Analgesic Nephropathy

Article Author:
Mansoor Keen
Article Editor:
Narothama Aeddula
Updated:
6/14/2019 9:25:49 PM
PubMed Link:
Analgesic Nephropathy

Introduction

As early as 1950, they recognised 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 US market in the early seventies. The drugs reported in this pathology include the usually used over-the-counter analgesics like aspirin, paracetamol/acetaminophen, and ibuprofen [1] Even though newer classes of analgesics/anti-inflammatory medications such as COX-2 inhibitors were hoped to be theoretically less likely a cause, there is now significant evidence pointing out 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, principally in the elderly, where ageing 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 NSAID use is considered generally safe, regular use for years can correspond with a risk of renal function deterioration and if unrecognised can advance to chronic kidney and end-stage renal disease.[2] The suggested action after diagnosis is to stop the causative analgesia/NSAID (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]

Etiology

The likely cause of analgesia/NSAID induced nephropathy has not been clearly established. but, the evidence so far from different case studies and controlled randomised trials appears to associate it to the hypotensive effects induced 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.[7][8]

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

Epidemiology

The incidence 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 US. There is almost a similar prevalence in Europe and Australia. However, increased risk has been observed in aged people with already impaired kidney function and eGFR.[9][10]

Pathophysiology

 The likely cause for impaired kidney function from long-term analgesia overuse is a hypotensive insult from inhibition of the prostaglandin pathway. Inhibition of the vasodilatory effect from prostaglandins pathway is the most recognised 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 nephropathy include features of interstitial fibrosis and occasionally papillary calcifications and metabolite deposits in the medullary zone.[11] A considerable amount of inflammatory changes also present with evidence of necrosis (papillary) in most cases. There can further be features of sloughed papillary changes detectable on CT scan.[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 and symptoms of this during the subtle presentation. From sterile pyuria, micro or gross haematuria to mild proteinuria, the first abnormalities include deranged urine concentrating capacity, irregularities in acidifying urine and abnormal sodium conservation.[3]

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

An insignificant proportion can present with renal colic and associated haematuria and will be evaluated for urinary bladder malignancies, which the patients of analgesia nephropathy are at increased risk (i.e., transitional cell carcinoma of uroepithelium). Women 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 haematuria, sterile pyuria, or proteinuria, to symptomatic anaemia with features of chronic kidney disease or acute presentations of urinary tract infection, specifically in women, further evaluation might get delayed. A routine urinary examination might not be essentially helpful, except for the features mentioned above. However, urinary PCR (protein creatinine ratio) as a next diagnostic step might turn out useful sometimes, when the presentation will be nephrotic.[21] 

Basic investigations include routine blood investigations, even considering extended anaemia profile. An ultrasound of abdomen especially kidney, the 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.[22]

Renal Biopsy is a gold standard but is not considered always appropriate.

A non-enhanced computed tomography abdomen is preferred and can show 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 thinning.

Pyelograms are not useful in the diagnosis and can even be harmful, provided that contrast can exacerbate the clinical picture and renal insult.

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 likely secondary 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 to prevent any further deterioration, especially pyelonephritis.

Urinary catheterisation has been discouraged in such patients to make infection riskless.

Overall, the clinical course of this is variable and depends mainly on the extent of renal damage, scarring, fibrosis and the reversibility of keeping kidney parenchyma.[12]

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

Differential Diagnosis

Several differentials require exclusion while considering this diagnosis because of less prevalence. As the common pathology in almost all patients with analgesic nephropathy is papillary necrosis, other common conditions can mimic this. 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.[24][25]

Some infections other than tuberculosis have also been implicated, 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 complete normal kidney function in most 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 is established damage and scarring to the renal tissue.

Complications

End-stage renal disease and related complications can be sequelae, 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 western countries, not promoting commercials for over-the-counter analgesia use has also 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

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, nephrologists, nurses, and pharmacists, who each lend their unique perspective in preventing and managing this. Studies have shown a significant decrease in the incidence and prevalence of this as compared to the seventies because of better patient education and other preventive measures. The physician, pharmacist, nurses and all health care professionals should emphasize to the patient the detrimental effects of long-term usage of analgesia. We should offer blood monitoring in the community for early recognition of this complication.


References

[1] Waddington F,Naunton M,Thomas J, Paracetamol and analgesic nephropathy: Are you kidneying me? International medical case reports journal. 2015;     [PubMed PMID: 25548527]
[2] Ozer EK,Goktas MT,Kilinc I,Bariskaner H,Ugurluoglu C,Iskit AB, Celecoxib administration reduced mortality, mesenteric hypoperfusion, aortic dysfunction and multiple organ injury in septic rats. Biomedicine     [PubMed PMID: 28024294]
[3] Albrecht B,Giebel S,McCarron M,Prasad B, Cyclooxygenase-2 inhibitor-induced acute interstitial nephritis. BMJ case reports. 2017 May 22;     [PubMed PMID: 28536229]
[4] Kovacevic L,Bernstein J,Valentini RP,Imam A,Gupta N,Mattoo TK, Renal papillary necrosis induced by naproxen. Pediatric nephrology (Berlin, Germany). 2003 Aug;     [PubMed PMID: 12774222]
[5] Segasothy M,Chin GL,Sia KK,Zulfiqar A,Samad SA, Chronic nephrotoxicity of anti-inflammatory drugs used in the treatment of arthritis. British journal of rheumatology. 1995 Feb;     [PubMed PMID: 7704463]
[6] Schwarz A, Analgesic-associated nephropathy. Klinische Wochenschrift. 1987 Jan 5;     [PubMed PMID: 3560785]
[7] Ungprasert P,Cheungpasitporn W,Crowson CS,Matteson EL, Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies. European journal of internal medicine. 2015 May;     [PubMed PMID: 25862494]
[8] Tian XY,Wong WT,Leung FP,Zhang Y,Wang YX,Lee HK,Ng CF,Chen ZY,Yao X,Au CL,Lau CW,Vanhoutte PM,Cooke JP,Huang Y, Oxidative stress-dependent cyclooxygenase-2-derived prostaglandin f(2α) impairs endothelial function in renovascular hypertensive rats. Antioxidants     [PubMed PMID: 21951274]
[9] Modig S,Elmståhl S, Kidney function and use of nonsteroidal anti-inflammatory drugs among elderly people: a cross-sectional study on potential hazards for an at risk population. International journal of clinical pharmacy. 2018 Aug;     [PubMed PMID: 29460083]
[10] Rahman S,Malcoun A, Nonsteroidal antiinflammatory drugs, cyclooxygenase-2, and the kidneys. Primary care. 2014 Dec;     [PubMed PMID: 25439535]
[11] Jochum E,Janssen U, [Chronic interstitial nephritis in an 18-year-old due to intake of a compound analgesic]. Medizinische Klinik (Munich, Germany : 1983). 2006 Oct 15;     [PubMed PMID: 17039326]
[12] Raghavan R,Shawar S, Mechanisms of Drug-Induced Interstitial Nephritis. Advances in chronic kidney disease. 2017 Mar;     [PubMed PMID: 28284381]
[13] Rodríguez Ourens MJ,Morales Martínez A, [Do we care the nephrotoxicity consequences of prescribing NSAID'S? Acute renal failure in 23 year old male]. Semergen. 2017 Mar;     [PubMed PMID: 27667146]
[14] Akhund L,Quinet RJ,Ishaq S, Celecoxib-related renal papillary necrosis. Archives of internal medicine. 2003 Jan 13;     [PubMed PMID: 12523925]
[15] Tsuchiya Y,Yabe K,Takada S,Ishii Y,Jindo T,Furuhama K,Suzuki KT, Early pathophysiological features in canine renal papillary necrosis induced by nefiracetam. Toxicologic pathology. 2005;     [PubMed PMID: 16105799]
[16] Jung JH,Kang KP,Kim W,Park SK,Lee S, Nonsteroidal antiinflammatory drug induced acute granulomatous interstitial nephritis. BMC research notes. 2015 Dec 16;     [PubMed PMID: 26674186]
[17] Leven C,Hudier L,Picard S,Longuet H,Lorcy N,Cam G,Boukerroucha Z,Dolley-Hitze T,Le Cacheux P,Halimi JM,Cornec Le Gall E,Hanrotel-Saliou C,Arreule A,Massad M,Duveau A,Couvrat-Desvergnes G,Renaudineau E, [Prospective study of drug-induced interstitial nephritis in eleven French nephrology units]. Presse medicale (Paris, France : 1983). 2014 Nov;     [PubMed PMID: 25218248]
[18] Praga M,Sevillano A,Auñón P,González E, Changes in the aetiology, clinical presentation and management of acute interstitial nephritis, an increasingly common cause of acute kidney injury. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2015 Sep;     [PubMed PMID: 25324356]
[19] Esteve JB,Launay-Vacher V,Brocheriou I,Grimaldi A,Izzedine H, COX-2 inhibitors and acute interstitial nephritis: case report and review of the literature. Clinical nephrology. 2005 May;     [PubMed PMID: 15909599]
[20] Bakris GL,Kern SR, Renal dysfunction resulting from NSAIDs. American family physician. 1989 Oct;     [PubMed PMID: 2679011]
[21] Vega J,Goecke H,Méndez GP,Guarda FJ, Nephrotic syndrome and acute tubular necrosis due to meloxicam use. Renal failure. 2012;     [PubMed PMID: 22963504]
[22] Kramer P, [Analgesic nephropathy]. Medizinische Klinik. 1975 May 16;     [PubMed PMID: 1134426]
[23] Ferreira DA,Cruz R,Venâncio C,Faustino-Rocha AI,Silva A,Mesquita JR,Ortiz AL,Vala H, Evaluation of renal injury caused by acute volume replacement with hydroxyethyl starch 130/0.4 or Ringer's lactate solution in pigs. Journal of veterinary science. 2018 Sep 30;     [PubMed PMID: 30041290]
[24] Chalhoub NE,Riley K,Siddiqui N,Assaly R,Shahrour K,Booth R,Duggan J, Renal Papillary Necrosis Due to Invasive Candida Infection in a Morbidly Obese Patient. The Journal of urology. 2015 Oct;     [PubMed PMID: 26184064]
[25] Kawaguchi Y,Mori H,Izumi Y,Ito M, Renal Papillary Necrosis with Diabetes and Urinary Tract Infection. Internal medicine (Tokyo, Japan). 2018 Nov 15;     [PubMed PMID: 29984778]
[26] Fadel MG,Carey M,Bolgeri M, Infected and obstructed kidney secondary to sloughed necrotic renal papilla. BMJ case reports. 2018 Oct 30;     [PubMed PMID: 30381308]
[27] Henderickx MMEL,Brits T,De Baets K,Seghers M,Maes P,Trouet D,De Wachter S,De Win G, Renal papillary necrosis in patients with sickle cell disease: How to recognize this 'forgotten' diagnosis. Journal of pediatric urology. 2017 Jun;     [PubMed PMID: 28341428]