# Tubulointerstitial Nephritis

## Introduction

Tubulointerstitial nephritis encompasses a heterogeneous group of inflammatory diseases primarily affecting the renal tubules and interstitium, accounting for 15 to 27 percent of acute kidney injury cases identified on renal biopsy. Acute interstitial nephritis is the most clinically relevant form, with drug-induced AIN being the predominant etiology. Chronic tubulointerstitial nephritis can lead to progressive CKD through tubular atrophy and interstitial fibrosis. Both forms are frequently underdiagnosed due to their non-specific clinical presentation.

## Acute Interstitial Nephritis

### Drug-Induced AIN (70-75% of Cases)

Drug-induced AIN accounts for 70 to 75 percent of all cases and is mediated by a delayed-type (type IV) hypersensitivity reaction that is not dose-dependent and can recur with re-exposure to the same drug or cross-reactive agents. Antibiotics are classic offenders, including penicillins such as methicillin and ampicillin, cephalosporins, fluoroquinolones, sulfonamides, and rifampin. NSAIDs cause AIN through a unique mechanism in which prostaglandin inhibition shifts arachidonic acid metabolism toward the lipotriene pathway, promoting T-cell recruitment; NSAID-induced AIN can occur alone or with concurrent minimal change disease, producing the distinctive AIN-MCD complex. Proton pump inhibitors are increasingly recognized as a cause of AIN, with a typical onset of 2 to 3 months after initiation and often an insidious presentation; PPIs are now responsible for up to 10 to 15 percent of drug-induced AIN cases. Immune checkpoint inhibitors, particularly PD-1 inhibitors such as nivolumab and pembrolizumab more so than CTLA-4 inhibitors like ipilimumab, cause AIN with a median onset of 3 to 12 months and an incidence of 2 to 5 percent. Other implicated drugs include allopurinol, phenytoin, carbamazepine, thiazide diuretics, mesalamine in IBD patients, and other 5-aminosalicylates.

| Drug Class | Examples | Typical Onset | Classic Triad (Fever/Rash/Eosinophilia) | Associated Glomerular Lesion | Key Feature |
|-----------|---------|---------------|---------------------------------------|----------------------------|-------------|
| Beta-lactam antibiotics | Methicillin, ampicillin, cephalosporins | Days to weeks | Most common (~30%) | None | Classic drug-induced AIN |
| NSAIDs | All NSAIDs | Weeks to months | Rare (<5%) | MCD (nephrotic-range proteinuria) | AIN-MCD complex; elderly patients |
| Proton pump inhibitors | Omeprazole, pantoprazole | 2–3 months (insidious) | Rare | None | Underdiagnosed; 10–15% of drug-induced AIN |
| Checkpoint inhibitors | Nivolumab, pembrolizumab > ipilimumab | 3–12 months | Uncommon | None | Biopsy before steroids; 2–5% incidence |
| Fluoroquinolones | Ciprofloxacin, levofloxacin | Days to weeks | Variable | None | Often with systemic hypersensitivity |
| Allopurinol | — | Weeks | Variable (may have DRESS) | None | Part of allopurinol hypersensitivity syndrome |

### Infection-Associated AIN

Infection-associated AIN can result from bacterial, viral, or fungal pathogens. Bacterial causes include pyelonephritis from ascending infection, leptospirosis, Legionella, and Mycobacterium tuberculosis which produces granulomatous interstitial nephritis. Viral causes include CMV, EBV, HIV, polyomavirus particularly BK virus in the post-transplant setting, hantavirus, and SARS-CoV-2. Fungal causes include histoplasmosis and coccidioidomycosis.

### Autoimmune/Systemic AIN

Several autoimmune and systemic diseases cause characteristic patterns of interstitial nephritis. Sarcoidosis produces granulomatous interstitial nephritis, often accompanied by hypercalcemia from 1-alpha-hydroxylase activity within granulomas and an elevated ACE level. Sjogren syndrome causes lymphocytic interstitial nephritis and may present with distal (type 1) renal tubular acidosis and hypokalemia. IgG4-related disease produces IgG4-positive plasma cell-rich tubulointerstitial nephritis with elevated serum IgG4 levels, often in association with other organ involvement such as autoimmune pancreatitis and sclerosing cholangitis. TINU syndrome, or tubulointerstitial nephritis and uveitis, typically affects adolescent and young adult females and requires monitoring for relapsing uveitis. SLE can cause lupus-associated tubulointerstitial nephritis independent of glomerular disease.

### Clinical Presentation

The classic triad of fever, rash, and eosinophilia is present in fewer than 10 percent of AIN cases and is most commonly associated with beta-lactam antibiotics. AKI with rising creatinine over days to weeks, which may be non-oliguric, is the typical presentation. Urinalysis reveals sterile pyuria, white blood cell casts, and mild proteinuria in a tubular pattern, generally less than 1 to 2 grams per day. Eosinophiluria, historically detected using the Hansel stain, has poor sensitivity of approximately 40 percent and specificity of 72 percent and should not be relied upon to make or exclude the diagnosis. NSAID-induced AIN often presents with nephrotic-range proteinuria due to concurrent minimal change disease, typically lacks the classic triad, and is more common in elderly patients. PPI-induced AIN is characteristically insidious in onset, may lack systemic hypersensitivity features, and can progress to chronic TIN if unrecognized.

<image>Clinical presentation comparison of drug-induced acute interstitial nephritis by drug class. Create a table with four columns for different drug classes: beta-lactam antibiotics, NSAIDs, proton pump inhibitors, and immune checkpoint inhibitors. For each column, show: typical onset after drug exposure (days, weeks, or months), likelihood of classic triad (fever, rash, eosinophilia), typical proteinuria level, associated glomerular lesion (MCD with NSAIDs, none with others), urine sediment findings, response to steroids, and risk of chronic kidney disease if untreated. Use a visual timeline showing days-to-weeks for beta-lactams, weeks-to-months for NSAIDs, months for PPIs, and months for ICIs. Highlight that the classic triad is rare except with beta-lactam antibiotics.</image>

### Diagnosis

The diagnosis of AIN requires a high index of clinical suspicion, typically prompted by AKI in the context of new drug exposure combined with suggestive urinalysis findings. Gallium-67 scanning or FDG-PET, which shows diffuse renal uptake, can support the diagnosis but is rarely used in clinical practice. Renal biopsy remains the gold standard and is indicated when the diagnosis is uncertain, when empiric corticosteroids are being considered, when there is failure to improve after drug discontinuation, or when checkpoint inhibitor nephrotoxicity needs to be confirmed before starting high-dose steroids. Biopsy findings on light microscopy include interstitial edema with an inflammatory infiltrate composed of lymphocytes, eosinophils, plasma cells, and macrophages, along with tubulitis in which inflammatory cells invade the tubular epithelium, and tubular injury or necrosis. Immunofluorescence is usually negative or pauci-immune, with occasional linear tubular basement membrane staining in the rare anti-TBM disease. Electron microscopy shows no immune deposits in most cases. Granulomatous interstitial nephritis suggests sarcoidosis, tuberculosis, drug-induced causes, GPA, or Crohn disease.

### Treatment

Discontinuation of the offending drug is the most important intervention, with recovery expected in 60 to 70 percent of cases. Corticosteroid therapy remains controversial, as no randomized controlled trials exist. However, observational data from the CTIN study group suggest that early corticosteroid treatment initiated within 7 days of diagnosis is associated with better renal recovery. The typical regimen consists of prednisone at 1 mg/kg/day with a maximum of 60 mg for 2 to 4 weeks, followed by a taper over 4 to 8 weeks. Steroids should be considered if there is no improvement 5 to 7 days after drug discontinuation, if biopsy confirms AIN, if AKI is severe, or if the causative agent is a high-risk drug such as a checkpoint inhibitor. For ICI-associated AIN, the checkpoint inhibitor should be held and prednisone at 1 mg/kg/day initiated with a taper over 4 to 8 weeks; most patients achieve partial or complete recovery, and cautious rechallenge with the ICI may be considered with nephrology monitoring. Sarcoidosis-related TIN requires corticosteroids and may need prolonged therapy with steroid-sparing agents such as azathioprine, MMF, or hydroxychloroquine. IgG4-related disease shows a dramatic initial response to corticosteroids, with rituximab used for relapsing disease.

## Chronic Tubulointerstitial Nephritis

### Etiologies

Chronic TIN results from a wide range of etiologies. Drug-related causes include analgesic nephropathy, historically caused by phenacetin and now rare, lithium, calcineurin inhibitors, and Chinese herb nephropathy caused by aristolochic acid. Metabolic causes include hypercalcemia with nephrocalcinosis, hypokalemic nephropathy, hyperuricemia in the form of chronic urate nephropathy which remains debated, and oxalosis. Obstructive causes encompass chronic urinary tract obstruction from benign prostatic hyperplasia or stones and reflux nephropathy. Heavy metal exposure includes lead nephropathy, which is associated with saturnine gout and proximal tubular dysfunction, and cadmium. Hereditary causes include medullary cystic kidney disease and autosomal dominant tubulointerstitial kidney disease with mutations in UMOD, MUC1, REN, HNF1B, and SEC61A1, as well as nephronophthisis. Hematologic causes include sickle cell nephropathy, light chain cast nephropathy, and multiple myeloma. Infectious causes include chronic pyelonephritis, BK virus particularly in transplant recipients, and xanthogranulomatous pyelonephritis.

### Clinical Features

Chronic TIN presents with insidious onset CKD that is often discovered incidentally. The urine sediment is typically bland, without red blood cell casts and with minimal hematuria. Proteinuria is tubular in pattern, consisting of low-molecular-weight proteins such as beta-2 microglobulin, retinol-binding protein, and alpha-1 microglobulin, with total proteinuria usually less than 2 grams per day. Tubular dysfunction manifests as concentrating defects with polyuria and nocturia, salt wasting, renal tubular acidosis of type 1 or type 4, and Fanconi syndrome. Imaging typically shows small kidneys bilaterally, except in infiltrative diseases or polycystic and cystic conditions.

### Analgesic Nephropathy

Analgesic nephropathy results from chronic ingestion of combination analgesics, historically containing phenacetin combined with aspirin and caffeine. Renal papillary necrosis is the hallmark finding, identified by the characteristic "ring sign" on intravenous pyelography or CT representing calcified necrotic papillae. Patients have an increased risk of transitional cell carcinoma of the renal pelvis and ureters. This entity is now rare in developed countries following the withdrawal of phenacetin from the market.

### Lithium Nephropathy

Lithium nephropathy encompasses multiple renal manifestations. Nephrogenic diabetes insipidus is the most common renal effect, occurring in up to 40 percent of long-term users and presenting with polyuria and polydipsia. The mechanism involves lithium entering collecting duct principal cells via the epithelial sodium channel (ENaC), where it inhibits glycogen synthase kinase-3 beta and leads to downregulation of aquaporin-2 water channels. Chronic tubulointerstitial nephritis develops with interstitial fibrosis, tubular atrophy, and microcysts, which represent a unique histologic feature of lithium nephropathy. Incomplete distal (type 1) renal tubular acidosis and hypercalcemia from lithium-induced hyperparathyroidism are additional renal effects. Amiloride is the treatment of choice for lithium-induced nephrogenic DI because it blocks lithium entry through ENaC, potentially ameliorating both the diabetes insipidus and further tubular injury. Lithium levels must be monitored as clearance may be reduced. The CKD risk increases 1.5 to 2-fold with more than 10 to 15 years of lithium use.

<image>Diagnostic approach algorithm for tubulointerstitial nephritis. Start with clinical suspicion: AKI or CKD with bland sediment and tubular-range proteinuria (<2 g/day). First branch: Acute vs Chronic TIN. For acute TIN: review medication list (recent drug additions in past days to months), check for systemic signs (fever, rash, eosinophilia, uveitis), urinalysis (sterile pyuria, WBC casts), and urine eosinophils (low sensitivity). If drug-induced suspected: discontinue drug, observe for improvement. If no improvement in 5-7 days: renal biopsy → if confirmed AIN: corticosteroids. For chronic TIN: evaluate for metabolic causes (calcium, potassium, uric acid), drug history (lithium, analgesics, CNIs), imaging for obstruction/stones, lead levels if risk factors, genetic testing if familial. Show key biopsy features for each: acute (interstitial edema, lymphocytic infiltrate, tubulitis, eosinophils) vs chronic (interstitial fibrosis, tubular atrophy, mononuclear infiltrate).</image>

### Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)

ADTKD, formerly known as medullary cystic kidney disease type 2, is caused by mutations in several genes including UMOD encoding uromodulin, MUC1, REN, HNF1B, and SEC61A1. The disease presents as progressive CKD without significant proteinuria or hematuria, with a bland urine sediment and small kidneys. UMOD mutations are associated with hyperuricemia and gout resulting from reduced urate excretion, with ESRD typically developing between ages 30 and 70. MUC1 mutations pose particular diagnostic challenges due to the variable nucleotide tandem repeat in the affected region. No specific treatment exists; management consists of supportive CKD care.

## Key Clinical Pearls

- The classic triad of AIN (fever, rash, eosinophilia) is present in <10% of cases; absence does not exclude the diagnosis
- PPI-induced AIN is increasingly recognized and underdiagnosed; consider in any patient with unexplained CKD or AKI on chronic PPI therapy
- Eosinophiluria has poor sensitivity and specificity for AIN; do not rely on it to make or exclude the diagnosis
- Early corticosteroid treatment (within 7 days of diagnosis/drug discontinuation) is associated with better renal recovery in observational studies; delay in steroid initiation and prolonged AKI duration predict incomplete recovery and chronic damage
- ICI-associated AIN requires renal biopsy confirmation before starting high-dose steroids; other diagnoses (ATN from hemodynamic causes, tumor infiltration) must be excluded

## References
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