Farid Nakhoul

Haptoglobin: Basic and Clinical Aspects

Haptoglobin is an abundant hemoglobin-binding protein present in the plasma. The function of haptoglobin is primarily to determine the fate of hemoglobin released from red blood cells after either intravascular or extravascular hemolysis. There are two common alleles at the Hp genetic locus denoted 1 and 2. There are functional differences between the Hp 1 and Hp 2 protein products in protecting against hemoglobin-driven oxidative stress that appear to have important clinical significance. In particular, individuals with the Hp 2-2 genotype and diabetes mellitus appear to be at significantly higher risk of microvascular and macrovascular complications. A pharmacogenomic strategy of administering high dose antioxidants specifically to Hp 2-2 DM individuals may be clinically effective.

Haptoglobin phenotype and vascular complications in patients with diabetes.

To the Editor: Vascular complications cause serious morbidity in patients with diabetes mellitus. Two such complications are diabetic nephropathy and restenosis after percutaneous transluminal coro...

Pulmonary hypertension is an independent predictor of mortality in hemodialysis patients

Pulmonary hypertension in patients with end-stage renal disease on hemodialysis is a newly described entity. To determine its impact, we measured selected clinical variables in the survival of 127 hemodialysis patients. Overall, pulmonary hypertension was found in 37 of these patients; it was already prevalent in 17 of them before initiation of dialysis and was associated with severe cardiac dysfunction. In the other 20 it developed after dialysis began, without obvious cause. These two subgroups of patients had similar survival curves, which were significantly worse in comparison to those without pulmonary hypertension. Following the initiation of hemodialysis, 20 patients with otherwise matched clinical variables survived significantly longer than the 20 who developed pulmonary hypertension after dialysis began. With univariate analysis, significant hazard ratios were found for age at onset of hemodialysis therapy (1.7), valvular diseases (1.8), pulmonary hypertension prevalence before hemodialysis (3.6) and incident after hemodialysis (2.4) for predicting mortality. In a multivariable Cox proportional hazard model, the development of pulmonary hypertension both before and after initiation of hemodialysis had significantly increased odds ratios and remained an independent predictor of mortality. Our study shows the incidence of pulmonary hypertension, after initiation of hemodialysis therapy, is a strong independent predictor of mortality nearly equal to that associated with long-standing severe cardiac abnormalities.

Pulmonary Hypertension in Hemodialysis Patients: An Unrecognized Threat

Pulmonary hypertension (PH) is a progressive, fatal pulmonary circulatory disease that accompanies many conditions (including left to right side shunt) with compensatory elevated cardiac output. PH also complicates chronic hemodialysis (HD) therapy immediately after the creation of an arteriovenous (AV) access, even before starting HD therapy. It tends to regress after temporary AV access closure and after successful kidney transplantation. Affected patients have significantly higher cardiac output. This syndrome is associated with a statistically significant survival disadvantage. The laboratory hallmark of this syndrome is reduced basal and stimulatory nitric oxide (NO) levels. It appears that patients with end‐stage renal disease (ESRD) acquire endothelial dysfunction that reduces the ability of their pulmonary vessels to accommodate the AV access‐mediated elevated cardiac output, exacerbating the PH. Doppler echocardiographic screening of ESRD patients scheduled for HD therapy for the occurrence of PH is indicated. Early diagnosis enables timely intervention, currently limited to changing dialysis modality or referring for kidney transplantation.

Pulmonary hypertension in chronic dialysis patients with arteriovenous fistula: pathogenesis and therapeutic prospective

Purpose of reviewEnd-stage renal disease patients receiving chronic haemodialysis via arteriovenous access often develop various cardiovascular complications, including vascular calcification, cardiac-vascular calcification and atherosclerotic coronary disease. This review describes recently published studies that demonstrate a high incidence of pulmonary hypertension among patients with end-stage renal disease receiving long-term haemodialysis via a surgical arteriovenous fistula. Both end-stage renal disease and long-term haemodialysis via arteriovenous fistula may be involved in the pathogenesis of pulmonary hypertension by affecting pulmonary vascular resistance and cardiac output. Recent findingsMorbidity and mortality from cardiovascular disease are greatly increased in patients on maintenance haemodialysis therapy. Using Doppler echocardiography, we found a significant increase in cardiac output in 40% of chronic haemodialysis patients, probably related to the large arteriovenous access or altered vascular resistance as a result of the local vascular tone and function expressed by the imbalance between vasodilators such as nitric oxide, and vasoconstrictors such as endothelin-1. SummaryWe propose different potential mechanisms as explanations for the development of pulmonary hypertension. Hormonal and metabolic derangement associated with end-stage renal disease might lead to pulmonary arterial vasoconstriction and an increase in pulmonary vascular resistance. Pulmonary arterial pressure may be further increased by high cardiac output resulting from the arteriole–venous access itself, worsened by commonly occurring anaemia and fluid overload.

Gold nanoparticle sensors for detecting chronic kidney disease and disease progression

AIM To study the feasibility of a novel nanomedical method that utilizes breath testing for identifying chronic kidney disease (CKD) and disease progression. MATERIALS & METHODS Exhaled breath samples were collected from 62 volunteers. The breath samples were analyzed using sensors based on organically functionalized gold nanoparticles, combined with support vector machine analysis. Sensitivity and specificity with reference to CKD patient classification according to estimated glomerular filtration rate were determined using cross-validation. The chemical composition of the breath samples was studied using gas chromatography linked with mass spectrometry. RESULTS A combination of two to three gold nanoparticles sensors provided good distinction between early-stage CKD and healthy states (accuracy of 79%) and between stage 4 and 5 CKD states (accuracy of 85%). A single sensor provided a distinction between early and advanced CKD (accuracy of 76%). Several substances in the breath were identified and could be associated with CKD-related biochemical processes or with the accumulation of toxins through kidney function loss. CONCLUSION Breath testing using gold nanoparticle sensors holds future potential as a cost-effective, fast and reliable diagnostic test for early detection of CKD and monitoring of disease progression.

Diagnosis and Classification of 17 Diseases from 1404 Subjects via Pattern Analysis of Exhaled Molecules

We report on an artificially intelligent nanoarray based on molecularly modified gold nanoparticles and a random network of single-walled carbon nanotubes for noninvasive diagnosis and classification of a number of diseases from exhaled breath. The performance of this artificially intelligent nanoarray was clinically assessed on breath samples collected from 1404 subjects having one of 17 different disease conditions included in the study or having no evidence of any disease (healthy controls). Blind experiments showed that 86% accuracy could be achieved with the artificially intelligent nanoarray, allowing both detection and discrimination between the different disease conditions examined. Analysis of the artificially intelligent nanoarray also showed that each disease has its own unique breathprint, and that the presence of one disease would not screen out others. Cluster analysis showed a reasonable classification power of diseases from the same categories. The effect of confounding clinical and environmental factors on the performance of the nanoarray did not significantly alter the obtained results. The diagnosis and classification power of the nanoarray was also validated by an independent analytical technique, i.e., gas chromatography linked with mass spectrometry. This analysis found that 13 exhaled chemical species, called volatile organic compounds, are associated with certain diseases, and the composition of this assembly of volatile organic compounds differs from one disease to another. Overall, these findings could contribute to one of the most important criteria for successful health intervention in the modern era, viz. easy-to-use, inexpensive (affordable), and miniaturized tools that could also be used for personalized screening, diagnosis, and follow-up of a number of diseases, which can clearly be extended by further development.

Reviews: Pathophysiology and Clinical Implications of Microbubbles during Hemodialysis

Microbubbles have been detected in the human circulation of end‐stage renal disease patients who are treated by hemodialysis throughout the past decade as a result of advanced ultrasound and Doppler technology. These detection tools uncovered signals of microbubbles, which originate in extracorporeal lines and tubing of hemodialysis machine, circulate in the blood stream until lodging in the capillary bed of various organs, mainly the lungs. During its course within the capillary, a bubble abrades the glycocalyx layer lining the surface of the vessels and thereafter obstructs blood flow through the capillary. This causes tissue ischemia, inflammatory response, and complement activation. Aggregation of platelets and clot formation occurs as well, leading to further obstruction of the microcirculation and subsequent tissue damage. In this review, we describe the biological and clinical effects of microbubbles during hemodialysis and discuss management with regard to prevention and treatment.

Pharmacogenomic effect of vitamin E on kidney structure and function in transgenic mice with the haptoglobin 2-2 genotype and diabetes mellitus

Polymorphic loci regulating oxidative stress are potential susceptibility genes for diabetic nephropathy (DN). Haptoglobin (Hp) is an antioxidant protein which serves to protect against oxidative stress induced by extracorpuscular hemoglobin. There are two alleles at the Hp locus, 1 and 2. The Hp 1 protein is a superior antioxidant to the Hp 2 protein. The Hp 2 allele has been associated with increased prevalence of DN and appears to be associated with a more rapid progression to end-stage renal disease. We sought to recapitulate this association between Hp genotype and DN in mice genetically modified at the Hp locus. We assessed morphometric, histologic, and functional parameters involved in the development and progression of DN in mice with diabetes mellitus (DM) with either the Hp 2-2 or Hp 1-1 genotype. Morphometric analysis demonstrated that glomerular and proximal tubular hypertrophy were significantly increased in Hp 2-2 DM mice. Histological analysis demonstrated that Hp 2-2 DM mice had significantly more collagen type IV, smooth muscle actin, and increased renal iron deposition. Studies of renal function demonstrated creatinine clearance time and albuminuria were increased in Hp 2-2 DM mice. Vitamin E provided significant protection against the development of functional and histological features characteristic of DN to Hp 2-2 DM but not to Hp 1-1 DM mice. These studies serve to strengthen the association between the Hp 2-2 genotype and diabetic renal disease and suggest a pharmacogenomic interaction may exist between the Hp genotype and vitamin E.

Retinal capillary basement membrane thickness in diabetic mice genetically modified at the haptoglobin locus

Individuals with diabetes mellitus (DM) homozygous for the haptoglobin (Hp) 1 allele are at decreased risk of retinopathy as compared to DM individuals with the Hp 2 allele. We sought to recapitulate these findings in DM mice genetically modified at the Hp locus.