26th June 2023

Tubulointerstitial Disease

Acute Interstitial Nephritis

Pathophysiology of Acute interstitial nephritis (AIN)

Acute interstitial nephritis involves damage to the renal interstitium and accounts for approximately twenty-five percent of all drug-induced acute kidney injuries. 85% of the kidney is made up of the interstitium, and it consists of a collection of cells, extracellular matrix, and fluid surrounding the kidney and is essentially the structural support for the tubular architecture and participates in fluid and electrolyte exchange. Injury to renal cells leads to the expression of new antigens, inflammatory cell infiltration and activation of pro-inflammatory cytokines. The infiltrating inflammatory cells, including lymphocytes, macrophages and eosinophils, cause oedema and fibrosis within the interstitium. This can lead to impaired renal function, however, there is minimal or no damage to the glomeruli or blood vessels. The most prevalent cause of acute interstitial nephritis is drug-induced, most commonly secondary to NSAIDs or penicillin. Typical symptoms are fever, rash and arthralgia and other features include hypertension, renal impairment, and eosinophilia.

Causes of AIN

• Drugs
  • Antibiotics – ampicillin, cephalosporins, sulphonamides, penicillin, rifampicin, ciprofloxacin, vancomycin
  • NSAIDs
  • Allopurinol
  • Aciclovir
  • Famotidine
  • Furosemide
  • Omeprazole
  • Phenytoin
• Infections
  • Bacteria – Corynebacterium diphtheriae, campylobacter, legionella, staphylococcus, streptococcus, Mycobacterium tuberculosis
  • Virus – HIV, hantavirus, Epstein-Barr
  • Other – Leptospirosis, Schistosoma
• Systemic diseases
  • Systemic lupus erythematosus
  • Sjogren’s syndrome
  • Sarcoidosis
• Tubulointerstitial nephritis with uveitis (TINU)
  • More prominent in younger age groups and more common in females
  • Presents with fever, weight loss and painful red eyes (often bilateral uveitis)
  • Urinalysis – leukocyturia and proteinuria

Diagnosis

• Urinalysis – proteinuria, leukocytes, occasional white cell casts, eosinophiluria
• Blood tests – signs of acute kidney injury, raised urea, raised creatinine, hyperkalaemia/hypokalaemia, eosinophilia.
• Renal biopsy – gold standard for diagnosis; lymphocytic and plasma cell infiltrates in the peritubular areas of the renal interstitium, normally with associated interstitial oedema.

Management

• Treat the underlying cause, particularly withdrawal of the offending drug, if identified.
• Supportive management of acute kidney injury
• Symptomatic treatment for rash
• Avoid nephrotoxic drugs

Chronic tubulointerstitial nephritis

Definition of chronic tubulointerstitial nephritis (CTIN)

In chronic tubulointerstitial nephritis there is scarring of the tubulointerstitium, characterised by tubular atrophy (defined as reduction in tubular diameter of more than fifty percent), and interstitial fibrosis. It presents as slowly progressive renal impairment and is normally asymptomatic, however, proteinuria, polyuria or nocturia may be present.

Causes of CTIN

• Drugs
  • Analgesics –paracetamol, aspirin, NSAIDs
  • Lithium
  • Calcineurin inhibitors – ciclosporin, tacrolimus
  • Cisplatin
• Metabolic
  • Hypercalcaemia
  • Hypokalaemia
  • Hyperuricaemia (gout)
• Chronic pyelonephritis
• Heavy metals
  • Lead, cadmium, gold, mercury
• Autoimmune
  • Sarcoidosis
  • Sjogren’s syndrome
  • Systemic lupus erythematosus (more associated with glomerular disease)
• Haematological/Malignancy
  • Sickle cell disease
  • Multiple myeloma
  • Lymphoproliferative disorders
• Structural
  • Reflux nephropathy
  • Obstructive nephropathy (most often secondary to renal calculus)
• Congenital
  • Polycystic kidney disease
  • Cystinosis
  • Dent disease
• Balkan endemic nephropathy – long-term exposure to aristolochic acid found in cereal products in Balkan areas plus a genetic predisposition
• Aristolochic acid nephropathy (found in herbal remedies)
• Progressive glomerular diseases (glomerulonephritides, diabetic nephropathy, hypertensive nephropathy).

Diagnosis

The diagnosis of chronic tubulointerstitial nephritis is normally a clinical diagnosis based on the possible underlying cause, the presenting features, examination findings and clinical judgement; however, there are some clinical tests to aid in the diagnosis.

• Urinalysis – proteinuria, leukocytes, occasional white cell casts
• Blood tests
  • Evidence of normocytic anemia is often disproportionate compared to the extent of the reduction in the glomerular filtration rate caused by reduced production of erythropoietin.
  • Increased urea and creatinine
  • Abnormal electrolytes – hypokalaemia, hyperkalaemia, hypocalcaemia, hypomagnesaemia, hyponatraemia
  • Metabolic acidosis – normal anion gap metabolic acidosis secondary to renal tubular acidosis
• Ultrasonography
  • Small kidney, increased echogenicity, scarring

Management

• Treat the underlying cause – for example, stop offending drug if this is the cause.
• Manage CKD – patient may need to undergo dialysis or renal transplant.

Renal papillary necrosis

Pathophysiology of renal papillary necrosis

It is characterised by coagulative necrosis of the renal medullary pyramids and papillae due to ischaemia and toxins affecting the kidney. The whole papillary tip (which is the most susceptible portion of the pyramid) and the inner medulla are necrotic, however, the outer medulla is occasionally preserved. The renal papillae are located where the openings of the collecting ducts enter the kidney and where urine passes into the ureters. The blood supply is from the vasa recta, and it is often damage to this structure that leads to necrosis.

Its presentation can vary from asymptomatic to renal failure. Symptoms include Nocturia, dysuria, pyuria, haematuria (usually microscopic), ureteral colic, back or flank pain. Obstructive symptoms of flank pain and colic can occur due to sloughed papillary cells.

Causes of renal papillary necrosis

The acronym ‘POSTCARDS’ is useful to remember these:

• Pyelonephritis (acute)
• Obstructive uropathy
• Sickle cell disease
• Tuberculosis/tubulointerstitial nephritis
• Chronic liver disease
• Analgesics/alcohol
• Renal transplant rejection
• Diabetes mellitus (worst prognosis)
• Systemic vasculitis

Diagnosis

• Urinalysis: haematuria, pyuria, proteinuria, sloughed papillae.
• Histology: Coagulative necrosis of the renal papillae and the medullary pyramids. Necrotic region bordered by neutrophils in the interstitium.

Management

• Treat or manage the underlying cause.
• Manage renal function with supportive care and fluid resuscitation.
• Antibiotics if pyelonephritis is the cause of renal papillary necrosis.
• Prognosis depends on the underlying cause; diabetes and old age are associated with a worse prognosis.