Tubulointerstitial Nephritis

Question 1

… … refers to a primary insult to the renal tubules and interstitium.

Answer 1

Tubulointerstitial nephritis refers to a primary insult to the renal tubules and interstitium.

Question 2

Tubulointerstitial nephritis (TIN) refers to inflammation of the renal tubules and interstitium that is most commonly the result of a hypersensitivity reaction to a medication (e.g. penicillin). This leads to acute inflammation with or without acute kidney injury (AKI).

Tubulointerstitial nephritis may be acute or chronic:

Answer 2

Acute TIN: develops over days or months. Majority of cases (~85%) due to drugs or infections. May cause AKI to variable severity.

Chronic TIN: develops over years. Continued tubulointerstitial insults lead to chronic inflammation and eventually fibrosis with decline in renal function. Most often seen with analgesic nephropathy, reflux nephropathy (due to chronic vesicoureteral reflux) or heavy metal nephropathy.

In this note, we mainly discuss acute TIN.

Question 3

A formal diagnosis of TIN (Tubulointerstitial nephritis) requires a renal biopsy.

Therefore, the incidence of TIN is probably underestimated. This is because a renal biopsy may not be performed in mild cases or in patients where the risk of a biopsy outweighs the benefit of the exact diagnosis.

Answer 3

A formal diagnosis of TIN requires a renal biopsy. Therefore, the incidence of TIN is probably underestimated. This is because a renal biopsy may not be performed in mild cases or in patients where the risk of a biopsy outweighs the benefit of the exact diagnosis.

Question 4

The most common cause of acute TIN is medications.

Approximately 85% of cases of acute TIN are due to medications or infections. The four major causes include:

Answer 4

Medications (70-75%): up to 50% of these are due to antibiotics
Systemic disease (10-20%): examples include sarcoidosis and Sjögren’s syndrome
Infections (4-10%): examples include Legionella and Leptospirosis
Tubulointerstitial nephritis and uveitis (TINU) syndrome (<5%)

Question 5

Commonly implicated drugs in Tubulointerstitial nephritis

Answer 5

NSAIDs
Antibiotics: Penicillin, Cephalosporins, Rifampicin, Ciprofloxacin, Co-trimoxazole
Proton pump inhibitors
Diuretics
5-aminosalicylates

Question 6

Rheumatological diseases are most commonly implicated in the development of acute TIN. These include systemic lupus erythematous, …., and … syndrome.

Answer 6

Rheumatological diseases are most commonly implicated in the development of acute TIN. These include systemic lupus erythematous, sarcoidosis, and Sjögren’s syndrome.

Question 7

Infections

Multiple infectious organisms can cause acute TIN. Commonly implicated organisms include:

Answer 7

Bacteria: Legionella, Leptospira, Streptococcus, Escherichia coli
Viruses: Cytomegalovirus, Epstein-Barr virus, Adenovirus
Fungi: Histoplasmosis, Coccidioidomycosis
Mycobacterium tuberculosis

Question 8

Tubulointerstitial nephritis uveitis syndrome

Answer 8

TINU syndrome

This is a rare syndrome of which the underlying cause is not completely understood. It is characterised by TIN with uveitis. Uveitis is typically anterior with features of a painful red eye, reduced acuity, photophobia, anterior chamber cells, conjunctival injection, and dry eyes. Diagnosis is based on the finding of both TIN and uveitis.

Question 9

Acute TIN is characterised by immune-mediated infiltration in the renal …

Answer 9

Acute TIN is characterised by immune-mediated infiltration in the renal interstitium.

Question 10

Acute TIN is characterised by immune-mediated infiltration in the renal interstitium.

Answer 10

In acute TIN, inflammatory cells infiltrate the renal interstitium and initiate a local inflammatory response leading to acute nephritis. Tubular damage occurs, which may be associated with a fall in glomerular filtration and an AKI. If renal dysfunction dose occur it is usually reversible. If inflammation continues and becomes chronic, it can lead to irreversible scarring and fibrosis.

The most common form of acute TIN is a drug hypersensitivity reaction. Components of the drug bind the tubular basement membrane and other interstitial components. This reaction is often IgE-mediated leading to infiltration of eosinophils. Peripheral and urinary eosinophils may be raised.

Question 11

The classic triad of acute TIN is …

Answer 11

The classic triad of acute TIN is fever, rash and eosinophilia.

Question 12

The classic triad of acute TIN is fever, rash and eosinophilia.
The classic triad is only observed in …% of patients. Eosinophils may also be present in the urine, but this is difficult to assess clinically.

Answer 12

The classic triad of acute TIN is fever, rash and eosinophilia.
The classic triad is only observed in 10% of patients. Eosinophils may also be present in the urine, but this is difficult to assess clinically.

Question 13

Symptoms of acute TIN

Answer 13

Asymptomatic: only finding may be abnormal renal function
Nausea & vomiting
Oliguria
Malaise
Arthralgia
Fever
Rash: maculopapular drug eruption commonly seen
Haematuria (unusual but seen in 5%)

Question 14

4 Signs of acute TIN

Answer 14

Eosinophiluria: eosinophils in urine
Haematuria (5%)
Proteinuria: usually non-significant quantity
Rash

The rash in acute TIN is usually a morbilliform drug eruption, also known as a maculopapular rash. This typically appears on the trunk first then spreads to the neck and limbs

Question 15

The rash in acute TIN is usually a morbilliform drug eruption, also known as a … rash. This typically appears on the trunk first then spreads to the neck and limbs

Answer 15

The rash in acute TIN is usually a morbilliform drug eruption, also known as a maculopapular rash. This typically appears on the trunk first then spreads to the neck and limbs

Question 16

Definitive diagnosis of TIN requires a renal ….

Answer 16

Definitive diagnosis of TIN requires a renal biopsy.

Question 17

Indications for biopsy

Renal biopsy is decided on a case by case basis for patients with suspected acute AKI secondary to TIN. Some typical indications are listed below

Answer 17

Characteristic clinical features in absence of culprit drug
Atypical presentation in presence of typical culprit drug
If systemic treatment would be initiated following biopsy
Kidney function does not improve following removal of culprit drug
Presentation with severe AKI

Question 18

The characteristic features of acute TIN on biopsy include interstitial oedema, … infiltration and tubular …. Granulomas may be seen, which could imply an underlying systemic disease (e.g. sarcoidosis) or infection-induced TIN.

Answer 18

The characteristic features of acute TIN on biopsy include interstitial oedema, leucocyte infiltration and tubular inflammation. Granulomas may be seen, which could imply an underlying systemic disease (e.g. sarcoidosis) or infection-induced TIN.

Question 19

The characteristic features of acute TIN on biopsy include interstitial …, leucocyte infiltration and tubular inflammation. … may be seen, which could imply an underlying systemic disease (e.g. sarcoidosis) or infection-induced TIN.

Answer 19

The characteristic features of acute TIN on biopsy include interstitial oedema, leucocyte infiltration and tubular inflammation. Granulomas may be seen, which could imply an underlying systemic disease (e.g. sarcoidosis) or infection-induced TIN.

Question 20

Bedside tests in TIN

Answer 20

Urinalysis: often proteinuria present with leucocytes
ECG: if hyperkalaemia
Urinary eosinophils: usually not completed in practice as absence does not exclude TIN and presence is not specific.
Protein/creatinine ratio: better estimation of protein loss.

Question 21

Routine bloods in TIN

Answer 21

The severity of AKI is variable in TIN. Some patients may have a mild elevation in creatinine, whereas others have a severe AKI needing renal replacement therapy.

Full blood count
Urea & electrolytes
Bone profile
Liver function tests
CRP/ESR
Venous blood gas: assess acid-base if AKI present

Question 22

Renal screen in TIN -

Answer 22

This refers to a series of blood tests completed in patients presenting with severe AKI to look for a serious underlying cause (e.g. myeloma or vasculitis).

Anti-nuclear antibodies
Complement
Anti-double stranded DNA (dsDNA)
Anti-glomerular basement (GBM)
Immunoglobulins
Protein electrophoresis
Anti-neutrophil cytoplasmic antibody (ANCA)

Question 23

Imaging in TIN

Answer 23

A renal ultrasound is needed to exclude obstructive uropathy and look at the overall architecture of the kidneys (e.g. big or small). Chest x-ray may be used to look for pulmonary oedema in severe AKI.

Question 24

What is done for a definitive diagnosis of TIN?

Answer 24

Renal biopsy is needed for a definitive diagnosis of TIN (see diagnosis)

Question 25

Treatment of TIN is usually..

Answer 25

Treatment of TIN is usually supportive with removal of the culprit medication(s).
Treatment of acute TIN depends on the underlying cause. We will focus on drug-induced TIN.

TIN secondary to an infection will usually resolve with treatment of the causative organism. Treatment of TIN in the context of a systemic illness depends on the underlying diagnosis.

Question 26

Drug-induced TIN

Answer 26

In the majority of cases, treatment involves discontinuation of the culprit medication(s) and close monitoring of the patient. In the context of polypharmacy, drugs may be discontinued sequentially (if AKI mild) or simultaneously (if AKI severe).

Close observation of renal function is needed for 3-7 days. Renal function should improve during this time. The suspected medication should be added to the patients allergy list. Failure to improve may warrant renal biopsy (if not already completed) and consideration of pharmacological intervention.

Question 27

Close observation of renal function is needed for 3-7 days following…

Answer 27

Drug induced TIN
Close observation of renal function is needed for 3-7 days. Renal function should improve during this time. The suspected medication should be added to the patients allergy list. Failure to improve may warrant renal biopsy (if not already completed) and consideration of pharmacological intervention.

Question 28

…: may be initiated for severe cases or if renal function fails to improve. Ideally TIN should be confirmed on biopsy prior to administration. Treatment is guided by the renal team in most cases and may include an initial ‘pulse’ of intravenous methylprednisolone.

Answer 28

Corticosteroids (e.g. prednisolone): may be initiated for severe cases or if renal function fails to improve. Ideally TIN should be confirmed on biopsy prior to administration. Treatment is guided by the renal team in most cases and may include an initial ‘pulse’ of intravenous methylprednisolone.

Question 29

Renal replacement therapy: patients with severe AKI may require temporary dialysis while the kidneys recover. Indications for dialysis are the same as other AKIs (e.g. refractory …, refractory .. overload, refractory … , uraemic complications).

Answer 29

Renal replacement therapy: patients with severe AKI may require temporary dialysis while the kidneys recover. Indications for dialysis are the same as other AKIs (e.g. refractory hyperkalaemia, refractory fluid overload, refractory acidosis, uraemic complications).

Question 30

NOTE: NSAID-induced TIN has limited response to …

Answer 30

NOTE: NSAID-induced TIN has limited response to corticosteroids

Question 31

Prognosis of acute TIN

Answer 31

Patients developing acute TIN may require acute renal replacement therapy (e.g. haemodialysis) but only 10% remain dialysis dependent. It is estimated that 40% will have an incomplete recovery in renal function.

Features associated with a decreased likelihood of renal recovery include:

Prolonged AKI (> 3 weeks)
NSAID-induced TIN
Certain histological features (e.g. interstitial granulomas, interstitial fibrosis)

Question 32

Features associated with a decreased likelihood of renal recovery include: (In acute TIN)

Answer 32

Prolonged AKI (> 3 weeks)
NSAID-induced TIN
Certain histological features (e.g. interstitial granulomas, interstitial fibrosis)

Question 33

A 27-year-old man presents to accident and emergency with a new drug rash. He developed an ankle sprain while playing football last weekend and started taking naproxen, which was prescribed by the GP. Over the last 48 hours he has developed a widespread maculopapular rash on his trunk, which is associated with myalgia and low-grade fevers. The examination is largely unremarkable. Formal blood tests are taken that show evidence of a new acute kidney injury. His creatinine is 189 (60-90 umol/L).

Which investigation is needed to make the definitive diagnosis?

A	Urinary eosinophils
B	Mid-stream urine MC&S
C	Urinary protein:creatinine ratio
D	Renal biopsy
E	Ultrasound kidney, ureter, bladder

Answer 33

This case likely represents NSAID-induced tubulointerstitial nephritis (TIN) that requires a renal biopsy for definitive diagnosis.
NSAIDs are a common culprit for the development of TIN. The classic presentation is fever, rash and eosinophilia, but this is only present in 10% of cases. Most cases will get better with removing the culprit medication and providing supportive treatment. The only way of definitively making the diagnosis is by performing a renal biopsy but this is not always needed. This is particularly true when a drug cause is suspected, and the medication can be identified and removed. Urinary eosinophils are rarely completed in clinical practice as the absence does not exclude the diagnosis and they are not specific (false positives).

Question 34

What are a common culprit for the development of TIN? (The classic presentation is fever, rash and eosinophilia, but this is only present in 10% of cases)

Answer 34

NSAIDs are a common culprit for the development of TIN. The classic presentation is fever, rash and eosinophilia, but this is only present in 10% of cases. Most cases will get better with removing the culprit medication and providing supportive treatment. The only way of definitively making the diagnosis is by performing a renal biopsy but this is not always needed. This is particularly true when a drug cause is suspected, and the medication can be identified and removed. Urinary eosinophils are rarely completed in clinical practice as the absence does not exclude the diagnosis and they are not specific (false positives).

Question 35

What is the most common cause of acute tubulointerstitial nephritis?

A	Sarcoidosis
B	Antibiotics
C	Leptospirosis
D	Mycobacterium tuberculosis
E	5-aminosalicylates

Answer 35

The most common cause of acute tubulointerstitial nephritis (TIN) is medications.
Medications account for up to 75% of cases of TIN of which antibiotics represent 50% of this group. Commonly implicated antibiotics include Penicillins, Cephalosporins, Rifampicin, Ciprofloxacin and Co-trimoxazole. Other commonly implicated medications include NSAIDs, proton pump inhibitors and diuretics. 5-ASA drugs can cause TIN but rarely. Other major causes of TIN include infections and systemic diseases (e.g. sarcoidosis).

Question 36

Acute interstitial nephritis (AIN/TIN) is a pattern of acute kidney inflammation, localized to the kidney tubulointerstitial space and usually triggered by medications.

Answer 36

Acute interstitial nephritis (AIN) is a pattern of acute kidney inflammation, localized to the kidney tubulointerstitial space and usually triggered by medications.