Interstitial Nephritides and Nephrotoxins

• Methicillin and other penicillins
• Cephalosporins
• Co-trimoxazole and other sulphonamides
• Rifampicin
• Ciprofloxacin
• Erythromycin
• Vancomycin²
• All NSAID's
• Diuretics- thiazides, furosemide, triamterene
• A large number of other drugs are being reported e.g. rosiglitazone,³ glucosamine.⁴ Antiretroviral agents and related therapies have demonstrated a range of nephrotoxic effects, including interstitial nephritis.⁵

This accounts for 6.5-15% of patients presenting with acute renal failure.
Almost all acute tubulointerstitial nephritides are caused by hypersensitivity reactions to drugs and are not mediated by direct toxicity.⁶

Diagnosis suggested when renal failure develops in association with systemic infection, drug reaction, sarcoidosis, Sjogren's syndrome or uveitis.

Aetiology

• Beta-lactams:
  These give characteristic clinical picture:
  • 2-60 days after treatment starts
  • Fever, maculopapular skin rash, hepatic involvement, haematuria
  • Renal failure requiring dialysis in around 30% of cases
• NSAIDs: Usually in the elderly who have taken the drug intermittently.
  • Renal failure starts several months to years after starting treatment and other signs of drug sensitivity are usually missing.
  • Abundant proteinuria and nephrotic syndrome occurs in most patients.
  • Renal biopsy; as well as interstitial changes shows diffuse podocyte foot-process fusion with minimal glomerular changes.¹
• Other causes of AIN:
  • Infection:
    • Mainly in children following septicaemia presents as acute pyelonephritis with renal micro-abscesses shown on biopsy.
    • Also viral infections e.g. Epstein-Barr,⁷ haemorrhagic fevers due to Hantaviruses found in Europe or HIV disease.
  • Immune disorder - lupus erythematosus, Sjogren's syndrome and sarcoidosis.
  • Idiopathic - found associated with anterior uveitis or iritis (TINU - tubulo-interstitial nephritis with uveitis) syndrome affecting mainly young women and girls fever, weight loss and renal failure.⁸

Presenting features

• Sudden onset acute renal failure, usually within days of exposure to the causative drug.
• Rash
• Fever
• Eosinophilia
• Elevated IgE levels

Investigations

• Mild-moderate proteinuria (<1-2g/day).
• Nephrotic syndrome only in AIN due to NSAID.
• Haematuria only with beta-lactam hypersensitivity.
• Eosinophilia and eosinophiluria suggests adverse drug reaction.
• Kidney normal size or enlarged.
• Ultrasound shows increased cortical echogenicity.

Firm diagnosis only possible by renal biopsy, which shows mononuclear cell infiltration in interstitium with interstitial oedema.

• Need also to investigate degree of tubular damage to exclude primary acute tubular necrosis.
• Also glomerular pathology looking for significant immune complex deposits and vasculitis to exclude lupus glomerulonephritis, mixed cryoglobulinaemia and systemic vasculitis.
• Also need to check that infiltrating cells are not from lymphomas or leukaemia.

Treatment

• Mainly is withdrawal of any responsible drug.
• High dose prednisone may help with a faster and more complete reduction in serum creatinine.

Pathology

Analgesic nephropathy produces renal papillary necrosis and chronic interstitial nephritis as result of long term excessive use of analgesics usually containing aspirin in combination with phenacetin (no longer available), paracetamol.
Renal damage is most apparent in the medulla starting as prominent thickening of the vasa recta capillaries with patchy areas of tubular necrosis. This is followed by papillary necrosis and secondary injury to the cortex with focal and segmental glomerulosclerosis, interstitial infiltration and fibrosis.

Aetiology and characteristic features

• 5-aminosalicylic acid:
  • Effect similar to that of aspirin to which it is chemically related.
  • Inflammation of the interstitium continues for several months or years after taking the drug.
  • M:F ratio 2:15.
  • Unlike analgesic nephropathy, interstitial nephritis seen during first year of treatment in significant proportion of cases.
  • Usually asymptomatic, so creatinine levels need monitoring in patients treated with 5-ASA for inflammatory bowel disease, initially every 3 months and then annually.
• Chinese herbs:
  • Chinese herbs nephropathy is known as a subacute interstitial nephritis attributed to aristolochic acid.
  • There has been a call for Xi Xin containing aristolochic acid to be forbidden in remedies in order to prevent these adverse effects.⁹
  • Main feature is extensive interstitial fibrosis with atrophy and tubular loss mainly in the cortex.
  • Proteinuria (<1.5g/day) with both albumin and low molecular weight proteins.
  • If disease more severe, then progressive renal failure may follow even if herbs excluded in future.
  • Diagnosis should be considered in patients with unexplained renal disease that progresses relatively rapidly and follows use of herbal remedies.
  • Steroids may slow rate of loss of renal function.
• Lithium:
  • It has been reported that long term lithium treatment is associated with chronic interstitial nephritis, but cases not firmly established.
• Radiation:
  • This may occur 6-12 months after radiotherapy with hypertension, anaemia and oedema.
  • 50% progress to chronic renal failure.
  • Alternatively, may develop over several years - presenting with hypertension and proteinuria sometimes.
• Ciclosporin:
  • This can cause acute and chronic nephrotoxicity.
  • It is common among patients receiving kidney, heart, liver, and pancreas transplants. However, it is rare after bone marrow transplant.
• Lead:
  • This only becomes evident years after exposure.
  • Nearly always associated with gout and hypertension.
  • Diagnosed by EDTA mobilisation test.
• Cadmium:
  • This is a highly toxic metal with the kidney as one of its most important target organs.
  • Causes a tubular proteinuria with low molecular weight plasma proteins.
  • High levels are highly toxic, but chronic low level exposure is associated with signs of early renal dysfunction.
  • However, there is no evidence of progression to chronic renal failure.
• Metabolic disorders:
  • Chronic hypokalaemia:
    • After 1 month characteristic vacuolar lesions in epithelial cells of usually proximal but sometimes distal tubules.
    • After more prolonged exposure to hypokalaemia, interstitial fibrosis, tubular atrophy and cyst formation in renal medulla.
  • Hyperoxaluria:
    • High levels of oxalate may rarely occur from inherited enzymatic abnormality, but usually are acquired from ingestion of oxalate precursors or increased GI absorption from inflammatory bowel disease or small bowel resection.
    • Results in microcrystallisation of calcium oxalate in kidney.
  • Hypercalcaemia:
    • Calcium becomes concentrated in the medulla and causes damage.
  • Chronic urate nephropathy:
    • Caused by microtophi of urate crystals in the interstitium.
    • Definite association only with serum urate concentrations >10 mg/dl (600μmol/l) in women and >13 mg/dl (780μmol/l) in men over prolonged periods.
    • But at lower levels also associated with high incidence of hypertension, diabetes mellitus, dyslipidaemia and nephrosclerosis.
  • Neoplasia:
    • Myeloma, amyloidosis or leukaemia
  • Immunological causes:
    • Systemic lupus erythematosus, Sjogren's syndrome and sarcoidosis
    • Vasculitides e.g. Wegener's granulomatosis
  • Genetic causes:
    • Medullary cystic disease or Alport's syndrome

Presentation

In moderate to advanced disease:

• Commonly found features are hypertension and anaemia with proteinuria that can be > 3.5g/day.
• Mostly there are no symptoms directly from the urinary tract, but may be flank pain and haematuria.
• Diagnosis suggested by:
  • Patients aged 30-70 years
  • They admit long term analgesic use for chronic headaches, low back pain or somatic complaints such as malaise and weakness
  • They may also have a history of peptic ulcer disease or symptoms

Investigations

• Full blood count
• Urea and electrolytes
• Urinalysis
• Ultrasound - may identify hydronephrosis seen in obstructive pathology
• CT scan - as above, but with greater resolution

Management

This will depend on the aetiology.
Generally consists of supportive treatment e.g. correction of anaemia.
In lead nephropathy whilst chelation therapy is of proven value and must be implemented in acute poisoning, it is unproven in chronic renal problems.

Prognosis

• Renal function stabilises or improves slightly on discontinuation of analgesics in early cases.
• In advanced disease, may continue to progress due to secondary changes associated with loss of nephrons and lead to end-stage renal disease.
• 8-10% patients develop urinary tract malignancy - commonest cause of bladder cancer in women under the age of 50.
• CT scan shows reduction in renal volume, bumpy renal contours, papillary calcifications.