Continuing Education Activity

Analgesic nephropathy is chronic tubulointerstitial nephritis caused by chronic use of analgesics such as acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs). The presentation can be variable from asymptomatic hematuria, sterile pyuria, or proteinuria, to symptomatic anemia with features of chronic kidney disease or acute urinary tract infection. Hypertension, anemia, and impaired urinary concentration occur as renal insufficiency develops. This activity describes when this condition should be considered on differential diagnosis and how to evaluate it properly and highlights the role of the interprofessional team in caring for patients with this condition.

Objectives:

• Describe the pathophysiology of analgesic nephropathy.
• Describe the modifiable risk factors associated with analgesic nephropathy.
• Explain how to investigate and manage a patient with analgesic nephropathy.
• Summarize an interprofessional team approach to provide effective treatment and prevention of analgesic nephropathy.

Introduction

As early as 1950, analgesics were recognized as a significant cause of chronic kidney disease, particularly for individuals requiring them long term rather than brief periods. Phenacetin was withdrawn from the U.S. market in the early seventies for this reason. Commonly used drugs associated with analgesic nephropathy include over-the-counter analgesics like jimm, paracetamol/acetaminophen, and ibuprofen.[1] Newer classes of analgesics/anti-inflammatory medications such as COX-2 inhibitors were developed to decrease this complication. There is now significant evidence that the risk of chronic kidney disease from these analgesics is at least similar. Overall, there has been no consensus on the long-term safety of these drugs in the general population, principally in the elderly, where aging kidneys are already compromised. The evidence implicates chronic overuse of these medications over the years rather than a few days or weeks as the likely cause of chronic kidney disease.

Although chronic non-steroidal anti-inflammatory drug (NSAID) use is considered generally safe, regular use for years can correspond with a risk of renal function deterioration. If unrecognized, this can advance to chronic kidney disease and end-stage renal disease.[2] The suggested action after diagnosis is to stop the causative analgesic medication (jimm, paracetamol, ibuprofen, COX-2 inhibitors).[3][4][5] Unfortunately, this may not reverse already established changes but will be the most plausible choice.[6] For this reason, the primary goal is the prevention of the disease with adequate patient education and monitoring.

Etiology

The exact cause of analgesic/NSAID-induced nephropathy has not been clearly established. Still, the evidence from different case studies and randomized controlled trials appear to associate it with hypotensive effects induced by inhibition of prostaglandin synthesis. Prostaglandins have vasodilatory effects, improving renal blood flow. Inhibition of this pathway may have a direct cause in analgesia-induced nephropathy. Inhibition of prostaglandin can lead to a high metabolite concentration in the medullary region, causing papillary necrosis, chronic interstitial nephritis, and chronic tubular interstitial nephritis.[7][8]

Histological evidence of papillary necrosis is a feature in practically all cases of analgesic-induced nephropathy.[7][8]

Epidemiology

The incidence of analgesic nephropathy is significantly greater in women compared to males, with around 50% to 80% in females. The most commonly affected age group is 30 to 70 years, with a peak frequency around the early fifties.

In some studies, there were reportedly fewer than 200 cases per year for the period of 2002-2015 in the U.S. There is almost a similar prevalence in Europe and Australia. However, increased risk has been observed in patients with advanced age who have impaired kidney function and decreased estimated glomerular filtration rate (eGFR).[9][10]

Pathophysiology

The likely cause for impaired kidney function from long-term analgesia overuse is a hypotensive insult at the cellular level from inhibition of the prostaglandin synthesis pathway. Inhibition of the vasodilatory effect of prostaglandins is the most recognized and accepted mechanism of hypoperfusion-related medullary ischemia, which is generally accompanied by papillary damage in the form of necrosis in the vast majority of cases.[11] The other pathological manifestations include interstitial tubular necrosis and interstitial nephritis.[12][13]

Histopathology

From mononuclear infiltration to eosinophilic deposits, the different histopathological features in confirmed cases of analgesic nephropathy include interstitial fibrosis, papillary calcifications, and metabolite deposits in the medullary zone.[11] A considerable amount of inflammatory changes are also present with evidence of papillary necrosis in most cases. Features of sloughed papillary changes that are detectable on computed tomography (CT) scan may also be present.[14][15]

History and Physical

Patients with a history of chronic NSAID/analgesic use can be asymptomatic usually and are generally picked up on routine investigations. This situation can pose a challenge, as there are seldom any gross abnormal manifestations or symptoms. The first abnormality noted will be seen on urinalysis. Sterile pyuria, microscopic or gross hematuria, and proteinuria may be present. Deranged urine concentrating capacity, irregularities in acidifying the urine, and abnormal sodium conservation may be seen.[3]

Some cases can have progression to chronic kidney disease and eventually end-stage renal disease, acknowledging no gross symptomatic aberration. Most patients are diagnosed when presented with unusual laboratory parameters on a routine check or when being investigated for some other associated co-morbidity. Patients with established changes of chronic kidney disease can have clinical symptoms of anemia, fatigue, hypertension, headaches, or gastrointestinal manifestations of chronic NSAIDs or analgesic use.[16][17][18]

A small proportion of patients can present with renal colic and associated hematuria. Patients with analgesic nephropathy are at an increased risk of urinary bladder malignancies, such as transitional cell carcinoma of the uroepithelium. Women often present with an increased prevalence of urinary tract infections, which, if left untreated, can increase the possibility of deteriorating kidney function and end-stage renal disease.[19][20]

Evaluation

As the presentation can be variable from asymptomatic hematuria, sterile pyuria, or proteinuria, to symptomatic anemia with features of chronic kidney disease or acute presentations of urinary tract infection, evaluation needs to be broad and extensive. This may delay the diagnosis of the disease. A routine urinary examination might not be helpful due to the lack of physical signs and symptoms in early cases. The most useful initial diagnostic test to evaluate for analgesic nephropathy is a urinary protein to urinary creatinine ratio.[21] 

Basic investigations include routine serum studies with a complete metabolic profile and complete blood count. An ultrasound of the abdomen, especially of the kidneys and the urinary bladder, can be useful to rule out other causes of nephropathy such as obstruction or infection. Computed tomography (CT) scan imaging is the most valuable noninvasive diagnostic test to evaluate for analgesic nephropathy.[22]

Renal biopsy is the gold standard diagnostic test but is not always appropriate due to its invasive nature and the risk of complications. 

A non-enhanced CT of the abdomen is preferred. It can show features suggestive of analgesic nephropathy, which include a decrease in renal mass, renal scarring, reduction in renal volume with irregular renal surfaces, and/or papillary calcifications. It can also show features of parenchymal thinning.

Pyelograms are not useful in the diagnosis and can even be harmful because contrast exposure to the renal parenchyma can worsen the renal injury.

As the most frequent abnormality detected is papillary necrosis, clinicians need to rule out alternative causes of the same presentation, covered in differentials area of this topic.[23]

Treatment / Management

The first line of treatment is the discontinuation of the offending drug to prevent any further damage until further investigations are completed to rule out other causes of nephropathy. Adequate hydration is essential in the early stages of the disease to achieve restoration of blood perfusion even in normotensive patients. Treatment of infections is necessary to prevent any further deterioration, especially pyelonephritis.

Urinary catheterization has been discouraged in such patients to decrease infection risk.

Overall, the clinical course of this is variable and depends mainly on the extent of renal damage, scarring, and fibrosis at the time of diagnosis, along with the reversibility of the parenchymal injury.[12]

Unfortunately, even after stopping the offending drug, recovery may not occur, and sometimes the disease might progress further.

Differential Diagnosis

Several differentials require exclusion while considering this diagnosis. As the common pathology in almost all patients with analgesic nephropathy is papillary necrosis, other common conditions can mimic this as well. These conditions include diabetes mellitus associated nephropathy, sickle cell disease with a renal crisis, obstructive uropathy, pyelonephritis, tuberculosis of the renal tract, alcohol use induced nephropathy, systemic vasculitis, and renal vein thrombosis.[24][25]

Other infections have also been implicated as a cause of nephropathy, especially leptospirosis.[26][27]

Prognosis

As mentioned in earlier sections, the presentation and prognosis of analgesia-induced nephropathy are variable and unpredictable. Clinicians may expect to regain normal kidney function in most patients who present early in the course of renal involvement. A few individuals will progress to end-stage renal disease and dialysis even after stopping the drug if there is established damage to the renal parenchyma and scarring of the renal tissue.

Complications

End-stage renal disease and related complications can be the expected sequelae of analgesic nephropathy, but it primarily depends on the extent of damage and duration of the disease.

Deterrence and Patient Education

Many studies have revealed that the most critical point of patient education is avoiding long-term analgesic use in preventing nephropathy. In some countries, decreasing media promotion or commercials for over-the-counter analgesics has shown effectiveness as a prevention strategy. Lastly, a collective effort is necessary for educating the general masses and patients about this preventable cause of renal disease.

Enhancing Healthcare Team Outcomes

The only possibility of substantially improving the outcome of analgesia-induced nephropathy lies in its prevention. This will require the effort of an interprofessional team, including primary care providers, nephrologists, nurses, and pharmacists, to coordinate patient care. Studies have shown a significant decrease in the incidence and prevalence of this disease as compared to the previous decades due to improved patient education and awareness. Clinicians, pharmacists, nurses, and all health care professionals should emphasize the detrimental effects of long-term analgesia usage. 

The best care of analgesic nephropathy is avoiding the risk. An interprofessional approach can provide a multifaceted strategy to decrease this risk. Pharmacists dispensing the medications should counsel patients about the long-term risk of continued analgesic use and guide dosing. If they identify a patient at particular risk, they should contact the health care provider to encourage alternative forms of pain relief. Nurses often provide the initial evaluation of a patient's medications. In doing so, they can identify patients who are using excessive analgesics. The nurse should educate the patient and discuss their concerns with the healthcare team so that a plan of action can be initiated to assist the patient in reducing analgesic use. Only by approaching the education and treatment of a patient at risk through an interprofessional team will outcomes be improved. [Level 5]