As early as 1950 analgesics obtained recognition as a significant cause of chronic kidney disease, especially for people using them long term rather than brief periods. Phenacetin was withdrawn from the US market for this reason in the early seventies. The drugs indicated in this pathology include the commonly used over the counter analgesics like aspirin, paracetamol/acetaminophen, and ibuprofen. Even though newer classes of analgesics/anti-inflammatory drugs such as COX-2 inhibitors were thought to be theoretically less likely a potential cause, there is now strong evidence suggesting that they are equally culpable causing chronic kidney disease in the long run. Overall there has been no consensus on the long term safety of these drugs in the general population, particularly in the elderly where aging kidneys are already compromised. However, the evidence implicates chronic overuse of these medications over a period of years, rather than a few days or weeks.
Although chronic NSAID use is generally safe, daily use of more than 12 months correlates with risk of renal impairment and if unrecognized can progress to chronic kidney disease and end-stage renal disease. It can present in various forms, including papillary necrosis. The recommended action after diagnosis is to stop the causative analgesia/NSAID (aspirin, paracetamol, ibuprofen, COX-2 inhibitors). Unfortunately, this may be insufficient completely reverse already established changes, but will still be the most reasonable option.
The likely cause of analgesia/NSAID induced nephropathy has not been clearly demonstrated. However, the evidence so far from various case studies and controlled randomized trials appears to attribute it to the hypotensive effects provoked by inhibition of the vasodilatory effects of prostaglandin synthesis, and high metabolite concentrations in the medullary region leading to papillary necrosis, chronic interstitial nephritis, and chronic tubular interstitial nephritis.
The incidence is significantly higher in women as compared to males with around 50 to 80% in females. The most commonly affected age group is 30 to 70 years with a peak incidence around the early fifties.
In some studies, there were reportedly fewer than 200 cases per year for the period 2002-2015 in the US; there is not much difference in prevalence in Europe and Australia. However, increased risk has been observed in the elderly population with already impaired kidney function and eGFR.
The likely possible explanation for impaired kidney function from long term analgesia overuse is a hypotensive insult from inhibition of the prostaglandin pathway. Inhibition of the vasodilatory effect prostaglandins pathway is the most recognized and accepted mechanism of hypoperfusion-related medullary ischemia, which is usually followed 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.
From mononuclear infiltration to eosinophilic deposits, the various histopathological features in established cases of nephropathy include features of interstitial fibrosis and occasionally papillary calcifications and metabolite deposits in the medullary region. A significant number of inflammatory changes also present with evidence of necrosis (papillary) in the vast majority of cases. There can also be features of sloughed papillary changes visible on CT scan as well.
Patients with a history of chronic NSAIDs/analgesics use can be asymptomatic even though early changes of nephropathy are obvious. This situation can present a challenge as there are hardly any gross abnormal symptoms and signs of this during the acute presentation. From sterile pyuria, micro or gross hematuria to mild proteinuria, the initial abnormalities include deranged urine concentrating ability, defects in acidifying urine and abnormal sodium conservation.
Some patients can have progression to chronic kidney disease/end-stage renal disease without noticing any gross symptomatic aberration. Most patients receive a diagnosis when they present with abnormal blood parameters on routine monitoring or when being evaluated for some other associated co-morbidity. Patients with established changes of the chronic kidney disease can have clinical manifestations of anemia, fatigue, hypertension, headaches or GI symptoms of chronic NSAIDs or analgesic use.
A small percentage can present with renal colic and associated haematuria and will also require further evaluation for urinary bladder malignancies, which the patients of analgesia nephropathy are at increased risk (i.e., transitional cell carcinoma of uroepithelium). Women tend to present with an increased frequency of urinary tract infections, which if left untreated can increase the likelihood of worsening kidney function and end-stage renal disease.
The presentation can be variable from asymptomatic hematuria, sterile pyuria, or proteinuria, to symptomatic anemia with features of chronic kidney disease and acute presentations of urinary tract infection, especially in women. A routine urinary examination might not be helpful except for the features mentioned above. However, urinary PCR (protein creatinine ratio) as a next diagnostic step might prove useful in some instances, where there can be a nephrotic range of protein loss. Basic investigations can include routine blood investigations, even considering extended anemia profile. An ultrasound of abdomen especially kidney, urinary bladder can be useful in looking for obstructive, infective or secondary causes. CT scan imaging is the most valuable diagnostic tool for uncovering specific features of NSAID/analgesia induced nephropathy.
Non-enhanced computed tomography abdomen is preferred and can demonstrate features suggestive of analgesic nephropathy which include decreased in renal mass, renal scarring, reduction in renal volume with irregular renal surfaces or/and papillary calcifications. It can also show features of parenchymal thining.
Uropyelograms are not useful in diagnosis and can be even harmful given that contrast can worsen the clinical picture and renal damage.
As the most prevalent abnormality observed is papillary necrosis, one needs to rule out other causes of the same presentation.
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 possible causes. 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 for prevention of any further deterioration, especially pyelonephritis; however, increased urinary catheterizations have been discouraged for use to prevent progression of or predisposition to infection.
Overall the clinical course of this is variable and depends mainly on the extent of renal damage, scarring, fibrosis and the reversibility of retaining kidney parenchyma.
Unfortunately, even after stopping the offending drug the changes of recovery may not occur quickly, and in some instances might progress further.
Several differentials require exclusion unless there is a more specific history. As the common pathology in almost all patients with analgesic nephropathy is papillary necrosis, other conditions can mimic like this needs to be excluded. These include diabetes mellitus type 2, sickle cell disease with a renal crisis, obstructive uropathy, pyelonephritis, tuberculosis of the renal tract, alcohol abuse, systemic vasculitis, and renal vein thrombosis.
As mentioned in earlier sections the presentation and prognosis of analgesia induced nephropathy are variable and unpredictable. One may expect to regain complete normal kidney function in the majority of patients who present in the early course of renal involvement, as compared to a few individuals who will progress to end-stage renal disease and dialysis even after stopping drugs if there are significant damage and scarring to the renal tissue.
End-stage renal disease and related complications can be possible sequelae, but it primarily depends on the extent of damage and duration of the disease.
Many studies have revealed the most critical point of patient education is avoiding long term analgesic use in preventing nephropathy.
In some western countries, not promoting commercials for over the counter analgesia use had also demonstrated effectiveness as a prevention strategy. Lastly, a collective effort is necessary for educating the general masses and patients for this preventable cause of end-stage renal disease.
Overall the likely possibility of eventually improving the outcome of condition analgesia induced nephropathy will require the effort of a multidisciplinary, interprofessional team involved in the care including physicians, nurses, and pharmacists, who each lend their unique perspective to treating and preventing this disorder. Studies show a documented decrease in the incidence and prevalence of this as compared to the seventies because of better patient education and other preventive measures. [Level V] The physician, pharmacist, and the nurse should heavily emphasize to the patient the detrimental effects of longterm usage of NSAIDs.
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