A potential role for immune activation in hemodialysis hypotension.

The necessary exposure of blood to biomembranes during hemodialysis has been viewed by many as an immunogenic challenge leading to an acute phase response. In this study we examined the relationship between hemodialysis-induced immune activation and intradialytic hypotension, using the acute phase reactant serum C-reactive protein (CRP) as a surrogate for immunogenic activation. The maximum percent change in mean arterial pressure (MAP) was found to correlate significantly with CRP (r = 0.67, p < 0.05) in nine consecutive patients with a history of symptomatic hypotension during hemodialysis. In contrast, no correlation was found between CRP and maximum percent change in MAP in eight consecutive hemodialysis patients without intradialytic hypotension. Since interleukin-6 (IL-6) is a major regulator of CRP, the relationship between these two proteins was examined. Plasma IL-6 levels were found to correlate both with CRP (r = 0.67, p < 0.05) and with mean maximum percent change in MAP (r = 0.70, p < 0.05) in hemodialysis patients with a prior history of hypotension. IL-6 levels did not correlate with CRP or blood pressure in the hemodynamically stable patients. The results suggest that immune activation working through IL-6, CRP and other cytokines may play a role in the pathogenesis of hemodialysis hypotension in some patients.

The inevitability of renal function loss in patients with hypercreatinemia.

UNLABELLED: Although it is anticipated that most patients with renal insufficiency will progress towards end-stage renal disease (ESRD) there have been few population-based studies to validate this assumption. We examined serial creatinines from 3,874 anonymous patients at an urban VA medical center who had a baseline creatinine of 1.4 mg/dl or greater to estimate the frequency of deterioration in renal function (DRF). DRF was defined as the first Cr (1stCr) value being lower than the last Cr (LCr) for each patient. The median follow-up was 48.3 +/- 0.5 months with 18 +/- 0.5 creatinine values per patient. The median 1stCr was 1.6 +/- 0.1 mg/dl with 32.2% of the patients having a 1stCr greater than or equal to 1.7 mg/dl. In the study group, 1,723 (44.4%) had DRF including 1,089 (41.4%) of those patients with a 1stCr of 1.4-1.7 mg/dl. However, 45 (36.6%) of those with a 1stCr value 3.0-5.0 mg/dl did not have DRF, the percent with stable creatinine in this group did not vary with length of follow-up. Over the study period, 299 (7.7%) of all the patients had a creatinine rise to 7.0 mg/dl, with 104 (4%) of those with a 1stCr of 1.4-1.7 mg/dl reaching this endpoint. CONCLUSION: A majority, but not all, patients with renal insufficiency lose renal function over time and those with even mild hypercreatinemia are at risk for deterioration in renal function. Hypercreatinemia, however, does not accurately discriminate between those renal insufficiency patients who are stable versus those at high risk for ESRD.

The outcome of the urban renal patient: the importance of social factors and center effects.

Caring for the urban renal patient can be a challenge to providers for many reasons. Although racial and socioeconomic factors have an impact on the health of this population, one must also consider the effect of the urban environment on the ill, especially those with renal disease. This article reviews the state of health among the poor and nonwhite minorities, who tend to inhabit the urban regions of this country, and then highlights the unique characteristics of those with renal disease. The impact of the Medicare end-stage renal disease (ESRD) program and center-specific quality of care on the outcome of the urban patient with ESRD is explored.

Preventing dialysis hypotension: a comparison of usual protective maneuvers.

BACKGROUND: Intradialytic hypotension (IH) is a common adverse event. Currently, there are several commonly utilized therapies of IH, but they have not been compared directly in the same group of patients. We performed the present study in order to learn which of these techniques is most effective so that a rational approach to treating IH could then be formulated. METHODS: A single-blinded, crossover study design of five different protocols was undertaken in 10 hemodialysis patients with a prior history of IH. Each patient first underwent one week (three dialyses) of standard dialysis (dialysate sodium 138 mEq/L). Then each patient was subjected to one week each (three dialyses) of the four test protocols, performed in random order in a blinded fashion. The specific protocols were as follows: high sodium dialysate, in which the patient was dialyzed using a dialysate sodium of 144 mEq/L; sodium modeling, during which the dialysate sodium declined from 152 to 140 mEq/L in the last half hour of dialysis; one hour of isolated ultrafiltration followed by three hours of isovolemic dialysis; and cool temperature dialysis in which the dialysate was cooled to 35 degrees C. RESULTS: Weight loss in each of the five protocols was essentially identical, varying between 2.9 and 3 kg. There were significantly fewer hypotensive episodes per treatment in the sodium modeling, high sodium, and cool temperature protocols as compared with the standard protocol (P < 0.05). Ultrafiltration followed by dialysis was associated with a significantly greater number of hypotensive episodes per treatment than any of the three test protocols (P < 0.05). Similarly, the number of nursing interventions required for IH per treatment was significantly greater in the standard dialysis and in the isolated ultrafiltration protocols compared with sodium modeling and cool temperature protocols (P < 0.05). The number of hypotensive signs and symptoms per treatment was also significantly reduced during the sodium modeling and cool temperature protocols compared with the standard protocol (P < 0.004 and P < 0.02, respectively). Again, the isolated ultrafiltration protocol resulted in significantly more hypotensive symptoms and signs than the three test protocols (P < 0.005). Finally, the nadir mean arterial pressures were significantly lower in the standard and isolated ultrafiltration protocols when compared with the three test protocols (P < 0.05). The upright postdialysis blood pressure was best preserved in the sodium modeling and cool temperature protocols compared with the standard and isolated ultrafiltration protocols (P < 0.05). CONCLUSION: This study supports the use of sodium modeling as a first step in combating IH. Also effective were the use of cool-temperature dialysate and a high-sodium dialysate. All three test protocols were well tolerated. As applied in this study, isolated ultrafiltration followed by isovolemic dialysis was notably less effective in reducing IH.

Theoretical basis and clinical evidence for differential effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor subtype 1 blockers.

Drugs that block the renin-angiotensin system have multiple mechanisms of action that may be beneficial in stabilizing or delaying progression of renal disease. The most important of these actions is the simultaneous control of both systemic and glomerular capillary hypertension. Angiotensin-converting enzyme (ACE) inhibitors are a class of drugs that have proven antihypertensive and antiproteinuric effects, with a demonstrated ability to delay progression of renal disease in conjunction with the ability to reduce systemic blood pressure. The mechanism of action for these drugs remains poorly described, but depends in part on an ability to reduce plasma angiotensin II levels and increase plasma bradykinin levels. Angiotensin II receptor subtype 1 (AT1) blockers differ in their mechanism of action from the ACE inhibitors. These drugs primarily block the binding of angiotensin II to its type 1 site. In so blocking the type 1 binding site, however, greater levels of circulating angiotensin II result, and the resultant biologic activity of angiotensin II or its metabolites such as angiotensin(1-7) and angiotensin(3-8) may be more directed to other angiotensin-binding sites. AT1 blockers have similar antihypertensive and antiproteinuric effects to those of ACE inhibitors and they may prove to be as useful as ACE inhibitors in delaying progression of renal disease. Because ACE inhibitors and AT1 blockers inhibit the renin-angiotensin system by different mechanisms, there is a possibility that combining them in clinical practice may prove efficacious for lowering blood pressure and for providing target organ protection.

Renal artery angioplasty and stent placement: predictors of a favorable outcome.

BACKGROUND: Renal artery stenosis is a common disorder and is an established cause of hypertension and renal insufficiency. Although treatment with renal artery stents has been shown to improve blood pressure and renal function for some patients, the patient population most likely to benefit is unknown. The current study was designed to determine which factors are predictive of improved blood pressure and renal function when patients with renal artery stenosis are treated with renal artery angioplasty and stent placement. METHODS: In a prospective evaluation 127 consecutively enrolled patients with renal artery stenosis in 171 vessels were treated with angioplasty and intravascular stents. Blood pressure and serum creatinine concentration were measured before stent placement and during the follow-up period. RESULTS: The mean length of the follow-up period was 15 +/- 14 months. Mean systolic blood pressure improved among patients with hypertension (from 177 +/- 26 mm Hg before stent placement to 151 +/- 24 mm Hg 6 months after stent placement (P <.001). The greatest improvement occurred among those with the highest baseline systolic blood pressure. This beneficial effect on blood pressure was sustained for 3 years. Sex, age, diastolic blood pressure, number of vessels into which stents were placed, serum creatinine concentration, presence of bilateral disease, race, and severity of stenosis were not predictive of improved blood pressure. Mean creatinine concentration was not significantly changed for the group as a whole. A significant decrease in serum creatinine concentration occurred among 43% of patients with baseline renal insufficiency. None of the examined variables was predictive of improvement. CONCLUSIONS: Renal artery angioplasty and stent placement produced a significantly greater reduction in systolic blood pressure among patients with the highest baseline systolic blood pressure. Other examined variables were not predictive of a significant improvement in blood pressure. No examined variable was predictive of improved renal function. We concluded that management of renal artery stenosis with renal artery angioplasty and stent placement is most likely to result in significant improvement in systolic blood pressure among patients with the highest baseline systolic blood pressure.

Renal artery disease in the elderly.

This brief review discusses the problem of atherosclerotic renal artery obstruction in the elderly. This disorder is common in the elderly; the overall incidence is estimated to be 10%. The disorder presents with new onset hypertension, a loss of control of BP or a decline in renal function in some patients. In others, the obstruction may be unmasked by the use of angiotensin converting enzyme inhibitors or angiotensin receptor blocker agents. The current approach to the diagnosis of renal artery obstruction is discussed as are the indications for invasive procedures. Careful patient selection for any invasive procedures is particularly important in the elderly since this population has a propensity to higher morbidity.

Regulation of the genes for 11beta-hydroxysteroid dehydrogenase type 1 and type 2 in the kidney of the Dahl rat.

BACKGROUND: An isoenzyme of 11beta-hydroxysteroid dehydrogenase (11beta-HSD), 11beta-HSD-2 confers aldosterone specificity on the mineralocorticoid receptor (MR) and is found collocated in renal cortical collecting duct cells with the MR. To investigate whether the salt sensitivity of the Dahl salt-sensitive (S) rat is due to 11beta-HSD deficiency, we measured 11beta-HSD-1 and 11beta-HSD-2 mRNA levels in the kidneys of Dahl-S and Dahl salt-resistant (R) rats. In addition, we studied the effects of gender, age and dietary sodium on expression of mRNA for the two isoforms. S and R rats were placed on low- or high-sodium (HNa) diets and sacrificed after 33 and 115 days. Rat kidney RNA was isolated and 11beta-HSD-1 and 11beta-HSD-2 mRNA levels were measured on Northern filter hybridization using isoform-specific probes. RESULTS: No strain differences were observed in the mRNA expression of the two isoforms of 11beta-HSD under any of the experimental conditions. No gender or age differences were observed in 11beta-HSD-2 mRNA but HNa diet almost doubled 11beta-HSD-2 mRNA (P<0.0009). 11beta-HSD-1 mRNA levels were consistently higher, more than double, in male rats versus females rats (P<0.0001), and in the 115-day-old rats versus the 33-day-old rats (P<0.0001). Dietary sodium intake did not affect 11beta-HSD-1 mRNA levels. CONCLUSIONS: There is no difference in the expression of the two isoforms of 11beta-HSD in the kidneys of the S and R rats, which might explain the salt sensitivity and higher blood pressure of the S rat. Renal 11beta-HSD-1 mRNA levels are higher in male than in female rats, and in the older rats of both strains. In the kidney, the 11beta-HSD-2 gene is regulated by sodium status but is not affected by gender or age.

Abnormal regulation of proximal tubule renin mRNA in the Dahl/Rapp salt-sensitive rat.

BACKGROUND: The precise pathogenesis of salt-sensitive hypertension in the Dahl rat is unknown. Abnormalities in renal hemodynamics and NaCl handling have been implicated, and may relate to changes in the activity of the intrarenal renin-angiotensin system. METHODS: Circulating, juxtaglomerular and intrarenal (glomerular and proximal tubular) renin were studied in Dahl/Rapp salt-sensitive and salt-resistant rats fed with a normal (0.5%) or high (4%) NaCl diet. Circulating and juxtaglomerular renin were assessed by measurement of plasma renin activity and renin secretory rates. Glomerular and proximal tubular renin mRNA were assessed by microdissection and quantitative competitive RT-PCR. RESULTS: Circulating and juxtaglomerular renin were suppressed by high dietary NaCl in salt-sensitive rats (plasma renin activity, 0.5%, 10.9 +/- 0.7 vs. 4%, 7.9 +/- 0.3 ng/ml/hr, P < 0.05; renin secretory rate, 0.5% 220 +/- 32 vs. 4%, 58 +/- 5 ng/mg/hr, P < 0.05). Glomerular renin mRNA was also suppressed by the higher salt diet in salt-sensitive animals (0.5%, 411 +/- 84 vs. 4%, 67 +/- 22 x 103 copies/glomerulus, P < 0.05). In contrast, proximal tubular renin was not suppressed by a high NaCl diet in salt-sensitive animals (0.5%, 13.9 +/- 2.7 vs. 4%, 12.1 +/- 3.6 x 103 copies/mm tubule, P = NS), but was suppressed in salt-resistant rats (0.5%, 9.5 +/- 2.8 vs. 4%, 3.2 +/- 1.2 x 103 copies/mm, P < 0. 05). CONCLUSIONS: Failure to suppress proximal tubular renin in response to high dietary NaCl may result in increased local generation of angiotensin II and enhanced proximal tubular NaCl absorption, and thereby contribute to the generation of salt sensitive hypertension.

Analgesic nephropathy.

At least two distinct forms of analgesic nephropathy are presently recognized. One form is classical analgesic nephropathy that is associated with habitual consumption of predominantly combination analgesic products. This disease takes many years to develop and is characterized by a dense interstitial fibrosis and the insidious development of renal failure. Renal papillary necrosis had been classically associated with this illness. New diagnostic tests to make an early diagnosis of the lesion may be on the horizon with the recognition that the non-contrasted CT scan may be useful. Further studies will be necessary to confirm this in the U.S. population of analgesic users. The second form of analgesic nephropathy is typically an acute renal failure associated with the use of nonsteroidal anti-inflammatory drugs. In part this disease has been predictable based on the fact that there is an at-risk population of patients who are more vulnerable to developing it. Other features of nonsteroidal induced toxicity are also recognized (see Table 3). It is hoped that the increased recognition that chronic and acute analgesic use may lead to renal failure will result in strategies that will apprise consumers and physicians of this risk, and thereby lead to reduction in the prevalence of these two forms of analgesic-related kidney disease.

Effect of sertraline hydrochloride on dialysis hypotension.

Hemodialysis hypotension (HH) is a very common disorder and has a multifactorial etiology. Autonomic dysfunction occurs in up to 50% of patients with end-stage renal disease (ESRD) and plays a key role in HH in some patients. Sertraline hydrochloride, a central nervous system serotonin reuptake inhibitor, has been shown to be an effective treatment of hypotension caused by autonomic dysfunction in disorders such as neurocardiogenic syncope and idiopathic orthostatic hypotension. This study sought to determine whether sertraline was effective in ameliorating HH. A retrospective chart analysis was performed that included nine consecutive patients (aged > or = 54 years, time on hemodialysis > or = 2.2 years) placed on sertraline (50 to 100 mg/d) for depression who also had HH (defined as prehemodialysis systolic blood pressure [SBP] < or = 100 mm Hg, > or = 40 mm Hg decrease in SBP during hemodialysis, SBP <90 mm Hg, any diastolic blood pressure <40 mm Hg, or a decrease in blood pressure-causing symptoms) before treatment with sertraline. The data from a 6-week pre-sertraline period were compared with the data from a 6-week sertraline period (defined as 6 weeks after drug begun). Blood pressure medications were unchanged during the trial period of sertraline. However, nadir mean arterial pressure recorded during a given dialysis session in the pre-sertraline period (55+/-4 mm Hg) was significantly lower than that recorded in the sertraline period (68+/-5 mm Hg; P < 0.05). In addition, the number of hypotensive episodes (same definition as HH) per dialysis session during the sertraline period was significantly lower than that during the pre-sertraline period (mean, 0.6+/-0.2 episodes per session v 1.4+/-0.3 episodes per session; P < 0.005). The number of therapeutic interventions required for hypotension during the sertraline period was also significantly less than that during the pre-sertraline period (mean, 1.7+/-0.8 interventions v 11.0+/-3.0 interventions; P < 0.005). The urea reduction ratio (62.7%+/-4.7% v 63.1%+/-9.3%; P = NS) and hematocrit (28.9%+/-0.8% v 29.5%+/-1.0%; P = NS) did not change significantly. It is concluded that the short-term (6 weeks) use of sertraline hydrochloride reduces HH in some patients with ESRD. A possible mechanism for this effect is sertraline-induced attenuation of the paradoxical sympathetic withdrawal that may underlie HH in some patients with ESRD.

Anemia, hypertension, and myocardial dysfunction in end-stage renal disease.

Cardiovascular disease remains the major cause of mortality in patients with end stage renal disease (ESRD). The pathophysiology of cardiac dysfunction in ESRD is complex and not fully understood. However, it appears that the two major determinants of left ventricular (LV) hypertrophy and dysfunction are anemia and hypertension, both of which are very common in ESRD patients. Early and aggressive correction of anemia and hypertension may have a significant impact on cardiac disease in ESRD patients. This article presents a discussion on the management of anemia and hypertension, and the current information available on the pathogenesis and management of LV dysfunction in ESRD.

Cardiac disease in chronic uremia: management.

Heart disease is a common cause of morbidity in end-stage renal disease (ESRD) patients. The management of heart disease in these patients requires a multidimensional approach to the management of heart failure, coronary disease, and arrhythmias, and to risk factors such as hypertension, anemia, secondary hyperparathyroidism, and electrolyte/acid-base disturbances. Coronary artery disease management includes use of antianginal drugs and revascularization of coronary arteries with angioplasty +/- stent placement or coronary artery bypass grafting. The long-term outcomes of these procedures need to be assessed and improved. Hypertension occupies a major role in the pathogenesis of heart disease in ESRD, and early and adequate control of hypertension is likely to have a major impact on the progression of cardiac disease. This entails the achievement of optimal volume status, combined with the appropriate use of antihypertensive agents such as calcium channel blockers, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, vasodilators, alpha-blockers, and central sympatholytic drugs. In ESRD patients, specific dialysis-related complications such as intradialytic hypotension and pericardial effusion may have additional effects on cardiac function and require attention. The choice of dialysate composition and membrane may influence clinical outcomes with specific effects on cardiac performance.

Regulation of glomerular and proximal tubule renin mRNA by chronic changes in dietary NaCl.

Renal adaptations to chronic changes in dietary NaCl and extracellular fluid volume involve both glomerular and tubular mechanisms that result in preservation of glomerular filtration rate and modifications of renal tubular transport to secure external NaCl balance. Although the systemic renin-angiotensin system (RAS) mediates some of these responses, the possible contributions of local glomerular and proximal tubule RASs in these adaptations have not been examined. Thus, in this study, glomeruli and proximal tubules were microdissected from rats adapted to high (4.0%), normal (0.5%), or low (0.01%)-NaCl diets, and renin mRNA was measured using quantitative competitive reverse transcription-polymerase chain reaction. After 4 days of the diets, glomerular renin mRNA abundance was increased 100% by the low-NaCl diet (P < 0.05) and suppressed 50% (P < 0.01) by the high NaCl diet compared with controls. Renin mRNA in proximal tubules was stimulated 230% (P < 0.05) by the low-NaCl diet and tended to be suppressed (68% decrease, not significant) by the high-NaCl diet. When the high-NaCl diet was continued for 2 wk, proximal tubule renin mRNA was suppressed by 89% (P < 0.05). This study provides evidence that glomerular and proximal tubule renin transcript levels are regulated by chronic changes in dietary NaCl, suggesting that local RASs contribute to the renal adaptations in response to chronic alterations in NaCl.