What’s new?

C Immunoglobulin G4-related (IgG4-related) disease is a newly

recognized multi-organ disorder that is associated with tubulo-

TUBULO-INTERSTITIAL DISORDERS

Tubulo-interstitial disordersAdnan Sharif

Simon Ball

interstitial disease

C The renal parenchymal changes associated with IgG4-related

disease are clinico-pathologically characteristic

C The pathogenesis of IgG4-related disease is poorly understood

C Recognition of this rare disorder is important as corticosteroid

therapy is often effective

AbstractChronic kidney disease (CKD) is accompanied by tubulo-interstitial

atrophy and fibrosis, regardless of the underlying cause. Disorders of

the renal vasculature, the glomeruli or urinary drainage all culminate in

chronic tubulo-interstitial damage, the severity of which is the histological

feature that correlates best with progression to end-stage renal failure

(ESRF). However, there are diverse conditions in which the tubulo-

interstitium is the primary site of damage; these may be considered

together without inferring a common aetiology or pathogenesis. The

diseases classified as tubulo-interstitial nephritis are considered in this

article.

Keywords acute renal failure; BK nephropathy; chronic renal failure;

drugs; IgG4-related disease; immune response; infection; interstitial

nephritis

Classification and pathology

Tubulo-interstitial disorders may be classified by their aetiology,

or according to their mode of presentation, into two broad

categories:

� acute interstitial nephritis (AIN)

� chronic interstitial nephritis (CIN).

AIN is characterized by an acute onset, often following a defined

insult (e.g. ingestion of a culprit drug). Tubulo-interstitial

inflammation occurs without significant atrophy or fibrosis1

(Figure 1). Conversely, CIN is characterized by tubulo-

interstitial atrophy and fibrosis, with varying degrees of inflam-

mation. The causes of CIN include direct toxicity, local

ischaemia, inflammation and, rarely, inherited disorders of

tubular proteins (nephronophthisis). Regardless of the cause,

a low-grade monocytic infiltrate may enter areas of atrophy and

fibrosis.2

Adnan Sharif MBChB is a Specialist Registrar in Renal Medicine at

University Hospital Birmingham, UK. He qualified from the University of

Edinburgh and has trained in Edinburgh and Cardiff before

commencing the West Midlands rotation. His special interests are

metabolic disorders post-transplantation and strategies to increase

organ procurement. Competing interests: none declared.

Simon Ball MA PhD FRCP is Consultant Nephrologist at University Hospital

Birmingham, UK. He qualified from Oxford University and University

College London. He trained in nephrology in London and Stevenage.

His main research interests include measuring the immune response to

HLA and blood group antigens. Competing interests: none declared.

MEDICINE 39:8 467

Clinical features

The precise mode of presentation differs between AIN and CIN,

and between different causes, but predominant tubulo-interstitial

damage has some typical effects. Patients often present with

renal impairment, uraemia and fluid overload but, occasionally,

presentation is with extra-renal manifestations such as fever,

skin rash and arthralgia, particularly in AIN.

Albuminuria is common but not large in amount (it may be

below the level of detection of conventional stick urinalysis), and

is generally not associated with the nephrotic syndrome (see

below). Low-molecular-weight proteinuria is common, but

seldom assessed.

Microscopic haematuria is variable and macroscopic haema-

turia uncommon with the exception of certain specific underlying

aetiologies, such as AIN caused by meticillin. In CIN it may

suggest a complicating uro-epithelial malignancy.

There may be defects in tubular handling of water, sodium

and hydrogen ions resulting in nephrogenic diabetes insipidus,

salt-losing nephropathy and renal tubular acidosis (RTA), which

can all lead to the initial presentation. Hypertension is variable.

Acute interstitial nephritis

Drug-induced AIN

AIN causes acute kidney injury (AKI). In the UK, the most

common cause is an idiosyncratic drug reaction; a thorough and

Figure 1 Renal biopsy showing tubulo-interstitial nephritis. Diffuse

monocytic infiltrate (with or without eosinophils) infiltration into tubules

and severe tubular damage. The glomerular structure is preserved with no

evidence of inflammation.

� 2011 Elsevier Ltd. All rights reserved.

Drugs causing tubulo-interstitial nephritis

Antibiotics Non-steroidal

anti-inflammatory

drugs (NSAIDs)

Anticonvulsants Others

Penicillinsa Ibuprofena Phenytoin Allopurinola

Sulphonamidesa Indometacina Sodium

valproate

Cimetidinea

Rifampicina Diclofenac Lamotrigine Phenindionea

Quinolonesa Piroxicama Furosemide

Vancomycin Cox 2 inhibitors Proton pump

inhibitors

Salicylates

a Drugs associated with renal granulomata.

Table 1

TUBULO-INTERSTITIAL DISORDERS

careful drug history including alternative medications is critical

(see Table 1). Patients may present with renal failure, flank pain

or extra-renal manifestations. Macroscopic haematuria is excep-

tional and mainly reported to occur with meticillin. Urinalysis

may reveal blood and protein, but generally not in the amounts

typical of acutely presenting glomerulonephritis. Eosinophilia

may be present, but is variable. Renal ultrasonography and

autoantibody screening are generally normal. The diagnosis is

established by renal biopsy. The drug responsible must be

stopped, and there is evidence that the use of corticosteroids

accelerates and improves recovery.3 Rarely, non-steroidal anti-

inflammatory drugs (NSAIDs) cause a ‘minimal-change’

glomerular lesion in addition to AIN, which presents with

nephrotic syndrome.

Infections causing AIN

Pyelonephritis is an ascending bacterial infection, characterized

by neutrophil inflammation centred on tubules. Tubulo-

interstitial nephritis can complicate various systemic infections

Infections causing tubulo-interstitial nephritis

Virus Bacteria Others

Hantaviridae Legionella Leishmania

Leptospira Toxoplasmaa

EpsteineBarr (EBV)a Mycobacterium

tuberculosisa

HIV Streptococcus

Measles Salmonella

Adenovirus Campylobacter

Immunocompromised Mycoplasma

Polyomavirus Chlamydia

Cytomegalovirus (CMV)

Herpes simplex virus (HSV) Brucella

a Infections associated with renal granulomata.

Table 2

MEDICINE 39:8 468

(see Table 2). Hantavirus causes haemorrhagic fever with renal

syndrome and is an important cause of AIN outside the UK. The

typical presentation is with non-specific systemic symptoms,

followed by acute renal failure (ARF), thrombocytopenia and

elevated hepatic enzymes.

BK virus is a polyomavirus that causes interstitial nephritis in

renal transplant patients.4 It usually presents as acute or

subacute deterioration of transplant function. The main differ-

ential diagnosis is acute rejection, and the main risk factor for BK

nephropathy is the amount of immunosuppression. The diag-

nosis is established by renal biopsy (Figure 2), although urine

cytology for ‘decoy cells’ and quantification of viral DNA in the

plasma by polymerase chain reaction (PCR) provide non-

invasive means of predicting those at risk. The outcome is vari-

able; treatment requires reduction of immunosuppressive load.

The role of antiviral agent remains uncertain. There may be

additional benefit from replacing a standard immunosuppressive

agent with leflunomide or an mammalian target of rapamycin

(mTOR) inhibitor, but clinical trials data are not yet available.

Multi-system inflammatory diseases causing

tubulo-interstitial nephritis

Several non-infectious inflammatory diseases may cause AIN or

CIN. They often respond to corticosteroids.

Sarcoidosis is associated with renal granulomata in about 20%

of patients, but clinically manifest tubulo-interstitial nephritis

(TIN) is less common. More often, hypercalcaemia causes

abnormal renal function. A putative predisposition to glomerular

disease remains unproven.

Sj€ogren’s syndrome is associated with TIN manifest as renal

impairment or renal tubular acidosis.

Systemic lupus erythematosus and Wegener’s granu-

lomatosis, although both typically causes of glomerular lesions,

can present with predominant tubulo-interstitial inflammation.

Figure 2 Renal transplant biopsy showing intranuclear basophilic viral

inclusions, chromatin clumping of infected cells and features of interstitial

nephritis.

� 2011 Elsevier Ltd. All rights reserved.

Practice points

C Tubulo-interstitial nephritis has many causes. The diagnosis is

usually made by renal biopsy, but determination of the precise

cause requires careful clinical assessment and the cause

frequently remains obscure

C Urinalysis may show little blood and protein

C Drug-induced acute interstitial nephritis (AIN) is a common

cause of acute renal failure, is an important differential diag-

nosis of acute tubular necrosis (ATN), and should be consid-

ered when recovery of renal function is delayed. (Patients with

ATN are generally in hospital and have commonly received

drugs that can provoke an AIN)

C Chronic interstitial nephritis (CIN) may complicate a recognized

disease or therapy; when this is not the case, there may be

extensive renal damage at presentation because symptoms

occur late

TUBULO-INTERSTITIAL DISORDERS

TIN with uveitis (TINU) is a syndrome in which uveitis gener-

ally coincides with or follows a TIN. TINU commonly presents in

childhood, but has been reported into late adulthood. The

differential diagnosis includes the multi-system diseases above.

IgG4-related disease is characterized by elevated serum

immunoglobulin G4 (IgG4) and renal interstitial infiltration of

IgG4-positive plasma cells. Although often associated with auto-

immune pancreatitis, clinico-pathological data of IgG4-related

disease causing tubulo-interstitial nephritis are emerging.5

Chronic interstitial nephritis

Analgesic nephropathy results from the ingestion of large quantities

of compound analgesics containing phenacetin. The role of non-

phenacetin-containing analgesics is plausible, but unproven. The

typical pathology is centred on the medulla with overlying scarring,

calcification and papillary necrosis. (Papillary necrosis may also

complicate sickle cell nephropathy, which resembles CIN. There is

prominent tubular dysfunction arising from medullary ischaemia.)

Balkan nephropathy and Chinese herbs nephropathy: Balkan

nephropathy is a form of CIN, the cause of which remains unde-

terminedalthough there is increasingevidence that it is related to the

ingestion of food contaminated with aristolochic acid. Environ-

mental andgenetic factors are likely to contribute to its pathogenesis

and eponymous geography. Chinese herbs nephropathy was iden-

tified in 1992 in Belgian women in which the causal agent has been

clearly identified as aristolochic acid contaminating a slimming

agent. In both conditions, there is progressive renal failure, and,

becauseof the substantial risk of uro-epithelialmalignancy, patients

require long-termurological surveillance (see Drugs and toxins that

damage the kidney inMedicine 2011; 39(6): 356e361).

Lithium toxicity: use of lithium as a therapeutic agent may be

complicated by nephrogenic diabetes insipidus, acute tubular

necrosis and, in the long-term, CIN. Development of renal

dysfunction in a patient taking lithium requires careful collabo-

ration between psychiatrist and nephrologist.

Heavy-metal intoxication:CIN fromheavymetal intoxicationmay

arise following environmental or industrial exposure, and perhaps

as a consequence of their presence in traditional medicines.

Radiation nephritis: includes an acute thrombotic micro-

angiopathy and, in the long term, a CIN. It may be ameliorated

by shielding and dose fractionation.

Calcineurin inhibitor toxicity: calcineurin inhibitors often cause

nephrotoxicity with vascular and tubulo-interstitial damage,

which may be ameliorated by dose reduction or withdrawal.

Eating disorders: CIN may develop in patients with eating

disorders. It causes renal impairment, and contributes to the

MEDICINE 39:8 469

complex electrolyte disturbances seen in such individuals. Long-

standing hypovolaemia and hypokalaemia may contribute to its

development although the role of chronic hypokalaemia as

a causative factor is controversial.

Late presenting CIN: many patients presenting with advanced

chronic renal failure and small, unscarred kidneys exhibit

evidence of predominant tubulo-interstitial non-glomerular

damage. This presentation is particularly common in the Indo-

Asian population, but no cause has been identified.6

Idiosyncratic drug reactions, infections and multi-system

inflammatory disorders may all present as a CIN rather than an

AIN. A

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3 Gonzalez E, Gutierrez E, Galeano C, et al. Early steroid treatment

improves the recovery of renal function in patients with drug-induced

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4 Dall A, Hariharan S. BK virus nephritis after renal transplantation. Clin J

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� 2011 Elsevier Ltd. All rights reserved.