Nephrotoxicity interstitial fibrosis

Calcineurin inhibitor nephrotoxicity presents as two distinct forms of renal injury. Acute nephrotoxicity is a dose-dependent, hemodynamically mediated disorder, not accompanied by particular or permanent structural changes which is reversible with decrease or discontinuation of the offending drug. On the other hand, calcineurin inhibitor-induced chronic nephrotoxicity is an insidious lesion, characterized by an irreversible and progressive renal interstitial fibrosis, which may cause important impairment in renal function and even stage 5 chronic kidney disease. 

As previously stated, there is abundant evidence that CSA markedly increases endothelin production and endothehn up-regulates TGF-(3 expression, which in its turn is clearly involved in CSA chronic nephrotoxicity. Therefore, the existence of an endothehn-TGF- (3 pathway in CSA-induced fibrosis was proposed [511]. Supporting this hypothesis, increased tubular cells endothelin mRNA expression was found in human biopsies with chronic CSA nephrotoxicity [488] and Ramirez et al found dramatic elevations in endothelin system components in CSA-treated rats that strongly correlate with renal structural lesions [446]. In contrast, experimental use of an endothelin receptor antagonist did not prevent interstitial fibrosis in the salt-depleted chronic CSA nephrotoxicity model [442, 443]. 

There are few data about pharmacological management of chronic CSA nephrotoxicity in the clinical setting. McCulloch et al studied the effects of nifedipine in CSA-induced interstitial fibrosis in renal transplantation. The authors compared three groups of patients (conventional CSA dose versus conventional CSA dose plus nifedipine versus low CSA dose plus azathioprine) measuring baseline cortical interstitial volume fraction after one, six and 12 months of therapy. After six and 12 months interstitial volume was lower in patients treated with CSA plus nifedipine as compared with... 

Andoh et al developed an experimental model of TAC-induced chronic nephrotoxicity using salt-depletion in rats [687, 704]. A particular characteristic of this model is that renal functional changes and structural injury occur with TAC blood levels equivalent to those found in treated patients, in a striking contrast with the CSA chronic nephrotoxicity model, where extremely high CSA blood levels are necessary to produce injury. In this TAC model, there is an early and dose-dependent decrease in GFR and RBF with a parallel RVR increase followed by a late development of renal interstitial fibrosis involving the itmer strip and medullary rays, arteriolar hyahnosis, tubular atrophy and hypertrophy and medullary thick ascending limb size variance. Structural injury showed a significant positive correlation with decreased renal function [687, 704,705]. 

Young BA, Burdmann EA, Johnson RJ, Alpers CE, Giachelli CM, Eng E, Andoh T, Bennett WM, Couser WG. Cellular proliferation and macrophage influx precede interstitial fibrosis in cyclosporine nephrotoxicity. Kidney Int 1995 48 439-448. 

Lithium carbonate 0.9-1.2gq.24hr Renal 100% 50-75% 25-50% Nephrotoxic adverse effects include nephrogenic diabetes insipidus, nephrotic syndrome, renal tubular acidosis, and interstitial fibrosis acute toxicity when serum levels > 1.2 mEq/L serum levels should be measured periodically 12 hr after dosing half life does not reflect extensive tissue accumulation plasma levels rebound after dialysis toxicity enhanced by volume depletion, NSAIDs, and diuretics Dose after dialysis NC Dose for GFR 10-50 ml/min... 

Nephrotoxicity associated with doxorubicin use is also dose dependent and occurs at the same time as doxorubicin-induced cardiotoxicity. Studies in animal models reveal glomerular effects, renal interstitial fibrosis, and vacuolization of tubules. However, clinical evidence of nephrotoxicity in the absence of cardiotoxicity is limited suggesting that dose reduction... 

Nephrotoxicity is a common toxicity and significant problem associated with the use of cyclosporine in humans. Three types of nephrotoxicity have been observed in patients receiving cyclosporine (1) an acute, reversible renal failure (2) acute vasculopathy or thrombotic microangiopathy and (3) chronic renal failure with interstitial fibrosis that may not be reversible. 

Acute renal toxicity may occur within days of initiating therapy. Serum creatinine concentration rises and creatinine clearance decreases. Hypertension, hyperkalemia, sodium avidity, and hypomagnesemia may occur. No urine sediment abnormalities are seen. Urinary enzyme excretions increase, but are not reliable indicators of toxicity. Renal biopsy reveals thickening of arterioles, mild focal glomerular sclerosis, proximal tubular epithelial cell vacuolization and atrophy, and interstitial fibrosis. Biopsy is useful to distinguish acute cyclosporine nephrotoxicity from renal allograft rejection, the latter being evidenced by cellular infiltration. ... 

The immunosuppressive drug cyclosporine A (CSA) has revolutionized transplant medicine. However, CSA induced-nephrotoxicity still represents a major therapeutic challenge. Chronic CSA nephropathy is characterized by a decrease in glomerular filtration rate (GFR), tubular atrophy, interstitial fibrosis and progressive renal dysfunction. It is difficult to delineate the mechanisms of CSA toxicity from clinical data since the majority of clinical experiences with CSA have been in renal transplant recipients. Animal models of CSA nephropathy have brought some insights, how-... 

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