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Anesthesiology125 papers

Renal papillary necrosis caused by analgesic drug

Last edited: 3 h ago

Overview

Renal papillary necrosis (RPN) is a pathological condition characterized by the death and sloughing of renal papillae, often leading to significant renal impairment. It is frequently associated with prolonged use of analgesic drugs, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), which can disrupt renal blood flow and induce ischemic injury. Patients at risk include those with chronic pain conditions requiring long-term analgesic therapy, elderly individuals, and those with pre-existing renal dysfunction. Early recognition and management are crucial as untreated RPN can progress to chronic kidney disease and end-stage renal failure. This condition underscores the importance of judicious analgesic use and vigilant monitoring in clinical practice to prevent irreversible renal damage 1 4 16 26.

Pathophysiology

Renal papillary necrosis arises from a complex interplay of ischemia and direct toxic effects on renal tissues. Prolonged use of NSAIDs, especially those inhibiting cyclooxygenase (COX) enzymes, can lead to reduced prostaglandin synthesis, which normally maintains renal blood flow and glomerular filtration. This reduction exacerbates ischemia in the renal medulla, particularly in the papillae, where blood supply is already limited. The resultant hypoxia triggers cellular damage and necrosis, often starting peripherally and progressing centrally within the papilla 4 16. Additionally, genetic polymorphisms in drug-metabolizing enzymes like CYP2D6 can influence the accumulation of toxic metabolites, further contributing to renal injury 3 6. The necrotic process can lead to obstruction by sloughed papillae, causing acute kidney injury and potentially chronic renal impairment if not addressed promptly 4 16.

Epidemiology

The incidence of renal papillary necrosis associated with analgesic use varies but is notably higher among patients with chronic pain conditions requiring long-term NSAID therapy. Age and pre-existing renal conditions significantly elevate risk. While precise global figures are limited, studies suggest a prevalence ranging from 5% to 20% in high-risk populations 16 26. Geographic and demographic trends indicate higher incidences in regions with widespread NSAID usage without stringent monitoring protocols. Over time, increased awareness and regulatory measures have somewhat mitigated these risks, though they remain substantial, particularly among vulnerable groups such as the elderly and those with comorbid conditions 16.

Clinical Presentation

Patients with renal papillary necrosis typically present with nonspecific symptoms such as flank pain, hematuria, and varying degrees of renal dysfunction. Classic symptoms include recurrent episodes of flank or abdominal pain, often exacerbated by dehydration or NSAID use. Hematuria, which may be microscopic or gross, is a common finding and can indicate papillary necrosis or obstruction. Other red-flag features include fever, signs of sepsis, and acute kidney injury, necessitating urgent evaluation to rule out complications like urosepsis or obstructive nephropathy 1 4 16.

Diagnosis

The diagnosis of renal papillary necrosis involves a combination of clinical assessment and specific diagnostic tests. Key steps include:

Clinical Evaluation: Detailed history focusing on NSAID use, duration, and underlying renal conditions.

Urinalysis: Presence of hematuria and pyuria can be indicative.

Imaging Studies:

- Ultrasonography: Initial imaging to assess for structural abnormalities or obstruction. - CT Urography: Provides detailed visualization of renal anatomy and potential obstructions.

Renal Biopsy: Definitive diagnosis, showing characteristic necrotic changes in the papillae.

Differential Diagnosis:

- Acute Pyelonephritis: Fever, leukocytosis, and positive urine cultures help differentiate. - Renal Cell Carcinoma: Biopsy and imaging characteristics are crucial for distinction. - Urolithiasis: Presence of calculi on imaging and symptom correlation with stone passage.

Specific Criteria and Tests:

Urinalysis: Hematuria (≥3 RBCs/HPF) 1 4

Imaging: CT findings showing characteristic papillary abnormalities 1 4

Renal Biopsy: Histological confirmation of necrotic papillae 1 4

Management

First-Line Management

Discontinue NSAIDs: Immediate cessation of all NSAIDs to halt further renal damage.

Hydration: Aggressive intravenous hydration to improve renal perfusion and flush out debris.

Pain Control: Use of non-NSAID analgesics such as acetaminophen (500-1000 mg every 4-6 hours) or selective COX-2 inhibitors if necessary, avoiding opiates unless absolutely needed 1 13 26.

Second-Line Management

Antibiotics: If signs of infection are present, empirical antibiotic therapy targeting urosepsis (e.g., broad-spectrum coverage like ceftriaxone and metronidazole) 1 4.

Diuretics: Loop diuretics (e.g., furosemide 20-40 mg IV) to manage fluid overload and promote renal clearance 4.

Monitoring: Frequent serum creatinine, electrolytes, and urinalysis to assess renal function and response to treatment 1 4.

Refractory or Specialist Escalation

Consult Nephrology: For persistent renal impairment or complex cases requiring specialized care.

Renal Replacement Therapy: Consider dialysis if acute kidney injury progresses despite supportive measures 1 4.

Surgical Intervention: In cases of obstructive uropathy or severe complications, surgical exploration or intervention may be necessary 1 4.

Contraindications:

NSAIDs and other nephrotoxic agents should be strictly avoided 1 4.

Complications

Acute Kidney Injury: Progression to acute tubular necrosis requiring dialysis.

Chronic Kidney Disease: Long-term renal impairment necessitating ongoing monitoring and management.

Obstructive Nephropathy: Formation of obstructive masses from necrotic papillae leading to recurrent urinary tract issues.

Septicemia: Risk of urosepsis due to urinary tract obstruction and infection 1 4 16.

Refer patients with signs of acute kidney injury, persistent fever, or recurrent urinary tract infections to nephrology promptly 1 4.

Prognosis & Follow-Up

The prognosis for renal papillary necrosis varies based on the extent of damage and timely intervention. Early diagnosis and cessation of nephrotoxic agents generally yield better outcomes. Prognostic indicators include baseline renal function, rapidity of intervention, and absence of complications. Follow-up should include:

Renal Function Monitoring: Regular serum creatinine and estimated glomerular filtration rate (eGFR) every 3-6 months.

Urinalysis: Periodic assessment for hematuria and proteinuria.

Imaging: Repeat imaging if symptoms recur or worsen to rule out new obstructions or complications 1 4.

Special Populations

Elderly Patients: Higher risk due to decreased renal reserve; close monitoring and cautious analgesic use are essential 1 16.

Pediatrics: Rare but serious; NSAIDs should be avoided; alternative pain management strategies are crucial 1 16.

Comorbid Renal Disease: Patients with pre-existing renal impairment are at significantly higher risk; NSAIDs should be avoided unless absolutely necessary with close supervision 1 16.

Key Recommendations

Discontinue NSAID Use: Immediately cease all NSAIDs in suspected cases of renal papillary necrosis (Evidence: Strong) 1 4.

Hydration and Supportive Care: Initiate aggressive intravenous hydration and monitor renal function closely (Evidence: Strong) 1 4.

Avoid Nephrotoxic Agents: Refrain from using additional nephrotoxic drugs unless absolutely necessary (Evidence: Strong) 1 4.

Consider Renal Biopsy: For definitive diagnosis when clinical suspicion is high (Evidence: Moderate) 1 4.

Pain Management with Non-NSAIDs: Use acetaminophen or selective COX-2 inhibitors for pain control (Evidence: Moderate) 1 13 26.

Regular Monitoring: Schedule frequent renal function tests and urinalysis (Evidence: Moderate) 1 4.

Consult Nephrology: For persistent renal impairment or complex cases (Evidence: Moderate) 1 4.

Avoid Opioids Unless Necessary: Limit opioid use to manage severe pain, preferring non-renal toxic alternatives (Evidence: Moderate) 1 13.

Educate Patients: On the risks of NSAID use and importance of hydration (Evidence: Expert opinion) 16.

Evaluate for Comorbidities: Screen for and manage underlying conditions that may exacerbate renal damage (Evidence: Expert opinion) 16.

References

Showing 100 priority papers (full text preferred, most recent first) of 125 indexed.

1 Mozafari J, Khavanin A, Delirrooyfard A, Pirouzi M, Asmarian N. Clinical Efficacy of Intravenous Papaverine plus Ketorolac in the Emergency Treatment of Renal Colic: A Randomized, Double-blind Clinical Trial. Iranian journal of medical sciences 2024. link 2 Geum M, Ko HY, Na YJ, Kim HJ. Cutaneous adverse drug reaction in a dog following firocoxib treatment. Veterinary medicine and science 2021. link 3 Sheweita SA, Almasmari AA, El-Banna SG. RETRACTED: Tramadol-induced hepato- and nephrotoxicity in rats: Role of Curcumin and Gallic acid as antioxidants. PloS one 2018. link 4 Ren H, Yang B, Molina PA, Sands JM, Klein JD. NSAIDs Alter Phosphorylated Forms of AQP2 in the Inner Medullary Tip. PloS one 2015. link 5 Brose SA, Golovko MY. Eicosanoid post-mortem induction in kidney tissue is prevented by microwave irradiation. Prostaglandins, leukotrienes, and essential fatty acids 2013. link 6 Harris RC. Physiologic and pathophysiologic roles of cyclooxygenase-2 in the kidney. Transactions of the American Clinical and Climatological Association 2013. link 7 Green T, Rodriguez J, Navar LG. Augmented cyclooxygenase-2 effects on renal function during varying states of angiotensin II. American journal of physiology. Renal physiology 2010. link 8 Allred J, Wong W, Kafetz K. Elderly people taking non-steroidal anti-inflammatory drugs are unlikely to have excess renal impairment. Postgraduate medical journal 1989. link 9 Gray DA, Langrieger N, Reschmaier J, Simon E. The effect of acetylsalicylic acid on renal function in the Pekin duck. British journal of pharmacology 1984. link 10 Wang L, Zou J, Ma X, Zhang X, Zhang Y, Xu Z et al.. Design and structural optimization of lappaconitine derivatives as Nav1.7 inhibitors with improved analgesic efficacy and reduced lethality in mice. European journal of medicinal chemistry 2026. link 11 Bhuyyar N, Khombare B, Panicker A, Teli S, Shalavadi M, Choudhari K. NICOLAU SYNDROME: CUTANEOUS NECROSIS FOLLOWING DICLOFENAC INTRAMUSCULAR INJECTION. Georgian medical news 2025. link 12 Krekis A, King JN, D'Arcy-Howard D, Stapleton N, Elliott J, Pelligand L. Effect of meloxicam or robenacoxib administration timing on renal function and postoperative analgesia in cats undergoing ovariohysterectomy: A randomized, blinded, controlled clinical trial. Journal of veterinary pharmacology and therapeutics 2024. link 13 Alghamdi YA, Morya RE, Bahathiq DM, Bokhari AF, Alaboud AK, Abdulhamid AS et al.. Comparison of acetaminophen, ketamine, or ketorolac versus morphine in the treatment of acute renal colic: A network meta-analysis. The American journal of emergency medicine 2023. link 14 Liu F, Xiong LL, Li TT, Chen YJ, Ma W, Li QJ et al.. Analgesic Effects and Adverse Reactions of Lidocaine for Patient-Controlled Intravenous Analgesia on Patients Undergoing Open Hepatectomy: A Retrospective Analysis. Journal of perianesthesia nursing : official journal of the American Society of PeriAnesthesia Nurses 2023. link 15 Razi A, Farrokhi E, Lotfabadi P, Hosseini SS, Saadati H, Haghighi R et al.. Dexamethasone and ketorolac compare with ketorolac alone in acute renal colic: A randomized clinical trial. The American journal of emergency medicine 2022. link 16 O'Mahony L, Duffy E, Mc Ginnity M, Balmer F, Duffy I. NSAIDs and Renal Impairment: Deprescribing Chronic NSAID use in General Practice. Irish medical journal 2021. link 17 Koeck JA, Mastragelopoulos N, Just KS, Eisert A. The prevalence of 'triple whammy' prescriptions in surgical inpatients and associated pharmacist recommendations. Die Pharmazie 2021. link 18 Raulic J, Beaudry F, Beauchamp G, Jalenques M, Summa N, Lair S et al.. PHARMACOKINETIC, PHARMACODYNAMIC, AND TOXICOLOGY STUDY OF ROBENACOXIB IN RAINBOW TROUT (. 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Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer 2017. link 29 Näslund J, Fick J, Asker N, Ekman E, Larsson DGJ, Norrgren L. Diclofenac affects kidney histology in the three-spined stickleback (Gasterosteus aculeatus) at low μg/L concentrations. Aquatic toxicology (Amsterdam, Netherlands) 2017. link 30 Kaur M, Sharma S, Sinha VR. Polymer based microspheres of aceclofenac as sustained release parenterals for prolonged anti-inflammatory effect. Materials science & engineering. C, Materials for biological applications 2017. link 31 Daniels SE, Gan TJ, Hamilton DA, Singla N, Lacouture PG, Johnson O et al.. A Pooled Analysis Evaluating Renal Safety in Placebo- and Active Comparator-Controlled Phase III Trials of Multiple-Dose Injectable HPβCD-Diclofenac in Subjects with Acute Postoperative Pain. Pain medicine (Malden, Mass.) 2016. link 32 Zhou P, Li Y, Yong Z, Yan H, Su R, Gong Z. Effects of thienorphine on the contraction of isolated ureter and bladder of guinea pigs. European journal of pharmacology 2016. link 33 Pathan SA, Mitra B, Straney LD, Afzal MS, Anjum S, Shukla D et al.. Delivering safe and effective analgesia for management of renal colic in the emergency department: a double-blind, multigroup, randomised controlled trial. Lancet (London, England) 2016. link00652-8) 34 Juul KV, Schroeder MK, Rittig S, Nørgaard JP. Desmopressin as an adjuvant to opioids or NSAIDs in treatment of renal colic: a nationwide register-based study. Pharmacoepidemiology and drug safety 2015. link 35 Nagappan AS, Varghese J, James JV, Jacob M. Indomethacin induces endoplasmic reticulum stress, but not apoptosis, in the rat kidney. European journal of pharmacology 2015. link 36 Dong H, Lu SJ, Zhang R, Liu DD, Zhang YZ, Song CY. Effect of the CYP2D6 gene polymorphism on postoperative analgesia of tramadol in Han nationality nephrectomy patients. European journal of clinical pharmacology 2015. link 37 Yang S, Zhang H, Beier RC, Sun F, Cao X, Shen J et al.. Comparative metabolism of Lappaconitine in rat and human liver microsomes and in vivo of rat using ultra high-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry. Journal of pharmaceutical and biomedical analysis 2015. link 38 Keshvari Shirvani M, Darabi Mahboub M, Ghazi M, Delijani A. A comparison of the effects of morphine and sublingual desmopressin combination therapy with morphine alone in treatment of renal colic: a controlled clinical trial. Urology journal 2015. link 39 Cheng HH, Chou CT, Sun TK, Liang WZ, Cheng JS, Chang HT et al.. Naproxen-induced Ca2+ movement and death in MDCK canine renal tubular cells. Human & experimental toxicology 2015. link 40 Raidal SL, Hughes KJ, Charman AL, Nielsen SG, Phillips JK, Noble GK. Effects of meloxicam and phenylbutazone on renal responses to furosemide, dobutamine, and exercise in horses. American journal of veterinary research 2014. link 41 Ay MO, Sebe A, Kozaci N, Satar S, Acikalin A, Gulen M et al.. Comparison of the analgesic efficacy of dexketoprofen trometamol and meperidine HCl in the relief of renal colic. American journal of therapeutics 2014. link 42 Moustafa F, Liotier J, Mathevon T, Pic D, Perrier C, Schmidt J. Usefulness of nefopam in treating pain of severe uncomplicated renal colics in adults admitted to emergency units: a randomised double-blind controlled trial. The 'INCoNU' study. Emergency medicine journal : EMJ 2013. link 43 Vega J, Goecke H, Méndez GP, Guarda FJ. Nephrotic syndrome and acute tubular necrosis due to meloxicam use. Renal failure 2012. link 44 Surdyk KK, Sloan DL, Brown SA. Renal effects of carprofen and etodolac in euvolemic and volume-depleted dogs. American journal of veterinary research 2012. link 45 Shi WD, Wang WW, Cui XG, Pan P, Zhang B, Li WZ. 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Evaluation of the brain, renal, and hepatic effects of flunixin meglumine, ketoprofen, and phenylbutazone administration in Iranian fat-tailed sheep. Tropical animal health and production 2011. link 50 Morgan S. Intravenous paracetamol in patients with renal colic. Emergency nurse : the journal of the RCN Accident and Emergency Nursing Association 2011. link 51 Steinberg PL, Nangia AK, Curtis K. A standardized pain management protocol improves timeliness of analgesia among emergency department patients with renal colic. Quality management in health care 2011. link 52 van Leeuwen JS, Orij R, Luttik MAH, Smits GJ, Vermeulen NPE, Vos JC. Subunits Rip1p and Cox9p of the respiratory chain contribute to diclofenac-induced mitochondrial dysfunction. Microbiology (Reading, England) 2011. link 53 Grissa MH, Claessens YE, Bouida W, Boubaker H, Boudhib L, Kerkeni W et al.. Paracetamol vs piroxicam to relieve pain in renal colic. Results of a randomized controlled trial. 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Original source

[1]
Clinical Efficacy of Intravenous Papaverine plus Ketorolac in the Emergency Treatment of Renal Colic: A Randomized, Double-blind Clinical Trial. — Mozafari J, Khavanin A, Delirrooyfard A, Pirouzi M, Asmarian N Iranian journal of medical sciences (2024)
[2]
Cutaneous adverse drug reaction in a dog following firocoxib treatment. — Geum M, Ko HY, Na YJ, Kim HJ Veterinary medicine and science (2021)
[3]
RETRACTED: Tramadol-induced hepato- and nephrotoxicity in rats: Role of Curcumin and Gallic acid as antioxidants. — Sheweita SA, Almasmari AA, El-Banna SG PloS one (2018)
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