Drug-induced acute tubulointerstitial nephritis (DI-ATIN) is primarily considered a T-cell–mediated delayed hypersensitivity reaction (type IV) occurring 7 to 10 days after exposure. The kidney susceptibility to hypersensitivity is influenced by factors such as high blood delivery and local drug metabolism. Drugs can induce antigens through various mechanisms. They can bind to circulating or intrinsic tubulointerstitial proteins in a process called haptenization (e.g., β-lactam antibiotics bind to lysine residues on circulating proteins, particularly albumin, to form an immunogenic complex); act as prohaptens such as sulfamethoxazole, which is modified by the CYP2C9 isoenzyme in the liver before spontaneously converting to the toxic nitroso-sulfamethoxazole, which then binds to cysteine residues on intracellular and extracellular proteins to form a hapten; or resemble native kidney antigens (molecular mimicry), leading to immune reactions.

Even though DI-ATIN is usually a type IV hypersensitivity reaction, it can cause injury through other pathways, too. Antitubular basement membrane (anti-TBM) TBM antibody deposition can occur with medications such as methicillin, rifampin, allopurinol, and phenytoin, which usually stain positive for IgG and C3 on immunofluorescence in a granular pattern. Nonsteroidal antiinflammatory drugs (NSAIDs) are implicated in a non–type IV drug-hypersensitivity reaction associated with lack of tissue eosinophil infiltrate on kidney biopsy. In addition, drugs and drug-hapten complexes can induce inflammation by directly forming immune deposits within the interstitium or precipitating in the form of circulating complexes. Examples of drugs that can cause this immune response include certain penicillins, cephalosporins, and phenytoin.

The kidney self-regulates the immune response through activation of suppressor T cells and downregulation of MHC class II expression. However, medications like checkpoint inhibitors used in cancer treatment can disrupt immune regulation. After antigens are presented, lymphocytes, neutrophils, macrophages, mast cells, and eosinophils infiltrate the interstitial space, with T lymphocytes constituting the majority of the infiltrative cells.

Certain antibiotics such as β-lactams (penicillins and cephalosporins), sulfonamides, and fluoroquinolones have been associated with ATIN. β-lactam antibiotics can lead to ATIN within a few days to a few weeks after antibiotic exposure. A hypersensitivity syndrome characterized by fever, morbilliform rash affecting the trunk, or eosinophilia is commonly observed with β-lactam antibiotics. About 75% of affected patients experience urinary abnormalities such as proteinuria, pyuria, or hematuria.

Sulfonamides tend to affect transplant recipients, HIV patients, and those with reduced kidney function more frequently due to their higher usage in these populations. Hypersensitivity syndromes are also common in this group.

Fluoroquinolones, especially ciprofloxacin, are commonly reported as a cause of DI-ATIN, likely due to their widespread use. Rifampin can induce dose-dependent ATIN accompanied by antirifampin antibodies, hemolytic anemia, thrombocytopenia, and hepatitis. Additionally, various antiviral agents have been associated with ATIN, especially in the HIV population.

The use of proton pump inhibitors (PPIs) for acid-related gastrointestinal disorders has been steadily increasing, and their association with ATIN has gained recognition. ^, According to a 10-year retrospective study in Australia, 64% of biopsy-confirmed cases of ATIN were linked to the use of PPIs. This kidney injury usually occurred 11 weeks after starting PPI treatment. In New Zealand, a population-based study revealed that PPI users had a fivefold higher risk of developing ATIN compared with nonusers, with the risk being particularly elevated in patients older than the age of 60. A similar study conducted in Ontario residents older than 66 years of age found a threefold increased hazard ratio for AKI and ATIN, requiring hospitalization within 120 days of initiating PPI therapy.

Diagnosing PPI-induced ATIN can be challenging because it often lacks systemic allergic symptoms. In fact, only a quarter of cases were suspected before kidney biopsy in a U.S. case series. PPI-induced ATIN generally has a favorable prognosis with 28.5% of cases showing complete recovery, 43% partial recovery, and 28.5% no recovery at 6 months’ follow-up. End-stage kidney failure (ESKF) has been reported in 11% to 12% of the cases. ^,

The use of PPIs has been linked to CKD, and it has been suggested that untreated episodes of AKI or ATIN might be the underlying cause.

NSAIDs including selective and nonselective cyclooxygenase (COX) inhibitors are commonly used for pain, fever, and inflammation. While their main drawback is gastrointestinal side effects, they can also cause various nephrotoxic effects, with hemodynamic AKI being the most prevalent. Selective COX-2 inhibitors (celecoxib) have fewer gastrointestinal side effects, but their nephrotoxic profile is similar to nonselective NSAIDs. The onset of ATIN is usually after 6 to 18 months of therapy, and hypersensitivity syndrome is rare.

Renal histology shows interstitial inflammation and tubulitis, but the intensity is less pronounced compared with other DI-ATIN forms, and interstitial eosinophils may be absent. Concomitant glomerular lesions can be observed, with minimal change disease being more common than membranous nephropathy. Lower degrees of inflammation seen on histology may be attributed to the antiinflammatory properties of these drugs and diversion of arachidonic acid metabolites into alternative pathways, suppressing immune function. Granulomatous lesions and TBM immune deposits have been reported with NSAIDs but are rare findings. Despite severe AKI, complete recovery in NSAID-induced ATIN has been described in approximately 70% of pediatric studies. ^,

With the advancement of cancer therapies, the nephrotoxic potential of various agents has come to light. Among them, targeted agents have shown efficacy in treating multiple cancers by specifically targeting gene mutations in malignant tissue and inhibiting oncogenic signaling cascades associated with tumor growth. Immune checkpoint inhibitors (ICPIs) stand out due to their increasing use, treatment effectiveness, and immune-related side effects. According to a narrative review by the Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors, the incidence of AKI in ICPI-treated patients can be as high as 10% to 30%. These inhibitors target ligands that bind inhibitory T-cell receptors, thereby activating host T cells and promoting infiltration of the tumor microenvironment and destruction of cancer cells. However, this immune activation can lead to T-cell invasion of other organs, with the skin, gastrointestinal tract, and liver being the most commonly affected. Kidney involvement presents in the form of autoimmune acute tubulointerstitial nephritis. Among them, ipilimumab, a monoclonal antibody against CTLA-4, is approved for advanced malignant melanoma, while nivolumab and pembrolizumab, PD-1 inhibitors, are approved for advanced melanoma and squamous cell lung cancer.

The largest series to date, a multicenter study of 138 patients with immune checkpoint inhibitor–associated AKI, revealed that lower baseline eGFR, PPI use, and combination therapy were independent risk factors for AKI. The median time for AKI development was 14 weeks after initiating ICPIs (ranging from 6 to 37 weeks) and 2 weeks after the last dose. It is worth noting that nearly 70% of patients were taking concomitant medications known to cause interstitial nephritis including antimicrobials, NSAIDs, and PPIs.

Clinically, most patients presented with proteinuria >0.3 g/g on urine protein–to–creatinine ratio (71%) and pyuria on urine sediment (≈50%). Peripheral eosinophilia, however, was not commonly observed (21%). Eighty-six percent of patients received corticosteroid treatment within 4 days of their serum creatinine doubling. Complete, partial, and no recovery of kidney function were observed in 40%, 45%, and 15% of patients, respectively.

Interestingly, rechallenge with ICPIs was attempted in 21% of cases, within an average of 1.8 months after the initial AKI episode. It is noteworthy that nearly 40% of these patients were receiving steroids at the time of rechallenge at doses ranging from 5 to 20 mg/day of prednisone. Unfortunately, 22% of patients experienced recurrent AKI within 1.4 months of rechallenge.

Before the ICPI era, the leading drugs associated with interstitial nephritis among cancer patients undergoing a kidney biopsy were ifosfamide (28%), bacillus Calmette-Guérin (12.5%), tyrosine kinase inhibitors (14%), and pemetrexed (9%). However, other drugs have been reported: BRAF inhibitors, bortezomib, platinum salts, lenalidomide, and many more. It is important to remember that cancer drugs cause AKI through several mechanisms including acute tubular necrosis, glomerulonephritis, and thrombotic microangiopathy. For a more detailed discussion on cancer and the kidney, see Chapter 57.

The immunologic mechanism underlying ATIN and the presence of extensive inflammatory infiltrate on kidney biopsy suggest that immunosuppressive therapy may be a viable treatment option. However, the use of corticosteroids in DI-ATIN is a controversial topic because existing evidence is derived from retrospective studies rather than randomized controlled trials, making it less definitive. These studies, which relied on clinical judgment to decide on steroid use, were small and underpowered to detect potential benefits. Nevertheless, they suggest that initiating a trial of corticosteroids within the first week of discontinuing the causative drug provides the greatest benefit ( Table 37.3 ). , ^, Late initiation of steroids has not shown improvement in kidney function, so in certain cases, drug withdrawal and steroid initiation are done simultaneously to prevent delays.

The initial approach involves discontinuing the offending agent. If kidney function fails to improve within 7 to 10 days of drug discontinuation, steroid therapy should be considered. Various corticosteroid regimens have been employed without significant differences in efficacy. ^{, ,} While no standardized approach exists, prednisolone is commonly administered at a dose of 1 mg/kg/day (maximum 60 mg/day) for 2 to 3 weeks, followed by a tapering period lasting 5 to 6 weeks. The majority of kidney function recovery occurs within the first 4 weeks of treatment. In cases where benefits continue to be observed during the tapering period, longer treatment courses can be considered until kidney function reaches its baseline level. However, using steroids for more than 8 weeks in total or tapering off for more than 5 weeks does not provide additional recovery advantages. ^, A multicenter, randomized, controlled clinical trial called PRAISE ( PR ednisolone Treatment Compared to Drug Withdrawal Alone in A cute I nter s titial N e phritis) is under way to provide further insights.

The response to steroids varies on the basis of kidney biopsy findings. Patients with more than 50% interstitial fibrosis on biopsy exhibit poor response, whereas those with neutrophilic infiltrate tend to have a favorable response. ^, Hence tissue diagnosis is crucial to not only initiate appropriate therapy but also evaluate the extent of scarring and potential for response. In cases where steroid therapy is not suitable, methotrexate, azathioprine, mycophenolate mofetil, or antitumor necrosis factor (anti-TNF) therapy can be used as steroid-sparing agents with promising outcomes. ^,

A variety of autoimmune disorders can lead to ATIN, more commonly in younger patients. The most common autoimmune diseases associated with interstitial nephritis include systemic lupus erythematosus (SLE), sarcoidosis, Sjögren syndrome, and tubulointerstitial nephritis and uveitis syndrome (TINU). Autoimmune TIN has a lymphocyte or plasma cell–rich infiltrate. Extraglomerular immune-complex deposition and immunofluorescence (IF) features are variable. Plasma cells are predominant in IgG4-related disease and Sjögren syndrome. Tubular basement membrane (TBM) immune-complex deposits are frequent in lupus, IgG4-related disease, and anti-LRP2 but are rare in Sjögren syndrome.

Lupus nephritis (LN) often presents with tubulointerstitial involvement, alone or in association with glomerular disease. While tubulointerstitial lesions have been reported in 50% to 70% of LN cases, current classifications focus primarily on glomerular lesions. Immune-complex deposits within the TBM drive the tubulointerstitial inflammatory lesion and are defined by positive stains for IgG, IgA, IgM, C1q, and C3 on immunofluorescence (“full house” pattern). ^, While these deposits are typically found in the TBM, the interstitium or peritubular capillary walls can also be affected. It is important to recognize that tubulointerstitial damage plays a significant role in predicting disease outcomes. In a study, 37% of patients with severe interstitial infiltrate progressed to kidney failure within 2 years.

Renal sarcoidosis manifests with various features including hypercalcemia, hypercalciuria, nephrocalcinosis, nephrolithiasis, and different glomerular lesions. Granulomatous interstitial nephritis is the most common intrinsic kidney lesion seen in 80% of cases. It is characterized by a diffuse inflammatory interstitial infiltrate that is composed of T lymphocytes, sometimes with noncaseating granulomas ( Fig. 37.2 ). Steroids are an effective therapy, although complete response is not always achieved, and some patients experience partial remission or no improvement in kidney function, leading to CKD. ^, Other immunosuppressive agents have been used in cases where steroids are not tolerated or are required long term.

Renal histology in sarcoidosis highlighting the inflammatory infiltrate and noncaseating granuloma.

Jones silver stain.

From Perazella MA. Clinical approach to diagnosing acute and chronic tubulointerstitial disease. Adv Chronic Kidney Dis . 2017;24:57–63.

Sjögren syndrome is a progressive autoimmune disorder primarily affecting the exocrine glands, such as the salivary and lacrimal glands. Kidney involvement is common, with estimates indicating it occurs in up to 40% of cases. Interstitial nephritis is the most frequently observed kidney lesion reported in more than 70% of biopsy series. ^{, ,} The primary feature of interstitial nephritis in Sjögren syndrome is lymphocytic infiltration, accompanied by tubular atrophy, tubulitis, and varying degrees of interstitial fibrosis. Tubular dysfunction manifests clinically as different tubulopathies, particularly distal RTA. The optimal treatment for interstitial nephritis in Sjögren syndrome remains uncertain. Immunosuppressive therapy including steroids, azathioprine, cyclophosphamide, rituximab, and hydroxychloroquine are commonly used.

Anti–LDL receptor–related protein 2 (LRP2) is an autoimmune disease manifested by IgG4 targeting brush border protein LRP2 (also known as “megalin”). The mean age of presentation is 73, and males are predominantly affected. LRP2 presents with AKI and subnephrotic levels of proteinuria, and patients progress to ESKF in 50% of cases. The IgG within the TBM deposits colocalizes only with LRP2 on confocal immunofluorescence, in contrast to other systemic diseases associated with IgG-containing TBM deposits, such as LN, IgG4-related kidney disease, and polyomavirus nephritis. Nonetheless, Anti-LRP2 nephropathy has been reported in patients with LN, minimal change disease, and low-grade B-cell lymphomas. Anti–B-cell agents such as rituximab or pulse corticosteroids with alkylating agents have shown variable success. However, immunologic remission has been associated with stabilization of kidney function after treatment with corticosteroids and cyclophosphamide.

Tubulointerstitial nephritis with IgM-positive plasma cells (IgMPC-TIN) is an entity that was described in 2017. Its major clinical features include high serum IgM (s-IgM) levels, distal renal tubular acidosis(100%), Fanconi syndrome (92%), and antimitochondrial antibodies (82%). Treatment with glucocorticoids is effective, although relapse can occur.

Other immune-related disorders that primarily affect the renal microvasculature and glomeruli, such as immune-complex diseases (SLE or IgA nephropathy) or pauci-immune vasculitides (ANCA), may have additional ATIN findings. Granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA) are types of ANCA-associated vasculitides that can cause granulomatous TIN and periglomerular eosinophilic infiltrate. MPO-ANCA-positive cases often show more tubulointerstitial inflammation or scarring.

Tubulointerstitial nephritis and uveitis (TINU) is a rare condition of unknown cause. The most comprehensive systematic review to date on 592 reported cases found that it predominantly affects females at a median age of 17 years. Drugs and genetic factors, such as HLA associations (e.g., DRB1 14, DQA1 01:04, and DQB1∗05 ), have been linked to susceptibility. ^{, ,} Additionally, infectious triggers like tuberculosis, Epstein-Barr infection, herpes zoster, and Campylobacter have been implicated. TINU has also been observed in conjunction with relapsing polychondritis.

TINU presents as a clinical syndrome primarily involving the eyes and kidneys. Generalized, nonspecific symptoms such as weight loss, fever, anemia, and hypergammaglobulinemia are the initial manifestations. Kidney involvement can appear as isolated proximal tubulopathy or Fanconi syndrome, while uveitis is usually bilateral and anterior. Even though it can occur before, during, or after the diagnosis of tubulointerstitial nephritis, uveitis often appears after the onset of renal symptoms (52% of cases).

Autoantibodies including ANCA, rheumatoid factor, anti-GBM antibody, and ANA are frequently observed in TINU patients. Renal histopathology commonly shows a predominance of CD3+ T lymphocytes, along with macrophages, plasma cells, and eosinophils. Granulomas are not common.

Steroids are the main treatment for both ocular and kidney manifestations. A 3- to 6-month course of prednisone is used, followed by a gradual taper to minimize the risk of relapse, which is relatively common. Other options to spare long-term steroid use include mycophenolic acid, methotrexate, cyclosporine, and cyclophosphamide. Adult age and the presence of posterior uveitis or panuveitis are associated with the development of CKD. However, ESKF is rare.

IgG4-related kidney disease (IgG4-RKD) is a systemic fibroinflammatory disorder that commonly affects middle-aged men and involves various organ systems including salivary glands, pancreas, retroperitoneum, and kidneys. Kidney involvement occurs in approximately 18% of cases, often in conjunction with other affected organs. Three different clinical phenotypes involving the kidney have been identified: obstructive uropathy from retroperitoneal fibrosis (the most common manifestation of IgG4-RKD), IgG4-related tubulointerstitial nephritis, and IgG-related glomerular lesions, particularly membranous nephropathy.

IgG4-related tubulointerstitial disease is rare compared with retroperitoneal fibrosis. It presents with acute, subacute, or chronic kidney dysfunction and mostly bland urinalysis with a median proteinuria of 0.6 g/g on urine protein–to-creatinine ratio. Elevated serum levels of IgG4 subclass antibodies and polyclonal hypergammaglobulinemia are seen in 94% and 90% of IgG4-RKD, respectively. In addition, hypocomplementemia (45%), a positive ANA (36%), and ANCA (22%) have been reported. It is important to note that elevated serum IgG4 levels are not specific to the disease because they can also be elevated in allergic, inflammatory, and neoplastic disorders. Imaging techniques such as contrast computed tomography (CT) or magnetic resonance imaging are abnormal in 61% of the cases, with pseudotumor (27%), low-density lesions primarily in the renal cortex (25%), and hypertrophy (19%) being among the most common findings. Pathologic tissue in IgG4-RKD is characterized by a plasma cell–rich tubulointerstitial nephritis with a predominance of IgG4-positive plasma cells. Interstitial fibrosis with a “storiform” pattern that is typified by a cartwheel appearance of arranged fibroblasts and inflammatory cells known as “bird’s eye” is characteristic of this disease. Immunohistochemistry shows >10 IgG4-positive plasma cells per high-power field (40× lens), which translates to an increased IgG4/IgG plasma cell ratio (>40%). Eosinophil infiltration is also frequent. TBM immune-complex deposits are found in 80% of cases and have nonspecific IF findings with positive IgG, kappa, and lambda, ±C3. Other reported kidney lesions include granulomatous ATIN, masslike kidney lesions ( Fig. 37.3 ).

IgG4-related kidney disease emulating malignancy.

(A) Magnetic resonance imaging (MRI) of the kidney with contrast showing multiple well-circumscribed right renal masses, the largest measuring 2.3 × 1.9 × 2.5 cm, with imaging characteristics suggestive of a malignancy, such as papillary renal cell carcinoma or lymphoma. (B) MRI of the kidney shows resolution of the right renal-enhancing lesions after treatment with steroids.

Images courtesy Dr. Mohamed G. Atta.

Treatment typically involves long-term glucocorticoid therapy, which generally yields favorable outcomes. However, a multidrug approach with agents like azathioprine, mycophenolic acid, or rituximab may be necessary. ^{, ,} Prognosis varies, and even individuals with significant fibrosis may respond well to immunosuppressive therapies, although relapses are common. In a recent retrospective study of 101 IgG4-RKD cases, IgG4 concentrations (≥5 g/L) were associated with more severe kidney disease. Complement consumption and the number of organs involved were associated with higher relapse rates, while rituximab as a first-line therapy has shown lower relapse rates. Recurrence after kidney transplantation has been reported.

Viral infections including cytomegalovirus (CMV), BK virus, and adenovirus are the primary causes of TIN in kidney transplant recipients. Prophylactic measures have successfully reduced CMV infections after transplantation. BK virus–associated nephropathy (BKVAN) affects 1% to 10% of recipients, peaking within 2 to 6 months post-transplantation. Adenovirus primarily affects the urinary tract within the first 3 months in 5% of recipients. The risk of CMV infection is highest when the donor is CMV seropositive and the recipient is seronegative. Besides infections, acute rejection can cause TIN, commonly presenting within the first-year post- transplant. Later episodes are usually due to nonadherence or deliberate reduction of immunosuppression. Cellular rejection is characterized by mononuclear cell infiltration, occasionally with eosinophils. Neutrophils are not common in cellular rejection and suggest infection or antibody-mediated rejection. T-cell–mediated rejection (TCMR) diagnosis is based on the Banff criteria.

Treatment of viral infections in kidney transplant recipients involves reducing immunosuppression and antiviral therapy. Antimetabolites are discontinued and may be resumed later at lower doses for high-risk rejection patients. For patients with CMV, serial viral monitoring and valganciclovir prophylaxis are recommended. Those with BK virus nephropathy require discontinuation of antimetabolites indefinitely, and reduction of calcineurin inhibitors is advised if viremia persists. Intravenous immunoglobulin can be considered. In cases of adenovirus infection, treatment includes immunosuppression reduction, cidofovir, and intravenous immunoglobulin. Finally, TCMR treatment varies on the basis of Banff criteria, involving increased immunosuppression and rabbit antithymocyte globulin in certain cases with minimal fibrosis and atrophy. For a more in-depth discussion, see Chapter 69 .