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Treatment of acute interstitial nephritis

Treatment of acute interstitial nephritis
Literature review current through: Jan 2024.
This topic last updated: Oct 28, 2022.

INTRODUCTION — Acute interstitial nephritis (AIN) classically presents as acute kidney injury (AKI) after the use of known offending drugs and is sometimes associated with the urinary findings of pyuria, hematuria, and white cell casts [1-4]. Less frequently, AIN may present as a component of DRESS (ie, drug reaction with eosinophilia and systemic symptoms) syndrome or be secondary to infection, sarcoidosis, or checkpoint inhibitor immunotherapy. Signs of systemic allergy, such as a maculopapular rash, peripheral eosinophilia, and eosinophiluria, are present in less than one-third of patients [5,6].

Proteinuria is common, but excretion is usually <1 g/day. However, nephrotic-range proteinuria may occur and presumably reflects cytokine-induced injury to the glomerulus or an underlying glomerular disease (eg, diabetic kidney disease). It is most often seen with AIN caused by nonsteroidal antiinflammatory drugs (NSAIDs) [7,8]. Histologically, AIN is characterized by the infiltration of T cells, macrophages, and plasma cells in the interstitial compartment. (See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'NSAID-induced AIN and nephrotic syndrome'.)

The treatment of AIN due to drugs will be reviewed here (algorithm 1). The manifestations and diagnosis of AIN and the approach to the management of patients diagnosed with infection-induced AIN, tubulointerstitial nephritis and uveitis, kidney sarcoidosis, and AKI due to checkpoint inhibitor immunotherapy are presented separately:

(See "Clinical manifestations and diagnosis of acute interstitial nephritis".)

(See "Tubulointerstitial nephritis and uveitis (TINU syndrome)".)

(See "Kidney disease in sarcoidosis".)

(See "Toxicities associated with immune checkpoint inhibitors", section on 'Kidney'.)

TREATMENT OF DRUG-INDUCED ALLERGIC INTERSTITIAL NEPHRITIS — Discontinuation of the potential causative agent is a mainstay of therapy; glucocorticoids are initiated in cases with severe impairment of kidney function or in patients who fail to improve with discontinuation of the offending drug.

There are no data from randomized, controlled trials or large observational studies that inform the treatment of AIN. Our approach is based upon low-quality data (algorithm 1).

Initial approach — The initial approach to treatment of AIN involves assessing the severity and the pace of progression of the injury.

Discontinue the offending agent — Our approach to drug discontinuation is as follows:

We discontinue the potentially offending drug in nearly all patients with suspected AIN.

If there are multiple potentially offending drugs, we generally discontinue them sequentially if the acute kidney injury (AKI) is mild; however, we discontinue them simultaneously if the AKI is severe.

However, we do not discontinue the potentially offending drug if the drug is a crucial treatment for a severe disease process, there are no reasonable alternatives, and the diagnosis is uncertain (eg, a kidney biopsy has not been performed).

Certain situations call for avoidance of entire classes and related classes of medications (eg, patients who develop AIN secondary to a cephalosporin should avoid other cephalosporins or penicillins).

Most cases of AIN are allergic reactions, as evidenced by frequent presence of systemic manifestations of hypersensitivity, absence of a dose-response relationship, improvement following cessation of the drug, and rapid recurrence following accidental re-exposure to the drug or a closely related antigen [9,10].

Patients with an imminent need for dialysis — Patients with AKI from suspected AIN that is severe enough to warrant dialysis within 24 to 72 hours of the initial evaluation should have a kidney biopsy and initiate glucocorticoid therapy without delay (unless contraindicated). Contraindications for a kidney biopsy are discussed in detail elsewhere. (See "The kidney biopsy", section on 'Contraindications'.)

In addition, treatment with glucocorticoids should be initiated promptly to limit the extent of damage caused by inflammation and to improve the chances of recovery. If biopsy can be performed on the same day as the initial evaluation, then waiting to start the glucocorticoids until immediately after the biopsy may be reasonable. However, sometimes dialysis may be necessary prior to the biopsy to reduce the risk of bleeding complications. In such situations, glucocorticoids should be initiated prior to biopsy since it should not alter the interpretability of the biopsy.

Some, but not all, contributors treat initially with 500 to 1000 mg of intravenous methylprednisolone daily for three days, followed by oral prednisone at 1 mg/kg daily for definitive management of AIN. Other contributors start prednisone therapy without first giving intravenous methylprednisolone. Thus, we think that either approach is reasonable.

Immunosuppressive therapy has been employed to treat AIN that persists despite discontinuation of the offending agent. However, the benefits of therapy are somewhat uncertain and based upon observational data, given the absence of randomized controlled trials to support this practice.

The best data supportive of glucocorticoid treatment come from a retrospective, multicenter study of 61 patients with biopsy-proven AIN, of whom 52 were treated with glucocorticoids [11,12]. Despite the small comparison group of nine patients who were not treated with glucocorticoids, those treated had a lower frequency of dialysis (4 versus 44 percent) and a lower serum creatinine level at 18 months (2.1 versus 3.7 mg/dL [186 and 327 micromol/L]). Among treated patients, those who started glucocorticoids within seven days of withdrawal of the offending drug were more likely to recover kidney function compared with those who started later (odds ratio [OR] 6.6, 95% CI 1.3-33.6). Other smaller studies have shown similar results [9,13,14].

However, not all studies have shown a benefit from glucocorticoids. As an example, in a retrospective analysis that included 95 patients with biopsy-proven, drug-induced AIN, 83 patients received prednisone and 12 did not [15]. There was no difference in the probability of recovery of kidney function at six months between the two groups. Additional retrospective studies have also questioned the benefits of glucocorticoids for AIN [4,16-19]. A lack of glucocorticoid effect in negative studies is thought to be due to inclusion of patients with more severe disease and those with nonsteroidal antiinflammatory drug (NSAID)-induced AIN, which does not respond to glucocorticoids [2,4,8]. (See 'NSAID-induced AIN' below.)

Patients without an imminent need for dialysis — Patients who develop AIN that is nonsevere without imminent need for dialysis may be observed for three to seven days after discontinuation of the potential offending agent. If the kidney function has not stabilized in this interval, then a kidney biopsy should be performed and glucocorticoids initiated, if AIN is confirmed. If a biopsy can be performed on the same day, then it may be reasonable to wait to start the glucocorticoids until immediately after the biopsy. We start prednisone at 1 mg/kg daily.

If kidney function stabilizes or improves during the three- to seven-day interval, then the offending medication should be added to the allergy list. In addition, if there is histologic confirmation of AIN, then the offending drug should be added to the allergy list as well.

NSAID-induced AIN — Nonsteroidal antiinflammatory drug (NSAID)-induced AIN does not generally respond to glucocorticoid therapy. The reasons for this are poorly understood. NSAID-induced AIN is discussed in detail elsewhere. (See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'NSAID-induced AIN and nephrotic syndrome'.)

Monitoring patients on therapy — Patients initiated on glucocorticoid treatment need to be monitored closely for response. Generally, if the offending agent is discontinued and glucocorticoids are initiated within seven days of appropriate interventions, then many, but not all, patients will begin to recover kidney function over the subsequent one to two weeks. Patients with other etiologies of AIN (ie, non-drug induced) may take longer to show initial recovery and require a longer overall duration of treatment.

Patients who show improvement in kidney function within one to two weeks of treatment may begin to taper after two full weeks of treatment at 1 mg/kg. Prednisone should be reduced by 10 mg every three to five days until a dose of 10 mg is reached, followed by a slower taper to prevent adrenal insufficiency. The total duration of treatment ranges from 4 to 12 weeks [2,9,13,14]. However, treatment length may be tailored to the individual with the assessment of response to, and side effects from, glucocorticoid therapy.

We take the following action in patients with drug-induced AIN who fail to recover within three to four weeks of withdrawing the offending agent and initiating glucocorticoids:

We consider alternate etiologies of AKI, especially if a biopsy was not performed to confirm AIN. If feasible, a biopsy should be performed at this time.

If AIN was confirmed by biopsy, then failure to recover may reflect substantial chronic kidney damage rather than acute inflammatory injury [20]. Thus, careful attention should be paid to the degree of interstitial fibrosis, presence of granulomatous inflammation, and other chronic histologic changes that may impact the degree of response to glucocorticoids. Such patients with severe chronic changes and no evidence of an acute inflammatory infiltrate are unlikely to improve and should have glucocorticoids tapered and discontinued.

However, if there is pathological demonstration of an inflammatory infiltrate composed of T cells, plasma cells, and eosinophils in the interstitium, then we would extend the course of glucocorticoids or replace the glucocorticoids with an alternative immunosuppressive agent. There are no high-quality data. However, in our practice, we would continue glucocorticoid therapy for a total of 8 to 12 weeks unless the patient developed a glucocorticoid-associated serious adverse event. If there is no response at 8 to 12 weeks, or if glucocorticoids could not be continued due to side effects, we would switch to mycophenolate mofetil (MMF). (See 'Patients who do not respond to initial therapy' below.)

Patients who do not respond to initial therapy — We use MMF, 1 to 2 g orally daily, in patients with biopsy-proven AIN and documented failure to respond to or withdraw from glucocorticoid therapy. Patients should be started at a dose of 1 g daily in divided doses and titrated up to a dose of 2 g daily, if tolerated.

There is limited experience with treating AIN with alternative immunosuppressive drugs. There are case reports and small series using MMF and cyclosporine [21,22] and anecdotal experience with use of cyclophosphamide.

MMF was used for 13 to 34 months in eight patients with biopsy-proven AIN who had responded to but who could not tolerate withdrawal of glucocorticoids after six months [21]. After addition of MMF, all patients were able to discontinue glucocorticoids, and only two patients failed to show improvement in serum creatinine (one with a positive antineutrophil cytoplasmic antibody [ANCA] and another with AIN of unknown etiology). The applicability of these results to drug-induced AIN is limited since this series only included two patients with drug-induced AIN.

TREATMENT OF ACUTE INTERSTITIAL NEPHRITIS DUE TO OTHER CAUSES — AIN can be seen in association with systemic diseases, autoimmune conditions, and the use of immune checkpoint inhibitors. (See "Clinical manifestations and diagnosis of acute interstitial nephritis", section on 'Etiology'.)

The treatment of AIN due to those causes is discussed elsewhere:

Sjögren's disease (see "Kidney disease in primary Sjögren's disease", section on 'Tubulointerstitial nephritis')

Sarcoidosis (see "Kidney disease in sarcoidosis")

Systemic lupus erythematosus (see "Lupus nephritis: Diagnosis and classification")

Immunoglobulin G4 (IgG4)-related disease

Tubulointerstitial nephritis and uveitis (TINU) syndrome (see "Tubulointerstitial nephritis and uveitis (TINU syndrome)", section on 'Management and prognosis')

Checkpoint inhibitory immunotherapy (see "Toxicities associated with immune checkpoint inhibitors", section on 'Kidney')

AIN can also occur as a component of DRESS, the treatment of which is discussed elsewhere. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)", section on 'Management'.)

AIN due to an infectious cause should be managed by appropriately treating the underlying infection.

PROGNOSIS — For drug-induced AIN, prognostic data are most available for methicillin, which is no longer available because it was estimated to cause AIN in up to 17 percent of patients who were treated for more than 10 days [2,9].

Recovery of kidney function was observed in the great majority of cases of AIN due to methicillin, either with discontinuation of the offending drug or with glucocorticoid therapy [2,9,16]. The proportion recovering kidney function appears to be lower in AIN due to drugs other than methicillin [2,16,23,24]. The prognosis of AIN due to other inciting factors (eg, sarcoidosis, infection) is not well described. Acute dialysis is often required [13,17,18], but only approximately 10 percent of patients remain dialysis dependent [3,4,23].

Recovery of kidney function is often incomplete, with persistent elevation of the serum creatinine concentration in up to 40 percent of patients [2,3]. As an example, in a review of published series of AIN in which many patients had a peak serum creatinine >5.5 mg/dL (500 micromol/L), the serum creatinine at the end of follow-up was less than 1.2 and 1.7 mg/dL (110 and 150 micromol/L) in 49 and 68 percent, respectively [2]. The final serum creatinine concentration did not correlate with the maximum value during AIN.

Clinical indicators of a decreased likelihood of recovery include prolonged kidney failure (greater than three weeks), AIN associated with nonsteroidal antiinflammatory drug (NSAID) use, and certain histologic findings (including interstitial granulomas, interstitial fibrosis, and tubular atrophy) on kidney biopsy. As an example, in a multicenter, retrospective study of 182 patients with biopsy-proven AIN treated with glucocorticoids, patients with >50 percent interstitial fibrosis on the initial biopsy were more likely to experience poor recovery (defined as <25 percent improvement in glomerular function) at six months compared with patients with a lesser degree of chronicity (odds ratio [OR] 8.7, 95% CI 2.7-27.4) [20].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Acute interstitial nephritis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Presentation – Acute interstitial nephritis (AIN) classically presents as acute kidney injury (AKI) after the use of known offending drugs and is sometimes associated with the typical urinary findings of pyuria, hematuria, and white cell casts. (See 'Introduction' above.)

Discontinue the offending drug – Most cases of AIN are allergic reactions, as evidenced by frequent presence of systemic manifestations of hypersensitivity, absence of a dose-response relationship, improvement following cessation of the drug, and rapid recurrence following accidental re-exposure to the drug or a closely related antigen. As such, discontinuation of the potential causative agent is a mainstay of therapy. Our approach to drug discontinuation is as follows (see 'Discontinue the offending agent' above):

We discontinue the potentially offending drug in nearly all patients with suspected AIN. Certain situations call for avoidance of entire classes and related classes of medications (eg, patients who develop AIN secondary to a cephalosporin should avoid other cephalosporins or penicillins).

If there are multiple potentially offending drugs, we generally discontinue them sequentially if the AKI is mild; however, we discontinue them simultaneously if the AKI is severe.

However, we do not discontinue the potentially offending drug if the drug is a crucial treatment for a severe disease process, there are no reasonable alternatives, and the diagnosis is uncertain (eg, a kidney biopsy has not been performed).

Glucocorticoid therapy in selected patients – In patients with biopsy-proven AIN, we suggest glucocorticoid therapy in addition to withdrawal of the offending agent rather than withdrawal of the offending agent alone (Grade 2C). An exception is nonsteroidal antiinflammatory drug (NSAID)-induced AIN, which does not generally respond to glucocorticoid therapy.

Our approach to timing of kidney biopsy and glucocorticoid therapy is as follows (see 'Patients with an imminent need for dialysis' above and 'Patients without an imminent need for dialysis' above and 'NSAID-induced AIN' above):

Patients with AKI from suspected AIN that is severe enough to warrant dialysis within 24 to 72 hours of the initial evaluation should have a kidney biopsy and initiate glucocorticoid therapy without delay (unless contraindicated). Some, but not all, contributors treat initially with 500 to 1000 mg of intravenous methylprednisolone daily for three days, followed by oral prednisone at 1 mg/kg daily for definitive management of AIN. Other contributors start prednisone therapy without first giving intravenous methylprednisolone. Thus, we think that either approach is reasonable.

Patients who develop AIN that is nonsevere without imminent need for dialysis may be observed for three to seven days after discontinuation of the potential offending agent. If the kidney function has not stabilized in this interval, then a kidney biopsy should be performed and glucocorticoids initiated if AIN is confirmed. We start prednisone at 1 mg/kg daily.

Monitoring and dose adjustment of glucocorticoids – Patients initiated on glucocorticoid treatment need to be monitored closely for response, which is usually seen within seven days of the onset of appropriate interventions. Patients who show improvement in kidney function within one to two weeks of treatment may begin to taper after two full weeks of treatment at 1 mg/kg. Prednisone should be reduced by 10 mg every three to five days until a dose of 10 mg is reached, followed by a slower taper to prevent adrenal insufficiency. However, treatment length may be tailored to the individual with the assessment of response to, and side effects from, glucocorticoid therapy. (See 'Monitoring patients on therapy' above.)

Glucocorticoid nonresponse – In patients with biopsy-proven AIN who do not respond to or who cannot tolerate prolonged glucocorticoid therapy, we suggest treatment with mycophenolate mofetil (MMF) (Grade 2C). (See 'Patients who do not respond to initial therapy' above.)

Prognosis – Clinical indicators of a decreased likelihood of recovery include prolonged kidney failure (greater than three weeks), AIN associated with NSAID use, and certain histologic findings (including interstitial granulomas, interstitial fibrosis, and tubular atrophy) on kidney biopsy. (See 'Prognosis' above.)

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