Analgesic Nephropathy


Article Author:
Mansoor Keen


Article Editor:
Narothama Aeddula


Editors In Chief:
Sisira Reddy
Joseph Nahas
CHOKKALINGAM SIVA


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Abbey Smiley
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
11/4/2019 8:05:57 PM

Introduction

As early as 1950, they recognized analgesics as a significant cause of chronic kidney disease, particularly for individuals requiring them long term rather than brief periods. They withdrew phenacetin 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 aspirin, 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 likely cause.

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 (aspirin, 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 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 [11], which is generally accompanied by papillary damage in the form of necrosis in the vast majority of cases. 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 CT scan may also be present.[14][15]

Toxicokinetics

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 noted on urinalysis. Sterile pyuria, microscopic or gross haematuria, and proteinuria may be present. Deranged urine concentrating capacity, irregularities in acidifying 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 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 complete metabolic profile and complete blood picture. 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 renal injury.

As the most frequent abnormality detected is papillary necrosis, one needs 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 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, the chances of 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. One 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 for 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. Physicians, 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 V]


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Analgesic Nephropathy - Questions

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A 65-year-old female with a history of ankylosing spondylitis managed by as needed over-the-counter pain medications presents with fever and confusion. She is found to have a urinary tract infection. She recovers after treatment with intravenous fluids and antibiotics. However, her kidney function did not recover to normal values. Outpatient renal biopsy reveals papillary necrosis of the renal tubules. What is the safest choice of pain management for this patient if needed?



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A 70-year-old male is admitted to the hospital with bilateral lower limb swelling and shortness of breath. He states he has rhinorrhea with severe myalgia and productive cough a few days prior to this admission. On examination today he is febrile and his blood pressure is 130/90 mmHg, heart rate is 101 bpm, and oxygen saturation is 92% on room air. He has a history of osteoarthritis for which he had been using as needed non-steroidal anti-inflammatory drugs (NSAIDs) for a long time. His investigations revealed leukocytosis, with neutrophilia and an estimated glomerular filtration rate of 30mL/min. Chest x-ray revealed a right lower zone infiltrate. Which of the following best explains the renal dysfunction seen in this patient considering the long history of analgesic use?



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A 68-year-old male with a medical history of rheumatoid arthritis treated with methotrexate and meloxicam presents to the clinic for follow up. Laboratory value review shows the estimated glomerular filtration rate of 45 mL/min. This was 60 mL/min 5 years ago. Urinalysis shows 3+ proteinuria. Which if the following is an expected complication of this disease?



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An 80-year-old female with a history of diabetes mellitus type 2 and osteoarthritis presents to the hospital with nausea and vomiting for the last 4 days. She is hypotensive and tachycardic on evaluation. Laboratory testing showed an elevated serum creatinine level with a decreased estimated glomerular filtration rate. Her home medications include sitagliptin and celecoxib. What is the next best step in the management of this patient?



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A 75-year-old male with a history of osteoarthritis presents to the clinic for a routine examination. His laboratory results reveal a creatinine of 1.8 mg/dL. He is advised hydration with repeat laboratory testing in 1 week. His repeat creatinine is 1.7 mg/dL with urinalysis showing proteinuria and pyuria. What will be the most likely finding on renal biopsy?



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Analgesic Nephropathy - References

References

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