Renal denervation: results of a single-center cohort study.

PURPOSE: To investigate the effect of renal denervation on office-based and 24-h ambulatory blood pressure measurements (ABPM) in a highly selective patient population with drug-resistant hypertension. MATERIALS AND METHODS: Patients with drug resistant hypertension eligible for renal denervation were included in the study population. Office blood pressure and ABPM were assessed prior to and after renal denervation. To detect procedure related renal or renal artery damage, magnetic resonance imaging (MRI) and angiography (MRA) were performed pre-interventional, one day post-interventional, and one month after renal denervation. RESULTS: Mean follow-up time between renal denervation and blood pressure re-assessment was 9.5 ±â€Š3.9 months. Between August 2011 and March 2013, 17 patients prospectively underwent renal denervation. Pre-interventional mean office blood pressure and ABPM were 177.3 ±â€Š20.3/103.8 ±â€Š20.4 mmHg and 155.2 ±â€Š20.5/93.7 ±â€Š14.5 mmHg, respectively. Post-interventional, office blood pressure was significantly reduced to 144.7 ±â€Š14.9/89.5 ±â€Š12.1 (p < 0.05). ABPM values remained unchanged (147.9 ±â€Š20.3/90.3 ±â€Š15.6, p > 0.05). The number of prescribed antihypertensive drugs was unchanged after renal denervation (4.7 ±â€Š2.0 vs. 4.2 ±â€Š1.2, p = 0.18). No renovascular complications were detected in follow-up MRI. CONCLUSION: After renal denervation, no significant decrease in ABPM was observed. These results may indicate a limited impact of renal denervation for drug resistant hypertension. KEY POINTS: • Renal denervation showed no significant effects on 24-h ambulatory blood pressure measurements. • A significant decrease in office blood pressure measurements may be explained by a potential detection bias. • Renal artery alterations were not observed on follow-up MRI scans.

Renal impairment after liver transplantation - a pilot trial of calcineurin inhibitor-free vs. calcineurin inhibitor sparing immunosuppression in patients with mildly impaired renal function after liver transplantation.

OBJECTIVES: Chronic kidney disease is frequent in patients after orthotopic liver transplantation (OLT) and has impact on survival. Patients receiving calcineurin inhibitors (CNI) are at increased risk to develop impaired renal function. Early CNI reduction and concomitant use of mycophenolat mofetil (MMF) has been shown to improve renal function. METHODS: The aim of this trial was to compare dose-reduced CNI/MMF versus CNI-free MMF/prednisone-based treatment in stable patients after OLT with respect to glomerular filtration rate (GFR). 21 patients (GFR 44.9 ' 9.9 mL/min/1.73m2 measured by 99m-Tc-DTPA-clearance, serum creatinine (SCr) 1.5 ' 0.42 mg/dL) were randomized either to exchange CNI for 10 mg prednisone (group 1; n = 8) or to receive CNI at 25% of the initial dose (group 2; n = 13) each in combination with 1000 mg MMF b.i.d. RESULTS: At month 12 mean SCr (-0.3 ' 0.4 mg/dL, p = 0.031) and GFR improved (8.6 ' 13.1 mL/min/ 1.73m superset2, p = 0.015) in group 2 but remained unchanged in group 1. Main side effects were gastroinstestinal symptoms (14.3%) and infections (4.8%). Two biopsy proven, steroid-responsive rejections occurred. In group 1 mean diastolic blood pressure (BP) increased by 11 ' 22 mmHg (p = 0.03). CONCLUSIONS: Reduced dose CNI in combination with MMF but not CNI-free-immunosuppression leads to improvement of GFR in patients with moderately elevated SCr levels after OLT. Addition of steroids resulted in increased diastolic blood pressure presumably counterbalancing the benefits of CNI withdrawal on renal function.

Beta-trace protein-based equations for calculation of GFR in renal transplant recipients.

Recently, we showed that serum beta-trace protein (BTP) is an alternative marker of glomerular filtration rate (GFR) in renal transplant recipients (RTR). We have now developed three BTP-based GFR formulae derived by multiple regression analyses from the patients who had participated in that study. Currently, we validated the diagnostic performance of these BTP-formulae in 102 consecutive RTR who underwent a technetium diethylenetriamine pentaacetic acid (DTPA) clearance for GFR measurement in comparison to the re-expressed Modification of Diet in Renal Disease (MDRD) equation and a recently proposed BTP-based equation (referred to as 'White equation'). The best-performing BTP formula was found to be: GFR = 89.85 x BTP(-0.5541)x urea(-0.3018). This equation estimated true GFR virtually without bias (+0.43 mL/min/1.73 m(2), not significant [NS]), while a small, but significant, overestimation was seen for the MDRD formula (+3.43 mL/min/1.73 m(2), p = 0.003). Precision and accuracies within 50% of true GFR (93.1% and 88.2%, respectively) tended to be higher for the BTP formula, but the differences did not reach significance. The White equation overestimated the true GFR by 9.43 mL/min/1.73 m(2)(p = 0.001), and was inferior with respect to precision and 50% accuracy (79.4%). BTP-based GFR calculations are reliable, and may serve as an alternative to the re-expressed MDRD equation.

Cystatin C-based calculation of glomerular filtration rate in kidney transplant recipients.

Cystatin C (Cys C) has been shown to be an alternative marker of renal function. However, estimation of the glomerular filtration rate (GFR) based on Cys C has received little attention. Recently, several Cys C-based equations were developed in different patient cohorts. To date, the benefit of a Cys C-based GFR calculation in patients after renal transplantation (RTx) remains to be elucidated. We compared the diagnostic accuracy of three Cys C-based formulae (Larsson, Hoek, Filler which used an immunonephelometric method) with the results of the Modification of Diet in Renal Disease (MDRD) formula. GFR was measured by means of technetium-diethylenetriamine pentaacetic acid ((99m)Tc-DTPA) clearance in 108 consecutive patients after RTx. Correlation coefficients of all calculated GFR estimates with the true GFR were high but did not differ significantly from one another (0.83-0.87). The MDRD and Filler equations overestimated GFR significantly, whereas the Larsson equation significantly underestimated GFR. Bias of the Hoek formula was negligible. Precision of the Hoek (8.9 ml/min/1.73 m(2)) and Larsson equations (9.6 ml/min/1.73 m(2)) were significantly better than MDRD equations (11.4 ml/min/1.73 m(2); P< or =0.035 each). Accuracy within 30% of real GFR was 67.0 and 65.1% for the MDRD and Filler formulae, and 77.1% for the Larsson and Hoek formulae, respectively. Accuracy within 50% of true GFR for the Hoek formula (97.2%) was better than for the MDRD equations (85.3%). Cys C-based formulae may provide a better diagnostic performance than creatinine-based equations in GFR calculation after RTx.

Calculation of glomerular filtration rate based on cystatin C in cirrhotic patients.

BACKGROUND: Plasma creatinine and creatinine clearance are of limited value for the estimation of renal function in cirrhotics. In these patients, cystatin C (Cys C) has been proposed as an alternative marker of glomerular filtration rate (GFR) and Cys C-based equations for calculation of GFR have been developed in non-cirrhotic patient cohorts. METHODS: We retrospectively analyzed correlation, bias, precision and accuracy of two Cys C-based formulae (Larsson and Hoek) for GFR estimation in comparison with two creatinine-based equations (Cockroft & Gault and MDRD). The Cys C was determined by an immunonephelometric method. The GFR was measured by means of inulin clearance in 44 consecutive patients with liver cirrhosis. RESULTS: On average, inulin clearance was 28.3 (95% CI: 29.2-41.3 ml/min/1.73 m2). Creatinine as well as Cys C-based equations overestimated the true GFR by 105-154%. However, Cys C-based equations showed significantly lower bias and higher precision than the creatinine-based formulae. Correlation and accuracy tended to be better with the Hoek and Larsson equation than with the Cockroft & Gault or MDRD formulae. Hoek and Larsson equations showed a similar diagnostic performance in all statistical procedures. CONCLUSION: Our data suggest a significant improvement of GFR estimation in liver cirrhotics by means of the Cys C-based Hoek and Larsson formulae. However, all estimates remain a crude approximation of true GFR and thus cannot replace gold standard methods.

Intravenous treatment of hyperhomocysteinemia in patients on chronic hemodialysis--a pilot study.

BACKGROUND: Treatment of hyperhomocysteinemia in patients with end-stage renal disease (ESRD) can be performed with the oral application of vitamins. However, this therapy rarely normalizes total homocysteine (tHcy) levels. Frequently, a rebound is observed after the end of treatment. Currently, no data are available about intravenous combination therapy with folic acid, pyridoxine (B6), and cyanocobalamin (B12). METHODS: We conducted a prospective pilot study comprising 13 patients on chronic hemodialysis treatment (63.7+/-4.9 years; 6 female, 7 male) for 27 weeks. The patients received 10 mg folic acid and 100 mg pyridoxine intravenously (IV) after each dialysis plus 1000 microg vitamin B12 IV once a week for 9 weeks. Between weeks 10 and 18 the patients received 10 mg folic acid, 100 mg vitamin B6 once a week, and 1000 microg vitamin B12 bimonthly IV. RESULTS: The therapy regimen decreased tHcy concentration (baseline: 30.5+/-2.2 micromol/L) significantly to 17.4+/-1.2 micromol/L, 15.6+/-1.0 micromol/L, and 16.4+/-0.1 micromol/L after 3, 6, and 9 weeks, respectively (p<0.01 vs. baseline concentration). The maximum reduction (-47.5+/-3.3%) of tHcy concentration was measured after 6 weeks of therapy. During the following maintenance therapy, tHcy-levels did not increase and no rebound of tHcy was detected during follow-up (week 27:16.5+/-1.97 micromol/L). CONCLUSION: The concept of a short, high-dose induction therapy with intravenous folic acid, pyridoxine, cyanocobalamin, and a subsequent low-dose maintenance regimen is effective in the treatment of hyperhomocysteinemia in patients with ESRD.

Cystatin C as an endogenous marker of glomerular filtration rate in renal transplant patients.

BACKGROUND: Serum creatinine is the most common endogenous marker used to estimate the glomerular filtration rate (GFR). However, creatinine depends considerably on muscle mass, and its tubular secretion increases, especially in chronic renal failure. Cystatin C is a 13-kD protease inhibitor which is produced by all nucleated cells and is independent of muscle mass and sex. Cystatin C is eliminated by glomerular filtration and metabolized by proximal tubular cells. Its measurement has been proposed as an alternative and more sensitive marker of GFR than creatinine in patients with slight to moderately decreased GFR. METHODS: We investigated serum cystatin C levels in comparison with creatinine as a single measurement for estimation of GFR in 173 patients after renal transplantation. GFR was calculated as creatinine clearance according to standard equations. RESULTS: Serum creatinine correlated well with cystatin C (r = 0.84; p < 0.0001). No significant differences were obtained for the comparison of the linear correlation of 1/creatinine with creatinine clearance (r = 0.77; p < 0.0001) and for the linear correlation of 1/cystatin C with creatinine clearance (r = 0.73; p < 0.0001). However, we found a significant advantage of cystatin C in detecting a clinical relevant reduction of kidney function (GFR <70 ml/min; p = 0.0047, McNemar test). CONCLUSION: Cystatin C is an alternative marker for the assessment of GFR in renal allograft recipients that may be superior to creatinine.

Renal functional reserve is well maintained in patients with advanced liver cirrhosis and ascites.

BACKGROUND: Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in healthy humans can be induced by amino acid stimulation. The rise in GFR from baseline to maximum is referred to as the renal functional reserve (RFR). Recently, we showed that the RFR is preserved in patients with compensated cirrhosis despite impaired renal function. In the present study, we evaluated RFR in decompensated cirrhotics with ascites. METHODS: Steady-state inulin- and para-aminohippurate (PAH) clearances were performed at rest and during amino acid infusion in 22 patients with decompensated liver cirrhosis and ascites. RESULTS: Baseline GFR and ERPF (means +95% confidence intervals) were: GFR 25.2 (21.1-29.2) ml min(-1), ERPF 266.6 (229.7-303.5). Amino acid infusion significantly increased GFR by 67% (38.3-95.8) to 34.6 (29.2-40.0) ml min(-1) (means + (95% confidence intervals), P < 0.001) and ERPF by 29% (11.9-46.3) to 326.3 (274.1-378.5) ml min(-1) (P = 0.002). Renal vascular resistance dropped by 13.4% (3.3-23.5) from 29.4 (24.8-33.9) mmHg ml(-1) min(-1) to 26.4 (22.0-30.7) mmHg ml(-1) min(-1) (P = 0.036). The improved kidney function was accompanied by a decrease in systemic aldosterone levels (P < 0.05). CONCLUSION: In patients with liver cirrhosis and ascites, amino acid infusion improves kidney function. Trials are warranted to test the long-term effects of amino acid infusions in patients with hepatorenal syndrome.

[Do polymorphisms of the SDF1 and CCR2b genes modify the course of hepatitis C or HIV/HCV co-infection?]. / Beeinflussen Polymorphismen des SDF1- und CCR2b-Gens den Verlauf der Hepatitis C und der HIV/HCV-Koinfektion?

BACKGROUND AND OBJECTIVE: Complementary to the CCR5-Delta32 mutation polymorphisms in the genes of CCR2b (CCR2b-V64 I) and stromal derived factor (SDF)-1 (SDF-1 3'A) affect the course of the human immunodeficiency virus (HIV) infection. While the CCR5-Delta32 mutation is also increased in chronic hepatitis C virus (HCV) infection it is unclear, whether the CCR2b-V64 I and the SDF-1 3'A polymorphisms also are associated with chronic HCV infection. METHODS: We analyzed the frequencies of the CCR2b-V64I and SDF1 - 3'A mutation in patients with HIV/HCV coinfection (n = 130), HIV infection (n = 105), HCV infection (n = 153) and 112 healthy blood donors. We stratified each group into homozygous mutations, heterozygous mutations and homozygous wild types, respectively. The resulting subsets were compared with respect to HIV and HCV loads, CD4 and CD8 cell counts. RESULTS: The mutant SDF1 - 3'A allele was found at 20.3 % frequency in patients with HCV infection and at 20.4 % frequency in patients with HIV/HCV coinfection, respectively. It was present in 27.1 % of the patients with HIV infection and 27.9 % of the healthy controls (not significant). The number of SDF-1 3) A homozygous patients was highest in patients with HIV/HCV coinfection and significantly different compared to the Hardy-Weinberg equilibrium (p = 0.010, chi (2) = 9.15). However, CD4- and CD8-cell counts or viral loads were not affected by this mutation. The frequency of the CCR2b-V64 I allele was similar in all patient groups. However, CCR2b-V64 I heterozygous patients showed HIV loads that were threefold lower than in CCR2b wildtype patients (22.9 x 103 vs. 6.4 x 103 copies/ml, not significant). Furthermore, hepatitis C viral loads were reduced roughly by 30 %. CONCLUSION: These results suggest that the SDF1 - 3'A and CCR2b-V64I mutations do not affect the course of HCV and HIV/HCV infection in the same manner as does the CCR5-Delta32 mutation.

Decreased frequency of HCV core-specific peripheral blood mononuclear cells with type 1 cytokine secretion in chronic hepatitis C.

BACKGROUND/AIM: Since the outcome of hepatitis C infection appears to be correlated with the immune response to the HCV core protein, the aim of this study was to investigate the T cell response to hepatitis C virus core and core-derived antigens. METHODS: As this response may be regulated importantly by differential secretion of cytokines, we determined the number of peripheral blood mononuclear cells (PBMC) that secreted IL-2, IL-4, IL-10, and IFN-gamma in response to a recombinant HCV core protein and a panel of 19 core-derived peptides, using the ELI-Spot-technique. Two groups of patients were studied: group A: 11 patients with previously self-limited HCV infection; group B: 12 patients with chronic hepatitis C. RESULTS: In group B significantly less IFN-gamma spot forming cells (SFC) could be detected, both after stimulation with the core protein (0.083+/-0.083 SFC vs. 1.3+/-0.4 SFC/10(5) PBMC; p = 0.005 and with the core-derived peptides (1.3+/-0.5 vs. 4.4+/-1.1 SFC SFC/10(5) PBMC; p = 0.007). By analyzing the cytokine response to each single peptide, we found IFN-gamma responses to peptides aa 39-63 and aa 148-172 in group A but not in group B (p<0.03). In group B also, fewer IL-2 secreting cells were found after peptide stimulation (p = 0.04). Whereas subjects of group B showed IL-10-specific responses to HCV peptides more frequently than patients with self-limiting hepatitis C (p = 0.03), the number of IL-4-producing cells was not different between the two groups. CONCLUSIONS: The data suggest that patients with persistent viremia and chronic liver disease (group B) have less PBMC showing type 1 cytokine (IL-2, IFN-gamma) responses to HCV core protein than patients with self-limited HCV infection (group A).

Antigen-specific cytokine response to hepatitis C virus core epitopes in HIV/hepatitis C virus-coinfected patients.

OBJECTIVE: Epidemiological data indicate that hepatitis C virus (HCV) infection runs a more rapid and severe course of disease in HIV-coinfected patients, probably because of an altered immune response. DESIGN: We investigated whether HCV-specific cytokine responses are affected by HIV coinfection. METHODS: Using triple colour flow cytometry on peripheral blood lymphocytes after stimulation with the four major immunodominant HCV core T cell epitopes, CT1-CT4, we determined intracytoplasmic production of IFN-gamma, IL-2, IL-4, IL-10 and CD30 expression, a putative surrogate marker of type 2 cells. Fifteen patients with asymptomatic HIV/HCV coinfection (group A), 15 patients with chronic HCV infection (group B) and 10 HIV-infected patients without hepatitis C (group C) were included in the study. RESULTS: In group A, HCV antigens induced significantly higher IL-2 and IFN-gamma production than groups B and C (P < 0.05). Groups A and B showed a similar induction of CD30, which was significantly higher than in group C (P < 0.001). Remarkably, in group A HCV antigens induced IL-4 production in addition to IL-10 and IFN-gamma in the CD30 subset, whereas in groups B and C no IL-4 induction was observed in this T cell subset (P < 0.002). CONCLUSION: Our data suggest that asymptomatic HIV coinfection importantly alters the HCV-specific cytokine response towards a greater production of proinflammatory type 1 cytokines. Moreover, the antiviral activity of type 1 cytokines may be modified by an increased production of type 2 cytokines in the CD30 subset. The altered cytokine pattern may contribute to the adverse natural course of hepatitis C in HIV coinfection.

Nitrite and nitrate levels in patients with cirrhosis of the liver: influence of kidney function and fasting state.

BACKGROUND: Increased serum nitrite/nitrate (NOx) levels, the stable metabolites of nitric oxide (NO), have been reported in patients with cirrhosis. NOx levels, however, are influenced not only by endogenous NO synthesis but also by urinary NOx excretion and dietary intake. We attempted to elucidate factors that influence NOx levels independently of endogenous NO production and to determine the conditions under which NOx levels reflect endogenous production in patients with cirrhosis and healthy controls. METHODS: NOx serum concentrations and urinary NOx excretion were determined by means of the Griess reaction in relation to Child-Pugh score, kidney function, fasting state, and after exposure to tap water. RESULTS: Multifactor regression analysis showed inulin clearance (P = 0.0074) and Child-Pugh score (P = 0.0001) to be independent factors predicting NOx levels in patients with cirrhosis. NOx serum levels correlated negatively with the inulin clearance (P < 0.0001), which deteriorated with progressive loss of liver function. NOx levels decreased by about 30% within a 24-h fasting period. After 24 h fasting urinary NOx excretion was not significantly increased in patients with advanced cirrhosis. CONCLUSION: NOx serum levels, taken as a surrogate for endogenous NO formation, have to be viewed with caution in patients with cirrhosis because they often have impaired kidney function. However, in steady-state conditions after an adequate fasting period NOx levels might be good prognostic markers in patients with cirrhosis since they reflect two possible sequelae of liver insufficiency-namely, increased NO formation and impaired kidney function.

Changing role of invasive aspergillosis in AIDS--a case control study.

OBJECTIVE: From December 1993 until January 1996 we observed 10 cases of invasive aspergillosis in a cohort of 140 patients with AIDS (7%). By contrast, no invasive aspergillosis was diagnosed in a cohort of 278 patients with AIDS between 1986 until 1993. METHODS: Case controls were assigned randomly to each patient with invasive aspergillosis from the total pool of HIV-infected patients. Patients with invasive aspergillosis were studied retrospectively by matched-pairs analysis with respect to risk factors, radiological, microbiological and autopsy findings. RESULTS: Patients with aspergillosis had more AIDS-defining events (3.5 [2-5] vs. 2 [2-3], median [range], P < 0.05) and a longer median survival time with full-blown AIDS (31.5 [14-45] months vs. 20.5 [5-32] months, P < 0.005) than their case controls. Patients with invasive aspergillosis tended to have lower white blood cell counts and exhibited significantly decreased median CD4 counts (7 [0-44]/mm3 vs. 27 [8-57]/mm3, P < 0.05). CONCLUSIONS: Due to better management of opportunistic diseases and improved antiretroviral therapy, the lifespan of patients with full blown AIDS is prolonged. Patients who have survived four or more AIDS-defining events are at risk for invasive aspergillosis. This risk is associated with low white blood cell counts and CD4 cell counts.

In vitro cytopathogenicity of the human immunodeficiency virus (HIV)-1 predicts survival in HIV-infected hemophiliacs independent from CD4 cell count.

In addition to quantification of viral load the graded cytopathogenicity of the human immunodeficiency virus may provide prognostic information for the course of HIV infection. However, the prognostic value of graded cytopathogenicity in addition to the CD4 count has not been evaluated in a large longitudinal study. Therefore a total of 216 HIV-seropositive hemophiliacs have been followed up from 1985 to 1998 (mean follow-up 70.4 +/- SD 26 months, median 72, range: 12 to 120 months). In vitro virulence was determined according to cytopathic effects on freshly isolated PBMC of healthy donors and graded from A (strongest cytopathogenic effect) to D (no cytopathic isolate effect). Survival was analyzed among patients with different virus isolates by Kaplan-Meier statistics (log rank) and factors independently associated with decreased survival were analyzed by Cox hazard regression analysis. - A virus isolate A was found in 22 (10.2%) patients, a virus isolate B was found in 21 (9.3%) patients, a virus isolate C was found in 9 (4.2%) and a virus isolate D was found in 10 (4.2%) patients. Mean survival times were 48 months (95% Confidence Interval (CI) = 36 - 60) in patients with isolate A, 72 months (CI = 36 - 108) with isolate B, 84 months (CI = 48-120) with isolate C, 72 months (60 - 96) with isolate D and 96 months (CI = 96 - 108) in patients with a negative virus culture (p < 0.001). Cox regression analysis indicated significant associations with outcome for young age (p <0.001), positive virus culture (p < 0.0001) and CD4 count (p < 0.0001) as independent predictors of survival. The presence of an isolate A revealed the strongest odds ratio (6.3, 95% CI 2.9-13.2). Our data indicate that the presence of a virus isolate A represents a strong risk factor for mortality in the course of HIV infection. Besides quantification of viral load and CD4 count, the graded cytopathogenicity may provide additional information for early and aggressive antiretroviral treatment, since the mean survival in patients with cytopathogenic virus isolates is reduced significantly.

Human immunodeficiency virus and hepatitis C virus coinfection.

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) share the same parenteral, sexual and vertical routes of transmission (McNair et al. 1992). This common epidemiology explains the high frequency of combined infections by hepatotropic viruses in HIV-infected patients. The aim of the present review is to clarify some important issues dealing with the reciprocal interactions between HIV and hepatitis C virus infections. The main topics include epidemiology, virological markers of HIV-infection, histopathology, natural course and treatment of hepatitis C in HIV-infected individuals.