Acute Drug Induced Interstitial Nephritis

Slide 1 · Acute drug-induced

interstitial nephritis

Etiology • immune mechanisms • morphology • clinical correlation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Recognize the drug-exposure and hypersensitivity pattern

Explain the immune mechanisms and defining biopsy changes

Integrate urinary findings, renal impairment, differential diagnosis, and recovery

Slide 3 · An acute inflammatory injury of tubules and interstitium

The disease is a drug-associated form of tubulointerstitial nephritis.

Inflammation is centered on the renal interstitium and commonly invades tubules.

Tubular dysfunction and acute kidney injury may accompany the lesion.

Edema • infiltrate • tubulitis

Schematic — not a histologic specimen

Slide 4 · Why this diagnosis deserves recognition

Withdrawal of the offending agent is often followed by recovery.

Improvement can require months rather than days.

Irreversible renal damage remains possible if the injury is not resolved.

Suspect a drug trigger

Identify the exposure

Withdraw the offending drug

Follow renal recovery

Schematic — conceptual sequence

Slide 5 · Tubulointerstitial disease: A different clinical emphasis

The renal tubular and interstitial compartments are the principal sites of injury. Classic nephritic or nephrotic syndromes are generally absent in isolated tubulointerstitial disease.

Tubulointerstitial emphasis

Glomerular emphasis

Tubular dysfunction and azotemia

Nephritic or nephrotic syndrome

Polyuria/nocturia can occur

More conspicuous glomerular urinary syndrome

Interstitial/tubular lesion

Primary glomerular lesion

Slide 6 · Tubular dysfunction explains characteristic symptoms

Reduced urine-concentrating ability can produce polyuria or nocturia.

Tubular transport defects may cause salt wasting.

Impaired acid excretion may cause metabolic acidosis.

Tubular damage

Defective reabsorption / secretion

Altered urine concentration, salt and acid handling

Schematic — conceptual sequence

Slide 7 · Drugs can injure kidneys through three routes

Hypersensitivity reactions cause interstitial inflammation.

Direct or indirect toxic effects can cause acute tubular injury.

Cumulative, often subclinical injury may produce chronic renal disease.

Immune response

Acute interstitial nephritis

Acute tubular injury

Tubular epithelial injury

Cumulative injury

Delayed chronic kidney disease

Slide 8 · What makes drug-induced AIN distinct?

The central feature is an immune inflammatory lesion rather than isolated tubular toxicity.

Eosinophils, tubulitis and edema may coexist in the biopsy.

The same medication class can also cause other forms of kidney injury.

IMMUNE TRIGGER

INTERSTITIAL INFLAMMATION

TUBULAR DAMAGE

Schematic — conceptual sequence

Slide 9 · Historical clue: Sulfonamides

Drug-associated acute interstitial nephritis was first reported after sulfonamide use.

Later reports implicated multiple unrelated medication classes.

The broad drug spectrum favors an idiosyncratic immune response rather than a single chemical toxicity.

Initial sulfonamide reports

Broader antibiotic and diuretic recognition

NSAIDs and other agents

Slide 10 · Principal medication groups

Synthetic penicillins and other antibiotics are classic causes. Diuretics and NSAIDs are prominent non-antibiotic examples.

Class / group

Examples named in Robbins

Synthetic penicillins

Methicillin; ampicillin

Other antibiotic

Rifampin

Diuretic

Thiazides

Anti-inflammatory agents

NSAIDs

Other medications

Allopurinol; cimetidine; immune checkpoint inhibitors

Slide 11 · Synthetic penicillins: Classic examples

Methicillin and ampicillin are specifically named as frequent triggers.

These agents illustrate the acute drug-hypersensitivity phenotype.

The medication history must include the interval after initiation.

METHICILLIN / AMPICILLIN

Synthetic penicillins

Slide 12 · Rifampin: A non-penicillin antibiotic trigger

Rifampin is specifically included among implicated synthetic antibiotics.

The diagnosis should not be restricted to beta-lactam exposure.

Causality rests on the compatible clinical course and pathologic pattern.

RIFAMPIN

Other implicated antibiotic

Slide 13 · Thiazide diuretics and interstitial inflammation

Thiazides appear in the list of acute drug-induced AIN triggers.

Some thiazide-associated cases may show interstitial nonnecrotizing granulomas.

Granulomas are a possible pattern—not a required finding.

THIAZIDES

Diuretic-associated AIN

Slide 14 · NSAIDs: More than one renal lesion

NSAIDs can produce immune-mediated acute interstitial nephritis.

They can also reduce renal prostaglandin-dependent perfusion.

Minimal change disease or membranous nephropathy may occur as distinct glomerular injuries.

Hemodynamic AKI

Acute AIN

Minimal change disease

Membranous nephropathy

Slide 15 · Allopurinol and cimetidine

Both drugs are specifically identified among miscellaneous triggers.

Their inclusion illustrates the varied pharmacologic classes involved.

A recent exposure is more informative than assuming that only antibiotics are implicated.

ALLOPURINOL / CIMETIDINE

Miscellaneous drug triggers

Slide 16 · Immune checkpoint inhibitors

Immune checkpoint inhibitors are explicitly included in the Robbins list.

Their association extends the etiologic spectrum to anticancer immunotherapy.

A new cancer treatment should be part of the renal exposure history.

IMMUNE CHECKPOINT INHIBITORS

Immunotherapy exposure

Slide 17 · Drug causality begins with the timeline

The typical reported onset is 2–40 days following exposure.

A compatible interval strengthens suspicion but does not, alone, prove causation.

The same history must be interpreted alongside urinary and renal findings.

Drug exposure

Latent interval: 2–40 days

Renal/systemic findings

Slide 18 · Immune latency explains delayed onset

The latent interval is one of the observations supporting hypersensitivity.

A delay separates drug contact from clinically recognizable renal inflammation.

This is a mechanistic distinction from immediate concentration-dependent toxicity.

Drug exposure

Immune recognition / response

Tubulointerstitial injury

Schematic — conceptual sequence

Slide 19 · The injury is not dose-dependent

A lack of relation between drug dose and onset of nephropathy. This supports an idiosyncratic immune process.

Immune hypersensitivity

Simple dose toxicity

Not necessarily dose related

Risk often follows exposure burden

Latent inflammatory response

Direct tubular injury mechanism

Re-exposure can recur

Toxicity depends on toxic conditions

Slide 20 · Recurrence after re-exposure is strong evidence

Clinical and pathologic manifestations can recur after re-exposure.

The same drug or a chemically related drug may trigger recurrence.

This is an etiologic observation—not a recommendation for diagnostic rechallenge.

Initial sensitizing exposure

Clinical recovery

Re-exposure

Recurrent AIN

Schematic — conceptual sequence

Slide 21 · The hypersensitivity phenotype is variable

Fever, rash and eosinophilia are recognized manifestations.

Urinalysis and kidney function may show more direct evidence of renal involvement.

Not every finding must be present simultaneously.

Systemic

Fever, rash, eosinophilia

Urinary

Hematuria, mild proteinuria, leukocyturia

Renal function

Creatinine rise; AKI; Sometimes oliguria

Slide 22 · Fever can signal a systemic drug reaction

Fever is one of the characteristic systemic features.

In a patient exposed to a relevant medication, fever plus urinary changes raises concern.

Fever is not specific: Infection remains a competing clinical explanation.

DRUG EXPOSURE

FEVER

RENAL ABNORMALITY

Schematic — conceptual sequence

Slide 23 · Rash is supportive, not universal

Rash occurs in about 25% of cases description.

Therefore, most affected patients in that description did not have rash.

Absence of rash cannot exclude acute drug-induced AIN.

~25%

Reported with rash

Slide 24 · Peripheral eosinophilia may be transient

Eosinophilia is among the classic hypersensitivity features.

The text specifically notes that it may be transient.

A normal count at a single time point does not negate the overall clinical pattern.

Peripheral eosinophilia

May be transient

Interpret with timing and other findings

Schematic — conceptual sequence

Slide 25 · Do not require the complete clinical triad

Fever, eosinophilia and rash vary across patients.

Rash is absent in many patients, and eosinophilia may be transient.

The clinical assessment must integrate exposure, urine and renal function.

Timing

Compatible medication exposure

Clinical signs

Signs may be incomplete

Kidney findings

Urine and creatinine changes matter

Slide 26 · Hematuria reflects renal involvement

Hematuria is a reported urinary abnormality in acute drug-induced AIN.

It accompanies rather than defines the drug hypersensitivity syndrome.

Interpret it together with proteinuria and leukocyturia.

HEMATURIA

Urinary finding

Slide 27 · Proteinuria is usually mild pattern

The usual urinalysis description specifies mild proteinuria. Marked nephrotic protein loss suggests an additional or alternative lesion.

Typical acute AIN

NSAID + minimal change disease

Mild proteinuria

Nephrotic syndrome may appear

Predominant interstitial lesion

Podocyte-associated glomerular lesion

Glomeruli usually normal

Coexistent glomerular involvement

Slide 28 · Leukocyturia often accompanies AIN

Urinary white blood cells are a typical feature.

The urinary leukocyte population can include eosinophils.

Leukocyturia must be interpreted alongside possible urinary infection.

Interstitial/tubular inflammation

Leukocytes in urinary space

Leukocyturia ± eosinophils

Schematic — conceptual sequence

Slide 29 · Rising creatinine and acute kidney injury

A rising serum creatinine or acute kidney injury with oliguria in about 50% of cases.

Kidney functional impairment may therefore be clinically prominent.

The estimated percentage is source-specific, not a universal diagnostic sensitivity.

~50%

Reported with creatinine rise or AKI with oliguria

Slide 30 · Oliguria marks more severe functional disturbance

Oliguria can accompany acute kidney injury in the reported syndrome.

It signals clinically important reduction in urine output.

Not all patients develop oliguria, even when histologic inflammation is present.

OLIGURIA

Possible AKI manifestation

Slide 31 · Integrating the clinical manifestations

The drug exposure is the starting etiologic clue.

Systemic hypersensitivity findings support—but do not establish—the cause.

Urinary abnormalities and rising creatinine indicate renal injury.

Exposure history

Systemic clues

Urine + creatinine

Suspect drug-induced AIN

Schematic integration, not a validated score

Slide 32 · Hypothesis: Drugs generate modified self antigens

Binding of drug to a tubular plasma-membrane or extracellular component.

The modified component is recognized as an altered self antigen.

An immune response then damages tubular structures.

Drug binding

Modified self antigen

Immune activation

Tubular / basement-membrane injury

Schematic — conceptual sequence

Slide 33 · Targets include tubular cells and basement membranes

The elicited immune reaction is directed against tubular cells or tubular basement membranes.

The location of antigenic targets explains why tubular and interstitial compartments dominate.

This connects the proposed mechanism to the characteristic microscopic distribution.

Tubular wall immune infiltration

Schematic — not a histologic specimen

Slide 34 · Type I hypersensitivity: Supporting evidence

Some patients show increased serum IgE.

IgE-containing plasma cells and basophils can occur in lesions.

These observations suggest involvement of the late phase of an IgE-mediated reaction.

IgE-associated immune response

Basophils / IgE+ plasma cells

Interstitial inflammatory injury

Schematic — conceptual sequence

Slide 35 · IgE-associated findings are not universal

The described IgE and basophil findings occur in some patients. They support one plausible immunologic route but do not characterize every case.

Observed in some cases

Not required in every biopsy

Increased serum IgE

No universal IgE finding stated

IgE-containing plasma cells

Mononuclear infiltrate may dominate

Basophils

Granulomas may accompany T-cell pattern

Slide 36 · Type IV hypersensitivity: Supporting evidence

Mononuclear inflammatory infiltrates suggest cellular immune participation.

Granulomatous reactions occur in some cases.

Positive drug skin tests in some patients support delayed T-cell-mediated hypersensitivity.

Drug-related antigen

T-cell-associated reaction

Mononuclear / granulomatous injury

Schematic — conceptual sequence

Slide 37 · Two immune pathways converge on the same lesion

Type I–associated and type IV–associated features are described in different cases.

Both may culminate in tubulointerstitial inflammation and tubular injury.

The tissue pattern is therefore more consistent than a single immune signature.

Drug-associated altered self antigen

Type I–associated response

Type IV–associated response

Tubulointerstitial inflammation

Schematic — alternative injury pathways

Slide 38 · The interstitium is the center of the lesion

Histology often shows marked expansion of the interstitium.

Edema and inflammatory cells separate injured tubular profiles.

The appearance is distinct from a purely glomerular lesion.

Interstitial immune cells

Schematic — not a histologic specimen

Slide 39 · Interstitial edema expands tissue spaces

Interstitial edema can be pronounced.

The widened interstitial compartment accommodates and accompanies inflammatory infiltrates.

Tubules may appear spatially separated in an educational tissue schematic.

Expanded interstitium / edema

Schematic — not a histologic specimen

Slide 40 · Lymphocytes and macrophages predominate

The typical mononuclear infiltrate principally comprises lymphocytes and macrophages.

This is the dominant inflammatory-cell description in the pathology text.

Eosinophils are possible but not obligatory.

Lymphocytes

Macrophages

Cell icons are conceptual, not photomicrographs

Slide 41 · Eosinophils and neutrophils are variable

Both eosinophils and neutrophils may be present.

They can form clusters and may occur in large numbers.

A diagnostic description should not imply that eosinophils are invariably present.

Eosinophils

Neutrophils

Cell icons are conceptual, not photomicrographs

Slide 42 · Plasma cells and mast cells may contribute

Smaller numbers of plasma cells and mast cells can occur in the infiltrate.

Their presence broadens the inflammatory-cell spectrum.

An infiltrate is best described by its overall composition and distribution.

Plasma cells

Mast cells

Cell icons are conceptual, not photomicrographs

Slide 43 · The medulla may have conspicuous inflammation

Inflammation can be more prominent in the medulla.

The source relates this to concentration of the inciting agent.

Sampling location can therefore influence the pattern seen on a section.

Cortex and tubules

Medullary concentration of agents

Schematic — regional concept, not specimen

Slide 44 · Tubulitis means inflammatory cells within tubules

Lymphocytes infiltrate tubular structures, a finding termed tubulitis.

Tubulitis is common in drug-associated acute interstitial nephritis.

It links interstitial inflammation directly to epithelial injury.

Inflammatory cells crossing the tubular epithelium

Schematic tubulitis — not a biopsy image

Slide 45 · Tubular injury is accompanied by regeneration

Biopsies may show variable degrees of tubular epithelial damage.

Regenerative change can accompany that injury.

The severity of epithelial change need not be identical in every affected tubule.

Tubular injury

Epithelial regeneration

Schematic — regional concept, not specimen

Slide 46 · Granulomas: A selected morphological variant

Interstitial nonnecrotizing granulomas can occur with some drugs.

Methicillin and thiazides are named examples.

The text associates this pattern with tubular rupture; Granulomas are not required for AIN.

Nonnecrotizing granulomatous pattern

Conceptual cell aggregate — not histology

Slide 47 · Glomeruli are usually spared

Glomeruli typically appear normal in the routine drug-induced AIN lesion. This reflects the tubulointerstitial rather than primarily glomerular target.

Most drug-induced AIN

Some NSAID-associated cases

Glomeruli morphologically normal

Coexistent minimal change disease

Tubular and interstitial changes dominate

Nephrotic syndrome can develop

Mild proteinuria typical

Podocyte lesion affects presentation

Slide 48 · Reading a biopsy: Integrate four compartments

Interstitial edema and mononuclear cells form the principal inflammatory pattern.

Tubulitis and variable epithelial injury support tubular participation.

Review eosinophils, granulomas, and glomerular appearance as modifiers.

Edema • infiltrate • tubulitis

Schematic — not a histologic specimen

Slide 49 · Histology identifies a pattern, not always a culprit

Prominent interstitial inflammation is compatible with drug-induced AIN.

Eosinophils or granulomas may strengthen a hypersensitivity impression.

An exposure history is still required to attribute the lesion to a particular drug.

Biopsy pattern

Medication timing

Clinical phenotype

Etiologic interpretation

Schematic integration, not a validated score

Slide 50 · NSAIDs cause several distinct renal syndromes

COX-dependent prostaglandin inhibition is a mechanism of hemodynamic injury.

NSAIDs can also cause acute hypersensitivity interstitial nephritis.

Glomerular injuries may coexist or occur as separate syndromes.

Perfusion-related AKI

Acute AIN

Minimal change disease

Membranous nephropathy

Slide 51 · NSAID hemodynamic AKI: A different mechanism

Cyclooxygenase inhibition reduces vasodilatory renal prostaglandin synthesis.

A resulting ischemic decrease in renal perfusion can cause acute kidney injury.

Other kidney disease or volume depletion increases vulnerability.

NSAID inhibits COX

↓ Vasodilatory prostaglandins

Renal ischemic risk

Acute kidney injury

Schematic — conceptual sequence

Slide 52 · NSAID-associated AIN is immune-inflammatory

NSAIDs can trigger acute hypersensitivity interstitial nephritis. This pathway differs from prostaglandin-related renal vasoconstriction.

Hemodynamic NSAID injury

NSAID-associated AIN

Prostaglandin suppression

Immune interstitial reaction

Reduced renal vasodilatation

Interstitial infiltrate and tubulitis

Ischemic mechanism

Inflammatory renal lesion

Slide 53 · Minimal change disease can coexist with NSAID AIN

NSAID-related podocyte injury may occur with or without interstitial nephritis.

Concomitant minimal change disease can generate nephrotic syndrome.

This modifies the usual expectation of mild proteinuria in AIN.

NSAID exposure

Interstitial AIN

Podocyte minimal change disease

Schematic — alternative injury pathways

Slide 54 · Membranous nephropathy is another NSAID pattern

Membranous nephropathy with nephrotic syndrome is listed as a rare NSAID complication.

Its pathogenesis is described as uncertain.

It must be distinguished from the more typical isolated tubulointerstitial injury.

MEMBRANOUS NEPHROPATHY

Rare NSAID-associated glomerular lesion

Slide 55 · Four NSAID patterns: Tissue and mechanism

A single agent class can affect hemodynamics, tubules, interstitium or podocytes. Use the phenotype and tissue compartment to distinguish them.

Renal syndrome

Pathogenic / morphologic emphasis

Hemodynamic AKI

COX inhibition; reduced vasodilatory prostaglandins

Acute AIN

Interstitial immune inflammation

Minimal change disease

Podocyte injury; sometimes concurrent AIN

Membranous nephropathy

Rare glomerular injury; mechanism uncertain

Slide 56 · AIN versus acute tubular injury

AIN is defined by prominent interstitial inflammation and tubulitis. Acute tubular injury emphasizes epithelial damage, often with ischemic or toxic mechanisms.

Acute interstitial nephritis

Acute tubular injury

Immune-inflammatory insult

Ischemic / toxic insult

Edema + interstitial cells

Predominant tubular epithelial injury

Tubulitis often present

Tubular epithelial changes central

Drug latency / hypersensitivity clues

Perfusion or toxin exposure context

Slide 57 · AIN versus pyelonephritis: Etiologic contrast

Both can involve the renal interstitium and tubules. Pyelonephritis belongs to the infection category in the source classification.

Drug AIN

Pyelonephritis

Drug-associated immune response

Infectious tubulointerstitial process

Latency, rash or eosinophilia may occur

Infection-oriented clinical context

Variable eosinophils and mononuclear cells

Neutrophilic inflammatory pattern may be prominent

Slide 58 · Other causes of tubulointerstitial nephritis

Infections, toxins, metabolic causes and immunologic disorders can involve the compartment. Obstruction, inherited disease and plasma-cell disorders also enter the broader differential.

Category in Robbins Table 20.8

Illustrative examples

Infections

Pyelonephritis; other infections

Metabolic / toxic

Urate; hypercalcemia; heavy metals

Immunologic

Transplant rejection; Sjögren syndrome; sarcoidosis

Other

Obstruction; light-chain cast nephropathy

Slide 59 · Clinical reasoning: Combine three independent clues

Document the sequence of drug exposure and onset of renal abnormalities.

Assess systemic hypersensitivity manifestations without demanding all three.

Correlate urinary, creatinine, and biopsy findings where available.

Chronology

Hypersensitivity

Renal findings

Coherent diagnosis

Schematic integration, not a validated score

Slide 60 · Not every interstitial nephritis has an identified drug

In approximately 30–40% of affected patients, no offending drug or mechanism is identified.

A drug history is essential but cannot resolve all cases.

Avoid forcing a medication attribution without plausible evidence.

30–40%

No identified drug or mechanism description

Slide 61 · The first corrective step is removing the trigger

Withdrawal of the offending medication is the key clinical implication emphasized by Robbins.

Subsequent improvement supports the etiologic assessment.

The time course may be gradual and requires follow-up.

Recognize possible AIN

Remove offending exposure

Monitor renal recovery

Schematic — conceptual sequence

Slide 62 · Recovery can be delayed or incomplete

Renal recovery after withdrawal may take several months.

Some patients sustain irreversible damage.

A falling creatinine is encouraging but does not erase the need to assess residual dysfunction.

Drug withdrawal

Recovery over time

Possible residual impairment

Slide 63 · Case 1: The antibiotic-associated pattern

An adult begins a synthetic penicillin and later develops fever, rash, hematuria and rising creatinine.

The exposure interval is compatible with the Robbins 2–40-day description.

Which pathologic compartment and mechanism should the learner predict?

Discussion prompt: Predict mechanism and biopsy compartment

Slide 64 · Case 1: Expected pathologic interpretation

The drug chronology and systemic findings support hypersensitivity.

Expected morphology includes interstitial edema, mononuclear cells and frequent tubulitis.

Eosinophils may be conspicuous but are not mandatory.

History

Compatible penicillin interval

Biopsy

Interstitial edema + tubulitis

Qualifier

Eosinophils variable

Slide 65 · Case 2: NSAID exposure with heavy proteinuria

A patient receiving an NSAID develops kidney dysfunction and nephrotic syndrome.

Does nephrotic protein loss fit the typical isolated interstitial nephritis pattern?

What additional glomerular lesion is listed in the text?

Discussion prompt: Predict mechanism and biopsy compartment

Slide 66 · Case 2: Why NSAIDs require a broader differential

Minimal change disease can accompany NSAID-related AIN and cause nephrotic syndrome. Membranous nephropathy is another, rarer NSAID-related possibility.

Interstitial phenotype

Glomerular phenotype

Interstitial infiltrate / tubulitis

Minimal change or membranous lesion

Usually mild proteinuria

Nephrotic-range presentation possible

Drug hypersensitivity context

Podocyte / glomerular involvement

Slide 67 · Clinicopathologic pattern recognition

The most informative sequence is exposure → immune response → interstitial inflammation → functional consequence.

The histologic core is edema, mononuclear infiltrates and tubulitis.

The clinical phenotype is variable; The absence of rash or eosinophils does not remove AIN from consideration.

Exposure

Immune activation

Interstitial + tubular lesion

Renal clinical findings

Schematic — conceptual sequence

Slide 68 · Five points to retain

Drug-induced AIN is an immune inflammatory tubulointerstitial disorder.

Latent onset, dose independence and recurrence after re-exposure support hypersensitivity.

Edema, mononuclear cells and tubulitis are central; Eosinophils/granulomas vary.

NSAIDs can also cause distinct hemodynamic and glomerular syndromes.

Drug withdrawal is important; Recovery may be slow or incomplete.

Slide 69 · References

Primary teaching source: Robbins, Cotran & Kumar, Pathologic Basis of Disease, 11th ed. (2026), Chapter 20: The Kidney, p. 846.

Parent section used for context: Tubulointerstitial Nephritis Induced by Drugs and Toxins, pp. 845–846.

For an authentic morphology example, consult Robbins Fig. 20.27 (figure not reproduced here).