Renal system function

Similarly, if renal system function is insufficient or nonexistent (failure), reabsorption and excretion of electrolytes may occur without response to the feedback mechanism or consideration of current levels of electrolytes. For example, in renal failure, potassium may be not be excreted and may even be reabsorbed, although the potassium level is already high because there is a failure of the usual feedback mechanism. Table 1-3 is a summary of regulation mechanisms for representative electrolytes. 

In the early phase of serious intraabdominal infections, attention should be given to preserving major organ system function. With generalized peritonitis, large volumes of intravenous (IV) fluids are required to maintain intravascular volume, to improve cardiovascular function, and to ensure adequate tissue perfusion and oxygenation. Adequate urine output should be maintained to ensure appropriate fluid resuscitation and to preserve renal function. A common cause of early death is hypovolemic shock caused by inadequate intravascular volume expansion and tissue perfusion. 

The ICH S7A guidance states that "supplemental" studies are meant to evaluate potential adverse pharmacodynamic effects on organ systems functions that are not acutely essential for the maintenance of human life and not addressed by the "core battery" or repeated dose toxicity studies when there is a cause for concern.25 Examples of physiological functions that fall into that category include, but are not limited to, the renal/urinary, immune, GI, endocrine and autonomic nervous systems. This section focuses on the renal and GI systems based on their potential impact on the clinical development program. 

Monitoring Periodic assessment of organ system functions, including renal, hepatic, and hematopoietic is advisable during prolonged therapy. 

The primary function of the renal system is the elimination of waste products, derived either from endogenous metabolism or from the metabolism of xenobiotics. The latter function is discussed in detail in Chapter 10. The kidney also plays an important role in regulation of body homeostasis, regulating extracellular fluid volume, and electrolyte balance. 

Other organ system function (e.g., renal, cardiovascular)... 

Renal cell cultures, which retain adequate renal cellular functions known to interact with xenobiotics or drugs, have the advantage of providing an experimental model that is not influenced by higher-order regulatory systems. Non cell culture based in vitro nephrotoxicity systems have been reviewed elsewhere [15]. 

OP compounds that are known to cause IMS are listed in Table 1. These compounds in general are highly lipid soluble, and in some cases, the metabolites of these OP compounds have a long-lasting half-life. Other contributing factors for IMS include the chemical structure of OP compounds, impairment of systemic functions (cardiovascular, hepatic, renal), and the time elapsed between ingestion of an OP and treatment. 

High plasma levels occur in renal failure, inflammation, and neoplasms, especially those associated with B lymphocytes. BMG assay may be used to test renal tubular function, particularly in kidney transplant recipients in whom rejection of the allograft manifests as diminished tubular function (see Chapter 45). Serial assays of BMG are also useful to monitor B-celi tumors. In acute leukemia and lymphoma with central nervous system (CNS) involvement, the level of BMG is increased in CSF and in Sjogren s syndrome with... 

Abnormalities in renal function tests may suggest compression of the renal system by the tumor. 

The impairment of critical cellular functions can result in systemic toxicities such as those associated with the neuromuscular system (tremor, cardiac arrhythmia, and paralysis). renal (microtubule function), and vasculature (leaky blood vessels). A noteworthy example is the acquired long QT syndrome (LQTS) associated with blockade of cardiac ion channels (14-16). LQTS results in cardiac arrhythmias, torsade de pointes, ventricular fibrillation, and can lead to sudden death. One such ion channel is the HERG protein, respon-... 

The renal system nephropathy and gradual deterioration of kidney functions. 

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