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.

Fatal nephrotic syndrome complicating allogeneic stem cell transplantation: a case report.

Disturbed kidney function is a common occurrence after bone-marrow transplantation. Sepsis, nephrotoxic medications, thrombotic microangiopathy and injury related to haemodynamic alterations are frequently accountable. Recently, attention has been given to immune-mediated glomerular damage, related to graft-versus-host disease. Herein we describe the fatal course of a nephrotic syndrome complicating allogeneic stem cell transplantation in a young woman with long-standing paroxysmal nocturnal haemoglobinuria. A post-mortem kidney biopsy revealed amyloidosis of the AA type. Physicians should be aware of the possibility that infections and inflammation accompanying the post-transplantation period may rarely promote the development of systemic amyloidosis or exacerbate silent pre-existing disease.

Mutational analysis of CLC-5, cofilin and CLC-4 in patients with Dent's disease.

BACKGROUND/AIMS: Dent's disease is caused by mutations in the chloride/proton antiporter, CLC-5, or oculo-cerebro-renal-syndrome-of-Lowe (OCRL1) genes. METHODS: Eighteen probands with Dent's disease were investigated for mutations in CLC-5 and two of its interacting proteins, CLC-4 and cofilin. Wild-type and mutant CLC-5s were assessed in kidney cells. Urinary calcium excretion following an oral calcium challenge was studied in one family. RESULTS: Seven different CLC-5 mutations consisting of two nonsense mutations (Arg347Stop and Arg718Stop), two missense mutations (Ser244Leu and Arg516Trp), one intron 3 donor splice site mutation, one deletion-insertion (nt930delTCinsA) and an in-frame deletion (523delVal) were identified in 8 patients. In the remaining 10 patients, DNA sequence abnormalities were not detected in the coding regions of CLC-4 or cofilin, and were independently excluded for OCRL1. Patients with CLC-5 mutations were phenotypically similar to those without. The donor splice site CLC-5 mutation resulted in exon 3 skipping. Electrophysiology demonstrated that the 523delVal CLC-5 mutation abolished CLC-5-mediated chloride conductance. Sixty percent of women with the CLC-5 deletion-insertion had nephrolithiasis, although calcium excretion before and after oral calcium challenge was similar to that in unaffected females. CONCLUSIONS: Three novel CLC-5 mutations were identified, and mutations in OCRL1, CLC-4 and cofilin excluded in causing Dent's disease in this patient cohort.

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.

Regulation of the renal sodium-dependent phosphate cotransporter NaPi2 (Npt2) in acute renal failure due to ischemia and reperfusion.

BACKGROUND: Acute renal failure (ARF) is associated with hyperphosphatemia and decreased urinary phosphate excretion. The present study was undertaken to characterize the effects of ARF due to ischemia and reperfusion on renal phosphate transport and on gene and protein expression of type IIa NaPi cotransporter (Npt2) the physiologically most relevant renal sodium-dependent phosphate cotransporter. METHODS: The following groups of rats with intact parathyroid glands were studied: (1) sham operated (sham); (2) after 1 h ischemia by bilateral renal artery clamping (I), and after 1 h ischemia and reperfusion of 1 h (I + R 1 h); (3) 24 h (I + R 24 h); (4) 48 h (I + R 48 h), and (5) 72 h (I + R 72 h) duration. The effect of ARF on Npt2 mRNA and protein expression was also examined after parathyroidectomy (PTX) of 2 and 4 days' duration. RESULTS: Ischemia and reperfusion were associated with increases in plasma creatinine, hyperphosphatemia, and with decreased tubular phosphate reabsorption. Npt2 mRNA was significantly downregulated in the cortex, maximal at 24 and 48 h of reperfusion. The degree of Npt2 mRNA downregulation was not affected by PTX of 2-4 days' duration. The abundance of Npt2 protein in proximal tubular apical brush border membrane was markedly decreased after reperfusion. Npt2 protein, however, was more abundant in PTX animals than in those with intact parathyroids and a similar degree of renal insufficiency. The immunohistochemical analysis of proximal tubular apical brush border membrane showed a progressive decrease of Npt2 protein labeling after ischemia and reperfusion, with progressive regeneration after 72 h. CONCLUSION: These results suggest that downregulation of Npt2 protein may contribute to the decreased tubular reabsorption of phosphate in acute ischemic renal failure and hyperphosphatemia.

Implementation of guidelines for metabolic syndrome control in kidney transplant recipients: results at a single center.

BACKGROUND: Cardiovascular disease is a leading cause of death among kidney transplant recipients. Metabolic syndrome increases the risk for cardiovascular events and decreases graft survival. Lately, guidelines for management of the metabolic syndrome, primarily hypertension, diabetes mellitus (DM) and hypercholesterolemia have dramatically changed in an attempt to decrease cardiovascular risks among kidney transplant recipients. In the present study we examined whether these guideline changes had impact on our management of post-transplantation patients and the subsequent treatment outcomes for these diseases. METHODS: Data were obtained from kidney transplant clinic files from two follow-up (FU) periods-between 1994-1997 and between 2008-2011. Demographic data, monitoring and screening frequency for cardiovascular risk factors, immunosuppression regimen, treatment for hypertension, diabetes and hyperlipidemia, treatment outcomes and graft function changes were compared between the two follow-up periods. RESULTS: There was a significant increase in the percentage of patients undergoing transplantation due to renal failure secondary to diabetes and/or hypertension. Patient monitoring and screening during the second FU period were less frequent, but more targeted, reflecting changes in clinic routines. Blood pressure was better controlled in the second FU period (p < 0.01), as was hypercholesterolemia (p < 0.001). High fasting glucose levels were more prevalent among patients in the second group (p < 0.005), although more patients received treatment for DM (p < 0.001). Significantly, fewer patients experienced deterioration of kidney functions during the second FU period (p < 0.001). CONCLUSIONS: We found that guideline changes had impact on clinical practice, which translated to better control of the metabolic syndrome. DM control is challenging. Overall, stability of kidney function improved.

Heart rate response to blood pressure variations: sympathetic activation versus baroreflex response in patients with end-stage renal disease.

BACKGROUND: Continuous systolic blood pressure (SBP) and interbeat intervals (IBI) recordings reveal sequences of consecutive beats in which SBP and heart rate change in opposite direction, representing negative feedback baroreflex mechanisms, as well as sequences in which SBP and heart rate change in the same direction (non-baroreflex), believed to represent feedforward control mechanisms. The present study was undertaken to assess the relationship between baroreflex and non-baroreflex sequences in end stage renal insufficiency. METHODOLOGY/PRINCIPAL FINDINGS: Continuous beat-to-beat SBP and IBI monitoring was performed in patients on chronic hemodialysis (HD, n=72), in age-matched patients after renal transplantation (TX, n=41) and healthy (control) individuals (C, n=34). The proportion of baroreflex and nonbaroreflex episodes and the b coefficients (the regression line slope of SBP-IBI correlation) were determined using a newly developed 1 minute sliding window method, the classical sequence technique and the "Z" coefficient method. Analysis using the 1 minute sliding window showed an increased proportion of baroreflex episodes in controls and HD, and predominance of nonbaroreflex episodes in TX. An increased proportion of nonbaroreflex episodes in TX patients relative to HD was also revealed by the "Z" method. Baroreflex and nonbaroreflex b coefficients obtained by all methods were markedly decreased in HD. This alteration was reversed at least partly in TX. In HD, both baroreflex and nonbaroreflex b coefficients were inversely correlated to age and CRP levels; in TX, the nonbaroreflex b coefficient was influenced by the type of calcineurin inhibitor. CONCLUSION/SIGNIFICANCE: Renal status affects the contribution of baroreflex and nonbaroreflex mechanisms and the strength of SBP-IBI relationship. The predominant contribution of nonbaroreflex mechanisms in TX may be suggestive of enhanced central sympathetic control. Our data may be relevant for understanding of the pathogenesis and selection of appropriate treatment of post-transplant hypertension.

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.

Delayed effect of blood pressure fluctuations on heart rate in patients with end-stage kidney disease.

The time delay of the baroreflex may be affected by decreased autonomic activity in uremia. To assess the magnitude and the time delay of heart rate response in patients with end-stage renal disease, continuous beat-to-beat intervals (IBI) and systolic blood pressure (SBP) recordings were monitored in hemodialysis (HD) patients (n = 72), in patients after renal transplantation (TX) (n = 41) and in age-matched controls (C) (n = 34). A 2-term prediction model was computed, in which each IBI change was represented as a function of SBP difference values of two immediately preceding beats. Baroreflex slope and the frequency domain variables low frequency (LF) α index, phase shift, and lag time were also calculated. b1 coefficient, representing the dependence of IBI difference with the first previous SBP difference was lower in HD than in Cs, but increased after TX. b1 correlated with age, baroreflex slope, and LF α, and b2 (the 2nd term), with both the phase shift between SBP and IBI and lag time. The latter was lower in Cs than in HD or transplanted patients. These findings show that the time delay of the heart rate response to SBP variations is increased in renal insufficiency. The prolonged delay may contribute to the circulatory instability in uremic patients.

Evaluation of intradialytic hypotension using impedance cardiography.

BACKGROUND: Hypotension during hemodialysis is frequent in patients with cardiovascular disease who have a limited physiological compensatory response. Recent advances in technology allow non-invasive monitoring of cardiac output and derived hemodynamic parameters. This prospective study evaluated episodes of intradialytic hypotension using clinical data and continuous non-invasive hemodynamic monitoring by impedance cardiography. METHODS: Forty-eight chronic hemodialysis patients, with prevalence for intradialytic hypotensive episodes, underwent evaluation with non-invasive impedance cardiography (Physioflow) before, during and after a regular dialysis session. RESULTS: During continuous non-invasive cardiac monitoring, a fall of systolic arterial blood pressure of 20% or more at least once during hemodialysis was detected in 18 patients (37.5%)--thereafter identified as the "Unstable" group. In 30 patients--thereafter called the "Stable" group, the blood pressure did not change significantly. During hypotension, a decrease in cardiac output was found in 11 of the 18 unstable patients, and a significant fall in peripheral resistance in the remaining 7. End-diastolic filling ratio was significantly lower in the unstable group. The most significant predictors associated with intradialytic hypotension were the presence of ischemic heart disease (P = 0.05), and medication with beta blockers (P = 0.037) and calcium channel blockers (P = 0.018). CONCLUSIONS: Hemodynamic changes in dialysis patients with hypotensive episodes included decreased cardiac output or decreased peripheral resistance. A lower end-diastolic filling ratio may be regarded as a marker for reduced preload in these patients. Non-invasive impedance cardiography may be used to evaluate risk factors for hypotension in dialysis patients.

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.

Autoimmune cholangiopathy associated with systemic lupus erythematosus.

We report a 39-year-old female who presented over 11 years with autoimmune cholangiopathy associated with kaleidoscopic manifestations of systemic lupus erythematosus (SLE), including, arthritis, skin changes, pleuritis, diffuse proliferative glomerulonephritis, lymphadenopathy, splenomegaly, hyperglobulinemia, and major depression. While antimitochondrial antibodies (AMA) were absent, antinuclear (ANA) and anti-DNA antibodies were detected in high titres associated with hypocomplementemia. The patient also had vitamin B12 deficiency and antiphospholipid antibodies. The patient required steroids and repeated courses of cyclophosphamide for the management of lupus nephritis, and ursodeoxycholic acid (ursolite) administration resulted in amelioration of cholestatic laboratory abnormalities. This unusual case report and review of literature illustrate that immune liver disease may be an important clinical manifestation of SLE, especially autoimmune cholangiopathy.

Predictors of haemodynamic instability and heart rate variability during haemodialysis.

BACKGROUND: The pathogenesis of haemodialysis-induced hypotension is multifactorial and may include autonomic nervous system dysfunction. The present study was undertaken to (i) determine heart rate variability (HRV) in chronic haemodialysis patients without and with haemodynamic instability (hypotension-prone) during ultrafiltration and (ii) identify patients at risk and the predictors of dialysis-related hypotension. METHODS: HRV was evaluated in 56 chronic haemodialysis patients without (stable; n = 27) and with symptomatic hypotension episodes (unstable; n = 29) during daytime, haemodialysis and night-time periods. Logistic regression analysis was performed in a model that included clinical and biochemical data and HRV measurements. RESULTS: HRV was significantly reduced in haemodynamically unstable as compared with the stable patients. LF/HF ratio, an index representative of sympathovagal balance, was significantly lower in unstable patients, especially in those with ischaemic heart disease and diabetes mellitus. In a logistic regression model including clinical data and HRV measurements, ischaemic heart disease and left ventricular systolic dysfunction were found to be the main predictors of haemodynamic instability. CONCLUSIONS: These data suggest that haemodynamic instability is strongly associated with a decreased HRV and an impaired sympathovagal balance, suggesting disturbed autonomic control in uraemic patients with cardiac damage. Patients with ischaemic heart disease, reduced left ventricular systolic function and decreased HRV may be at the highest risk to be haemodynamically unstable during haemodialysis. The role of early detection and treatment of ischaemic heart disease in preventing symptomatic hypotensive episodes in these patients remains to be determined.

Regulation of NaPi-IIa mRNA and transporter protein in chronic renal failure: role of parathyroid hormone (PTH) and dietary phosphate (Pi).

Chronic renal failure (CRF) is associated with a high fractional phosphate excretion (FEPi), secondary hyperparathyroidism, and resistance to parathyroid hormone (PTH). This study was undertaken to characterize the role of PTH and dietary Pi in the regulation of PTH/PTH-related peptide receptor (PTHrP-R) mRNA and NaPi-IIa mRNA and protein in CRF. The following groups of rats were studied: (1) sham-operated (control); (2) CRF: 6 weeks after 5/6 nephrectomy (NPX); (3) NPX and parathyroidectomy (NPX + PTX); (4) NPX rats fed a low-Pi diet (NPX + LP); (5) sham-operated rats fed a low-Pi diet (control + LP); (6) sham-operated after PTX (control + PTX). Expression of NaPi-IIa mRNA and PTH/PTHrP-R mRNA was determined in the renal cortex by Northern hybridization. NaPi-IIa protein abundance was determined in cortical brush border membranes by immunoblotting. In NPX rats creatinine clearance decreased to 40 +/- 4%, PTH/PTHrP-R mRNA to 52.1 +/- 2% and NaPi-IIa mRNA to 41.2 +/- 5.5% of control. The PTH/PTHrP-R and NaPi-IIa mRNA in the NPX + PTX and NPX + LP group was similar to that in NPX. NaPi-IIa protein abundance was reduced in NPX compared with control, but was increased dramatically in NPX + PTX and NPX + LP compared to NPX, paralleled by a decrease in FEPi. These findings suggest that the elevated FEPi in CRF is maintained by decreased NaPi-IIa mRNA and NaPi-IIa protein abundance. In contrast, the observed decrease in FEPi with PTX or LP diet in CRF is mediated, at least partly, by increased NaPi-IIa protein abundance with no change in NaPi-IIa mRNA, suggesting post-transcriptional regulation of the NaPi-IIa transporter.