Renal urinary system

Autonomic discharge results in stimulation of ADH release due to a neurotransmitted NE effect (a 1) on the mag-nocellular neurons in the hypothalamic paraventricular nuclei. This promotes increased retention of water, which, in turn, promotes the effective blood volume. In addition, autonomic discharge causes the release of neurotransmitter 

NE at the JGA of the kidney and this stimulates the release of renin (/ ]), ultimately resulting in aldosterone-mediated sodium retention at the nephron. The overall result is preservation and promotion of vascular volume due to isotonic fluid retention, decreased urine flow, and decreased glomerular filtration rate, all of which are attributable to neurotransmitted NE. 

Paradoxically, elevated levels of E and NE can cause a reduction in plasma volume that can lead to hemoconcen-tration and poor tissue perfusion however, the mechanism of this effect is not known. This is said to be the cause of orthostatic hypotension in untreated patients with pheochro-mocytoma, a tumor of chromaffin tissue that produces excessive amounts of NE most of these patients have reduced plasma volume but exhibit hypertension while in the reclining position. 

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Nephrolithiasis A condition marked by the presence of renal calculi (stones) in the kidney or urinary system. 

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. 

Urinary system-. Groups of 20 male Fischer 344 rats were given 0.05%7V-ethyl-jV-hydroxyethylnitrosamine (EHEN) for two weeks in the diet followed by di(2-ethyl-hexyl) phthalate [purity unspecified] at a concentration of 0 or 1.2% in the diet for 24 weeks. Rats were killed at 27 weeks. Di(2-ethylhexyl) phthalate increased the numbers of rats with renal (tubular) cell tumours (EHEN + di(2-ethylhexyl) phthalate 65% versus 20% for EHEN alone p < 0.01) and the mean number of tumours per kidney (EHEN + di(2-ethylhexyl) phthalate 1.1 versus EHEN alone 0.2,< 0.01) (Kurokawa etal., 1988). 

Medical conditions based in nearly all physiological systems can produce coincident sleep disturbances and sleep deprivation. This includes disorders of the cardiovascular (chronic heart failure), pulmonary (asthma), gastrointestinal (hepatic failure), renal (urinary tract infections, polyuria), endocrine (diabetes, hypothyroidism, hyperthyroidism), and neurological (Parkinson s disease,... 

Since allopurinol blocks xanthine conversion to uric acid, urinary xanthine excretion is increased, creating a risk of xanthine crystal formation in the urinary system or even in muscles this can result in nephrolithiasis (12). It is still an open question whether a predisposition to renal disease or renal disease itself is required to precipitate these adverse effects. It is also not known whether increased excretion of orotic acid, due to an interaction of allopurinol with pyrimidine formation, has any consequences for these adverse effects or for its role in reducing glucose tolerance. 

Nephrolithiasis (formation of kidney stones) does not present as classic nephrotoxicity since GFR is usually not decreased. Drug-induced nephrolithiasis represents abnormal crystal precipitation in the renal collecting system, potentially causing pain, hematuria, infection, or occasionally urinary tract obstruction with renal insufficiency. 

In contrast to urinary uromucoid, which consists of about 9% sialic acid (B3), stone uromucoid contains no sialic acid (K1,M1). This desialylation of mucosub-stances to a mineralizable matrix may occur in the urine, because sialidase is one of the renal enzyme systems regularly present in urine (Ml). Consequently, significant higher urinary sialidase activities are present in stone patients than are found in healthy males (V4). The age of the patient also correlates with the sialidase activity. The sialidase activity increases with age. Therefore, it is expected that elderly patients may have more desialylated glycoproteins, which increases the risk for stone formation. 

In the normal human kidney 98-100% of the filtered urate is reabsorbed. Substrate regulated secretion and postsecretory reabsorption of urate are considered to be the quantitatively most important renal transport systems for the regulation of the urinary excretion of urate (7). 

Urinary system In a prospective study, 87 patients with persistent >1 g per day proteinuria despite being on RAS blocker who were treated with add-on spironolactone (25 mg per day) therapy showed an acute fall in eGFR (5.1 9.4mL/min/1.73m ) in the first month of treatment with stabilisation thereafter [38]. Add-on spironolactone (n=32) therapy to a pre-existing antihypertensive regimen in patients with resistant HTN related to stage 3 CKD showed an increase in serum creatinine from 1.5 0.3 to 1.8 0.5mg/dl (P<0.0004) and the eGFR decreased from 48.6 8.7 to 41.2 11.5 mL/min/1.73 m (P< 0.0002). Acute renal failure occurred in one patient, which was resolved with discontinuation of spironolactone [35]. 

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