INTRODUCTION:

Non-Steroidal Anti Inflammatory Drugs (NSAIDs) which are approved by the FDA substantially used either by prescription or over-the-counter for the use of Antipyretic, anti-inflammatory and analgesic agents.^1,2,3These are used for different conditions like rheumatologic disease, (rheumatoid arthritis and Musculo skeletal disorders ^3,4 and also for the prevention of patent ducts arteriosus check-in babies² In recent studies they are used for the pain due to kidney stones it works better than opioids.⁴ NSAIDs are classified grounded on their chemical structure and selectivity towards cyclooxygenase.

Grounded on their structural differences they are Salicylates, indole acetic acid by-products (e.g: Indomethacin), Phenylacetic acid by-products (e.g: Diclofenac, Aceclofenac), Phenyl propionic acid by-products (e.g: Ibuprofen, Naproxen, Ketoprofen), Enolic acid derivatives (Oxicams).¹

NSAIDs are generally safe but when used for a longer duration may lead to gastrointestinal and Cardiac adverse effects which are well known^2,4but increase the threat of Renal function deterioration and lead to CKD and end-stage kidney injuries^4,5which may also increase morbidity, generally in older Patients because, they are with lower physiological function, muscle mass, GFR and leads to comorbidities for those conditions they use other medicines like anti hypertensives, Anti-depressants, Anti Coagulants which may lead to drug interactions.⁴

Mechanism:

NSAIDs act mainly by inhibiting the cyclooxygenase enzyme both COX-1 and COX-2 which involves the conversion of arachidonic acid (which is released from cell membrane phospholipids) to prostaglandins G₂ and then prostaglandins H₂ with the help of prostaglandin G/H synthase. Then prostaglandin H₂ converts into Prostanoids which are tissue-specific isomerases like prostaglandin I₂, Prostaglandin D₂, Prostaglandin E₂, and Prostaglandin F₂, Thromboxane A₂ whereas arachidonic acid is also converted into lipoxygenase and then converts into leukotrienes which induces bronchoconstriction, Asthma.

Figure 1: Mechanism

Table 1: Effects of Prostanoids:

PGE₂

PGE₂ and PGI₂

PGI₂ and TXA₂

1. Gastric protection

2. Increase mucus production

3. Increase bicarbonate

4. Increase mucosal blood inflow

1. Afferent arteriolar vasodilation

2. Increase Glomerular Filtration Rate

3. Increase sodium and water excretion

Vascular (COX-2: PGI₂)

1. Vasodilation

2. Inhibit platelet aggregation

3. Platelet (COX-1: TXA₂)

4. Vasoconstriction

Table 2: NSAID Induced adverse effects

COX 1 Inhibition

Cox 2 Inhibition

Cox 1and2 Inhibition

Peptic ulcers

GI bleeding

Stroke

Myocardial Infarction

Sodium and water retention

Hypertension

Hemodynamic acute kidney injury

Prostanoids have different functions based on their location in different tissues. PGE₂ involves in gastric protection, and usage of NSAIDS leads to inhibition of COX-1 which causes peptic ulcers, and GI bleeding both PGE₂ and PGI₂ are involved in Afferent arteriolar vasodilatation and increase of sodium and water excretion, usage of NSAIDs leads to inhibition of both COX-1and COX-2 which causes sodium and water retention, Hypertension, Hemodynamic acute kidney injury along with these PGI₂ and TXA₂ involves in vasodilation and inhibits platelet aggregation. NSAIDs inhibit PGI₂and TXA₂ which leads to coagulation that causes Atherosclerosis, stroke, and myocardial infarction.^1,3,4,6 Along with these conditions NSAIDs may also cause hepatic cirrhosis.⁷

COX-1 inhibition with NSAIDs may lead to many side effects because it involves cleansing various systems, especially in kidneys it helps in glomerular filtration maintenance due to this prolonged usage of NSAIDs may affect mainly Kidneys in diseased people than normal people with regular function. COX-2 works mainly on water and electrolytic maintenance in renal function, inhibition of COX-1 with NSAIDs may lead to severe damage to the kidney while the patient is in dehydration, low renal perfusion or has pre-existing renal diseases.⁷

Pathophysiology Of Kidney Related to NSAIDs:

Kidneys play many important functions in the body to maintain balance by excreting waste from the body through different regulatory mechanisms like prostaglandin synthesis which helps in maintaining glomerular filtration rate (GFR) and renal homeostasis in volume depletion.⁸

NSAIDs inhibit the Cyclooxygenase enzyme thereby inhibiting prostaglandin synthesis mainly PGE₂, PGD₂, and PGI₂(Prostacyclin) in kidneys which are responsible for vascular dilatation, enhance Renal perfusion and diminish renal vascular resistance with redistribution of blood flow from cortex to nephrons in the juxta-medullary region. In general Vasodilation acts as a negative feedback mechanism on Renin Angiotensin Aldosterone System and the sympathetic nervous system results in culminates in blood flow to the organ.^4,7,9 This mechanism is inhibited by NSAIDs which leads to an increased metabolic concentration in the medullary region⁵, a decrease in total renal perfusion, GFR along with sodium and water retention results in Renal vasoconstriction, and Medullary ischemia causes Acute Kidney injury.¹⁰ Chronic use of these NSAIDs causes chronic effects like papillary necrosis or interstitial nephritis which leads to Chronic Kidney Injury.^4,5,9Acute renal failure is short-term and can be reversible after discontinuation of NSAIDs.⁹ PGE₂, To a lesser extent PGF_2, ceases the transportation of sodium and chloride from thick ascending limb and collecting ducts and causes Natriuresis. Along with these actions, PGE₂ also inhibits the action of the Antidiuretic hormone (Vasopressin) which leads to Diuresis.^4,8 NSAIDs also cause edema due to an increase in sodium and water levels in the body by inhibiting PGE₂.^4,11 NSAIDs cause various Renal abnormalities like Acute kidney injury, chronic kidney injury, and interstitial nephritis.⁴

Acute Kidney Injury:

Acute Kidney Injury (AKI) is a clinical syndrome that represents continuous renal injury from Asymptomatic changes in kidney function to kidney failure and then death. This condition is defined as sudden damage to the kidney leading to GFR reduction¹², and an increase in urea, creatinine, and nitrogen waste substances levels in the blood within hours to a few days.⁴

NSAIDs induced Acute Kidney injuries are two types. One is Haemodynamically mediated which includes prerenal injury/ Acute tubular necrosis and the other is Immune-mediated which includes Acute interstitial nephritis.

AKI is caused due to NSAIDs which have a higher risk than other factors¹² mainly in neonates, elderly patients, and in the cardiovascular, liver, kidney, or with reduced circulating blood volume, also in patients using NSAIDs combined with diuretics and RAAS inhibitors in that especially Haemodynamically mediated type.^4,11

Prostaglandins help in maintaining blood flow in volume-depleted conditions like heart failure, chronic kidney disease, liver failure, and hypovolemic shock and increase renal perfusion and GFR, inhibition of this process by NSAIDs may lead to decrease intra medullary renal perfusion, ischemia which causes AKI.^4,13

NSAID-induced AKI has no specific symptoms which include dyspnoea, fatigue, confusion, nausea, ankle/leg edema, and reduced urine output. Reduced volume, Absolute/postural hypotension, dry mucous membranes, and low jugular venous pressure.¹²

Some studies provide evidence that Nonselective COX inhibitors like Acetylsalicylic Acid and Ibuprofen cause less nephrotoxicity than Selective COX inhibitors.⁴This condition is reversible when discontinuation of NSAIDs. It usually occurs in 0.5% to 1% of patients who are on chronic use of NSAIDs.¹¹

Tubulointerstitial Nephritis:

Acute tubulointerstitial nephritis is the second form of mechanism for Acute kidney injury⁴ which is specified by immune-mediated inflammatory cell infiltrate of renal interstitium showing inflammation, edema, and fibrosis.^13,14 TIN can lead to chronic kidney disease due to chronic changes in the interstitium.^10,14,15 Exact reason for Acute interstitial nephritis is unclear¹², but it may cause due to genetic, environmental factors, drug-induced (beta-lactam antibiotics, NSAIDs), infection, and autoimmune.¹⁴ among these factors are NSAIDs (phenoprofen, ibuprofen, naproxen)⁴ induced is the main reason, especially in children.¹⁵

It is unclear which mechanism NSAIDs induced AIN^4,12 but antigen-driven immunopathology is the key mechanism. The presence of helper induced and suppressor cytotoxic T lymphocytes in the inflammatory infiltrate suggest that T-cell mediated hypersensitivity reactions and cytotoxic T- cell injury results in interstitial infiltration leading to edema, oliguria, proteinuria⁴ when NSAIDs inhibit cyclooxygenase Arachidonic acid converts to Leukotrienes, which leads in activation of T helper cells.¹² Restoration of renal function occurs after a few days of drug interruption.^4,12 Chronic TIN may lead to reduced GFR due to fibrosis of the Interstitium, prolongation of these inflammatory reactions may cause accumulation of extracellular matrix which is not reversible.¹⁴

Clinical manifestations of TIN are hypersensitivity reactions like rash, fever, arthralgia, eosinophilia^13,15 and edema, painful stretching of the renal capsule which leads to abdominal, loin pain due to tubulointerstitial infiltrate of inflammatory cells.¹⁴TIN is diagnosed through biopsy¹⁴, elevated levels of creatinine¹³ and it can be treated by using corticosteroids¹²/ immunosuppressants¹⁶, dialysis.¹³ NSAIDs should be avoided in the future to avoid reoccurrence.¹

Chronic Kidney Injury:

Chronic Kidney Injury (CKD) is defined as an abnormality in kidney structure/ function for more than 3 months.¹⁷ CKD can occur due to regular episodes of AKI. During AKI abnormal changes like fibrosis, tubular loss, vascular rarefaction, glomerulosclerosis, and chronic Interstitial inflammation leads to chronic kidney insufficiency and End-Stage Kidney Disease.¹⁰ It is also a progression of Interstitial Nephritis and Interstitial fibrosis if NSAIDs are consumed continuously.^4,8 There is no clear mechanism for the development of CKD with the long-term usage of NSAIDs. But usage of NSAIDs regardless of class either selective or non-selective which have more half-life, higher doses for more than a year is a primary risk factor for developing CKD^1,4, along with these other factors like MI, Stroke, DM, RA, Gout, calculus in both kidney and Ureter may also cause CKD.⁷ The progression of CKD is different based on their initial GFR and comorbidities in patients using NSAIDs. CKD patients may also develop AKI after usage of NSAIDs. Opioids are riskier compared to NSAIDs. In CKD stages 1 and 2 management is like patients without renal disease if they are not exposed to any risk factors. In CKD stage 3 patients may experience less nephrotoxicity while exposing risk factors like NSAIDs for up to 5 days. At this stage monitoring of side effects is required in chronic use due to the high risk. In CKD Stage 4 which is highly prone to AKI at this stage, NSAIDs should be given in low doses with high frequency and low half-lives with close monitoring.¹ Usually, prostaglandins are synthesized whenever required for their regular body functions like vasodilation in the afferent arteriole and increasing blood flow.¹⁰Inhibition of this process may lead to papillary necrosis and then Chronic renal injury. Papillary necrosis may also be developed from intermediate reactive metabolites which deviate from regular Arachidonic cascade or from phospholipids accumulation in the renal papillae. Immunological reactions are also occurred with the help of growth factors, and cytokines and develop interstitial fibrosis in the interstitium.⁸ Symptoms of CKD include blood in urine, frothy urine(Albuminuria), nocturia, loin/flank pain, reduced urine output occurs less commonly and fatigue, lack of appetite, weight loss, vomiting, nausea, peripheral edema, metallic taste confusion, shortness of breath occurs in severe conditions, symptoms which are based on the systemic cause are blood vomiting, an allergic rash, lymphadenopathy, auditory disability, neuropathy based on urinary obstruction increase in urgency, frequency of urination, incomplete bladder emptying.¹⁷CKD can be diagnosed based on GFR<60mL/min/1.73m2; Albuminuria; Creatinine; Sedimentation Rate, histology/imaging of kidney; Kidney tubular disorders; Renal transplantation history.¹⁷ Continuation of NSAIDs induced AKI leads to permanent kidney damage and will not return to its baseline function.⁸ Kidney function can be recovered if the usage of NSAIDs is short-term (up to 6 weeks).⁹

CONCLUSION:

NSAIDs are safer, effective, and tolerated, but have some clinical issues when they are abused. These are available as over-the-counter drugs in developing economies. Paracetamol also causes side effects that lead to frequent hospitalization.⁵ NSAIDs can be tolerated for short periods in children, Active healthy individuals.^[18] Therefore AKI is uncommon when treated at recommended doses, but close monitoring is required when they are in dehydration, a known cause of kidney disease, or using any nephrotoxic drugs.² AKI is reversible after stopping NSAIDs usage but in ATIN complete recovery will not occur. Educating the patients to avoid over-the-counter usage and sharing knowledge about side effects.²Clinicians should also educate about prescribing NSAIDs to patients who are having renal diseases, usage of other medications, and have any comorbidities.¹⁹ Prescribing NSAIDs in low doses with less half-life decreases the risk of patients developing kidney injuries. Physicians should educate the patients not to take NSAIDs in the long term which can also develop CKD in patients without having any renal disease.²

REFERENCES:

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Received on 08.06.2022 Modified on 10.08.2022

Res. J. Pharmacology and Pharmacodynamics.2022;14(4):268-272.

DOI: 10.52711/2321-5836.2022.00046

Type of Adverse effect	Risk factor	Actions	Prevention/Treatment
Water and Electrolyte disorder: Hyperkalaemia Hyponatremia Metabolic Acidosis	Usage of NSAIDs	PGE2 andPGI2 cause Inhibition of Renal vasodilatation, Activating RAAS Mechanism	Usage of NSAIDs should be stopped
Acute Kidney Injury	Comorbidities like Hepatic disease, renal disease, cardiac failure, hypovolemia, older age	Hemodynamic changes/ decreasing Renal Perfusion	Avoid/Discontinuation of NSAIDs in Comorbidity conditions
Acute Interstitial Nephritis	Usage of NSAIDs for Longer duration especially Phenoprofen, Naproxen, Ibuprofen	Immunological reactions	Usage of NSAIDs should be stopped
Chronic Kidney Disease	Usage of NSAIDs for a longer duration	Hemodynamic changes	Avoid/Discontinuation of NSAIDs in Comorbidity conditions
Papillary necrosis	Use of NSAIDs mainly Phenacetin overuse, a combination of Aspirin and Acetaminophen	Interstitial ischemia and fibrosis in the renal medulla (Analgesic nephropathy)	Discontinuation of NSAIDs