Helge Hohage

Sympathetic Nerve Activity in End-Stage Renal Disease

Background—Uremia is proposed to increase sympathetic nerve activity (SNA) in hemodialysis patients. The aims of the present study were to determine whether reversal of uremia by successful kidney transplantation (RTX) eliminates the increased SNA and whether signals arising in the diseased kidneys contribute to the increased SNA in renal failure. Methods and Results—We compared muscle sympathetic nerve activity (MSNA) in 13 hemodialysis patients wait-listed for RTX and in renal transplantation patients with excellent graft function treated with cyclosporine (RTX-CSA, n=13), tacrolimus (RTX-FK, n=13), or without calcineurin inhibitors (RTX-Ø, n=6), as well as in healthy volunteers (CON, n=15). In addition to the above patients with present diseased native kidneys, we studied 16 RTX patients who had undergone bilateral nephrectomy (RTX-NE). Data are mean±SEM. MSNA was significantly elevated in hemodialysis patients (43±4 bursts/min), RTX-CSA (44±5 bursts/min), RTX-FK (34±3 bursts/min), and RTX-Ø (44±5 bursts/min) as compared with CON (21±3 bursts/min), despite excellent graft function after RTX. RTX-NE had significantly reduced MSNA (20±3 bursts/min) when compared with RTX patients. MSNA did not change significantly with RTX in 4 hemodialysis patients studied before and after RTX (44±6 versus 43±5 bursts/min, P =NS). In contrast, nephrectomy resulted in reduced MSNA in all 6 RTX patients studied before and after removal of the second native kidney. Conclusions—Despite correction of uremia, increased SNA is observed in renal transplant recipients with diseased native kidneys at a level not significantly different from chronic hemodialysis patients. The increased SNA seems to be mediated by signals arising in the native kidneys that are independent of circulating uremia related toxins.

ACE Inhibitor Versus β-Blocker for the Treatment of Hypertension in Renal Allograft Recipients

Angiotensin-converting enzyme (ACE) inhibitors have been shown to slow the progression of chronic renal failure. However, the value of ACE inhibitors for the treatment of hypertension in renal allograft recipients has not been established. ACE inhibitors dilate the efferent glomerular arteriole, an effect that may aggravate the decrease in glomerular filtration rate resulting from cyclosporine-induced vasoconstriction at the afferent glomerular arteriole. Therefore, the goal of this double-blind, randomized study was to compare the antihypertensive and renal effects of the ACE inhibitor quinapril with those of the beta-blocker atenolol in renal allograft recipients in whom hypertension developed 6 to 12 weeks after transplantation. All patients received cyclosporine as an immunosuppressant and had stable graft function (serum creatinine concentration, <220 micromol/L) at entry into the study. Twenty-nine patients who received quinapril (daily dose titrated between 2.5 and 20 mg) and 30 patients who received atenolol (daily dose titrated between 12.5 and 100 mg) completed the 24-month study. The two groups did not differ in age, sex ratio, height, and weight before entry into the study. Quinapril decreased diastolic blood pressure from 96+/-1 to 84+/-1 mm Hg (average throughout treatment period), and atenolol decreased diastolic blood pressure from 96+/-1 to 83+/-1 mm Hg. The serum creatinine concentration did not change significantly in either group after 24 months (129+/-8 micromol/L at entry and 148+/-19 micromol/L after 24 months in the quinapril group and 131+/-6 micromol/L at entry and 152+/-15 micromol/L after 24 months in the atenolol group; P=NS for both groups). After 24 months, the change in urinary albumin excretion from baseline was -10+/-15 mg/d in the quinapril group and 52+/-32 mg/d in the atenolol group (P=0.03). These results show that quinapril and atenolol are effective antihypertensive drugs when used after renal transplantation. Moreover, compared with atenolol, quinapril has no adverse effects on graft function. The relative reduction in albuminuria observed with quinapril as compared with atenolol could indicate a beneficial effect of quinapril on long-term graft function.

Withdrawal of Cyclosporine or Tacrolimus After Addition of Mycophenolate Mofetil in Patients With Chronic Allograft Nephropathy

There has been a need for a prospective, randomized, controlled trial to determine whether the addition of mycophenolate mofetil (MMF) to a calcineurin inhibitor (CNI)‐based regimen or MMF addition followed by CNI withdrawal is an effective treatment for chronic allograft nephropathy (CAN). We conducted the first randomized, prospective study to compare the introduction of MMF with or without CNI withdrawal in long‐term transplant recipients with histologically proven CAN and deteriorating renal function. The primary endpoint was renal function as indicated by the slope of the inverse serum creatinine vs. time at 32 weeks after randomization. After an interim analysis found a greater‐than‐expected difference between groups in the slopes of the inverse serum‐creatinine, the study was stopped for ethical reasons. There were 20 patients in the MMF/CNI continuation and 19 patients in the MMF/CNI withdrawal groups (mean time post‐transplant 7 years). Renal function improved in the dual‐therapy compared with the triple‐therapy group (p = 0.002). Blood pressure decreased in the dual‐therapy group with a significant difference between groups at 35 weeks (p = 0.04). No acute rejections occurred. Long‐term patients with CAN experience a significant improvement in renal function and blood pressure when CNIs are replaced by MMF.

Influence of smoking on baroreceptor function: 24 h measurements.

OBJECTIVE Recent studies showed that smoking four cigarettes per hour impairs baroreflex sensitivity in humans. In this study, baroreceptor function was qualified more precisely by 24 h measurements using the new portable Portapres system, allowing a continuous non-invasive registration of blood pressure curves. METHODS Twenty-four smoking individuals (12 male/12 female) who smoked more than 10 cigarettes per day for more than 6 years were investigated. Thirty non-smokers (15 male/15 female) served as controls. Data were evaluated separately for the 08:00-22:00 h and 22:00-08:00 h periods. RESULTS Within one 24 h period, smokers showed a higher blood pressure [female: mean arterial blood pressure (MAP) 85.5 mmHg; male: MAP 93 mmHg] compared to non-smokers (female: MAP 80 mmHg; male: MAP 90 mmHg). During daytime (08:00-22:00 h), this difference reached a level of statistical significance (P< 0.05) in female subjects. Heart rate was significantly higher in smokers (female: 86 bpm; male: 80 bpm) compared to non-smokers (female: 77 bpm; male: 70 bpm) during the 24 h observation period. The number of sequences (seq) in smokers surpassed the number of sequences in non-smokers by about 53 seq/day, which corresponds to a significant difference of 4.5%. At night the sympathetic -systolic blood pressure/-pulse interval (-SBP/-PI) sequences of the smoking group predominated over the -SBP/-PI sequences in the non-smoking group. On the other hand, the parasympathetic +SBP/+PI sequences were significantly less in smokers between 22:00 and 08:00 h. The regressions (i.e. D pulse interval/D SBP [ms/mmHg]), which represent the baroreceptor sensitivity, were clearly smaller in smokers. CONCLUSIONS The present study provides evidence that chronic tobacco (nicotine) abuse causes pathological alterations of autonomic nervous blood pressure regulation which can be measured under normal living conditions and may be described as sympathovagal dysbalance and decreased baroreceptor sensitivity. Taken together with processes such as elevated catecholamine blood levels, these alterations may explain the higher risk of cardiovascular diseases.

Comparison of quinapril versus atenolol: effects on blood pressure and cardiac mass after renal transplantation

Based on epidemiologic facts on elevated cardiovascular mortality in renal allograft recipients, an echocardiographic 2-year follow-up in hypertensive renal allograft recipients was conducted. This study provides evidence that, in contrast to atenolol, quinapril, independent of blood pressure reduction, reduces left ventricular hypertrophy and improves left ventricular diastolic function in this population.

Influence of Dialysis Procedure, Membrane Surface and Membrane Material on Iopromide Elimination in Patients with Reduced Kidney Function

Haemodialysis for the elimination of contrast medium in patients with advanced renal failure is a common procedure. Even though sufficient elimination with the use of regular low-flux membranes is documented, large differences in results have been reported in prior investigations. We, therefore, compared Cuprophan and polysulfone dialysers with different surface areas to haemofiltration with different amounts of substitution fluid in 40 patients with compromised renal function after coronary angiography. Plasma iodine concentrations were measured by fluorescent excitation analysis. At constant blood flow rates of 200 ml/min, Cuprophan membranes with 1.3 m2 surface area had a clearance rate of 87 ml/min, whereas polysulfone membranes of comparable size displayed a significantly higher clearance rate of 147 ml/min. Polysulfone membranes with 1.8 m2 surface area showed a small but insignificant increase in the iodine clearance (162 ml/min), while Cuprophan membranes displayed an increase in clearance rates (121 ml/min). Additional ultrafiltration led to a further increase in the plasma clearance of both membranes and reduced urinary iodine excretion. Haemofiltration was comparable to haemodialysis in terms of efficacy and thus represents an alternative method. Clearance of iopromide during haemodialysis with polysulfone membranes is higher than with Cuprophan membranes. Elimination rates can be further increased by additional ultrafiltration. Haemofiltration is comparable to haemodialysis regarding contrast medium elimination.

Cyclosporine A modulates baroreceptor function in kidney transplant recipients

Cyclosporine has been described to increase the sympathetic tone. Alterations in sympathetic tone may contribute to baroreceptor dysfunction. Therefore, in this study baroreceptor function in 20 kidney transplant recipients was investigated under both low and high cyclosporine whole blood concentrations using the sequence analysis technique. The sympathetic nerve activity was estimated by calculating the low frequency oscillation of heart rate and blood pressure following Fast Fourier Transformation (FFT). Besides cyclosporine, azathioprine and prednisolone no other drugs were used. The increase in cyclosporine whole blood levels (from 101+/-13.4 ng/ml to 469+/-52 ng/ml) did not change mean arterial blood pressure significantly (83.7+/-2.5 vs. 82.2+/-2.0 mm Hg). Baroreflex sensitivity in +PI/+RR (+pulsinterval/+blood pressure) sequences, however, increased from 11.2+/-0.4 to 13.0+/-0.5 ms/mm Hg, whereas it was reduced in -PI/-RR (-pulsinterval/-blood pressure) sequences (14.4+/-0.3 to 12.5+/-1.1 ms/mm Hg). The increase in cyclosporine whole blood concentrations was associated with an increase in low frequency oscillation of heart rate (430+/-12 to 461+/-13) and blood pressure (452+/-9 to 469+/-12), indicating an enhanced sympathetic tone. Our results provide evidence that cyclosporine A by itself alters baroreceptor function. An imbalance between the sympathetic and parasympathetic nervous system due to an enhanced sympathetic tone may explain the reduction in -PI/-RR and the increase in +PI/+RR sequence baroreflex sensitivity.

Kidney transplantation improves baroreceptor sensitivity

Kidney transplant recipients as well as patients on hemodialysis frequently share an increased risk of cardiovascular diseases. Besides other factors, modulations in central neural blood pressure regulation have to be considered as a pathogenetic factor. In this study, baroreceptor function as a possible modulator of blood pressure and the activity of the generating components of the sympathetic nervous system were estimated in 20 kidney transplant recipients, 20 normotensive patients on hemodialysis and 20 age-matched volunteers using the sequence analysis technique and Fast Fourier Transformation (FFT). No blood pressure differences could be measured (83.7+/-2.5 vs. 82.5+/-3.8 vs. 79.2+/-2.4 mm Hg). Pulse interval-blood pressure sequences and the slope of delta pulse interval/delta mean arterial blood pressure of these sequences, representing baroreceptor sensitivity, did not differ between kidney transplant recipients and controls (11.2+/-1.4 vs. 13.4+/-1.3 ms/mm Hg), whereas in hemodialysis patients a reduced baroreceptor sensitivity (5.2+/-1.2 ms/mm Hg) was detected. The 66-129 mHz component (Mayer waves) of heart rate and blood pressure spectrum in normals (650+/-57 and 630+/-70 modulus) significantly (p<0.05) exceeded its equivalent in kidney transplant recipients (430+/-32 and 452+/-27 modulus) and patients on hemodialysis (375+/-38 and 394+/-40 modulus). In conclusion, our study provided evidence that both in kidney transplant and dialysis patients a decreased activity of the generating compounds of the sympathetic nervous system can be detected as compared to healthy volunteers. In contrast to hemodialysis patients, the baroreceptor sensitivity is unaffected in kidney transplant recipients and may, therefore, not contribute to the development of cardiovascular diseases.

Influence of Age on the Prognosis of Renal Transplant Recipients

With aging, morphologic organ changes due to arteriosclerosis, hypertension, or diabetes increase, and renal transplantation tends to become less successful. We analyzed the outcome of transplantation in 123 recipients who underwent renal transplantation between January 1988 and December 1989. We assessed patient and graft survival after 1, 5, and 6 years as well as mortality and transplant failure and the incidence of rejections. We compared the results of patients aged under 60 years (group 1, n = 60) with the findings of patients aged over 60 years (group 2, n = 63). Immunosuppression was with ciclosporin A and prednisolone without exception. In patients under the age of 60, the overall patient survival at 1, 5, and 6 years was 97, 95, and 90% and was significantly compromised in recipients over the age of 60 (92, 80, and 75%). The 1-, 5- and 6-year graft survival rates were 92, 90, and 90% in recipients aged over 60 years and 88, 82, and 79% in recipients under the age of 60 years. The incidence of rejection was significantly higher in recipients under the age of 60. Patient mortality was mainly due to cardiovascular complications and transplant failure mainly related to transplant thrombosis. In older patients, renal transplantation is thought to be an option of survival rate improvement in comparison with hemodialysis. The incidence of transplant rejection is significantly lower, and this indicates a promising result regarding the long-term prognosis. As cardiovascular complications present as the main mortality factors of both transplant and patient, the prognosis is considered to be highly dependent on screening and treatment of these risk factors.

Effects of Diadenosine Polyphosphates on Systemic and Regional Hemodynamics in Anesthetized Rats

Diadenosine polyphoshates (Ap4A, Ap5A, Ap6A) induce vasodilatation or vasoconstriction in various isolated vessels and influence central and peripheral hemodynamics. The influence of diadenosine polyphoshates on hemodynamics was studied in anesthetized rats in vivo. Mean arterial blood pressure (MABP) and heart rate (HR) measured in the carotid artery decreased with Ap4A, Ap5A and Ap6A. Renal blood flow (RBF), femoral blood flow (FBF) and cardiac output (CO) were evaluated by an ultrasonic transit-time method. Renal superficial blood flow (RSBF) was measured by laser Doppler flowmetry. CO, RBF and RSBF were decreased initially by all three diadenosine polyphosphates. FBF was also slightly decreased. Total peripheral (TPR), renal (RVR) and femoral (FVR) vascular resistances were calculated. TPR was transiently increased by the dinucleotides following by a decrease. RVR and, to a lesser extent, FVR were also increased. These data show that diadenosine polyphosphates have effects on both the heart and the peripheral blood vessels. The effects on the heart and MABP were dominated by bradycardia and hypotension. In the kidney, diadenosine polyphosphates induced a predominant vascoconstriction. The effects on skeletal muscle blood flow were much smaller. Thus, the three diadenosine polyphosphates studied differ in the effects on heart and peripheral vessels.