J Med Cases

Journal of Medical Cases, ISSN 1923-4155 print, 1923-4163 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Med Cases and Elmer Press Inc

Journal website https://www.journalmc.org

Case Report

Volume 13, Number 7, July 2022, pages 322-329

Acute Interstitial Nephritis Induced by Clozapine

Figure 1. Periodic acid-Schiff staining displaying moderate mononuclear inflammation (circle) with associated tubular atrophy (arrow).

Figure 2. Hematoxylin and eosin staining demonstrating moderate mononuclear interstitial inflammation (square) with plasma cells and eosinophil (arrow).

**Table 1.** Laboratory Values During Hospitalizations
Parameters	On presentation	Reference range
HPF: high power field.
The first admission labs
Sodium (mmol/L)	141	135 - 145
Potassium (mmol/L)	4.0	3.5 - 5.1
Chloride (mmol/L)	108	98 - 106
CO₂ (mmol/L)	27	23 - 29
Anion gap (mmol/L)	10	8 - 14
Blood urea nitrogen (BUN) (mg/dL)	9	8 - 24
Creatinine (Cr) (mg/dL)	1.2	0.7 - 1.3
Glomerular filtration rate (mL/min)	60	> 90
White blood cells (× 10³/mm³)	6.5	4 - 10
Hemoglobin (g/dL)	15.6	14 - 16
Platelets (× 10³/mm³)	152	150 - 450
The second admission labs
Sodium (mmol/L)	137
Potassium (mmol/L)	3.5
Chloride (mmol/L)	104
CO₂ (mmol/L)	20
Blood urea nitrogen (BUN) (mg/dL)	12
Creatinine (Cr) (mg/dL)	1.61
Glomerular filtration rate (mL/min)	44
White blood cells (× 10³/mm³)	6.3
Hemoglobin (g/dL)	14.3
Platelets (× 10³/mm³)	224
Total creatinine phosphokinase (U/L)	32	35 - 232
Thyroid-stimulating hormone (mIU/mL)	0.9	0.5 - 4.5
Serum lithium level (mmol/L)	0.9	0.5 - 1.5
Urine analysis
Specific gravity	1.010
pH	6.0
Protein	None
Glucose	None
Blood	1+
Nitrite	Negative
Leucocyte esterase	Negative
White blood cells	5/HPF
Red blood cells	14/HPF
The third admission labs
Sodium (mmol/L)	135
Potassium (mmol/L)	4.8
Chloride (mmol/L)	102
CO₂ (mmol/L)	20
Blood urea nitrogen (BUN) (mg/dL)	19
Creatinine (Cr) (mg/dL)	2.1
Glomerular filtration rate (mL/min)	33
White blood cells (× 10³/mm³)	4.7
Hemoglobin (g/dL)	11.7
Platelets (× 10³/mm³)	144
Urine analysis
Specific gravity	1.026
pH	5.0
Protein	2+
Glucose	None
Blood	1+
Nitrite	Negative
Leucocyte esterase	Negative
White blood cells	21/HPF
Red blood cells	8/HPF

Table 1. Laboratory Values During Hospitalizations

Parameters

On presentation

Reference range

HPF: high power field.

The first admission labs

Sodium (mmol/L)

141

135 - 145

Potassium (mmol/L)

4.0

3.5 - 5.1

Chloride (mmol/L)

108

98 - 106

CO₂ (mmol/L)

23 - 29

Anion gap (mmol/L)

8 - 14

Blood urea nitrogen (BUN) (mg/dL)

8 - 24

Creatinine (Cr) (mg/dL)

1.2

0.7 - 1.3

Glomerular filtration rate (mL/min)

> 90

White blood cells (× 10³/mm³)

6.5

4 - 10

Hemoglobin (g/dL)

15.6

14 - 16

Platelets (× 10³/mm³)

152

150 - 450

The second admission labs

Sodium (mmol/L)

137

Potassium (mmol/L)

3.5

Chloride (mmol/L)

104

CO₂ (mmol/L)

Blood urea nitrogen (BUN) (mg/dL)

Creatinine (Cr) (mg/dL)

1.61

Glomerular filtration rate (mL/min)

White blood cells (× 10³/mm³)

6.3

Hemoglobin (g/dL)

14.3

Platelets (× 10³/mm³)

224

Total creatinine phosphokinase (U/L)

35 - 232

Thyroid-stimulating hormone (mIU/mL)

0.9

0.5 - 4.5

Serum lithium level (mmol/L)

0.9

0.5 - 1.5

Urine analysis

Specific gravity

1.010

6.0

Protein

None

Glucose

None

Blood

Nitrite

Negative

Leucocyte esterase

Negative

White blood cells

5/HPF

Red blood cells

14/HPF

The third admission labs

Sodium (mmol/L)

135

Potassium (mmol/L)

4.8

Chloride (mmol/L)

102

CO₂ (mmol/L)

Blood urea nitrogen (BUN) (mg/dL)

Creatinine (Cr) (mg/dL)

2.1

Glomerular filtration rate (mL/min)

White blood cells (× 10³/mm³)

4.7

Hemoglobin (g/dL)

11.7

Platelets (× 10³/mm³)

144

Urine analysis

Specific gravity

1.026

5.0

Protein

Glucose

None

Blood

Nitrite

Negative

Leucocyte esterase

Negative

White blood cells

21/HPF

Red blood cells

8/HPF

**Table 2.** Clinical Characteristics of AIN From Clozapine
Author	Age/gender	Other antipsychotics	Antibiotic use	Symptom onset	Fever	CRP	Symptoms subsided after stopping clozapine	Clozapine dose	Eosinophilia
AIN: acute interstitial nephritis; CRP: C-reactive protein; BID: twice a day; F: female; M: male.
Bassetti et al, 2021 [5]	54/F	Lurasidone, quetiapine	Yes	2 days	Yes	Not mentioned	Yes	50 mg daily	Not available
McLoughlin et al, 2019 [6]	56/F	Multiple typical and atypical antipsychotics	Yes	7 days	Yes	Elevated	Yes	275 mg daily	Present
Davis et al, 2019 [7]	59/M	Lithium, fluoxetine, fluphenazine, quetiapine, amantadine, depakote	No	21 days	No	Not mentioned	Yes	62.5 mg daily	Present
Caetano et al, 2016 [8]	25/M	Multiple but names not mentioned	No	20 days	Not mentioned	Elevated	Yes	300 mg daily	Not available
Chan et al, 2015 [9]	29/F	Quetiapine, sodium valproate	Yes	7 days	Yes	Not mentioned	Yes	700 mg daily	Not available
Parekh et al, 2014 [10]	54/M	Valproate	Yes	14 days	Yes	Elevated	Yes	100 mg daily	Not available
An et al, 2013 [11]	38/M	Lithium, valproate, risperidone	No	14 days	Yes	Elevated	Yes	200 mg daily	Not elevated
Mohan et al, 2013 [12]	53/F	Valproate	Yes	12 days	Yes	Not mentioned	Yes	200 mg daily	Present
Kanofsky et al, 2011 [13]	28/M	Lithium, valproate, haloperidol, perphenazine, benztropine	Yes	12 days	Yes	Not mentioned	Yes	125 mg daily	Present
Hunter et al, 2009 [14]	57/F	Lithium, valproate, olanzapine, levomepromazine, haloperidol	Yes	2 days	Yes	Elevated	Yes	12.5 BID (rechallenge)	Not mentioned
Siddique et al, 2008 [15]	26/M	Lithium, valproic acid. risperidone, clonazepam	No	14 days	Yes	Not mentioned	Yes	125 mg daily	Present
Au et al, 2004 [16]	33/M	Valproate, gabapentin, risperidone	Yes	2 weeks	Yes	Not mentioned	Yes	100 mg daily	Present
Estebanez et al, 2002 [17]	69/M	Valproate	No	3 months	Unable to obtain	Unable to obtain	Yes	Unable to obtain	Unable to obtain
Fraser et al, 2000 [18]	49/M	Flupentixol, thioridazine, mianserin	Yes	35 days	Yes	Not mentioned	Yes	200 mg daily	Not present
Southall et al, 2000 [19]	24/F	Not mentioned	No	8 days	Yes	Elevated	Yes	300 mg daily	Present
Elias et al, 1999 [20]	38/F	Lithium, trifluoperazine, fluphenazine, venlafaxine	No	11 days	No	Not mentioned	Yes	125 mg BID	Not mentioned

Table 2. Clinical Characteristics of AIN From Clozapine

Author

Age/gender

Other antipsychotics

Antibiotic use

Symptom onset

Fever

CRP

Symptoms subsided after stopping clozapine

Clozapine dose

Eosinophilia

AIN: acute interstitial nephritis; CRP: C-reactive protein; BID: twice a day; F: female; M: male.

Bassetti et al, 2021 [5]

54/F

Lurasidone, quetiapine

Yes

2 days

Yes

Not mentioned

Yes

50 mg daily

Not available

McLoughlin et al, 2019 [6]

56/F

Multiple typical and atypical antipsychotics

Yes

7 days

Yes

Elevated

Yes

275 mg daily

Present

Davis et al, 2019 [7]

59/M

Lithium, fluoxetine, fluphenazine, quetiapine, amantadine, depakote

21 days

Not mentioned

Yes

62.5 mg daily

Present

Caetano et al, 2016 [8]

25/M

Multiple but names not mentioned

20 days

Not mentioned

Elevated

Yes

300 mg daily

Not available

Chan et al, 2015 [9]

29/F

Quetiapine, sodium valproate

Yes

7 days

Yes

Not mentioned

Yes

700 mg daily

Not available

Parekh et al, 2014 [10]

54/M

Valproate

Yes

14 days

Yes

Elevated

Yes

100 mg daily

Not available

An et al, 2013 [11]

38/M

Lithium, valproate, risperidone

14 days

Yes

Elevated

Yes

200 mg daily

Not elevated

Mohan et al, 2013 [12]

53/F

Valproate

Yes

12 days

Yes

Not mentioned

Yes

200 mg daily

Present

Kanofsky et al, 2011 [13]

28/M

Lithium, valproate, haloperidol, perphenazine, benztropine

Yes

12 days

Yes

Not mentioned

Yes

125 mg daily

Present

Hunter et al, 2009 [14]

57/F

Lithium, valproate, olanzapine, levomepromazine, haloperidol

Yes

2 days

Yes

Elevated

Yes

12.5 BID (rechallenge)

Not mentioned

Siddique et al, 2008 [15]

26/M

Lithium, valproic acid. risperidone, clonazepam

14 days

Yes

Not mentioned

Yes

125 mg daily

Present

Au et al, 2004 [16]

33/M

Valproate, gabapentin, risperidone

Yes

2 weeks

Yes

Not mentioned

Yes

100 mg daily

Present

Estebanez et al, 2002 [17]

69/M

Valproate

3 months

Unable to obtain

Yes

Unable to obtain

Fraser et al, 2000 [18]

49/M

Flupentixol, thioridazine, mianserin

Yes

35 days

Yes

Not mentioned

Yes

200 mg daily

Not present

Southall et al, 2000 [19]

24/F

Not mentioned

8 days

Yes

Elevated

Yes

300 mg daily

Present

Elias et al, 1999 [20]

38/F

Lithium, trifluoperazine, fluphenazine, venlafaxine

11 days

Not mentioned

Yes

125 mg BID

Not mentioned

**Table 3.** Kidney Function Parameters and Management of AIN From Clozapine
Author	Onset of renal failure	Urine eosinophils	Hematuria	Proteinuria	Renal imaging	Renal biopsy	Steroids	Dialysis needs	Residual dysfunction
AIN: acute interstitial nephritis; CT: computed tomography; USS: ultrasound scan.
Bassetti et al, 2021 [5]	18 days	Not available	Not available	Not available	Normal size and morphology	Not done	Yes	No	None
McLoughlin et al, 2019 [6]	Not mentioned in initial exposure, 2 days after rechallenge	Not available	Present	Not available	Both kidney 13.3 cm and mild prominences of both pelvises	Acute interstitial nephritis with 90% plasma cells	Yes	No	Yes
Davis et al, 2019 [7]	21 days	Not available	Not available	Present	Not mentioned	Not done	Not used	No	Yes
Caetano et al, 2016 [8]	24 days	Not available	Not available	Not available	Normal kidneys	Not done	No mention	No	No
Chan et al, 2015 [9]	7 days	Present	Present	Present	Normal sized kidneys	Tubulointerstitial nephritis, eosinophil rich infiltrates with occasional granulomas	No	No	No
Parekh et al, 2014 [10]	6 weeks	Not available	Present	Present	Bilaterally enlarged kidney and increased cortical echogenicity	Tubulointerstitial nephritis	Yes	No	No
An et al, 2013 [11]	19 days	Not available	Present	Present	CT diffuse swelling of both kidneys	Not done	No	Yes	No
Mohan et al, 2013 [12]	3 months	Not available	Not available	Present	Not available	AIN with 50% interstitial scarring	Yes	No	Yes
Kanofsky et al, 2011 [13]	13 days	Not performed	Not available	Present	Not available	Not done	Yes	No	No
Hunter et al, 2009 [14]	1 month in initial exposure, 2 days after rechallenge	Not mentioned	Yes	Yes	Not available	Not done	No	No	No
Siddique et al, 2008 [15]	2 weeks	Present	Not mentioned	Yes	Not available	Not done	Yes	No	At discharge 1.36
Au et al, 2004 [16]	2 weeks	Not mentioned	Yes	Yes	USS bilateral echogenicity	Not done	No	No	At discharge 4.1
Estebanez et al, 2002 [17]	3 months	Unable to obtain	Unable to obtain	Yes	Unable to obtain	Acute interstitial nephritis	Yes	No	Unable to obtain
Fraser et al, 2000 [18]	42 days	Not mentioned	Not mentioned	Not mentioned	Not mentioned	Florid interstitial nephritis	Yes	Yes	No
Southall et al, 2000 [19]	8 days	Not mentioned	Yes	Yes	Not mentioned	Not done	No	No	No
Elias et al, 1999 [20]	11 days	Not mentioned	Not mentioned	Not mentioned	Not mentioned	Mononuclear cell interstitial infiltrate, frequent eosinophils, prominent granulomatous component	No	Yes	No

Table 3. Kidney Function Parameters and Management of AIN From Clozapine

Author

Onset of renal failure

Urine eosinophils

Hematuria

Proteinuria

Renal imaging

Renal biopsy

Steroids

Dialysis needs

Residual dysfunction

AIN: acute interstitial nephritis; CT: computed tomography; USS: ultrasound scan.

Bassetti et al, 2021 [5]

18 days

Not available

Normal size and morphology

Not done

Yes

None

McLoughlin et al, 2019 [6]

Not mentioned in initial exposure, 2 days after rechallenge

Not available

Present

Not available

Both kidney 13.3 cm and mild prominences of both pelvises

Acute interstitial nephritis with 90% plasma cells

Yes

Davis et al, 2019 [7]

21 days

Not available

Present

Not mentioned

Not done

Not used

Yes

Caetano et al, 2016 [8]

24 days

Not available

Normal kidneys

Not done

No mention

Chan et al, 2015 [9]

7 days

Present

Normal sized kidneys

Tubulointerstitial nephritis, eosinophil rich infiltrates with occasional granulomas

Parekh et al, 2014 [10]

6 weeks

Not available

Present

Bilaterally enlarged kidney and increased cortical echogenicity

Tubulointerstitial nephritis

Yes

An et al, 2013 [11]

19 days

Not available

Present

CT diffuse swelling of both kidneys

Not done

Yes

Mohan et al, 2013 [12]

3 months

Not available

Present

Not available

AIN with 50% interstitial scarring

Yes

Kanofsky et al, 2011 [13]

13 days

Not performed

Not available

Present

Not available

Not done

Yes

Hunter et al, 2009 [14]

1 month in initial exposure, 2 days after rechallenge

Not mentioned

Yes

Not available

Not done

Siddique et al, 2008 [15]

2 weeks

Present

Not mentioned

Yes

Not available

Not done

Yes

At discharge 1.36

Au et al, 2004 [16]

2 weeks

Not mentioned

Yes

USS bilateral echogenicity

Not done

At discharge 4.1

Estebanez et al, 2002 [17]

3 months

Unable to obtain

Yes

Unable to obtain

Acute interstitial nephritis

Yes

Unable to obtain

Fraser et al, 2000 [18]

42 days

Not mentioned

Florid interstitial nephritis

Yes

Southall et al, 2000 [19]

8 days

Not mentioned

Yes

Not mentioned

Not done

Elias et al, 1999 [20]

11 days

Not mentioned

Mononuclear cell interstitial infiltrate, frequent eosinophils, prominent granulomatous component

Yes