2 Table 1: Factors implicated in the pathogenesis of hypertension in end-stage renal disease. Sodium and volume excess The renin-angiotensin-aldosterone system The sympathetic nervous system Endothelium-derived vasodepressor substances Endothelium-derived vasoconstrictor substances Erythropoietin use Divalent ions and parathyroid hormone Atrial natriuretic peptide Structural changes in the arteries Pre-existent essential hypertension Miscellaneous Anemia/ Hypoxia A-V ﬁstula Vasopressin Serotonin Thyroid function Calcitonin gene-related peptide angiotensin II in conjunction with estimation of SNS activity by means of radiotracer dilution and intraneural recordings of muscle sympathetic nerve activity (MSNA) [8]. Total body norepinephrine (NE) spillover, an index of overall SNS activity, was increased by 100% and MSNA by 60% in the hypertensive patients compared with healthy subjects, which supports the role of SNS activity in the maintenance of hypertension in these patients [8]. The pathogenesis of hypertension in patients with CKD is multifactorial and may vary depending on the underlying disease (Table 1). Activation of the RAAS, sodium retention, and volume expansion have long been recognized as the most important factors [10, 11]. However, clinical experience indicates that volume depletion and inhibition of the RAAS do not necessarily result in normalization of BP. This suggests that other factors may play a role. Among those, activation of the SNS appears to have a prominent role. Plasma NE levels are frequently increased in hemodialysis patients [12, 13] and in patients with early CKD and hypertension compared with healthy subjects and with nor- motensive CKD patients [14]. Direct recording of neuronal activity from postganglionic MSNA in the peroneal nerves of patients on chronic dialysis treatment has shown a greater rate of SNS discharge than in control subjects [15]. Moreover, MSNA in hypertensive hemodialysis patients with native kidneys were 2.5 times more frequent than those in hemodialysis patients after bilateral nephrectomy or in healthy subjects. Our studies on 5/6 nephrectomized rats have provided the most convincing evidence yet for a role of the sympathetic nervous system in the pathogenesis of International Journal of Hypertension hypertension associated with CKD [16]. The turnover rate of NE, which is a marker of SNS activity, was greater in two areas of the brain involved in the noradrenergenic control of BP (posterior hypothalamic (PH) nuclei and the locus coeruleus) of CKD rats compared to that of control rats. Moreover, microinjection of a neurotoxin, 6-hydroxy- dopamine, in the PH signiﬁcantly reduced BP in CKD rats [17]. The secretion of NE from the PH was also greater in CKD rats than in control animals [16]. We postulated that the activation of these nuclei in the central nervous system results from impulses generated in the aﬀected kidney which are transmitted to the central nervous system. The kidney is richly innervated with baroreceptors and chemoreceptors [18–20]. Renal aﬀerent nerves are connected directly or indirectly to a number of areas in the central nervous system that contribute to BP regulation [21]. Stim- ulation of renal receptors by adenosine, urea, or electrical impulses evoke reﬂex increases in SNS activity and BP [22, 23]. Renal aﬀerent impulses play an important role in the genesis of hypertension in several other experimental models, including the one-kidney one-clip and two-kidney one-clip Goldblatt hypertension in rats, the one-kidney one- wrap Grollman hypertension in the rat, or in the spon- taneously hypertensive rat (SHR) [24–27]. Furthermore, bilateral dorsal rhizotomy at the level T-10 to L-3 resulted in almost complete normalization of BP in 5/6 nephrectomized rats [28]. This suggests that increased renal sensory inputs from the injured kidney to the central nervous system may contribute to the development of hypertension in CKD rats. Kidney damage can raise BP even in the absence of renal insuﬃciency. The injection of phenol in the lower pole of one kidney leads to an immediate elevation of BP and activation of the central SNS activity, which can be prevented by renal denervation [16, 29]. There is also convincing evidence that the SNS plays an important role in the pathogenesis of hypertension observed in patients with CKD caused by polycystic kidney disease [30]. However, not all types of injury to the kidney lead to an increase in blood pressure. For example, burning, administration of alkali, acids, or methanol caused no eﬀects [29]. This is of relevance, since clinical experience indicates that not all renal injuries in humans are associated with hypertension. For example, in the absence of renal insuﬃciency, IgA nephropathy is more likely to be associated with hypertension than membranous glomerulonephritis or minimal change disease (Table 2) [31]. These ﬁndings support the notion that increased aﬀerent nervous inputs from kidneys with renal diseases may send signals to integrative sympathetic nuclei in the central nervous system and contribute to the pathogenesis of hypertension. The normalization of BP that follows bilateral nephrectomy may be largely due to elimination of these aﬀerent impulses. Identiﬁcation of the factor(s) responsible for the intrarenal activation of these aﬀerent pathways, or for the stimulation of sympathetic output from the brain, may lead to a new understanding of the pathophysiology of sympathetic overactivity and hypertension in renal disease and, hopefully, to novel therapies based on speciﬁc inhibitors of these activating factors.