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Interstitial Nephritis


Interstitial Nephritis

Article Author:
Ruchi Naik
Article Editor:
Pavan Annamaraju
Updated:
10/23/2020 3:08:55 PM
For CME on this topic:
Interstitial Nephritis CME
PubMed Link:
Interstitial Nephritis

Introduction

The diagnosis of acute interstitial nephritis (AIN) was first described in a kidney biopsy specimen by William Thomas Councilman, the chief pathologist of Brigham Hospital in 1898. In a post mortem review of 42 cases, he described nonsuppurative interstitial lesions found predominantly in patients with streptococcal infection, which were later implicated in the immunopathogenesis of acute kidney injury (AKI). Over the years, AIN has been linked to a variety of infections, drugs, and systemic disorders.[1][2]

Etiology

Acute interstitial nephritis is associated with medications, infections, and systemic diseases. Drugs are the most common cause of AIN in all age groups. Antibiotics (penicillins, cephalosporins, ciprofloxacin) and nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently associated with AIN. Proton pump inhibitors (PPIs), 5-aminosalicylates, rifampin, allopurinol, and acyclovir are other common drugs that can cause AIN. AIN is also recognized as the most common renal lesion in AKI cases associated with immune checkpoint inhibitors (e.g., pembrolizumab).[3] In theory, any drug can precipitate AIN, and the list of the offending medications has been growing over time.  

Infections with the following organisms can cause AIN:

  • Bacteria- E. coli, Campylobacter, Salmonella, streptococci
  • Viruses- Human immunodeficiency virus (HIV), cytomegalovirus, Epstein-Barr virus, measles, mumps, polyoma, herpes simplex virus
  • Spirochetes- Leptospirosis, syphilis 
  • Parasites- Toxoplasmosis, leishmaniasis
  • Fungi - Histoplasmosis, coccidioidomycosis

Systemic disorders that have been found to cause AIN include sarcoidosis, Sjogren’s syndrome, IgG-4 related systemic disease, and systemic lupus erythematosus (SLE).

Idiopathic AIN is noted in certain unique disease entities such a TINU syndrome (tubulointerstitial nephritis and uveitis syndrome) and anti-tubular basement membrane (anti-TBM) disease. TINU syndrome presents with acute onset of granulomatous bilateral uveitis (redness, pain, and photophobia) and abnormal renal function from interstitial nephritis. Renal involvement usually precedes the eye manifestations but can occur concurrently. TINU is common in children and younger adults age < 20 years, although cases are reported in older age groups greater than 60. Women are affected more than men with no specific ethnic predominance. TINU is seen in 1%-2% of ophthalmology practices, but it represents up to a third of symptomatic acute bilateral uveitis cases in patients younger than 20 years. The pathogenesis of TINU remains elusive. A combination of genetic susceptibility (Class II human leukocyte antigen subtypes), autoimmune, infectious, and iatrogenic factors are suspected of playing a role.[4][5] A definitive diagnosis of TINU can be established by the combination of the presence of typical uveitis and interstitial nephritis on renal biopsy (histopathology) or by the presence of typical uveitis and meeting all three clinical criteria:[6]

  • Abnormal creatinine or reduced creatinine clearance
  • Abnormal urinalysis (low-grade proteinuria, microscopic hematuria, sterile pyuria, white blood cell casts, eosinophiluria, elevated b2 microglobulin)
  • Systemic illness for more than two weeks (fever, weight loss, fatigue, and elevated erythrocyte sedimentation rate, anemia, abnormal liver enzymes)

Anti-TBM disease presents with acute kidney injury or chronic kidney disease in all age groups. Polyuria and polydipsia are the usual accompanying symptoms. Microscopic hematuria and sub-nephrotic range proteinuria can be seen. Anti-TBM antibodies are implicated in the pathogenesis of this disease. The anti-TBM antibodies are directed against the tubulointerstitial nephritis antigen, specifically in the kidney's proximal tubular basement membrane (TBM). Antibody formation can be triggered by drug exposure. The characteristic findings that clinch the diagnosis are the presence of anti-TBM antibodies in the serum, interstitial mononuclear infiltrate with tubulitis, tubular injury on light microscopy, and strong linear IgG staining along the TBM on immunofluorescence. Electron microscopy does not show any immune complexes.[7]

Epidemiology

A kidney biopsy is required to establish the diagnosis of AIN affirmatively. Since in real-world practice, not all suspected AIN cases are biopsied either due to improvement in the renal function after stopping the offending agent or the condition is treated empirically, the true incidence of AIN is likely underestimated. According to large retrospective biopsy registries, AIN was present in 1% to 10% of all kidney biopsies, most of which were performed for suspected glomerulonephritis.

Among the biopsies performed specifically for AKI evaluation, the incidence of AIN was higher, ranging from 6.5% to 35%. Drug-induced AIN represents almost two-thirds of all cases of AIN. Infections (10% to 15%), systemic disorders (10% to 15%), and idiopathic causes (5% to 10%) account for the majority of the other causes of AIN. Elderly patients are more vulnerable to drug-induced AIN as compared to younger ones.[2][8]

Pathophysiology

The immune mechanism mediates the pathogenesis of drug-induced AIN. Drugs act as haptens that bind to the cytoplasmic or extracellular components of tubular cells during secretion and generate a host immune response. In some patients' serum, IgE levels are elevated, suggesting a type -1 hypersensitivity reaction. While in other cases, the latent period between drug exposure and development of a rash, eosinophilia, and presence of positive skin tests to drugs suggests a T-cell mediated type-IV hypersensitivity reaction.

The exact pathophysiology of infection associated with AIN is still unclear, though some mechanisms are proposed. Some microbial antigens can deposit in the interstitium (planted antigen) that can mimic a normally present antigen in the tubular basement membrane, inducing an immune response directed against this antigen. Additionally, direct cytopathic effects of the microorganism or the cytokine-mediated inflammation can explain the kidney damage.[8][9]

As outlined above, anti-TBM antibodies are implicated in the pathogenesis of the anti-TBM disease. The anti-TBM antibodies are directed against the tubulointerstitial nephritis antigen, specifically in the kidney's proximal tubular basement membrane (TBM). 

The pathogenesis of TINU is likely multifactorial. The ubiquitous findings of predominantly lymphocytic and monocytic interstitial infiltrate in the kidney biopsies and association with HLA specific subtypes support cellular immunity's role. More specifically, a delayed hypersensitivity type reaction mediated by the T-helper cell type TH1/TH17 axis is implicated in the pathogenesis of TINU syndrome.[2][5][10][11]

Histopathology

Interstitial edema and mononuclear cell infiltration, mostly T- lymphocytes into the tubules and interstitial space, are seen on light microscopy. Scattered plasma cells, macrophages, and occasionally noncaseating granuloma with eosinophils can also be found in the lesion. Interstitial fibrosis is often present. The extent of fibrosis is a key prognostic factor for renal recovery. When the AIN is associated with infection, the pathogen-specific molecular protein can be identified in the tissue samples.[11][12]

History and Physical

Acute interstitial nephritis typically presents with non-oliguric acute kidney injury, but oliguria can be present. The latent period between drug exposure and renal failure onset could be several weeks to months (e.g., NSAIDs) if the patient were naive to the drug. In contrast, a second exposure to the drug can lead to renal manifestations within a matter of a few days. 

Patients may remain asymptomatic or have non-specific symptoms such as nausea, vomiting, malaise, and flank pain. In a case series of 121 patients with AIN, 40% developed dialysis requiring renal failure. The other specific clinical features may be related to the AIN's underlying etiology, such as sarcoidosis or SLE. Drug-induced AIN typically presents with an allergic-type reaction with a skin rash, low-grade fever, and eosinophilia, though all three manifestations are infrequently present in a patient.  

The extrarenal manifestations of infection-associated AIN are mostly specific to infectious disease. Similarly, AIN's clinical features associated with systemic disorders correlate with the spectrum of that particular disorder (e.g., SLE, sarcoidosis, or Sjogrens). TINU is associated with bilateral uveitis and renal failure in young children and adolescents.[8][13][14]

Evaluation

When evaluating a patient with AKI, clinicians must pay attention to the temporal relationship between the timing of onset of AKI and exposure to a potential culprit drug. The classic triad of low-grade fever, skin rash and eosinophilia is present in only 10% of drug-induced AIN cases.

The most common urinary findings include sterile pyuria (82%) and subnephrotic range proteinuria (93%). White blood cell (WBC) casts can be present on sediment examination. Nephrotic range proteinuria can be seen with NSAIDs if there is a concomitant presence of minimal change disease or membranous nephropathy. Microscopic hematuria is reported in 67% of cases. Peripheral eosinophilia is seen in approximately 35% of drug-induced AIN cases and is less common with NSAIDs. Urine eosinophils, once considered a diagnostic marker, have proven to lack sensitivity and specificity, making it an unreliable test for making the diagnosis. A kidney biopsy is necessary for a definitive diagnosis.[8][13][14][15]

Treatment / Management

The mainstay of treatment of drug-induced AIN is the timely discontinuation of the offending drug. A renal biopsy must be promptly performed to establish a definitive diagnosis. The possibility of the absence of AIN on biopsy may impact a patient's medication regimen. The extent of interstitial fibrosis and delay in corticosteroid therapy initiation are risk factors linked to residual renal damage. If renal failure is severe, supportive therapy with dialysis may be required.  

There is a paucity of data from randomized controlled trials to guide the treatment for AIN. Observational studies have shown improved renal recovery with early initiation of corticosteroids. Corticosteroids suppress the T cell-mediated inflammation and may plausibly mitigate the development of fibrosis and residual renal damage. The available prospective studies with the limited study population have shown no differences in the efficacy of oral versus intravenous pulse doses of steroids to treat AIN. One of the potential regimens of steroid therapy can be administering intravenous methylprednisolone 500 mg for three days, followed by oral prednisone 1mg/kg for two weeks with a subsequent taper over 4 to 6 weeks.

Evidence of renal recovery is expected to be seen by two weeks on steroid therapy. In a study of 182 patients with biopsy-proven AIN, high dose steroid use for more than three weeks and steroid tapering over five weeks did not significantly benefit renal function recovery. Corticosteroids are considered for the treatment for AIN associated with sarcoidosis, TINU, and anti-TBM antibody-mediated disease with variable results.[2][8][9][10][11][13][16][17][18]

Differential Diagnosis

All other causes of AKI can be considered in the differential diagnosis of AIN. Vasculitis can present with AKI and a rash. The vasculitic rash is usually purpuric, while in drug-induced AIN, a maculopapular rash consistent with an allergic pattern is noted. Atheroembolic disease can present with a rash (livedo reticularis) and peripheral eosinophilia. Pre-renal AKI is associated with a history and exam findings consistent with volume depletion and clinically responds well with a fluid challenge. Post-renal AKI can be identified by renal imaging. Acute tubular necrosis (ATN) can be seen in the context of drug toxicity (e.g., vancomycin) and is associated with granular or muddy brown casts in urine sediment. Dysmorphic red blood cells (RBCs), red cell casts, and nephrotic range proteinuria are seen in glomerular diseases.

Prognosis

Initial studies of methicillin-associated AIN showed a favorable recovery of renal function in a majority of patients. However, recent reports of drug-induced AIN show higher residual renal damage rates in 40% to 50% of cases. NSAID-associated AIN portends a poor prognosis. The prognosis of AIN associated with other etiologies has not been fully understood. The factors associated with incomplete renal recovery are delay in the initiation of corticosteroid therapy, the duration of AKI, NSAIDs-associated AIN, and interstitial fibrosis, tubular atrophy on a renal biopsy.[2][8][9]

Complications

AKI, incomplete renal recovery with residual CKD are the major complications of AIN.

Deterrence and Patient Education

Antibiotics, NSAIDs, and proton pump inhibitors are commonly prescribed and over the counter medications that can precipitate AIN. While patients may or may not develop AIN's clinical symptoms, it can result in an irreversible loss in renal function. Therefore, patient education regarding the adverse effects is paramount. The patients must be advised to limit the use of these medications except when clearly indicated under the treating clinician's close supervision. If the patient develops any clinical symptoms such as nausea, vomiting, or a rash, they should seek medical attention.

Enhancing Healthcare Team Outcomes

Drug-induced AIN is the most common form of AIN. Many over-the-counter and common prescription medications can cause AIN. The clinicians play a crucial role in selecting medication based on patients' conditions and monitoring adverse reactions. A nephrologist should be consulted to evaluate the cause of renal failure and provide recommendations on medication management, renal biopsy, and devise a treatment plan. A pathologist can confirm the presence of AIN on a renal biopsy specimen. Pharmacists and nurses are vital to educating the patients about the adverse effects of medications. In severe cases of AIN, the patient may be hospitalized. Interprofessional care coordination by clinicians, nurses, pharmacists, and other health professionals is vital to enhancing patient-centered care and improving patient safety and outcomes.


References

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