CASE PRESENTATIONS
Patient 1
A 65-year-old black woman came to the emergency room of Jackson Memorial Hospital complaining of shortness of breath and leg swelling of 1-month duration. Her physician had retired and she had not been seen by a doctor in 5 years. She presented with a history of dyspnea on minimal exertion, two-pillow orthopnea, and paroxysmal nocturnal dyspnea. There was no history of chest pain, myocardial infarction, or diabetes mellitus. She had quit smoking 10 years previously. She had no family history of coronary artery disease, but a younger brother had hypertension and renal failure and was receiving dialysis.
The patient's height was 5 feet 2 inches and her weight was 150 pounds. Blood pressure was 170/100 mm Hg; pulse, 100 beats/min and regular; and respirations, 28 breaths/min. On physical examination, she appeared to be in moderate respiratory distress. Funduscopic examination showed arteriovenous nicking. An S3 and S4 gallop were heard on cardiac auscultation. The point of maximal impulse (PMI) was felt in the sixth intercostal space. Lung examination revealed bibasilar dullness to percussion and rales halfway up bilaterally. The abdomen was soft, with mild tenderness on deep palpation of the right upper quadrant and no masses. The liver was three fingerbreadths below the costal margin. The extremities were warm, with palpable pulses and 2+ pitting edema below the knees.
Laboratory studies revealed a serum creatinine of 6.9 mg/dL and a blood urea nitrogen (BUN) of 107 mg/dL. The serum sodium was 137 mmol/L; potassium, 5.2 mmol/L; chloride, 98 mmol/L; and bicarbonate, 17 mmol/L. The total cholesterol was 160 mg/dL; high-density lipoprotein cholesterol (HDL-C), 44 mg/dL; low-density lipoprotein cholesterol (LDL-C), 96 mg/dL; and triglycerides, 160 mg/dL. The findings on an electrocardiogram indicated left-ventricular hypertrophy (LVH). A chest radiograph showed cardiomegaly, bilateral pleural effusions, and pulmonary vascular redistribution. A renal ultrasound demonstrated bilaterally small, echogenic kidneys with no obstruction. An echocardiogram revealed concentric LVH and an ejection fraction of 35%. The urinalysis showed 3+ protein and 2 to 5 red blood cells, 10 to 20 white blood cells, and 1 to 2 granular casts per high-power field. The 24-hour urinary protein excretion was 2.5 g. Creatinine clearance was 7 mL/min. The hemoglobin was 8.5 g/dL; hematocrit, 25%; and glucose, 102 mg/dL.
Treatment was initiated with furosemide, amlodipine, and metoprolol. After diuresis, the orthopnea and the paroxysmal nocturnal dyspnea improved, and the blood pressure decreased to 160/95 mm Hg. The chest radiograph findings also improved. However, the pedal edema persisted. It was decided that the patient had chronic renal failure secondary to hypertension and that placement of an arteriovenous fistula for hemodialysis was indicated. The patient was discharged after she was instituted on a sodium- and potassium-restricted diet and was scheduled to return to the outpatient clinic in 1 week for follow-up and further control of blood pressure.
Patient 2
A 50-year-old woman was referred to the Franz Volhard Clinic in Berlin for the evaluation of arterial hypertension1. At that time, she was taking no antihypertensive medications. The condition had been diagnosed when she was 15 years old, but no treatment had been initiated. At age 31, her blood pressure increased precipitously during her only pregnancy, which nevertheless culminated in the otherwise uncomplicated delivery of a daughter. Subsequently, a variety of medications only modestly controlled the patient's blood pressure. Seven years ago, an extensive evaluation was performed at another hospital, but control of her blood pressure was not achieved. Her only complaints were occasional nausea, headache, and lightheadedness. She denied dyspnea on exertion, chest pain, or visual disturbances. There was no history of cerebrovascular or cardiovascular disease. The rest of her medical history was unremarkable, with the exception of brachydactyly. A geneticist at another university had seen her when she was 27 years old, and type E brachydactyly was diagnosed. No connection between the brachydactyly and hypertension was made at that time.
The patient was born in Silesia (Poland). Her mother also had had brachydactyly, as did other members of the family. Her brother, the sole sibling, did not have brachydactyly. Since moving to Germany, she had no further contact with any of her family members. Her daughter's development apparently was normal. The patient could give no information regarding the daughter's blood pressure, or even whether the blood pressure had ever been measured.
The patient was 157 cm tall and weighed 47 kg. Her blood pressure was 280/160 mm Hg; pulse, 80 beats/min and regular; and respirations, 16 breaths/min. The physical examination, with the exception of short stature and brachydactyly, was unremarkable. Funduscopic examination disclosed no hemorrhages or exudates. The heart was not palpably enlarged. She had no cardiac murmurs or gallops. The lungs were clear to auscultation. No bruits were heard over any vessels.
Laboratory examination showed normal blood count, urinalysis, and serum chemistries, including electrolytes. The creatinine clearance was 76 mL/min; sodium excretion, 122 mmol/day; potassium excretion, 38 mmol/day; and calcium excretion, 1.3 mmol/day. Plasma renin activity and plasma aldosterone (supine posture) were 14 ng/mL/hour and 666 pg/mL, respectively; the urinary aldosterone excretion was 16.7 
g/day. Bilateral adrenal vein aldosterone sampling revealed no lateralization. Plasma and urinary norepinephrine values were normal. The renal and adrenal ultrasound examinations were normal. An echocardiogram disclosed moderate concentric LVH without diastolic dysfunction and with a preserved ejection fraction. A 24-hour ambulatory blood pressure measurement confirmed severe hypertension; however, the nocturnal blood pressure decrease was preserved. Her blood pressure was successfully reduced with hydrochlorothiazide, triamterene, amlodipine, enalapril, and carvedilol. She did not return to the clinic and was lost to follow-up.
DISCUSSION
DR. LEOPOLDO RAIJ (Professor of Medicine, Director of Hypertension, Nephrology-Hypertension Division; Vice Chair, Vascular Biology Institute; University of Miami School of Medicine; Chief, Nephrology-Hypertension Section, Veterans Affairs Medical Center, Miami, Florida): I have chosen this case from our own hospital to contrast with a case presented at a Nephrology Forum 2 years ago by Dr. Freidrich Luft1. Although both patients presented with severe hypertension, end-organ injury differed dramatically in each. We will use these patients to analyze the factors that I believe affect the relationships between hypertension and end-organ damage. The prevalence of renal failure, LVH, and stroke, the major causes of morbidity and mortality in hypertension, varies between 10% and 40% in different populations of hypertensives2. A recent study reported the relationship between blood pressure and mortality due to coronary artery disease (CAD) independently of smoking and hypercholesterolemia among men worldwide3. In this 25-year follow-up, the investigators found that the relative increase in mortality from CAD for a given increase in blood pressure was similar among the populations of different countries. However, the actual rates of mortality for CAD were higher in northern Europe and the United States compared with Japan and Mediterranean southern Europe. This study documents striking variations of end-organ disease in humans with hypertension of similar severity, alterations that might be conditioned by genetic as well as environmental factors3. My thesis is that end-organ damage results from end-organ susceptibility, which is conditioned by genetic factors and often modified by environmental factors. During my discussion I will particularly focus on abnormalities that affect glomerular regulation of flows and pressures and on abnormalities that might affect inflammatory responses elicited in response to injury induced by the hemodynamic stress of hypertension.
The angiotensin II–nitric oxide axis in hypertension
Three major factors participate in the pathogenesis of hypertension via the angiotensin II-nitric oxide axis: abnormal vascular tone, alterations in salt and volume regulation, and remodeling of the vessel wall resulting in a reduction of the lumen-to-wall ratio4,5.
Angiotensin II (Ang II) is a powerful vasoconstrictor with pleiotropic actions, including stimulation of growth-promoting responses as well as production of reactive oxygen species6. In the kidney, the vasoconstrictor effect of Ang II is particularly effective at the level of the mesangium and the efferent arteriole4,5,6. The effect of Ang II in the afferent arteriole is diminished by the vasodilatory effect of nitric oxide (NO)7 as well as molecules synthesized via the cytochrome P-450-dependent pathway8. Nitric oxide appears to be a more effective modulator of Ang II-mediated vasoconstriction in cortical than in medullary nephrons.
Most of the actions of Ang II are systematically antagonized by NO9Figure 1. Nitric oxide is a vasodilator with anti-growth and anti-thrombogenic activity that plays important roles in maintaining the homeostasis of the vascular wall and preventing damage of end organs. The production of NO is continuous, thereby imparting a constant vasodilatory effect, which contributes to maintaining a resting vascular tone4. On the other hand, Ang II production is not as constant, and its physiologic role is sustaining vascular tone in response to a decrease in blood volume and/or renal perfusion pressure10.
Figure 1.
Nitric oxide-angiotensin II (Ang II)-endothelin-1 (ET-1)-aldosterone interactions. Abbreviations are: 
, superoxide anion; MC, mesangial cells; VSMC, vascular smooth muscle cell; AT1, Ang II type 1 receptor; AT2, Ang II type 2 receptor; ACE, angiotensin-converting enzyme; 
, inhibition; ---
, upregulation (from9, with permission).
Nitric oxide might have a regulatory role in salt excretion by directly decreasing tubular sodium reabsorption and increasing renal medullary blood flow. Angiotensin II is predominantly antinatriuretic; it increases tubular sodium reabsorption and modulates the feedback regulation of renin release at the macula densa4,11. Synthesis of endothelin-1, a powerful vasoconstrictor, is up-regulated by Ang II and down-regulated by NO.
Angiotensin II affects growth-related processes directly and indirectly by means of synthesis of growth factors such as transforming growth factor-
(TGF-) and platelet-derived growth factor12. But NO down-regulates TGF- and is an important inhibitor of growth-related responses in mesangial cells, vascular smooth muscle cells, and extracellular matrix13. Nitric oxide is a powerful inhibitor of platelet aggregation and of the expression of adhesion molecules that participate in vascular inflammatory responses. Also, NO down-regulates the synthesis of both angiotensin II-converting enzyme (ACE) as well as the synthesis of angiotensin type 1 receptors14. Furthermore, inhibition of NO synthesis increases synthesis of Ang II and ACE in the kidney as well as in the aorta15. The interaction between NO and endothelin-1, however, appears to be more important under pathologic than physiologic conditions9,16.
Angiotensin II's ability to activate NADH/NADPH oxidases has received much attention. Angiotensin II drives the production of superoxide anion by activating NADH/NADPH oxidases present in vascular smooth muscle, endothelial and mesangial cells, and aortic adventitial fibroblasts17,18,19. Superoxide anion () activates mitogen-activated protein (MAP) kinases and leads to vascular smooth muscle and mesangial cell hypertrophy as well as hyperplasia19. Superoxide anion has very high affinity for NO, and the interaction of superoxide and NO generates peroxynitrite, which is by itself a powerful oxidant molecule. Peroxynitrite induces release of zinc from the zinc-thiolate center of nitric oxide synthase (NOS), which results in NOS functional uncoupling due to a shift of this enzyme from its dimeric form to a monomeric form20. Paradoxically, a dysfunctional NOS produces more
than NO and initiates a vicious circle that maintains increased
production and decreased bioactivity of NO20.
Vascular remodeling is an active process of adaptation of the vascular beds to the hemodynamic workload imposed by hypertension21,22. In vessels, it is characterized by changes in the media-to-lumen ratio, and in the glomerulus by an increase in size and number of mesangial cells and/or the amount of mesangial matrix12,13,22,23. In the heart, remodeling produces myocyte hypertrophy and increased matrix21,22. In many patients these adaptive changes are often maladaptive, leading to ischemia to vascular territories, renal failure, LVH, and heart failure, as well as CAD24. The vascular remodeling that occurs in hypertension and atherosclerosis is in part due to the loss of NO bioactivity, which results in a functional imbalance between Ang II and NO Figure 19,21.
What have we learned from experimental studies?
Studies in genetic models of hypertension have greatly contributed to our understanding of the relationship between blood pressure and renal disease2,23,25,26. We performed comparative studies in spontaneously hypertensive rats (SHR) and Dahl salt-sensitive rats (DS)2,22,23. The DS rat is a strain that develops hypertension only when given high dietary salt. Preglomerular resistance does not increase in DS rats that are fed a high-salt diet and become hypertensive, whereas in SHR appropriate autoregulation via an increase in preglomerular resistance prevents glomerular hypertension. We demonstrated that at similar levels of systemic hypertension, glomerular hypertension accompanied by glomerular injury developed in DS rats but not in SHR25Figure 2.
Figure 2.
Glomerular hemodynamic changes in hypertension. Spontaneously hypertensive rats (SHR) have effective preglomerular resistances. Systemic hypertension is not transmitted to the glomeruli and they do not develop glomerulosclerosis. Dahl salt-sensitive rats (DS) have ineffective preglomerular resistances. Systemic hypertension is transmitted to the glomeruli and they develop glomerulosclerosis. (Adapted from25.)
Full figure and legend (309K)Substrains of SHR and Brown Norway rats share a major histocompatibility complex. Thus, transplantation of a kidney from a Brown Norway rat into a uninephrectomized hypertensive SHR does not result in immunologic rejection. The kidney does, however, suffer severe hypertensive injury27. This demonstrates that the kidney of the Brown Norway rat is inherently more susceptible to hypertension-induced damage than is the kidney of SHR. At present, the reasons for this susceptibility are not known. Fawn-hooded rats are genetically hypertensive and develop glomerular injury. In response to an increase in perfusion pressure, these rats have an impaired ability to increase preglomerular resistance. The deficit is myogenic in origin and is already present during the prehypertensive stage in these rats26,28.
In glomerular hypertension, the endothelium and mesangium are the most vulnerable glomerular structures22. Studies by Lee et al suggested that endothelial cell injury initiates glomerulosclerosis in response to hypertensive glomerular damage and that the process involves local upregulation of Ang II synthesis that increases expression of TGF- and matrix proteins29.
Glomerular hyperfiltration is an early manifestation of diabetic nephropathy, which is linked to a decrease in preglomerular resistances30. However, only 20% to 30% of patients with insulin-dependent diabetes mellitus (IDDM) develop nephropathy30,31. It is tempting to speculate that the genetic susceptibility for renal disease in IDDM is in part linked to a genetically conditioned impairment in renal autoregulation, which is aggravated by the diabetic milieu. Indeed, recent studies have demonstrated that in hypertensive DS rats, but not in either normotensive DS rats or hypertensive SHR rats, up-regulation of the glucose transporter GLUT-1 is linked to a concomitant up-regulation of TGF-32. Also, an increased number of GLUT-1 results in increased glucose transport into mesangial cells, even in the presence of normoglycemia; both mesangial intracellular increase in glucose as well as TGF- up-regulate the synthesis of matrix protein, including collagen and fibronectin, which are harbingers of glomerulosclerosis. These studies clearly establish a previously unrecognized link between hemodynamic factors (glomerular hypertension) and biochemical metabolic factors (glucose)32. Furthermore, these studies would explain the sensitivity to hypertensive injury of the diabetic kidney as well as the beneficial effect of ACE inhibitors and Ang II receptor blockers, which reduce glomerular pressure and concomitantly inhibit the nonhemodynamic effects of Ang II, including suppression of TGF-12,33.
The antagonistic interaction between NO and Ang II is particularly evident in the kidney. Experimentally, inhibition of NO synthesis increases the expression and up-regulates the synthesis of ACE and Ang II14,15. In the glomerulus, a shift in the balance between NO and Ang II toward the latter can affect mesangial function and disturb the glomerular microcirculation by causing a decrease in the glomerular ultrafiltration coefficient. More important, mesangial cells respond to Ang II by increasing
production19, which within the glomerulus further decreases the bioactivity of NO, generates peroxynitrite, fosters mesangial cell hypertrophy, and increases mesangial matrix, a harbinger of glomerular sclerosis22.
Blood flow to the renal tubules and the renal interstitium is postglomerular; thus obliteration of glomerular capillaries due to hypertensive injury produces tubulointerstitial ischemia34. Proteinuria, a manifestation of glomerular injury, can further aggravate tubulointerstitial injury and inflammation35. The importance of inflammation in amplifying hemodynamically initiated renal injury was clearly shown in studies of hypertensive mice with complement deficiency. Indeed, those studies showed that hypertension induced by deoxycorticosterone acetate (DOCA) and salt resulted in dramatically less glomerular and tubulointerstitial disease in mice deficient in the fifth component of the complement system (C5) compared with similarly hypertensive congenic mice, in which levels of the fifth component of the complement are normal36Figure 3. Mice deficient in C5 cannot assemble the membrane attack complex (MAC), which is necessary for complement-mediated tissue injury. In humans, immunofluorescence studies of renal biopsy specimens showed heavy deposition of the MAC in patients with hypertension and diabetic nephropathy37. Further demonstration of the importance of the host response to injury comes from recent reports suggesting that patients who have a genetic condition that results in an impaired inflammatory response to acute infections, which results in increased morbidity/mortality due to these infections, are, paradoxically, less prone to develop atherosclerosis, a disease with a strong inflammatory component38.
Figure 3.
Role of complement in hypertensive glomerulopathy. Congenic mice sufficient and deficient in the fifth component of the complement system (C5) were made hypertensive with deoxycorticosterone acetate (DOCA), uninephrectomy, and 1% saline in the drinking water. After 16 weeks, the two groups were similarly hypertensive; however, C5 mice developed less renal injury, suggesting that complement activation participates in hypertensive renal injury (from36, with permission).
Full figure and legend (23K)Hemodynamic forces such as cyclic strain and shear stress, which are increased in hypertension, increase endothelial NOS mass and activity and increase NO production39,40. Thus, in hypertension the "normal adaptive" response of the vascular endothelium to the increased hemodynamic workload is to up-regulate NOS2,39,40. Therefore failure of the "normal adaptive" response would foster vascular injury; however, deficiency in either the production or the bioactivity of NO becomes clearly manifested only when the hemodynamic workload of hypertension necessitates an increase in NO production to reduce vascular tone and prevent maladaptive growth changes of the muscle and extracellular matrix of the heart and vessels9. Given the growing evidence for NO in vascular pathophysiology, we extended our studies in DS rats and SHR to investigate the role of NO in hypertensive renal disease as well as its relationship with changes occurring in the left ventricle and large vessels such as the aorta2,23,25.
Compared with the respective normotensive counterparts, we found that aortic NOS mass was increased 106% in SHR but was reduced by 73% in DS rats. In the kidney, NOS mass was increased 89% in SHR and reduced 49% in DS Figure 4. Aortic hypertrophy did not occur, and LVH increased only 15% in SHR, whereas in hypertensive DS rats, aortic hypertrophy and LVH were increased by 36% and 88%, respectively. In fact, a significant negative correlation existed between NOS activity and aortic hypertrophy and LVH2Figure 5.
Figure 4.
Link between nitric oxide (NO) and end-organ injury in hypertension. Nitric oxide synthase (NOS) in aortas and kidneys from normotensive Dahl salt-sensitive rats (DS) and Wistar-Kyoto (WKY) rats and hypertensive DS and spontaneously hypertensive rats (SHR). Systolic blood pressure (SBP): DS-0.5% 133 
3 mm Hg; DS-4.0% 220 8 mm Hg; WKY 137 3 mm Hg; and SHR 220 9 mm Hg. *P < 0.5 vs. DS-0.5%; **P < 0.5 vs. WKY. Values are mean SE. DS rats were from the Brookhaven strain (from9, with permission).
Figure 5.
Link between nitric oxide (NO) and end-organ injury in hypertension. Urinary protein excretion (UproV), glomerular injury score (GIS), left ventricular hypertrophy (LVH), and aortic hypertrophy score in hypertensive Dahl salt-sensitive (DS-4%) (systolic blood pressure 220 8 mm Hg), and spontaneously hypertensive rats (SHR) 220 9 mm Hg. Values are mean SE. DS rats were from the Brookhaven strain (from9, with permission).
Our studies agree with research showing that endothelial NOS knockout mice had a larger increase in vessel wall thickness (due to vascular smooth muscle hyperplasia) in response to hemodynamically mediated vascular injury than did wild mice40. In the aggregate, these studies support the notion that NO plays an important protective role in maintaining cardiorenal homeostasis, particularly by mitigating vascular smooth muscle hypertrophy and hyperplasia, preventing interstitial fibrosis, and reducing leukocyte-mediated inflammation21,22.
From the bench to the bedside: Are Dahl salt-sensitive rats a paradigm of salt-sensitive hypertension in humans?
Bigazzi et al reported that hypertensive salt-sensitive patients are more likely to manifest hyperinsulinemia, hyperlipidemia, and microalbuminuria than are non-salt-sensitive hypertensive patients41. Reaven, Twersky, and Chang demonstrated that the DS rats manifest a defect in insulin-stimulated glucose uptake by isolated adipocytes42. These metabolic changes do not vary as a function of salt intake and thus suggest that in DS rats, as in salt-sensitive humans, the susceptibility to the development of endothelial dysfunction and cardiorenal disease is part of the cluster of abnormalities that predisposes to hypertension43. Microalbuminuria is a harbinger of diabetic nephropathy in about 30% of patients with IDDM44. However, several studies have established that microalbuminuria is a marker of cardiovascular morbidity in nondiabetic patients with essential hypertension as well as in patients with type 2 diabetes mellitus41. Because microalbuminuria is common in salt-sensitive hypertensive patients, it might be a useful predictor of salt sensitivity, renal disease, and LVH in patients with essential hypertension43,45,46. Indeed, studies in the United States, Europe, and Japan have confirmed that the incidence of LVH and cardiovascular events is higher in salt-sensitive hypertensive patients42,46,47.
Several studies have shown that NO-mediated, endothelium-dependent relaxation contributes to the maintenance of vascular compliance. In the aorta, impaired vascular compliance contributes to the development of LVH because it increases the impedance to left-ventricular function48. In some African American patients, impaired vascular relaxation mediated by NO precedes hypertension49. It is interesting to speculate that these patients might become salt sensitive over time. Further, aging per se is accompanied by an increased prevalence of hypertension, salt sensitivity, and decreased endothelium-dependent relaxation mediated by NO50.
Are there populations of humans with characteristics similar to those of SHR?
Patient 2 is an example of patients with a form of autosomal-dominant hypertension characterized by brachydactyly and severe hypertension who have minimal LVH, no renal injury, normal endothelial function, absence of retinopathy, and no salt sensitivity1. Similar families have been described in the United States and Canada.
In summary, comparisons of experimental and epidemiologic studies clearly indicate that in hypertension end-organ injury affects all organs, although the severity of end-organ injury varies considerably. At the same time, the prevalence of the major causes of morbidity and mortality in hypertension—namely, LVH, renal failure, and CAD—varies in different populations of hypertensive patients and suggests that susceptibility to cardiovascular and renal disease is not uniform.
In hypertension, an increase in the pressure workload fosters adaptive changes in the endothelium, the vascular smooth muscle, the extracellular matrix of vessels, the kidney, and the heart. In many patients, the end-organs' adaptive changes to hypertension are, in fact, maladaptive. Environmental and metabolic factors conspire to induce an imbalance between NO and Ang II, and this imbalance appears to play a pivotal role in conditioning individual susceptibility for the development and progression of end-organ failure from hypertension.
QUESTIONS AND ANSWERS
DR. NICOLAOS E. MADIAS (Dean ad interim, Tufts University School of Medicine, Boston, Massachusetts): Overactivity of the Na+/H+ antiporter (NHE-1 isoform) has been identified in a variety of cell types of patients with type 1 diabetes and nephropathy as compared to those without nephropathy31. Also, an overactive NHE-1 isoform has been found in immortalized lymphocytes of hypertensive subjects51. Is it known whether such overactivity in hypertension is confined to patients with associated renal injury?
DR. RAIJ: I am not aware of a study that has addressed this issue.
DR. OLIVER LENZ (Staff Physician, Nephrology-Hypertension Division, Vascular Biology Institute, University of Miami School of Medicine, Miami, Florida): Multiple lines of evidence suggest that the risk for a given individual to develop glomerulosclerosis and the rate of progression are largely under genetic control52,53,54,55. Several studies have been undertaken to identify quantitative trait loci and candidate genes associated with the risk of developing renal disease, most notably in the course of diabetes and hypertension53,55,56. In patients with hypertension, a polymorphism in the angiotensinogen gene has been associated with hypertension, and an insertion/deletion polymorphism in the ACE gene might be associated with renal disease57,58. However, the clinical relevance of these data is controversial59. Do you think the genome holds the key to the prevention of end-stage renal disease in hypertension?
DR. RAIJ: I do believe that the genome holds one of the keys to the prevention of end-stage renal disease and hypertension. However, it would be naïve of us to think that environmental and social conditions do not participate in the modification of genetic influences.
DR. MURRAY EPSTEIN (Nephrology Division, University of Miami School of Medicine): In addition to variations in Ang II and NO, could differences in aldosterone determine an individual's susceptibility for developing end-organ disease? We recently reported that selective aldosterone blockade with eplerenone reduces proteinuria in diabetic hypertensive patients60. Furthermore, this effect is additive to ACE inhibition. Consequently, differences in aldosterone levels or aldosterone responsiveness might influence susceptibility to target organ disease60.
DR. RAIJ: I find that comment very interesting, particularly because most studies either in patients with diabetic nephropathy or in hypertensive patients with chronic renal failure have shown that inhibition or blockade of the renin-angiotensin system reduces the risk of progression by approximately 30%. This suggests that there is enough room for other agents such as aldosterone blockers to have additive or synergistic effects.
DR. EDGAR A. JAIMES (Nephrology Section, VA Medical Center, and Nephrology-Hypertension Division, University of Miami School of Medicine): I would like to add that aldosterone has significant inflammatory effects in different tissues including the kidneys, and these actions seem to be independent from those of Ang II61,62.
DR. RAIJ: Yes, I am aware of those studies, and I find them very exciting. Furthermore, the studies by Karl Weber and his group also strongly suggest that aldosterone has an important fibrotic effect63. I wonder whether these effects are also important in the kidney.
DR. BARRY J. MATERSON (Medical Director for Managed Care, University of Miami School of Medicine): Given the growing body of clinical and experimental evidence regarding the combination of ACE inhibitors or AT1 receptor blockers with spironolactone or eplerenone, is there any evidence in vitro that any two of these drugs or all three together increase the up-regulation of nitric oxide synthase? I should note that this presumes that ACE inhibitors as well as ARBs "de-repress" NOS by either reducing Ang II generation or blocking its receptors. It also presumes that mineralocorticoid receptor blockers have anything to do with the issue.
DR. RAIJ: Experimentally and clinically, normalization of blood pressure as well as specific actions of ACE inhibitors and AT1 receptor blockers improve NO bioactivity via multiple pathways that I discussed. Whether blockade of aldosterone will also increase NO independently of its effect on blood pressure is unknown. My laboratory is currently engaged in those studies.
DR. DEBASISH BANERJEE (Renal Fellow, Nephrology Hypertension Division, University of Miami School of Medicine): My question is in the context of the elevation of nocturnal systolic blood pressure as an early marker of one's increased susceptibility for developing microalbuminuria in type 1 diabetes. In that study, the systolic–in contrast to the diastolic–blood pressure elevation at night was associated with renal injury64. Can early changes in systolic blood pressure be used as a clinical marker to identify the high-risk patient?
DR. RAIJ: I am not aware of any studies, other than the one that you quoted64, that have suggested that mild systolic hypertension initiates progressive glomerular injury. My speculation would be that in patients with abnormal autoregulation of preglomerular resistances, either continuous or intermittent elevations in systolic blood pressure initiate glomerular injury and progressive renal failure. In this context, I find the studies by Gnudi et al32 and Lurbe et al64 quite exciting. On the other hand, there is no question that systolic hypertension is an important risk factor in the progression of renal failure. In fact, systolic hypertension imposes a similar increase in risk for the development of cerebrovascular accident and renal disease.
DR. MADIAS: You mentioned that you can identify endothelial dysfunction in certain people prior to clinical disease. Have any studies looked into whether defective renal autoregulation accompanies this endothelial dysfunction?
DR. RAIJ: No, although these studies need to be done.
DR. RICHARD A. PRESTON (Chief, Division of Clinical Pharmacology, University of Miami School of Medicine): We determined sVCAM, sICAM, and von Willebrand factor (vWF) levels in severe hypertensives (SHT), mild hypertensives (MHT), and normotensive (NT) volunteer subjects and found all three markers to be greater in SHT and MHT than in NT, but they did not differ between SHT and MHT. Further, we found no correlation between the markers and blood pressure. Concentrations of soluble adhesion molecules and vWF might depend more strongly on factors in the hypertensive microenvironment other than the absolute level of blood pressure per se. This suggests that mechanisms other than the endothelial expression of adhesion molecules are important in mediating the accelerated target organ injury observed in severe hypertension in humans and that the response of endothelial markers to blood pressure varies significantly in the severely hypertensive population65,66.
DR. RAIJ: Your studies are potentially very important. In the context of the two cases that I presented, the up-regulation of inflammatory and fibrogenic molecules might have greater injurious potential in patients similar to the first patient than the second. Indeed, it will be fascinating to explore this possibility by studying hypertensive individuals with high susceptibility to end-organ injury and those fairly resistant, such as patients similar to Patient 2. On the other hand, blood levels of these molecules might not quite express what is going on in the "hypertensive microenvironment" as you suggest.
DR. BAUDOUIN LECLERCQ (Staff Physician, Nephrology-Hypertension Division and Vascular Biology Institute, University of Miami School of Medicine): During your presentation, you showed that in rats, end-organ damage was induced, at least partially, by sodium chloride. Is information available about the influence of salt intake or salt sensitivity on the interaction between Ang II and NO?
DR. RAIJ: It's difficult to extrapolate animal data to humans. But I can tell you that in vitro and in vivo studies have shown that salt can up-regulate AT1 receptors. Our rats manifest an up-regulation of AT1 receptors; at least, there's a "functional up-regulation" of AT1 receptor-mediated activity in our salt-sensitive rats. But I do not know how that is mediated at a molecular level.
DR. MADIAS: Some data have implicated the number of nephrons that humans or experimental animals are born with–as a consequence of malnutrition or other circumstances–as a factor predisposing to renal injury in a hypertensive subject. Can you tell us about that?
DR. RAIJ: As you pointed out, the data suggest that DS rats have fewer nephrons than do SHR rats. The natural adaptation to a reduction in renal mass is an increase in the glomerular filtration rate/nephron that is mediated by dilating pre-glomerular arterioles. Rats with reduced renal mass (for example, the remnant kidney model) develop hypertension, have impaired glomerular autoregulation of flows and pressures, and sustain glomerular injury. Indeed, induction of the classic remnant kidney in rats that up-regulate NOS in response to this maneuver does not result in hypertension or glomerular injury (abstract; Erdely A et al, J Am Soc Nephrol 11:617A, 2000).
DR. DAVID ROTH (Chief, Nephrology and Hypertension Division, University of Miami School of Medicine): We know that in renal transplantation in humans, a cadaver kidney from an African American donor transplanted into a white recipient has about a 25% to 30% increased risk of graft failure compared to an organ from a white donor. These are kidneys harvested from individuals with no known history of hypertension or renal disease. In the context of the article by Churchill and colleagues, in which a kidney from a Brown Norway rat transplanted into an SHR is far more susceptible to hypertensive injury27, and knowing as we do that the incidence of renal disease in African Americans is several times that of the white population, do you think that genetic characteristics or other factors accompany the kidney into the recipient and that these explain the higher incidence of graft failure in this setting?
As a follow-up, are you aware of any studies that examined the family history of the organ donor and correlated a strong donor family history of hypertension with outcome in the recipient?
DR. RAIJ: Those are two fascinating questions, both of which are testable. I would hope that we could develop clinical studies that will be able to answer those questions.
DR. CARLOS ABRAIRA (Endocrinology Division, University of Miami School of Medicine): The hypothesis of a differential regulation of intraglomerular pressure in the presence of arterial hypertension, and its potential critical role on the development or progression of diabetic nephropathy, is very attractive and testable. A fraction of type 2 diabetic patients are vulnerable to renal insufficiency due to diabetes67. At least one-half of type 1 diabetic patients will never develop it regardless of duration67.
On the other hand, given enough time, virtually all diabetic patients develop retinopathy68. Nonetheless, blood pressure control is very effective in preventing or delaying the appearance or progression of lesions in the retina69. Does intravascular pressure regulatory dysfunction play a role in the susceptibility of the eye to hypertensive damage in diabetes?
DR. RAIJ: My expertise in the area of autoregulation in blood flow in the retina is very limited. However, I am familiar with some studies that have reported that ACE inhibitors might be more effective than other agents in arresting the progression of retinopathy in diabetics69. I know that you are conducting an important multicenter study looking at risk factors in type 2 diabetics. You might be able to elucidate some aspects of your question when you analyze your data at the completion of the study.
References
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