2-microglobulin may help diagnose and monitor disease activity in TIN. Screening for TIN should be implemented in children with inflammatory bowel disease, uveitis, or IgG4-associated MAD.

Allergic interstitial nephritis (AIN) is the most common form of acute interstitial nephritis. It is most often caused by exposure to a drug.

AIN is often associated with an acute decline in renal function and may be associated with permanent renal insufficiency.

The hallmark pathologic finding of AIN is a marked inflammatory infiltrate of the renal interstitium. 

The classic clinical picture of AIN (i.e., fever, rash, eosinophilia) was well-described with the use of methicillin, which caused AIN 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.[1][2][3]

Etiology

AIN 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 AIN are 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 AIN 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.[4][5][6]

Epidemiology

The frequency of AIN is likely underestimated, as the diagnosis can only be definitively confirmed with biopsy evaluation.

Renal biopsies are often deferred as a clinical suspicion often guides therapy.

 In addition, older adults subject to polypharmacy are more likely to develop AIN but may not be considered good candidates for a renal biopsy.

Given the lack of strong evidence to pursue immunosuppressant therapy, it is often the case that a biopsy would not change the treatment plan beyond discontinuing the likely offending agent.

When evaluating renal biopsies performed for acute kidney injury, interstitial nephritis was noted in 13% to 18% of cases.  

Pathophysiology

AIN is characterized by an inflammatory infiltrate in the renal interstitium.

The classic clinical triad of rash, fever, and eosinophilia is only present in about 10% of cases.

Worsening renal function, eosinophilia (about 30% of cases), eosinophiluria, WBCs 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.

Histopathology

AIN can be definitively diagnosed by renal biopsy.  Light microscopic evaluation typically reveals interstitial infiltrate with T-lymphocytes and monocytes, and possibly eosinophils, neutrophils, and plasma cells.

Tubulitis, with inflammatory infiltration of the tubular basement membrane, often is noted. Prolonged exposure to an offending drug may result in interstitial fibrosis and tubular atrophy, which portends a worse prognosis.


“What has been needed is a biological diagnostic tool that is safe, easy to get and measure, simple to interpret, consistent across patient populations and most importantly, extremely accurate at identifying AIN.” says Chirag Parikh, Ph.D., director of the Division of Nephrology at Johns Hopkins University School of Medicine and senior author of the new paper.

To find such a biomarker, Parikh and his colleagues looked for a substance linked to AIN’s most distinct characteristic, inflammation of the renal tubules, formally known as tubulitis.

Knowing that cytokines – proteins secreted by immune cells known as CD4+ T lymphocytes -are the agents causing inflammation of the tubules, the researchers measured the amounts of 12 urine and 10 blood plasma proteins in samples from 79 adult, biopsy-confirmed AIN patients, and compared them to the amounts in 186 adult kidney biopsy patients without an AIN diagnosis.

The results, reviewed independently by three pathologists, showed that none of the plasma biomarkers were associated with AIN, but that two proteins – tumor necrosis factor-alpha (TNF-α) and interluken-9 (IL-9) – were consistently seen in the urine of AIN patients.

Neither cytokine was present in the control samples, either in plasma or urine.

“Because both cytokines are seen in allergic diseases such as atopic dermatitis and food allergies, and AIN most often is the result of an allergic response, it makes sense to consider using them as diagnostic tools,” Parikh says.

“Additionally, we knew that IL-9 leads to the accumulation of mast cells that release histamine and other chemicals that induce allergic responses, and kidney biopsies from AIN patients frequently reveal the presence of mast cells,” he adds.

“This suggests that IL-9 may be the stronger link to AIN, and perhaps, the better candidate as a future predictive biomarker.”

To test the sensitivity of using IL-9 in this manner, the researchers compared its AIN-detecting ability in patients whose disease was confirmed by pathologists who evaluated biopsied material or was symptomatically diagnosed by clinicians prior to the biopsies.

“If biopsy diagnoses are considered 100% accurate, then IL-9 had a very comparable ranking of 84%, and this was significantly better than the 62 to 69% achieved by clinicians without biopsies,” Parikh says.

The next step for the research team, Parikh says, will be to verify the findings of this study in a larger group of patients and get support for the development of TNF-α and IL-9 as tools to complement AIN diagnosis by biopsy. He says the hope is that later, biomarkers can replace kidney biopsies altogether.

“Biopsy is currently the ‘gold standard’ for AIN diagnosis, but we believe that biomarkers will one day be a more robust, more accurate, more cost effective and more patient-friendly method,” Parikh says.

More information: Dennis G. Moledina et al. Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis, JCI Insight (2019). DOI: 10.1172/jci.insight.127456
Provided by Johns Hopkins University School of Medicine

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