Rubin Zhang

Obesity-hypertension: the effects on cardiovascular and renal systems

Longitudinal and cross-sectional studies suggest that a large number of obese patients have a high prevalence of hypertension. This association causes the following changes: insulin and leptin resistance with a suppressed biologic activity of natriuretic peptide, which contributes to sodium retention with concomitant expanded cardiopulmonary volume and increased cardiac output. The cellular metabolism of cations may be altered in obesity and may lead to changes in vascular responsiveness and increased vascular resistance. These changes lead to structural adaptations in the heart characterized by concentric-eccentric left ventricular hypertrophy. The hypertrophic condition provides the basis for the development of congestive heart failure and cardiac arrhythmias that may explain the higher rates of cardiac sudden death in those patients. In the kidneys, obesity hypertension may initiate a derangement of renal function. The increased deposit of interstitial cells and of extracellular matrix between the tubules induces higher interstitial hydrostatic pressure and tubular sodium reabsorption. The consequent increase in renal flow and glomerular filtration enhances albuminuria excretion and the susceptibility to the development of renal damage. In summary, the hemodynamic and structural adaptations related to obesity hypertension is the cause of greater risk for adverse cardiovascular and renal events.

Hypertension and the Metabolic Syndrome

The cause of hypertension in the metabolic syndrome is complex and multifactorial and all of the elements of the metabolic syndrome, including obesity, insulin resistance, and the characteristic dyslipidemia probably are involved in mediating changes ultimately resulting in hypertension and modifying its course. Of these elements, obesity may play the most important and pivotal role in creating the conditions that lead to hypertension in the metabolic syndrome. This is not to say that the other elements of the syndrome are less important, and, as we gain more insight into the processes involved, we should be able to better manage the disease and tailor our therapeutic interventions appropriately.

Kidney transplantation: The evolving challenges

Kidney transplantation is the treatment of choice for patients with end stage renal disease. Kidney transplantation not only improves the quality of life but also prolongs life. Over the last decade, the short-term allograft survival rate has been improved dramatically. Chronic allograft nephropathy and death from cardiovascular diseases become predominant causes of later graft loss. Prevention and treatment of these disease processes require a comprehensive approach. The ever-increasing shortage of organ supply becomes the greatest challenge for the transplant community and modern medicine. More and more patients are waiting for organs; many of them are dying while waiting. Xenotransplantation and organ engineering and cloning are promising techniques and can potentially provide organs for transplantation in the future.

Hypertension after Kidney Transplantation: Impact, Pathogenesis and Therapy

Hypertension (HTN) contributes to the high incidence of cardiovascular disease mortality as well as chronic allograft nephropathy (CAN) and late graft failure in renal transplant recipients. The mechanisms are complex and may involve pathogenic factors attributable to the host, allograft, and immunosuppressive drugs. Calcium channel blockers should be used to ameliorate the nephrotoxicity of calcineurin inhibitors in the early years after transplantation. Angiotensin-converting enzyme inhibitors and angiotensin-2 type-1 receptor blockers are safe and effective, have antiproteinuric effects, slow the progression of CAN, and may provide survival benefits. Diuretics and/or beta-adrenergic receptor blockers are frequently added in combination regimen. Appropriate adjustment of the immunosuppressive drugs should also be considered for the long-term care of kidney recipients with HTN.

Kidney disease and the metabolic syndrome

The epidemic of metabolic syndrome contributes to the rapid growth of cardiovascular and renal diseases. Hyper-hemodynamics, impaired pressure natriuresis, excess excretory load, insulin resistance, endothelial dysfunction, chronic inflammation, and prothrombotic status individually and interdependently initiate renal injury in metabolic syndrome. The prevention and treatment of kidney disease require a multifactorial approach. Weight loss through diet control and exercise can reverse many pathophysiologic processes. Pharmacologic intervention includes insulin sensitizers, tight glycemic and lipid control, blockage of renin angiotensin aldosterone system, and anti-inflammatory and antithrombotic therapies. Each peroxisome proliferator-activated receptor isoform plays a distinct role in metabolic syndrome, and their agonists may prevent or reverse the early renal injuries.

Hypertension in chronic dialysis patients: pathophysiology, monitoring, and treatment.

The prevalence of hypertension in the population with ESRD is very high, approaching 100% in some populations, and may account for the fact that cardiovascular disease continues to be the leading cause of morbidity and mortality in ESRD. The pathophysiology of hypertension in ESRD is reviewed, suggesting multifactorial causes; a dominant cause is that of volume expansion and an inappropriate increase in systemic vascular resistance because of activation of the renin-angiotensin system. The primary goal in the treatment of hypertension should be to attain a dry-weight and maintain volume control through limiting salt and fluid intake and ultrafiltration of excess fluids. If this approach is unsuccessful, an array of antihypertensive medications are available to help control blood pressure in patients with ESRD.

Renal and cardiovascular considerations for the nonpharmacological and pharmacological therapies of obesity-hypertension

Obesity-associated hypertension is a common disease that involves a complex pathogenesis. Failure to control hypertension (HTN) in obese subjects provides a great threat to their renal and cardiovascular functions. The treatment of obesity-associated HTN is often difficult, and requires nonpharmacological and/or pharmacological approaches. Weight reduction is the cornerstone of the therapies of obesity-HTN, as it reverses the multiple components of its pathogenesis. When weight loss cannot be sustained or fails, pharmacological means should then be used. Angiotensin-converting enzyme inhibitors (ACEI) are the drug of choice: they can reduce blood pressure, protect the kidney and heart, and improve the metabolic abnormalities in obese subjects. Angiotensin-2 type-1 receptor blockers have a renoprotective benefit similar to ACEI, and they provide an important alternative to the use of ACEI. Diuretics are very effective in African-American obese hypertensives, but small doses should be used to avoid adverse effects on metabolic profiles. Long-acting calcium channel blockers are also effective and have the advantage of no adverse metabolic effects. Nondihydropyridine calcium channel blockers may provide additional renal and cardiovascular protective effects. The beta-adrenergic receptor blockers can cause further weight gain and metabolic abnormalities in obese subjects; therefore, careful monitoring is needed. There are few clinical data that support the efficacy and benefit of centrally acting alpha-2 agonists and alpha-adrenergic receptor antagonists in the treatment of obesity-HTN.

Tesaglitazar, a Dual Peroxisome Proliferator- Activated Receptor Agonist (PPARα/γ), Improves Metabolic Abnormalities and Reduces Renal Injury in Obese Zucker Rats

Metabolic syndrome increases the risk of developing diabetes as well as cardiovascular and kidney diseases. This research studied the effects of tesaglitazar, a dual-acting peroxisome proliferator-activated receptor (PPAR)α/γ agonist, on metabolic abnormalities and kidney injury in obese Zucker rats (OZR). Lean Zucker rats (LZR) and OZR were used as control groups. Tesaglitazar (1 µmol/kg/day) was given for 8 weeks in the treatment group (OZR-T). Metabolic parameters, 24-hour urine albumin excretion, and tail blood pressure were measured. Glomerular filtration rate by inulin clearance, abdominal fat and renal histology were determined at the end of the study. In comparison with the OZR and OZR-T groups, the LZR control animals’ parameters were significantly more favorable in all measures. Tesaglitazar treatment in OZR significantly reduced nonfasting glucose, C-reactive protein levels and improved dyslipidemia. Body weight, blood pressure and urine albumin excretion were lower, but the adjusted glomerular filtration rate higher, in the OZR-T group than in the OZR controls. Glomerular area, mesangial expansion and tubulointerstitial changes were ameliorated, and the glomerular expression of desmin was markedly more decreased in the OZR-T group than in the OZR controls. Therefore, the PPARα/γ agonist tesaglitazar significantly improved metabolic abnormalities and renal function, decreased blood pressure, and protected against glomerular and interstitial damage in OZR.