Mechanisms of Renal Adverse Drug Reactions

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Chapter: Pharmacovigilance: Renal Adverse Drug Reactions

Drugs may adversely affect renal function by induc-ing structural injury to components of the nephron and/or by interfering with the filtration and transport processes or regulatory pathways.


MECHANISMS OF RENAL ADVERSE DRUG REACTIONS

Drugs may adversely affect renal function by induc-ing structural injury to components of the nephron and/or by interfering with the filtration and transport processes or regulatory pathways (Table 38.2).


Drugs interfering with glomerular blood flow may induce functional renal impairment. Cyclosporine and epinephrine cause preglomerular arteriolar vasocon-striction resulting in a decrease in intra-glomerular pressure and filtration pressure. In clinical condi-tions in which systemic vasoconstriction is promi-nent like dehydration or heart failure, glomerular blood flow is critically dependent from a counteract-ing vasodilation of the preglomerular arteriole medi-ated by compensatory PGE2 and PGI2 production (Whelton, 1999). In the same patients, maintenance of adequate glomerular filtration pressure is also depen-dent of postglomerular vasoconstriction mediated by angiotensine II. Disruption of these counter-regulatory mechanisms by the administration of NSAIDs or of drugs interfering with angiotensine II (ACE inhibitors and angiotensine II receptor blockers) can produce clinically important and even severe deterioration in renal function. When NSAIDs and ACE inhibitors are co-prescribed there is an accrued risk for functional renal impairment. This drug combination should be avoided, especially in elderly patients and those taking diuretics (Adhiyaman et al., 2001).

The publication of the Randomized Aldactone Eval-uation Study (RALES) (Pitt et al., 1999) promoted the combined use of the anti-aldosterone agent spirono-lactone and ACE inhibitors in heart failure patients. In the setting of this randomised clinical trial, the incidence of severe hyperkalaemia was minimal, patients with renal failure or pre-existing hyper-kalaemia being excluded from the trial. In subse-quent years, however, case reports of life-threatening hyperkalaemia in patients treated with spironolactone appeared in the literature (Schepkens et al., 2001). It became evident that hyperkalaemia is episodic in these patients and linked to ARF. The main causes for ARF in this setting were dehydration and wors-ening heart failure. In a population-based time-series analysis recently conducted in Canada, an increase was found in hyperkalaemia-associated morbidity and mortality in elderly patients after abrupt increases in the prescription rate for spironolactone following the publication of RALES (Juurlink et al., 2004).

Drug-induced immune nephropathies include glomerulopathies and tubulointerstitial nephritis. NSAIDs are known to induce both types of renal injury. A review of NSAID-induced nephropathy reported an incidence of 39.2% of minimal change glomerulopathy, 19.6% of tubulointerstitial nephri-tis, 13.4% of focal glomerular sclerosis and 8.2% of other types of nephropathy (Ravnskov, 1999). Gold salts previously used in rheumatoid arthritis induce a membranous glomerulopathy. The disease is related neither to dose nor to the duration of treatment, but susceptible seemed to be genetically controlled, HLA DR3-positive patients being more prone to develop this adverse reaction. Drug-induced interstitial nephri-tis represents a minority of ARF cases. Clinically, the disease is characterised by bilateral lumbar pain, fever and skin rash. Many patients exhibit hyper-eosinophylia, hypereosinophyluria and increased IgE serum levels. In renal biopsy the characteristic lesions are interstitial mononuclear cell infiltrates and tubular cell injury. Most often renal function recovers after withdrawal of the drug with or without concomitant steroid therapy. The drugs that are most frequently responsible for tubulointerstitial nephritis are anti-biotics, mainly -lactams, and NSAIDs.

The particular susceptibility of the tubular cell to nephrotoxic injury has several reasons. Tubular solute transport and other renal metabolic processes utilise considerable oxygen and are susceptible to the action of metabolic inhibitors. It is worthwhile to note that the S3-segment of the proximal tubule has the highest rate of oxygen consumption per gram of tissue of the whole body. Moreover, the renal tubular epithelium is the only place where protein-bound drugs dissociate, traverse the renal epithe-lium and either accumulate in the proximal tubular cell or reach the tubular lumen. An abundance of tubular enzymes involved in tubular transport may be blocked, in view of the high urinary to plasma concentration ratios exceeding 1000 in some cases. Typical tubulotoxic drugs that are extensively stud-ied are the aminoglycoside antibiotics (Verpooten, Tulkens and Molitoris, 2003). Aminoglycosides are polar drugs that are freely filtered via the glomeru-lar membrane. Following binding to megalin in the proximal tubular brush border, aminoglycosides traf-fic via the endocytic system to lysosomes, where they accumulate in large amounts. In lysosomes, aminogly-cosides induce an intense phospholipidosis by inhibit-ing phospholipidases A and C and sphingomyelinase. This phospholipidosis occurs rapidly involving all major phospholipids and is responsible for the forma-tion of the so-called ‘myeloid bodies’ (Figure 38.1). At present it is unknown whether phospholipidosis is linked to tubular cell necrosis. Besides lyso-somes, aminoglycoside-induced alterations of mito-chondria have also been described. More recently, proteomic analysis following gentamicin administra-tion indicated energy production impairment and a mitochondrial dysfunction occurring in parallel with the onset of nephrotoxicity (Charlwood et al., 2002). The severity of aminoglycoside nephrotoxicity can be dissociated from the height of the peak of the amino-glycoside blood level. It became evident that for a given total daily dose the toxicity was greatest when the daily dose was being divided into multiple small administrations. The reason for this apparent paradox is that the renal cortical drug uptake is saturable, so that maintaining a low blood level maximises tubular cellular drug uptake (Verpooten et al., 1989).


In the distal part of the nephron, urine is concen-trated, and the likelihood of crystalline precipitation increases substantially. ARF may result from tubular obstruction due to intratubular precipitation of the drug or its metabolite. This mechanism has been incriminated in the clinical syndrome of bilateral flank pain and ARF associated with the use of suprofen (Henann and Morales, 1986; Hart, Ward and Lifs-chitz, 1987). This renal adverse drug reaction led to the withdrawal of this NSAID from the market in 1986 (Chapter 1 of this book). Because suprofen is a uricosuric agent, one might speculate that it could lead to intratubular or ureteral precipitation of uric acid (Abraham et al., 1988). More recently, there have been reports of this type of renal adverse event following high-dose intravenous acyclovir and during treatment with protease inhibitors.

The immunosuppressive drug cyclosporine is of particular interest since it can display all types of nephrotoxicity (reviewed in Bosmans and De Broe, 2006). Cyclosporine profoundly alters renal and glomerular haemodynamics. Administra-tion of cyclosporine induces a decline in glomeru-lar filtration rate (GFR) and renal blood flow by vasoconstriction at the level of the afferent arte-rioles. Catecholamines, endothelin and eicosanoids like thromboxane are potential mediators of this effect. Effects of cyclosporine on tubular func-tion consist of increased proximal reabsorption of sodium resulting in decreased distal sodium deliv-ery interfering with the potassium secretory capacity of the distal tubule. This pathophysiologic effect may explain the observed hyperkalaemic metabolic acidosis in cyclosporine-treated kidney allograft recipients. Besides these functional side effects, cyclosporine induces morphologic alterations in the kidney. First, cyclosporine induces dose-dependent acute tubular changes consisting of isometric vacuoli-sation of tubular cells, accumulation of eosinophilic bodies representing giant mitochondria and micro-calcifications in proximal tubules. These patho-logic alterations are reversible after dose reduction or withdrawal of cyclosporine. In contrast to the acute injury, chronic administration of cyclosporine may lead to irreversible histopathologic lesions. They include renal arteriolar damage (the so-called cyclosporine associated arteriolopathy), tubular atro-phy and focal or striped interstitial fibrosis as well as glomerular sclerosis (Figure 38.2). Clinically, chronic cyclosporine nephrotoxicity is associated with hypertension, progressive renal failure and a vari-able degree of proteinuria. Thrombotic microangiopa-thy is an uncommon but serious adverse effect of cyclosporine. The striking morphologic changes, resembling haemolytic-uraemic syndrome, are exten-sive thrombotic processes in the renal microcircu-lation, with several glomerular capillaries occluded by thrombi extending from the afferent arterioles (Verpooten et al., 1987). Laboratory findings include thrombocytopenia, haemolytic anaemia and deterio-rating renal function.



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