DRUG NEPHROTOXICITY

Ifemed Journal of Medicine, 2005

Asangansi I. E., Oshin A. O., Akinloye A. O.

Final year Clinical Students, College of Medicine, University of Ibadan, Ibadan, Nigeria
ABSTRACT
Many drugs can injure the kidneys, but they cause renal injury via only a few common mechanisms.
Many patients who develop renal injury after drug exposure have identifiable risk factors that can be modified or that should
preclude the use of these drugs in the first place. In this paper, an analysis is presented of these risk factors for drug
nephrotoxicity. Methodology was mainly document analysis of key literature. Recommendations are then made from the study.
INTRODUCTION
Nephrotoxicity can be defined as renal disease or dysfunction that arises as a direct or indirect result of exposure to
medicines, and industrial or environmental chemicals. Drug nephrotoxicity is therefore any renal dysfunction attributable to
drugs.
Drug nephropathies are not restricted to a single type of renal injury. Drugs target one or more discrete anatomical
regions of the kidney and may affect only one cell type. The resulting insult to the kidney may result in a spectrum of
nephropathies that are indistinguishable from those that do not have a chemical etiology1
BRIEF HISTOLOGY AND PHYSIOLOGY
The nephron is the functional unit of the kidney and consists of a continuous tube of highly specialized heterogeneous
cells, which show sub-specialization along the length of nephrons and between them. It is the major organ of excretion and
homeostasis for water-soluble molecules; because it is a metabolically active organ, it can concentrate certain substances
actively. In addition, its cells have the potential to bioconvert chemicals and metabolically activate a variety of compounds.
Since the kidney excretes many drugs, it is routinely exposed to high concentrations of these drugs or their metabolites
or both. Furthermore, the kidney has several features that allow nephrotoxins to accumulate. It is highly vascular, receiving
about 25% of the resting cardiac output. The proximal renal tubule presents a large area for nephrotoxin binding and transport
into the renal epithelium. Reabsorption of the glomerular filtrate progressively increases intraluminal nephrotoxin
concentrations, while specific transport pathways in the kidney may engender site-specific toxicity.1
MECHANISMS OF TOXICITY
Many drugs can injure the kidney but they cause renal injury via only a few mechanism. Renal injury can be in the form
of acute renal failure, nephrotic syndrome and chronic renal failure.
ACUTE RENAL FAILURE
Drugs can cause acute renal failure by three mechanisms:
Pre-renal
Intrinsic
Obstructive.
PRE-RENAL
Some drugs can cause acute renal failure by reducing the volume or pressure or both of blood delivered to the kidney;
the resulting renal failure is therefore termed prerenal. Patients at risk are those who already have compromised renal blood
flow such as with bilateral renal artery stenosis, or with decreased effective circulatory volume as with cirrhosis, nephrotic
syndrome, or congestive heart failure. Because of hypovolemia, urine volume and sodium excretion are low while osmolality is
high. The urine sediment is usually without casts, red blood cells and white blood cells.
INTRINSIC/RENAL
Three types of intrinsic acute renal failure exist:
Acute tubular necrosis
Acute interstitial nephritis
Thrombotic microangiopathy
Acute tubular necrosis
Mechanisms of injury are multiple but may overlap, including direct tubular toxicity, deranged cellular energy
production, free radical injury, heme tubular toxicity, abnormal phospholipid metabolism, and intracellular calcium toxicity. 2
Osmolar changes in the kidney with vacuolization injury and acute tubular necrosis have been observed with intravenous
immunoglobulin, mannitol, and polyethylene glycol, which is a carrier in drugs such as lorazepam.3

For most drugs that cause acute tubular necrosis, the target is predominantly either the early or late segments of the
proximal tubule. Perhaps the most critical determinant of nephrotoxicity is the extent of drug or toxin uptake within cellular
targets in the kidney.2 Urine microscopy usually shows dark granular casts and renal epithelial cell casts, while the fractional
excretion of sodium ([urine sodium/plasma sodium]/[urine creatinine/serum creatinine]) is often more than 2% to 3% (normal
value < 1%).
Acute interstitial nephritis
Acute interstitial nephritis presents with systemic manifestations of a hypersensitivity reaction such as fever, rash, and
arthralgias. Allergic interstitial nephritis is an idiosyncratic reaction but reported as a possible side effect of a myriad of drugs.
Antibiotics are by far the most common culprits. There is no way to prevent this side effect; one can only promptly recognize the
syndrome and discontinue the offending agent.
Essentially a renal biopsy diagnosis, the constellation of ongoing fever, rash, progressive renal failure, and eosinophilia
during prolonged antibiotic therapy should raise suspicion of the diagnosis. Although penicillins and cephalosporins are wellrecognized culprits, almost any antibiotic can cause it occasionally. The fluoroquinolone ciprofloxacin is now a well-recognized
cause of allergic interstitial nephritis.4, 5
Urinary findings include white blood cells, red blood cells, and white cell casts. Eosinophilia or eosinophiluria or both
are present in more than 75% of cases, except in cases due to NSAIDs, in which fever, rash, and eosinophilia are typically absent.
Thus, the absence of eosinophilia does not exclude. Although the clinical picture is highly suggestive, the diagnosis can be
confirmed only by kidney biopsy, which is indicated if the diagnosis is uncertain or if the renal failure progresses or persists in
spite of stopping the offending drug. The major histologic findings are interstitial edema and variable cellular infiltration by
eosinophils, plasma cells, T lymphocytes, monocytes, and neutrophils. In rare cases, granulomas may be seen on kidney biopsy;
patients with granulomas may also present with uveitis. In most cases, acute interstitial nephritis is reversible when the
offending agent is stopped.4
Thrombotic microangiopathy
Thrombotic microangiopathy can cause severe acute renal failure. In general, the pathologic hallmark of thrombotic
microangiopathy is hyaline thrombi in the microvasculature of many organs. Changes in the kidney include afferent arteriolar
and glomerular thrombosis and thickening of the glomerular capillary wall on electron microscopy due to the deposition of
fibrin-like materials.
Thrombotic microangiopathy may manifest with fever, hemolytic anemia, thrombocytopenia, renal dysfunction, and
central nervous system disease the full pentad of symptoms of thrombotic thrombocytopenic purpura (TTP) most frequently
seen in adults. However, not all patients present with the full pentad, and physicians should consider this possibility in any
patient who develops Coombs-negative hemolytic anemia, thrombocytopenia, and renal failure after exposure to drugs
Urinalysis shows microscopic hematuria, subnephrotic proteinuria, hyaline, and few granular casts. The reticulocyte count is
elevated, haptoglobin levels are low, schistocytes are present in the peripheral blood smear, and the lactate dehydrogenase level
is high.
The most important first step in treating drug-induced TTP-HUS is to stop the offending drug. Overall mortality is high,
though many patients may survive on chronic dialysis. Steroids are of no proven benefit in this syndrome.
OBSTRUCTIVE
Drug-associated obstruction of urine outflow can occur at several sites: within the tubules or the ureters (due to crystal
formation), and outside the ureters (due to retroperitoneal fibrosis caused by agents such as methysergide). 4 Risk factors for
crystal-induced acute renal failure include severe volume depletion (chronic diarrheal states, diuretic use, congestive heart
failure, and capillary leak syndromes), underlying renal insufficiency, bolus drug administration, and metabolic disorders such
as metabolic acidosis or alkalosis. In addition, patients with human immunodeficiency virus (HIV) infection may be at increased
risk because they often have some of the above risk factors and often take multiple drugs. The urine sediment may contain red
cells, white cells, and crystals.
NEPHROTIC SYNDROME
The nephrotic syndrome is due to glomerular dysfunction and marked by heavy proteinuria. Drugs implicated include
gold, NSAIDs, penicillamine, interferon, and captopril. Patients may present with edema, proteinuria, and hypoalbuminemia.
Membranous nephropathy is the most common form reported, though minimal change nephropathy has also been seen with
NSAIDs, as discussed below.
Treatment is by stopping the drug and this often leads to resolution of nephrotic syndrome. However, irreversible injury
has also been described.
CHRONIC RENAL INSUFFICIENCY
Chronic renal insufficiency caused by drugs generally presents as tubulointerstitial disease. It is important to note that
for some drugs (e.g., cyclosporine, lithium), the mechanism of acute renal toxicity may be different from that of chronic renal
injury. Patients may present with slowly progressive elevation of creatinine, with or without renal tubular dysfunction
syndromes.
These syndromes may manifest as renal tubular acidosis, renal potassium wasting, concentration defects, and tubular
proteinuria. These syndromes may also occur without renal failure. In some cases, the renal damage is reversible when the

offending drug is stopped, but in other cases it is irreversible. Frequently reversible forms include those due to 5- aminosalicylic
acid, 6 mesalamine, and ifosfamide, while lithium and cyclosporine cause irreversible injury.
ANALGESIC NEPHROPATHY
Analgesic nephropathy, simply, is renal dysfunction caused by analgesics. It may be a consequence of the excessive
consumption of mixed analgesics or single analgesic use. Originally, phenacetin was common to all of these mixtures, which led
to the conclusion that this drug was the only cause of "phenacetin kidney". Subsequently, a variety of analgesics and NSAIDs
have been shown to have the potential to cause RPN and interstitial nephritis. 7, 8
Diagnosis is often made by coupling the history of analgesic abuse with morphological evidence of renal papillary necrosis
and chronic interstitial nephritis. The resultant lesions can be recognized by radiological examinations or ultrasonography and
consist of calcifications along the line of Hodson, shrinking of the kidneys resulting in irregular contours, and decreased length
of both kidneys. Necrotic papillae may be voided in the urine and this is occasionally observed.
At least two countries have legislated to prevent phenacetin from being sold over the counter. 1This legislation has had the
effect of a change in analgesic formulation, usually towards that of a single drug such as aspirin or paracetamol (acetaminophen).
In Sweden, the removal of phenacetin resulted in the progressive decline in the incidence of analgesic nephropathy. This began
approximately 6 years after the removal of phenacetin and the major impact was seen after 12 years. In Australia, phenacetin was
removed from combination analgesics by 1976 and replaced with acetaminophen (the principle metabolite of phenacetin); by
1979 legislation prohibited the over-the-counter sale of combination analgesics. According to the Australia-New-Zealand Dialysis
and Transplant Registry, this has resulted in a progressive decline in the incidence of analgesic nephropathy in patients
presenting with end-stage chronic renal failure in dialysis and transplant programmes. Paracetamol, which largely replaced
phenacetin in analgesic mixtures), is assumed to be involved in the pathogenesis of RPN. An increased risk of renal disease was
found in daily users of paracetamol in North Carolina, USA.9
Table 1 Common drugs and the pathology caused (modified from Guo & Nzerue 4)
DRUGS

ACUTE RENAL
FAILURE
PRERENAL

ACE INHIBITORS
ACYCLOVIR
AMINOGLYCOSIDES
ANALGESIC ABUSE
CEPHALOSPORINS
CIPROFLOXACIN
COCAINE
COX-2 INHIBITORS
DIURETICS
GOLD
INDINAVIR
LITHIUM
MANNITOL
NSAIDS
PENICILLINAMINE
PENICILLINS
QUININE
RIFAMPIN
SULPHONAMIDES
VALPROIC ACID

NEPHROTIC
SYNDROME
INTRINSIC

OBSTRUCTIVE

CHRONIC
RENAL
FAILURE

NEPHROPROTECTIVE MEASURES

Guidelines to preventing drug-induced nephrotoxicity

In brief, the best clinical approach to drug-induced nephrotoxicity is prevention, which starts with the recognition that druginduced renal injury occurs and is seen predominantly in patients at risk. The following steps are necessary:
Anticipate. Be aware of nephrotoxic potential of specific drugs.
Identify patients at risk (those with renal insufficiency, dehydration, salt-retaining states, diabetes, and multiple
myeloma). Assess for risk factors (table 2)
Be aware of increased risk in elderly patients.
Carefully assess the benefits of prescribed drugs against potential risk.
Whenever possible, select diagnostic procedures or therapeutic measures without nephrotoxic potential.
Avoid dehydration mandatorily in high-risk patients. Pretreatment hydration is very important.
Limit total daily dosage and duration of treatment with certain drugs.
Adjust the daily dosage to ongoing alterations in the GFR.
Avoid a combination of potentially nephrotoxic drugs.
Urinary alkalinization to prevent renal failure from sulphonamides, methotrexate, triamterene, etc.
Table 2 Risk factors for nephrotoxicity
Patient-related factors
Age, sex, race
Previous renal insufficiency
Specific diseases (diabetes mellitus, hypertension, sickle cell disease, multiple myeloma, proteinuric disease, SLE)
Sodium-retaining states (cirrhosis, heart failure, nephrosis)
Dehydration and volume depletion
Acidosis, potassium and magnesium depletion
Hyperuricemia, hyperuricosuria
Sepsis, shock
Renal transplantation
Drug-related factors
Inherent nephrotoxic potential
Dose
Duration, frequency, and form of administration
Repeated exposure
Drug interactions
Combined or closely associated use of diagnostic or therapeutic agents with added or synergistic nephrotoxic potential (e.g.,
radiocontrast agents, aminoglycosides, nonsteroidal anti-inflammatory drugs, cisplatin, angiotensin-converting enzyme
inhibitors)
CONCLUSION
Although the exact incidence of drug-induced nephrotoxicity is not known, it is important for clinicians to be aware of
the risks in certain patients and to know which drugs are the most commonly implicated. The latter include radiocontrast
agents, aminoglycosides, nonsteroidal anti-inflammatory drugs, and angiotensin converting enzyme inhibitors. Other
medications also have nephrotoxic potential when they are prescribed in specific patient populations.
RECOMMENDATIONS
1.

Epidemiological studies (e.g. prospective studies in general population groups exposed to nephrotoxic chemicals or
involved with analgesic abuse) should be reinforced.

2.

More effort should be made to establish the role of drugs in the etiology of renal disease at the earliest diagnostic stage
(e.g., history taking, renal biopsy for features).

3.

A deeper understanding of the mechanisms of action of nephro-toxicants will be helpful in the prevention and clinical
management of unwanted renal effects, and may help in predicting the nephrotoxic potential for new drugs and
chemicals.

REFERENCES
1.

Principles and methods for the assessment of nephrotoxicity associated with exposure to chemicals. International
Programme on Chemical Safety (IPCS), World Health Organization, Geneva 1991.

2.

Zager RA. Pathogenetic mechanisms in nephrotoxic acute renal failure. Semin Nephrol 1997; 17:314.

3.

Laine GA, Hossain SM, Solis RT, Adams SC. Polyethylene glycol nephrotoxicity secondary to prolonged high-dose
intravenous lorazepam. Ann Pharmacother 1995; 29:11101114.

4.

Guo X, Nzerue C. How to prevent, recognize, and treat drug-induced nephrotoxicity. Cleveland Clinic Journal of
Medicine April 2002 Volume 69, Number 4.

5.

Allon M; Lopez EJ; Min KW. Acute renal failure due to ciprofloxacin. Arch Intern Med 1990 Oct; 150(10):2187-9.

6.

Agharazii M., Marcotte J., Boucher D. Chronic interstitial nephritis due to 5-aminosalicylic acid. Am J Nephrol 1999;
19:373376.

1.

Burry, A., Cross, R., Axelsen, R. Analgesic nephropathy and the renal concentrating mechanism. Pathol. Annu., 1997 12:
1-31.

2.

Schwarz, A. Analgesic-associated nephropathy. Klin. Wochenschr. 1987, 65: 1-16.

3.

Sandler, D.P., Smith, J.C., Weinberg, C.R., Buckalew, V.M., Dennis V.W., Blythe, W.B., & Burgess, W.P. Analgesic use
and chronic renal disease. New Engl. J. Med. 1987, 320: 1238-1243.

4.

Vaamonde C A. Risk factors in nephrotoxicity. In: Strauss J, (ed). Pediatric Nephrology Seminars. Amsterdam: Martinus
Nijhoff/W Funk Publishers, Amsterdam 1986:49-85.