Rebecca Backenroth

Sympathetic Nervous System Function and Dysfunction in Chronic Hemodialysis Patients

Adequate sympathetic nervous system activation is essential for the compensatory mechanisms of blood pressure maintenance during the hemodialysis (HD) procedure. Chronic sympathetic nervous system overactivity, however, may lead to the development of hypertension and cardiovascular disease in HD patients. The present review focuses on recent findings on the sympathetic nervous system activity in these patients. Sympathetic overactivity has been demonstrated directly by muscle sympathetic nerve activity recordings (MSNA) in chronic renal disease, but only rarely in HD patients. In the latter, sympathetic activity has mostly been assessed using indirect methodology. Decreased heart rate variability, increased blood pressure variability (BPV), and suppressed baroreflex function are believed to represent chronic sympathetic overactivity in HD patients. The HD procedure and ultrafiltration are associated with enhanced sympathetic activity and baroreflex activation. During most episodes of intradialytic hypotension, the baroreflex is adequately activated; sympathetic withdrawal with bradycardia, however, has been reported during excessive hypovolemia. Sympathetic overactivity is also believed to be a mechanism associated with intradialytic hypertensive episodes and refractory hypertension. While successful renal transplantation is associated with improvement of heart rate variability (HRV), improvement and restoration of baroreflex function, persistent sympathetic overactivity has been documented in transplanted patients using MSNA recordings. Decreased HRV and baroreflex function have been reported to be associated with increased mortality and morbidity in HD patients. The predictive value of sympathetic outflow assessed by MSNA has yet to be determined. Optimization of HD treatment, pharmacological interventions, and renal sympathetic denervation are several approaches targeting sympathetic overactivity to improve cardiovascular morbidity and mortality.

Restoration of baroreflex function in patients with end-stage renal disease after renal transplantation

BACKGROUND Renal transplantation improves the uraemic autonomic dysfunction and heart rate variability (HRV). The effects of successful transplantation on blood pressure variability (BPV) and baroreflex function are not well defined. METHODS BPV, HRV and baroreceptor indices were determined in (1) 52 non-diabetic chronic haemodialysis patients, (2) 44 transplanted patients, 24 in the first year after renal transplantation (< or =1 year) and 20 at least 1 year (>1 year) after renal transplantation, and (3) 41 control individuals with normal renal function, age-matched to (1) and (2). Power spectrum analysis of interbeat intervals (IBI) and systolic blood pressure (SBP) was performed in the low-frequency (LF 0.04-0.15 Hz) and the high-frequency (HF 0.15-0.40 Hz) bands. Spontaneous baroreceptor sensitivity (BRS) was determined by the sequence (slope) and spectral (alpha coefficient) techniques. RESULTS In haemodialysis patients, BPV was increased, while HRV, BRS slope and LF alpha and HF alpha coefficients were markedly decreased as compared to control individuals. Renal transplantation was associated with normalization of BPV at short term (< or =1 year) and long term and with improvement of HRV at a long-term (>1 year) follow-up. In patients with long-standing functioning grafts (>1 year), baroreceptor indices were significantly increased and returned to values similar to those of the control subjects. CONCLUSIONS Our data show that renal transplantation improves blood pressure and HRV and restores baroreflex function to near normal range on the long-term follow-up. These effects may contribute to the improvement of blood pressure control and survival after successful transplantation.

Sympathetic activation and baroreflex function during intradialytic hypertensive episodes.

Background The mechanisms of intradialytic increases in blood pressure are not well defined. The present study was undertaken to assess the role of autonomic nervous system activation during intradialytic hypertensive episodes. Methodology/Principal Findings Continuous interbeat intervals (IBI) and systolic blood pressure (SBP) were monitored during hemodialysis in 108 chronic patients. Intradialytic hypertensive episodes defined as a period of at least 10 mmHg increase in SBP between the beginning and the end of a dialysis session or hypertension resistant to ultrafiltration occurring during or immediately after the dialysis procedure, were detected in 62 out of 113 hemodialysis sessions. SBP variability, IBI variability and baroreceptor sensitivity (BRS) in the low (LF) and high (HF) frequency ranges were assessed using the complex demodulation technique (CDM). Intradialytic hypertensive episodes were associated with an increased (n = 45) or decreased (n = 17) heart rate. The maximal blood pressure was similar in both groups. In patients with increased heart rate the increase in blood pressure was associated with marked increases in SBP and IBI variability, with suppressed BRS indices and enhanced sympatho-vagal balance. In contrast, in those with decreased heart rate, there were no significant changes in the above parameters. End-of- dialysis blood pressure in all sessions associated with hypertensive episode was significantly higher than in those without such episodes. In logistic regression analysis, predialysis BRS in the low frequency range was found to be the main predictor of intradialytic hypertension. Conclusion/Significance Our data point to sympathetic overactivity with feed-forward blood pressure enhancement as an important mechanism of intradialytic hypertension in a significant proportion of patients. The triggers of increased sympathetic activity during hemodialysis remain to be determined. Intradialytic hypertensive episodes are associated with higher end-of- dialysis blood pressure, suggesting that intradialytic hypertension may play a role in generation of interdialytic hypertension.

Baroreflex sensitivity and sympatho-vagal balance during intradialytic hypotensive episodes.

Objectives The role of the baroreflex function in the pathogenesis of hemodialysis-associated hypotension is controversial. Complex demodulation technique (CDM), providing continuous assessment of the amplitude of cardiovascular oscillation over time, is particularly suitable to assess dynamic changes in autonomic nervous system and baroreceptor sensitivity (BRS) during dialysis. In the present study, CDM was used to determine the effects of dialysis treatment on BRS and to characterize BRS changes during acute intradialytic hypotension. Methods Continuous beat-to-beat blood pressure and interbeat intervals (IBIs) were monitored in 93 chronic patients without (n = 70) and with (n = 26) hypotension during 96 dialysis sessions. The amplitudes of SBP and DBP, IBIs, and BRS change in the low-frequency (around center frequency of 0.09 Hz) and high-frequency (around center frequency of 0.30 Hz) ranges were followed during the whole dialysis session. Results Hemodialysis treatment was associated with increased low-frequency BRS, especially in sessions without hypotension. Hypotensive episodes were associated with significant increases in both low-frequency BRS and high-frequency BRS, mainly in patients with severe hypotension. The magnitude of the increase in baroreflex indices was proportional to the decrease in blood pressure. Low-frequency IBI/high-frequency IBI ratio, a marker of sympatho-vagal balance, did not significantly change during hypotension. Conclusion Our study shows that the baroreflex mechanism is preserved and adequately activated during intradialytic hypotension. Other factors, such as ischemic heart disease, left ventricular dysfunction, and inadequate arteriolar tone, rather than failure of baroreflex function, are more likely to be responsible for dialysis-induced hypotension.

Glycerol-induced acute renal failure attenuates subsequent HgCl2-associated nephrotoxicity: correlation of renal function and morphology.

Glycerol induced acute renal failure (ARF) is known to attenuate subsequent mercuric chloride nephrotoxicity. This protection was evaluated in rats. Glycerol induced varying degrees of renal insufficiency. After 14 days, when serum creatinine (SCr) creatinine clearance (CCr) and fractional excretion of sodium (FENa) had returned to baseline, injection of mercuric chloride caused significantly milder renal insufficiency in recovered rats than in controls (SCr 356 +/- 46 vs. 475 +/- 19 mumol/L; CCr 0.12 +/- 0.02 vs. 0.02 +/- 0.02 mL/min, p < .05; and mortality 0 vs. 45%, respectively, p < .01). A striking finding was that the degree of renal insufficiency induced by mercuric chloride correlated inversely with the degree of renal insufficiency previously induced by glycerol (r = -0.496, p < .05 for SCr and CCr), but there was no correlation with other measures of previous renal function such as urine volume, sodium excretion, or FENa. Glycerol induced ARF also attenuated the renal toxicity of mercuric chloride injected 4 days after glycerol, before full recovery of renal function. The decrements in renal function after the two insults were also inversely related (r = -0.76, p < .01). A third renal insult with a second mercuric chloride injection after three weeks was still attenuated. However, after the third insult, there was no longer an inverse or any statistical relationship with previous measurements of renal function. Histopathology revealed a good correlation between peak Scr after glycerol, and percentage of tubules undergoing re-generation 14 days later (r = 0.97, p < .01). There was an inverse correlation between Scr after mercuric chloride (administered 14 days after glycerol) and percentage of tubular regeneration seen two days later (r = -0.79, p < .05). The correlations of SCr and CCr with regeneration was greater than the correlations with tubular necrosis, suggesting that the regenerative process is involved in the protection from repeated renal insults. In conclusion, glycerol-induced ARF attenuates subsequent mercuric chloride renal insult. The attenuation correlates directly with the initial glycerol-induced damage, so that the more severe the initial renal insufficiency, the milder the renal insufficiency following subsequent mercuric chloride. This protection can be seen as early as 4 days and also 14 days after previous renal insult. The degree of renal tubular regeneration correlates well with the protection seen, and probably plays a role in acquired renal resistance to repeated insults.

Blood Pressure and Heart Rate Variability in Patients on Conventional or Sodium-Profiling Hemodialysis

Background. Autonomic nervous system dysfunction and dialysate sodium (Na) concentration are believed to play a role in the pathogenesis of hemodialysis-related hypertension. The present study was undertaken to determine whether increases in blood pressure in hemodialysis patients are associated with changes in heart rate variability (HRV), a measure of the autonomic nervous system function, and long-term exposure to increased dialysate Na concentration. Methods. Baseline clinical, biochemical data and HRV of patients undergoing increased Na profiling dialysis (High-Na, n = 9) and on conventional treatment (Control, n = 11) were compared with those obtained after one year of study. Results. After one year, the mean predialysis systolic blood pressure (SBP) increased in seven patients of the High-Na and in five of the Control group, and decreased or remained unchanged in the remaining subjects. Initial HRV was significantly higher in patients with increased SBP, and it increased further in these patients after one year. At the end of the study, post-dialysis plasma Na, osmolality, and weight gains were significantly higher in the High-Na group. No significant correlation, however, was found between individual changes in intradialytic sodium elimination and the alterations in blood pressure. Conclusion. These data suggest that the dialysate sodium concentration, a most important determinant of interdialytic weight gain and fluid balance, is only partly correlated with long-term changes in blood pressure. An increased blood pressure over time may develop in a subset of hemodialysis patients with higher HRV, suggestive of increased sympathetic activity.

DOES TYPE 2 DIABETES MELLITUS DELAY RENAL FAILURE IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

Autosomal dominant polycystic kidney disease (ADPKD) is a common renal disease without an effective therapeutic intervention to delay renal failure. Within kindreds, renal dysfunction often develops at a similar age in affected individuals, although there are known modifying factors. Two kindreds with ADPKD have shown a striking pattern of delayed onset of renal insufficiency in those individuals also suffering from type 2 diabetes mellitus. Eight nondiabetic patients with ADPKD had onset of dialysis or renal death at ages 38–52 years, (mean ± SEM 46 ± 1.9, n = 7) as compared with four diabetics who started dialysis or are still off dialysis at the age of 61 ± 2.8 years (p < 0.01). Two of the four diabetics still have reasonable renal function at age 61 and 66. The diabetes was diagnosed at age 32 ± 2 years and was treated with oral hypoglycemics for 19 ± 2 years before institution of insulin. Cardiovascular disease dominated the clinical picture in the diabetics. In conclusion, onset of renal failure in ADPKD was delayed for over 15 years in individuals who also suffered from type 2 diabetes mellitus, in two ADPKD kindreds. Possible mechanisms are discussed, including glibenclamide inhibition of the cystic fibrosis transmembrane conductance regulator. The striking delay associated with type 2 diabetes mellitus in ADPKD induced renal failure should be evaluated further.