William L. Henrich

Stenting and Medical Therapy for Atherosclerotic Renal-Artery Stenosis

BACKGROUND Atherosclerotic renal-artery stenosis is a common problem in the elderly. Despite two randomized trials that did not show a benefit of renal-artery stenting with respect to kidney function, the usefulness of stenting for the prevention of major adverse renal and cardiovascular events is uncertain. METHODS We randomly assigned 947 participants who had atherosclerotic renal-artery stenosis and either systolic hypertension while taking two or more antihypertensive drugs or chronic kidney disease to medical therapy plus renal-artery stenting or medical therapy alone. Participants were followed for the occurrence of adverse cardiovascular and renal events (a composite end point of death from cardiovascular or renal causes, myocardial infarction, stroke, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for renal-replacement therapy). RESULTS Over a median follow-up period of 43 months (interquartile range, 31 to 55), the rate of the primary composite end point did not differ significantly between participants who underwent stenting in addition to receiving medical therapy and those who received medical therapy alone (35.1% and 35.8%, respectively; hazard ratio with stenting, 0.94; 95% confidence interval [CI], 0.76 to 1.17; P=0.58). There were also no significant differences between the treatment groups in the rates of the individual components of the primary end point or in all-cause mortality. During follow-up, there was a consistent modest difference in systolic blood pressure favoring the stent group (-2.3 mm Hg; 95% CI, -4.4 to -0.2; P=0.03). CONCLUSIONS Renal-artery stenting did not confer a significant benefit with respect to the prevention of clinical events when added to comprehensive, multifactorial medical therapy in people with atherosclerotic renal-artery stenosis and hypertension or chronic kidney disease. (Funded by the National Heart, Lung and Blood Institute and others; ClinicalTrials.gov number, NCT00081731.).

Urinary Diagnostic Indices in Acute Renal Failure: A Prospective Study

A prospective analysis of the value of urinary diagnostic indices in ascertaining the cause of acute renal failure was undertaken. Our results show that in the setting of acute oliguria a diagnosis of potentially reversible prerenal azotemia is likely with urine osmolality greater than 500 mosm/kg H2O, urine sodium concentration less than 20 meq/litre, urine/plasma urea nitrogen ratio greater than 8, and urine/plasma creatinine ratio greater than 40. Conversely, a urine osmolality less than 350 mosm/kg, urine sodium concentration greater than 40 meq/liter, urine/plasma urea nitrogen ratio less than 3, and urine/plasma creatinine ratio less than 20 suggest acute tubular necrosis. A significant number of oliguric patients will not have urinary indices that fall within these guidelines. In this setting, urine sodium concentration divided by the urine-to-plasma creatinine ratio (the renal failure index) and the fractional excretion of filtered sodium provide a reliable means of differentiating reversible prerenal azotemia from acute tubular necrosis.

Increased Ionized Calcium and Left Ventricular Contractility during Hemodialysis

Routine hemodialysis is associated with an increase in left ventricular contractility that is independent of a change in preload, but the mechanisms responsible are unknown. We investigated the importance of three distinct effects that regularly occur in hemodialysis and could potentially improve left ventricular contractility: the removal of uremic toxins, the increase in the plasma ionized calcium concentration, and the increase in the plasma bicarbonate concentration. Three different dialysates were used for each of eight stable patients on long-term hemodialysis, and left ventricular contractility was assessed by two-dimensional echocardiography before and after each dialysis. In the first procedure neither the ionized calcium nor the bicarbonate concentration was allowed to increase, and left ventricular contractility did not improve. In the second procedure, ionized calcium increased (from 4.4 to 5.4 mg per deciliter, P less than 0.001), bicarbonate concentration was held constant, and contractility increased (from 0.74 to 0.93 circumferences per second, P less than 0.005). In the third procedure, ionized calcium was kept constant, the bicarbonate concentration increased (from 19 to 24 mmol per liter, P less than 0.001), but contractility did not increase. These results suggest that the increase in ionized calcium that occurs in regular dialysis is a key factor in the improvement in left ventricular contractility observed during the procedure.

Kidney-Heart Interactions: Epidemiology, Pathogenesis, and Treatment

Heart disease accounts for approximately half of the deaths of patients with ESRD (1–3). In the past 5 yr, there has been increasing recognition of both coronary artery disease (CAD) and left ventricular hypertrophy (LVH) in ESRD patients, as these are the two typical presentations of heart disease in ESRD patients. It is also clear that many patients with chronic kidney disease (CKD) and a GFR of <60 ml/min are at risk for heart disease; many of these patients succumb to heart disease before reaching dialysis (4–6). This review includes a brief overview of the problem, a discussion of CAD and LVH, and an examination of the benefits of reducing BP and proteinuria on both the heart and the kidney and concludes with a brief section on treatment options for individuals with this disorder. A growing awareness of heart disease in individuals with kidney disease as a major public health concern has increased sharply because of the revelation that there are millions of Americans with reduced kidney function (2). This fact, coupled with the understanding that many individuals with CKD do not reach dialysis because they die of heart disease (6), has expanded the concern about heart disease in both patients with CKD and patients with ESRD. Of interest is that whereas many superb prospective, randomized clinical trials have defined the scope of the appropriate therapy for heart disease in patients with normal kidney function, relatively few trials have addressed the issue in patients with kidney disease. Thus, the literature on cardiovascular disease (CVD) has focused on individuals without kidney disease, and guidelines regarding the management of heart disease in patients with ESRD in CKD, therefore, are largely opinion based (7). The two clinical presentations of heart disease in patients with kidney disease are atherosclerotic …

Renin expression in renal proximal tubule.

Angiotensinogen, angiotensin-converting enzyme, and renin constitute the components of the renin-angiotensin system. The mammalian renal proximal tubule contains angiotensinogen, angiotensin-converting enzyme, and angiotensin receptors. Previous immunohistochemical studies describing the presence of renin in the proximal tubule could not distinguish synthesized renin from renin trapped from the glomerular filtrate. In the present study, we examined the presence of renin activity and mRNA in rabbit proximal tubule cells in primary culture and renin mRNA in microdissected proximal tubules. Renin activity was present in lysates of proximal tubule cells in primary culture. Cellular renin content in cultured proximal tubule cells was increased by incubation with 10(-5) M isoproterenol and 10(-5) M forskolin by 150 and 110%, respectively. In addition, renin transcripts were detected in poly(A)+ RNA from cultured proximal tubule cells by RNA blots under high stringency conditions. In microdissected tubules from normal rats, renin mRNA was not detectable with reverse transcription and polymerase chain reaction. However, in tubules from rats administered the angiotensinogen-converting-enzyme inhibitor, enalapril, renin was easily detected in the S2 segment of the proximal tubule. We postulate the existence of a local renin-angiotensin system that enables the proximal tubule to generate angiotensin II, thereby providing an autocrine system that could locally modulate NaHCO3 and NaCl absorption.

Recent Advances in the Prevention and Management of Intradialytic Hypotension

Intradialytic hypotension continues to play a significant role in the morbidity and in some cases the mortality associated with maintenance hemodialysis. Greater precision in the determination of dry weight using bioimpedance technology and biofeedback systems designed to prevent rapid fluctuations in blood volume have recently been shown to decrease the frequency of this complication. Pharmacologic strategies designed to maintain peripheral vascular resistance in patients with insufficient release of endogenous vasoconstrictors continue to be explored. The sudden development of intradialytic hypotension may respond to specific antagonists to hypotensive mediators.

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.

The Role of Renal Nerves and Prostaglandins in Control of Renal Hemodynamics and Plasma Renin Activity during Hypotensive Hemorrhage in the Dog

The effects of hypotensive hemorrhage (HH) on renal hemodynamics and plasma renin activity (PRA) during prostaglandin (PG) synthesis inhibition were examined in three groups of dogs. In each group of animals arterial blood pressure was lowered by a 30% decrement. In the first group of eight control animals, HH was not associated with a significant change in glomerular filtration rate (GFR, 42-36 ml/min, NS); renal blood flow (RBF) declined significantly, from 234 to 171 ml/min, P < 0.05. In the second group of eight animals, pretreated with RO 20-5720 (RO, 2 mg/kg), a competitive inhibitor of PG synthesis, HH was associated with a significant fall in GFR (43-17 ml/min, P < 0.001) and RBF (195-89 ml/min, P < 0.001). In the third group of eight animals, pretreatment with indomethacin (IN, 10 mg/kg), a chemically dissimilar PG inhibitor, HH was also associated with a significant fall in GFR (38-8 ml/min, P < 0.001) and RBF (150-30 ml/min, P < 0.001). Renal denervation attenuated this renal ischemic effect of HH in the presence of PG inhibition. In the RO group, GFR (34 vs. 17 ml/min, P < 0.005) and RBF (145 vs. 89 ml/min, P < 0.025) were significantly greater in denervated vs. innervated kidneys during HH. Similarly, in animals treated with IN, a significantly higher GFR (28 vs. 8 ml/min, P < 0.005) and RBF (101 vs. 30 ml/min, P < 0.005) occurred in denervated as compared to innervated kidneys during HH. With HH, the increase in PRA in the control group (3.34-11.68 ng/ml per h, P < 0.005) was no different than that observed in the RO group (4.96-18.9 ng/ml per h, P < 0.001) or IN group (4.71-17.8 ng/ml per h, P < 0.001). In summary, the present results indicate that renal PG significantly attenuate the effect of HH to decrease GFR and RBF. Furthermore, renal denervation exerts a protective effect against the enhanced renal ischemic effects which occur in the presence of PG inhibition during HH. Finally, PG inhibition does not alter the effect of HH to cause an increase in PRA.

Stage IV Chronic Kidney Disease

A 54-year-old woman with type 2 diabetes presents for care. Her creatinine level has increased from 1.1 mg per deciliter (97 μmol per liter) 4 years ago to 3.1 mg per deciliter (274 μmol per liter) at the most recent measurement (estimated glomerular filtration rate, 26 ml per minute per 1.73 m2 of body-surface area). Her urinary protein excretion is 2.8 g per 24 hours. Her blood pressure is 155/90 mm Hg, and the glycated hemoglobin level is 7.6 mg per deciliter. Her current medications include an oral hypoglycemic agent, an angiotensin-converting–enzyme inhibitor, a statin, and a thiazide diuretic. How should her case be managed?

Characterization of hepatic cytochrome P4503A activity in patients with end‐stage renal disease

The cytochrome P450 (CYP) oxidative enzyme system, located primarily in the liver and small intestine, is responsible for metabolism and detoxification of numerous endogenous and exogenous substances. The most abundant CYP enzyme, CYP3A, is known to be involved in the metabolism of more than 200 commonly used medications. In experimental models of renal failure, both hepatic function and CYP enzyme content are reduced; however, direct evidence in humans is lacking. Evaluation of drug metabolism in patients with end‐stage renal disease is important because these patients use a large number of medications and are at risk of adverse reactions and drug‐drug interactions.