Interstitial nephritis NSAIDs

Acute renal failure due to NSAIDs is usually due to prerenal causes but may be caused by acute interstitial nephritis. Usually the worsening in renal function does not depend on dose (Muhlberg and Platt 1999). Use of NSAID is thus risky and may affect the elimination of concomitant medications. 

Aspirin and similar NSAIDs can cause other toxic side effects if used improperly or if taken by patients who have preexisting diseases. For instance, serious hepato-toxicity is rare with normal therapeutic use, but high doses of aspirinlike drugs can produce adverse changes in hepatic function in patients with liver disease.85,99 Likewise, aspirin does not seem to cause renal disease in an individual with normal kidneys,84 but problems such as nephrotic syndrome, acute interstitial nephritis, and even acute renal failure have been observed when aspirin is given to patients with impaired renal function, or people with decreased body water (volume depletion).35,102... 

Fenoprofen, a propionic acid derivative, is the NSAID most closely associated with the toxic effect of interstitial nephritis. This rare toxicity may be associated with a local T cell response in renal tissue. 

The concomitant administration of ibuprofen antagonizes the irreversible platelet inhibition induced by aspirin. Thus, treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin. Rare hematologic effects include agranulocytosis and aplastic anemia. Effects on the kidney (as with all NSAIDs) include acute renal failure, interstitial nephritis, and nephrotic syndrome, but these occur very rarely. Finally, hepatitis has been reported. 

These findings from special renal studies and the clinical trial data indicate that inhibition of Cox-2 does not eliminate the renal effects of NSAIDs because Cox-2-derived prostanoids are involved in normal renal function. However, the kidney contains considerably more Cox-1 than Cox-2, and the localization of the two isoforms is different It is not yet known whether the Cox-2 inhibitors will be safer in subgroups of patients prone to develop acute renal failure with NSAIDs, such as those patients with severe volume depletion, congestive heart failure, or hepatic cirrhosis with ascites (Bosch-Marce et al., 1999). Also, it is not known whether rare events, such as interstitial nephritis or papillary necrosis, will occur with long-term use of Cox-2 inhibitors, although studies in animals suggest that such events may be related to Cox-1 inhibition, since only Cox-1 is found in the papilla. Therefore, Cox-2 inhibitors may not produce these serious adverse effects (Khan etal., 1998). 

A retrospective analysis of acute renal insufficiency related to NSAID therapy in France showed that clo-metacin was most frequently implicated. Cases of functional renal insufficiency and interstitial nephritis with nephrotic syndrome were reported (SEDA-12, 84). 

Whether selective COX-2 inhibitors can cause the other types of renal toxicity that are associated with non-selective NSAIDs (that is acute interstitial nephritis, nephrotic syndrome with or without renal insufficiency) is not known. 

Renal papillary necrosis and interstitial nephritis with the nephrotic syndrome have been documented (27,28). Other cases of the nephrotic syndrome, with or without renal insufficiency, which were apparently due to minimal-change nephropathy (which is relatively more common in NSAID users), have been reported (29,30). The unusual feature of diclofenac-associated renal interstitial mucinosis has been described (SEDA-17, 109). 

Like many other NSAIDs, ketoprofen can cause acute interstitial nephritis (10). Renal insufficiency and the nephrotic syndrome due to membranous glomerulonephritis (an unusual cause of NSAID-induced nephrotic syndrome) have been described in an elderly patient taking long-term ketoprofen (SEDA-12, 86). 

A series of 11 spontaneously reported cases in which renal impairment was associated with the use of nimesulide has been described (17). The adverse events were represented by acute renal insufficiency n — 2), acute deterioration of chronic renal insufficiency n — 3), fluid retention n = 4), and oliguria and macro hematuria n = 1 each). The patients had a median age of 57 (range 17-81) years and six had some predisposing condition (chronic renal insufficiency, heart failure, diabetes, use of diuretics) to NSAID-induced functional renal impairment. Apart from one patient, nimesulide was taken for a very short time (less than 8 days). A favorable outcome ensued after withdrawal of therapy in aU patients. The acute deterioration of renal function described in these patients pointed to hemodynamically mediated renal impairment in all cases, with the exception of one man in whom interstitial nephritis was suspected. 

NSAIDs can produce a spectrum of renal diseases functional renal insufficiency, nephrotic syndrome with or without interstitial nephritis, renal papillary necrosis and... 

Membranous nephropathy is rare and causes the nephrotic syndrome, usually with minimal-change glomerulopathy, with or without interstitial nephritis (SEDA-11, 85). A retrospective study provided more data on the frequency and clinical characteristics of membranous nephropathy associated with NSAIDs (158). It confirmed that it is rare (13 of 125 patients diagnosed during the last 20 years met the strict criteria for NSAID-associated membranous nephropathy), and the nephrotic syndrome is reversible after prompt withdrawal. The pathogenesis is unknown but seems to be immune-mediated, given the characteristic deposition of IgG and C3. 

NSAID-induced renal toxicity, comprising interstitial nephritis and renal papillary necrosis. The condition, named analgesic nephropathy, was not uncommon and was serious. In a number of cases malignancies in the urinary tract also occurred. 

It is worth emphasizing that the same drug is capable of inducing several types of renal injury, e.g. NSAIDs may lead to intrarenal hemodynamic disturbances as well as to acute tubular necrosis, acute interstitial nephritis with or without nephrotic syndrome, and sometimes to various glomerular and arteriolar diseases [50,51]. 

Allergic interstitial nephritis Penicillins, rifampin, sulfonamides, thiazides, cimetidine.phenytoin, allopurinol, furosemide, NSAIDS, ciprofloxacin, pantoprazole, omeprazole, atazanavir, bevacizumab Rash, fever, eosinophilia, eosinophiluria, pyuria... 

In recent years, however, several case reports have been published, suggesting an association between the use of 5-ASA and the development of a particular type of chronic tubulo-interstitial nephritis, characterized by an important cellular infiltration of the interstitium [26, 27]. In some cases, it was shown that this cellular infiltration was not disappearing upon arrest of the drug, even after a period of more than one year [28]. Although acute renal failure under non-steroidal antiinflammatory drugs (NSAID) is well documented, the risk for developing chronic lesions remains controversial. 

Acute deterioration of renal function Salt and water retention The concept of "renal sparing" NSAIDs Nephrotic syndrome with interstitial nephritis Chronic renal failure/papillary necrosis Other NSAID-induced renal syndromes Renal effects of COX-2 inhibitors 424 428 430 431 432 434 435... 

The NSAID-induced abnormahties of renal function, in descending order of chnical frequency, are (i) fluid and electrolyte disturbances (ii) destabilizahon of con-troUed hypertension (hi) decompensated congestive heart failure (iv) acute deterioration of renal function (v) nephrotic syndrome with interstitial nephritis and (Vi) chronic renal failure/papillary necrosis [1, 3-5]. 

Proteinuria/ Interstitial nephritis t recruitment and activation of lymphocytes, likely through leukotriene formation, affecting glomerular and peritubular permeability Fenoprofen use, possibly female gender, advanced age Discontinue NSAID, support with dialysis and steroids, if needed... 

The observation by Schwarz et al. [90] are germane to the influence of NSAID-induced AKI on the development of chronic renal failure. While NSAIDs accounted for only 20% of the cases of acute interstitial nephritis [90], nearly 2 out of every 3 patients from the NSAID subgroup was found to have permanent renal impairment at follow-up which represented the greatest frequency of any of the drug-induced acute interstitial nephritis. 

Nonsteroidal anti-inflammatory drugs (NSAIDs Group toxicity decreases renal function and platelet aggregati and stroke 3n may cause nephrotic syndrome, interstitial nephritis, hyperkalemia, sodium retention carries increased risk of CVD, Ml, ... 

Tubulointerstitial nephritis can be either acute or chronic in nature. Acute interstitial nephritis is characterized by an acute renal interstitial inflammatory response with urinary eosinophils and nonoliguric acute renal failure. The more common drugs that induce acute interstitial nephritis include penicillins, rifampicin, sulfonamides, and cimetadine. Chronic tubulointerstitial nephritis is most commonly associated with the long term use of large amounts of analgesics and antiinflammatory agents (e.g., NSAIDs). 

NSAID-induced acute renal failure is treated by discontinuation of therapy and supportive care. Renal failure may be severe, but recovery is usually rapid and dialysis is rarely necessary. Occasionally the hemodynamic insult is sufficiently severe to cause frank tubular necrosis, which can prolong recovery. The differential diagnosis of NSAID hemodynamically-mediated acute renal failure must include NSAID-induced acute interstitial nephritis, with or without the nephrotic syndrome, because steroid therapy may benefit this type of renal injury. 

NSAlD-induced AIN has a different clinical presentation than that seen with most other drugs. Patients are typically over age 50 (reflecting NSAID use for degenerative joint disease), the onset is delayed a mean of 6 months from initiation of therapy, and ex-trarenal symptoms are observed in only 10% of patients. Concomitant nephrotic syndrome (proteinuria >3.5 g/day) occurs inmorethan70% of patients. Eenoprofen-allergic interstitial nephritis is considered the prototype for NSAlD-induced AIN because it accounts for nearly 50% of cases. ... 

Symptomatic polyuria and polydipsia can be reversed by discontinuation of lithium therapy or ameliorated with amiloride or NSAIDs during continued lithium therapy (see Chap. 49). Acute renal failure is usually reversible with supportive care, including dialysis to reduce toxic blood lithium concentrations. Progressive chronic interstitial nephritis is treated by discontinuation of lithium therapy, adequate hydration, and avoidance of other nephrotoxic agents. 

---