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This is renal failure associated with inflammation of the renal interstitium, ie the area of the kidney between the nephrons.
Most of the cells are fibroblasts which, as well as being an essential part of the integrity of the interstitial matrix, have various endocrine functions, including production of erythropoietin and prostaglandins. The interstitium is important because any molecule that moves from the tubules to the blood has to cross the interstitial space and vice versa.
There are two main forms of the disease - acute interstitial nephritis and chronic tubulointerstitial nephritis.
The most common cause (40-60% of cases) is a drug hypersensitivity reaction. Many drugs have been implicated; the following are those most frequently involved:
- Methicillin and other penicillins.
- Co-trimoxazole and other sulfonamides.
- All non-steroidal anti-inflammatory drugs (NSAIDs).
- Diuretics- thiazides, furosemide, triamterene.
A large number of other drugs are being reported - eg:
Antiretroviral agents and related therapies have also demonstrated a range of nephrotoxic effects including interstitial nephritis.
Acute interstitial nephritis
This accounts for 6.5-15% of patients presenting with acute kidney injury. Almost all acute tubulointerstitial nephritides (AIN) are caused by hypersensitivity reactions to drugs and are not mediated by direct toxicity.
Diagnosis is suggested when renal failure develops in association with systemic infection, drug reaction, sarcoidosis, Sjögren's syndrome or uveitis.
These give a 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.
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 occur in most patients.
- Renal biopsy; as well as interstitial changes, this shows diffuse podocyte foot-process fusion with minimal glomerular changes[1, 7].
Other causes of AIN
- Immune disorder - systemic lupus erythematosus (SLE), Sjögren's syndrome and sarcoidosis.
- Idiopathic - found associated with anterior uveitis or iritis (tubulointerstitial nephritis with uveitis (TINU)) syndrome affecting mainly young women and girls - fever, weight loss and renal failure.
- Sudden onset acute kidney injury (usually within days of exposure to the causative drug).
- Elevated immunoglobulin E (IgE) levels.
Results of investigations
- Mild-to-moderate proteinuria (<1-2 g/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 is only possible by renal biopsy, which shows mononuclear cell infiltration in interstitium with interstitial oedema.
- There is a need also to investigate the degree of tubular damage in order 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, there is a need to check that infiltrating cells are not from lymphomas or leukaemia.
- Mainly, this is withdrawal of any responsible drug.
- High-dose prednisolone may help with a faster and more complete reduction in serum creatinine.
Chronic tubulointerstitial nephritis
Analgesic nephropathy produces renal papillary necrosis and chronic interstitial nephritis as a result of long-term excessive use of analgesics usually containing aspirin in combination with phenacetin (no longer available), and 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
Chronic kidney disease due to analgesic nephropathy is a common cause of renal failure in Europe.
The mechanism of action is not exactly defined but related to metabolism of phenacetin/paracetamol to reactive intermediates that accumulate in the renal medulla at high concentrations at the papillary tip where they are able to damage the cells lining the duct by oxidation. Aspirin exacerbates this by depleting glutathione that would detoxify the reactive intermediates. It also reduces renal blood flow by inhibiting prostaglandins.
5-aminosalicylic acid (5-ASA)
- 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.
- Male:female ratio is 2:15.
- Unlike analgesic nephropathy, interstitial nephritis is seen during the first year of treatment in a significant proportion of cases.
- It is usually asymptomatic, so creatinine levels need monitoring in patients treated with 5-ASA for inflammatory bowel disease, initially every three months and then annually.
- 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.
- The main feature is extensive interstitial fibrosis with atrophy and tubular loss mainly in the cortex.
- Proteinuria (<1.5 g/day) with both albumin and low molecular weight proteins.
- If disease is more severe then progressive renal failure may follow even if herbs are 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 the rate of loss of renal function.
It has been reported that long-term lithium treatment is associated with chronic interstitial nephritis but cases are not firmly established.
- This may occur 6-12 months after radiotherapy, with hypertension, anaemia and oedema.
- 50% progress to chronic kidney disease.
- Alternatively, it may develop over several years - presenting with hypertension and proteinuria sometimes.
- 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.
- This only becomes evident years after exposure.
- It is nearly always associated with gout and hypertension.
- It is diagnosed by EDTA mobilisation test.
- This is a highly toxic metal with the kidney as one of its most important target organs.
- It 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 kidney disease.
- Chronic hypokalaemia:
- After one month, there are 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 the renal medulla.
- High levels of oxalate may rarely occur from inherited enzymatic abnormality but usually are acquired from ingestion of oxalate precursors or increased gastrointestinal absorption from inflammatory bowel disease or small bowel resection.
- Results in microcrystallisation of calcium oxalate in the kidney.
- Calcium becomes concentrated in the medulla and causes damage.
- Chronic urate nephropathy:
- Caused by microtophi of urate crystals in the interstitium.
- There is definite association only with serum urate concentrations >10 mg/dL (600 μmol/L) in women and >13 mg/dL (780 μmol/L) in men over prolonged periods.
- However, at lower levels it is also associated with a high incidence of hypertension, diabetes mellitus, dyslipidaemia and nephrosclerosis.
- Myeloma, amyloidosis or leukaemia.
- Immunological causes:
- SLE, Sjögren's syndrome and sarcoidosis.
- Vasculitides - eg, granulomatosis with polyangiitis.
- Genetic causes:
- Medullary cystic disease or Alport's syndrome.
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 there may be flank pain and haematuria.
- Diagnosis is 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.
- Ultrasound - may identify hydronephrosis seen in obstructive pathology.
- CT scan - as above, but with greater resolution.
This will depend on the aetiology. Generally it consists of supportive treatment - eg, 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.
- Renal function stabilises or improves slightly on discontinuation of analgesics in early cases.
- In advanced disease, it may continue to progress due to secondary changes associated with loss of nephrons and lead to end-stage kidney disease.
- 8-10% of patients develop urinary tract malignancy - the most common cause of bladder cancer in women under the age of 50.
- CT scan shows reduction in renal volume, bumpy renal contours and papillary calcifications.
Further reading and references
Perazella MA, Markowitz GS; Drug-induced acute interstitial nephritis. Nat Rev Nephrol. 2010 Aug6(8):461-70. doi: 10.1038/nrneph.2010.71. Epub 2010 Jun 1.
Hong S, Valderrama E, Mattana J, et al; Vancomycin-induced acute granulomatous interstitial nephritis: therapeutic options. Am J Med Sci. 2007 Oct334(4):296-300.
Castledine C, Wright D, Kingdon E; Rosiglitazone as a cause of acute interstitial nephritis. Nephrol Dial Transplant. 2006 Jul21(7):1994-5. Epub 2006 Feb 28.
Rosiglitazone (Avandia, Avandamet): Recommended withdrawal from clinical use; Medicines and Healthcare products Regulatory Agency (MHRA) Safety Information (archived content)
Audimoolam VK, Bhandari S; Acute interstitial nephritis induced by glucosamine. Nephrol Dial Transplant. 2006 Jul21(7):2031. Epub 2006 Feb 27.
Wyatt CM, Klotman PE; Antiretroviral therapy and the kidney: balancing benefit and risk in patients with HIV infection. Expert Opin Drug Saf. 2006 Mar5(2):275-87.
Patrakka J, Lahdenkari AT, Koskimies O, et al; The number of podocyte slit diaphragms is decreased in minimal change nephrotic syndrome. Pediatr Res. 2002 Sep52(3):349-55.
Verma N, Arunabh S, Brady TM, et al; Acute interstitial nephritis secondary to infectious mononucleosis. Clin Nephrol. 2002 Aug58(2):151-4.
Sessa A, Meroni M, Battini G, et al; Acute renal failure due to idiopathic tubulo-intestinal nephritis and uveitis: "TINU syndrome". Case report and review of the literature. J Nephrol. 2000 Sep-Oct13(5):377-80.
Yang HY, Lin JL, Chen KH, et al; Aristolochic acid-related nephropathy associated with the popular Chinese herb Xi Xin. J Nephrol. 2006 Jan-Feb19(1):111-4.