Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial.

CONTEXT: Incidence of end-stage renal disease due to hypertension has increased in recent decades, but the optimal strategy for treatment of hypertension to prevent renal failure is unknown, especially among African Americans. OBJECTIVE: To compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (ramipril), a dihydropyridine calcium channel blocker (amlodipine), and a beta-blocker (metoprolol) on hypertensive renal disease progression. DESIGN, SETTING, AND PARTICIPANTS: Interim analysis of a randomized, double-blind, 3 x 2 factorial trial conducted in 1094 African Americans aged 18 to 70 years with hypertensive renal disease (glomerular filtration rate [GFR] of 20-65 mL/min per 1.73 m(2)) enrolled between February 1995 and September 1998. This report compares the ramipril and amlodipine groups following discontinuation of the amlodipine intervention in September 2000. INTERVENTIONS: Participants were randomly assigned to receive amlodipine, 5 to 10 mg/d (n = 217), ramipril, 2.5 to 10 mg/d (n = 436), or metoprolol, 50 to 200 mg/d (n = 441), with other agents added to achieve 1 of 2 blood pressure goals. MAIN OUTCOME MEASURES: The primary outcome measure was the rate of change in GFR; the main secondary outcome was a composite index of the clinical end points of reduction in GFR of more than 50% or 25 mL/min per 1.73 m(2), end-stage renal disease, or death. RESULTS: Among participants with a urinary protein to creatinine ratio of >0.22 (corresponding approximately to proteinuria of more than 300 mg/d), the ramipril group had a 36% (2.02 [SE, 0.74] mL/min per 1.73 m(2)/y) slower mean decline in GFR over 3 years (P =.006) and a 48% reduced risk of the clinical end points vs the amlodipine group (95% confidence interval [CI], 20%-66%). In the entire cohort, there was no significant difference in mean GFR decline from baseline to 3 years between treatment groups (P =.38). However, compared with the amlodipine group, after adjustment for baseline covariates the ramipril group had a 38% reduced risk of clinical end points (95% CI, 13%-56%), a 36% slower mean decline in GFR after 3 months (P =.002), and less proteinuria (P<.001). CONCLUSION: Ramipril, compared with amlodipine, retards renal disease progression in patients with hypertensive renal disease and proteinuria and may offer benefit to patients without proteinuria.

Renal mucormycosis in the HIV patient.

Mucormycosis is an increasingly recognized opportunistic infection. It usually affects patients with debilitating conditions such as cancer, diabetes mellitus, renal failure, and extensive burns. Mucor infection has also been described in human immunodeficiency virus (HIV) patients. The most common clinical presentations are the cerebral, cutaneous, and renal forms. We describe a unique case of bilateral renal mucormycosis presenting with renal failure in an HIV-infected patient. In the immunosuppressed host, a history of intravenous (IV) drug abuse associated with symptoms of pyelonephritis should alert the clinician to the possibility of mucor infection. Blood and urine culture are often negative. The diagnosis is made histologically in most cases. The treatment of HIV patients with mucormycosis and renal failure includes hemodialysis, nephrectomy, and intravenous amphotericin in addition to antiretroviral therapy. Bilateral renal involvement with Mucor carries a poor prognosis.

Oncotic pressure and edema formation in hypoalbuminemic HIV-infected patients with proteinuria.

Human immunodeficiency virus nephropathy (HIVN) continues to challenge nephrologic consultative services at major urban institutions. Although noted in the literature, the decreased incidence of peripheral edema in HIVN has been unexplained to date. In HIV patients, total proteins frequently are found to be elevated due to an elevated globulin fraction. The impact that plasma proteins, specifically globulins, have on the total oncotic pressure has not been reported in HIVN, but may play a role in the paucity of edema noted in this proteinuric population. To evaluate the contributions of serum globulin to the total oncotic pressure and the presence or absence of edema in HIVN, we randomly selected 27 patients with proteinuria greater than 2.5 g/24 hr and serum albumin less than 3.1 g/dL from patients presenting to the nephrology outpatient clinic at the University of Miami/Jackson Memorial Hospital. Seventeen of the patients (63%) had a known diagnosis of HIV infection (group 1). These patients were subdivided into two subgroups: those presenting with clinically evident edema on physical examination (n = 7 [41%]; group 1A) and those who had an absence of edema (n = 10 [59%]; group 1B). Conversely, group 2 comprised 10 patients without known HIV infection, of whom six (60%) had edema (group 2A) and four (40%) did not (group 2B). Blood pressures were noted, and mean arterial pressure was calculated using standard formulas. Serum albumin, serum total proteins, and urine total proteins were measured using standard laboratory methods. Oncotic pressures for albumin (alpha), globulin (beta), and total protein (c) were calculated using the following formula: COPpl = alpha(2.8c + 0.18c2 + 0.012c3) + beta(0.9c + 0.12c2 + 0.004c3). We used Student's t-test to analyze the data. There is no significant difference between the albumin concentrations of HIV patients without edema (group 1B) and non-HIV patients with edema (group 2A), with mean concentrations of 2.3 +/- 0.1 g/dL versus 2.3 +/- 0.15 g/dL, respectively (P = NS). Group 1B, however, has a total oncotic pressure of 17.1 +/- 1.5 mm Hg, whereas both groups with edema (groups 1A and 2A) have statistically significant lower total oncotic pressures (12.1 +/- 2.3 mm Hg and 12.9 +/- 1.1 mm Hg, respectively; P < 0.05). The globulin oncotic pressures may account for some of the differences in total oncotic pressures, being significantly higher for those patients without edema in group 1B compared with group 2A (7.1 +/- 0.9 mm Hg v 3.9 +/- 0.4 mm Hg, respectively; P < 0.05). In patients with HIV, however, the presence or absence of edema is mandated by albumin concentration because both groups have similar globulin concentrations (group 1A 3.1 +/- 0.1 g/dL v group 1B 3.8 +/- 0.3 g/dL; P = NS). Mean arterial pressure does not play a role in edema formation in this study because the HIV patients without edema had the higher blood pressures (group 1B 97.8 +/- 4.7 mm Hg v group 2A 84.7 +/- 5.5 mm Hg; P < 0.05). We conclude that globulins play an important role in maintaining oncotic pressure in low albumin states. HIVN patients with increased serum immune globulin may benefit from higher globulin oncotic pressure, delaying the onset of clinical edema in the setting of proteinuria.

Achievement and safety of a low blood pressure goal in chronic renal disease. The Modification of Diet in Renal Disease Study Group.

The Modification of Diet in Renal Disease Study showed a beneficial effect of a lower-than-usual blood pressure (BP) goal on the progression of renal disease in patients with proteinuria. The purpose of the present analyses was to examine the achieved BP, baseline characteristics that helped or hindered achievement of the BP goals, and safety of the BP interventions. Five hundred eighty-five patients with baseline glomerular filtration rate between 13 and 55 mL/min per 1.73 m2 (0.22 to 0.92 mL/s per 1.73 m2) were randomly assigned to either a usual or low BP goal (mean arterial pressure < or = 107 or < or = 92 mm Hg, respectively). Few patients had a history of cardiovascular disease. All antihypertensive agents were permitted, but angiotensin-converting enzyme inhibitors (with or without diuretics) followed by calcium channel blockers were preferred. The mean (+/- SD) of the mean arterial pressures during follow-up in the low and usual BP groups was 93.0 +/- 7.3 and 97.7 +/- 7.7 mm Hg, respectively. Follow-up BP was significantly higher in subgroups of patients with preexisting hypertension, baseline mean arterial pressure > 92 mm Hg, a diagnosis of polycystic kidney disease or glomerular diseases, baseline urinary protein excretion > 1 g/d, age > or = 61 years, and black race. The frequency of medication changes and incidence of symptoms of low BP were greater in the low BP group, but there were no significant differences between BP groups in stop points, hospitalizations, or death. When data from both groups were combined, each 1-mm Hg increase in follow-up systolic BP was associated with a 1.35-times greater risk of hospitalization for cardiovascular or cerebrovascular disease. Lower BP than usually recommended for the prevention of cardiovascular disease is achievable by several medication regimens without serious adverse effects in patients with chronic renal disease without cardiovascular disease. For patients with urinary protein excretion > 1 g/d, target BP should be a mean arterial pressure of < or = 92 mm Hg, equivalent to 125/75 mm Hg.

Effects of ketamine sedation on glucose clearance, insulin secretion and counterregulatory hormone production in baboons (Papio hamadryas).

Since the effects of ketamine sedation seem to differ between subspecies of baboons, we assessed the endocrine response to an intravenous glucose tolerance test (IVGTT) in 12 hamadryas baboons. The first phase insulin secretion, basal insulin, and glucose levels, as well as the glucose clearance, were significantly lower in sedated baboons as compared to fully awake animals. Glucagon and cortisol were significantly higher, while growth hormone was lower during ketamine sedation. Papio hamadryas appears to be a promising pre-clinical model for the study of endocrine replacement therapy in insulin-dependent diabetes. However, the data obtained must be interpreted with the knowledge that the anesthetic employed to allow for testing of the animals does have an effect on the parameters described in this report.

Observations on renal replacement services in Russia, Belarus and Lithuania.

This report describes the current financial, technical and medical status of nephrology, dialysis and renal transplant services in these countries with the hope of helping our colleagues there to upgrade their standards of care. The general impression is that physicians as well as administrators in these countries are eager to improve conditions of patient care despite a disastrous economical climate. Our view is that we can help by providing literature, textbooks, journals, travel funds, by offering visiting fellowships to individual physicians, and by forming partnerships between nephrology centres.

Review of the literature: severe hyperphosphatemia.

A patient with a markedly elevated serum phosphorus level (23.9 mg/dL) is described, followed by a brief review of severe hyperphosphatemia. Elevated serum phosphorus levels may be artifactual or true. True hyperphosphatemia is usefully subdivided according to (a) whether phosphorus is added to the extracellular fluid from a variety of exogenous or endogenous sources, or (b) whether the urinary excretion of phosphorus is reduced from either decreased glomerular filtration or increased tubular reabsorption. Severe hyperphosphatemia, defined herein as levels of 14 mg/dL or higher, is almost invariably multifactorial--usually resulting from addition of phosphorus to the extracellular fluid together with decreased phosphorus excretion. The hyperphosphatemia of the patient described herein appeared to result from a combination of dietary phosphorus supplementation, acute renal failure, acute pancreatitis, and ischemic bowel disease, complicated by lactic acidosis.

Uptake of atrial natriuretic peptide and production of cGMP in cultured human glomerular endothelial cells.

Interactions between human glomerular endothelial cells and atrial natriuretic peptide (ANP) were studied with 125I-alpha-human-ANP binding and intracellular accumulation of cGMP. Uptake for alpha-hANP (1-28 or 5-28) by homogeneous cultures of human glomerular endothelial cells was dose and time dependent with optimal uptake occurring after 30 min of incubation at 37 degrees C. Scatchard analysis of the specific binding data with a two-compartmental model identified both high (Kd = 0.3 nM)- and low (Kd = 10 nM)-affinity receptors, with a binding site density of 12,000 and 18,060 receptors per cell, respectively. alpha-hANP markedly stimulated glomerular endothelial cell-associated cGMP. After a 2-min incubation, cGMP increased 1.3-fold (from 17.88 +/- 1.29 to 23.33 +/- 3 pmol/mg of protein), in the presence of 1 nM ANP, to more than threefold (from 21 +/- .1 to 80.5 +/- 14.5 pmol/mg of protein) with 1 microM ANP (P < 0.05). In contrast, a 10 microM concentration of the clearance receptor C-ANP4-23 increased cGMP by 1.6 +/- 0.6 fold. ANP stimulation of intracellular cGMP was 100 times more sensitive in human glomerular endothelial than in mesangial cells. In comparison, higher doses of bradykinin were necessary to evoke similar responses in glomerular endothelial cells. In the presence of 10 microM bradykinin, cellular cGMP increased by 1.75 +/- 0.6-fold versus control cells. However, unlike ANP, bradykinin-stimulated cGMP synthesis was significantly inhibited by prior treatment with oxyhemoglobin (10(-5) M), an inhibitor of soluble guanylate cyclase, and NG-nitro-L-arginine (NO2Arg), a specific inhibitor of endothelial-derived relaxing factor (EDRF).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-converting enzyme-inhibited renography for the diagnosis of ischemic kidneys.

This report synthesizes the literature and the authors' experience in the use of angiotensin-converting enzyme-inhibited renography for the diagnosis of hypertension associated with critical renal arterial disease. The pathophysiology underlying the performance of the test and its interpretation are provided. The test is not a screening test of patients with hypertension. The need for preselection of patients is emphasized. The differences in using glomerular versus tubular radioisotopic agents are identified. Patient preparation, testing procedure, and interpretation of the data are reviewed. Clinical conditions, other than those in which hypertension is associated with critical disease of the main renal artery, in which false-positive renographic tests have occurred, are listed.

Effect of protein diets on the renal function of baboons (Papio hamadryas) with remnant kidneys: a 5-year follow-up.

To assess the progression of renal disease and the effects of protein intake in a species phylogenically close to humans, 14 adolescent baboons (Papio hamadryas) were subjected to infarction of one third of the left kidney and, 2 months later, to right nephrectomy. They were then randomized to a synthetic protein diet containing either 8% or 25% casein. Hemodynamic and metabolic measurements were obtained in awake animals every 4 months. Modest proteinuria developed immediately after left kidney infarction, and hypertension after right nephrectomy. Proteinuria and hypertension, however, were similar in both groups and did not progress for the next 60 months. Inulin clearance markedly increased with implementation of the synthetic diet in baboons given 25% protein, in contrast to animals given 8% protein, averaging 46.6 +/- 4.7 mL/min versus 28.2 +/- 2.6 mL/min, respectively, after 4 months. The glomerular filtration rate (GFR) changed little immediately thereafter and, at 1 year, averaged 43.0 +/- 1.4 mL/min and 28.0 +/- 4.3 mL/min, respectively. During the next 4 years, however, inulin clearance steadily decreased in baboons fed 25% protein. The inverse correlation between inulin clearance and time of follow-up was y = 48.5 - 0.36x (r = -0.879, P < 0.001) in baboons fed 25% protein and y = 29.0 - 0.11x (r = -0.625, P < 0.02) in baboons fed 8% protein. Nevertheless, after 5 years, the mean GFR was still significantly greater in animals given the 25% protein diet than in baboons fed 8% protein, averaging 29.1 +/- 0.6 mL/min and 24.1 +/- 1.0 mL/min, respectively (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Baseline characteristics in the Modification of Diet in Renal Disease Study.

The Modification of Diet in Renal Disease Study is randomized, multicenter, clinical trial designed to determine the effects of three levels of dietary control of protein and phosphorus and two levels of blood pressure control on the rate of decline of kidney function among persons with chronic renal disease. Study participants were assigned to one of two studies, Study A or Study B, depending on their GFR just before randomization. Within each study, participants were randomly allocated to one of two levels of blood pressure control and to one of two dietary interventions according to separate 2 x 2 factorial designs. A total of 840 men and women aged 18 to 70 were randomized. This report summarizes the demographic, biochemical, and clinical characteristics of the randomized participants at the time of entry into the trail, overviews the protocol and purposes of the baseline period before randomization, and evaluates the balance among the treatment intervention groups within Studies A and B at the time of randomization. Major indicators of renal function were found to be well balanced among the treatment groups. Selected baseline characteristics of participants in the Modification of Diet in Renal Disease Study are compared with those of other renal clinical trials and with those of new cases of treated ESRD reported in the United States Renal Data System.

Culture of endothelial cells from baboon and human glomeruli.

Whereas mesangial and epithelial cells from glomeruli are commonly grown in vitro, there has been a failure to isolate and propagate human glomerular capillary endothelial cells. This study defines the conditions for the reproducible isolation and growth of homogeneous monolayers of primate (baboon and human) glomerular capillary endothelial cells. Using selective media and growth factors, the following criteria were identified to optimize the isolation and proliferation of glomerular endothelial cells: (1) collagenase treatment of isolated glomeruli; (2) requirement for 20% serum, endothelial cell growth factor and heparin; (3) requirement of fibronectin as surface matrix; and (4) isolation from donors less than 60 years old, as premature senescence was directly proportional to the age of the human kidney donor. Under these conditions, primary cultures with an endothelial cell composition greater than 70% were reproducibly obtained. Homogeneous endothelial monolayers were developed from 20 of 23 human kidneys, and maintained for 5 to 10 passages, depending on the age of the kidney donor. Purification to homogeneity was achieved by patch cloning or by fluorescence-activated cell sorting. Glomerular capillary endothelial cells exhibited a cobblestone morphology at confluence, expressed factor VIII-related antigen, angiotensin converting enzyme activity, and endocytosed acetylated low-density lipoproteins. Electron microscopy revealed the presence of intracellular Weibel-Palade bodies and caveolae and microvillous projections on the luminal surface. Glomerular cells also stained positive for Ulex europaeus, a lectin characteristic of human endothelial cells. In addition, preliminary results indicate that human glomerular endothelial cells increase intracellular cyGMP in response to alpha-human 5 to 28 atrial natriuretic peptide and intracellular free calcium in response to thrombin.

Progression of renal disease: current concepts and therapeutic approaches.

The pathogenesis of progressive renal disease includes systemic hypertension and intrarenal factors that may be hemodynamic or metabolic in origin and involve mediators of inflammation. Most current information derives from experiments in rodents. In other species (rabbit, dog, baboon) subjected to renal mass reduction, a greater variety of pathologic changes is apparent than in rats. Clinical trials at controlling progression of renal disease are compounded by numerous factors; and it is not evident that extrapolation can safely be made from results of animal studies to human disease. The mechanism(s) of renal disease progression in humans, therefore, remain largely unknown. Current therapeutic recommendations in patients with chronic renal disease include limitation of phosphorus absorption, correction of lipid abnormalities and control of systemic blood pressure. The latter can be achieved with a variety of agents some of which, like angiotensin converting enzyme inhibitors and calcium antagonists, may be preferred because of specific intrarenal effects.

HIV infects glomerular endothelial and mesangial but not epithelial cells in vitro.

The infectivity of human immunodeficiency virus (HIV-1) in human glomerular cells was evaluated by exposing homogeneous cultures of human glomerular capillary endothelial, mesangial and epithelial cells to HIV in vitro. Infectivity and HIV expression was assessed by: 1) the measurement of p24 antigen production from culture supernatants; 2) the presence of p24 antigen intracellularly by immunofluorescence; 3) levels of P24 antigen production or syncytia formation following the cocultivation of glomerular cells exposed to HIV with normal human peripheral blood mononuclear cells or MT-2 lymphocytes; and 4) the presence of intracellular HIV DNA by polymerase chain reaction. The results indicate that HIV can infect and replicate in glomerular capillary endothelial cells and in a small percentage of mesangial cells, but not in human glomerular epithelial cells in vitro.

Report of the Working Party Group for Patient Selection and Preparation.

Captopril renography is a valuable test in the diagnosis of patients with renal artery stenosis. We examined the criteria for selecting patients for this procedure and the best methods for preparing the patient for renography.

The nephropathology in human immunodeficiency virus (HIV-1) infection.

The nephropathology observed in patients with HIV infection is reviewed. A characteristic, though not specific, nephropathy associated with HIV infection can be encountered in HIV carriers, in patients with AIDS-related complex and in patients with AIDS. HIV-associated nephropathy typically exhibits the features of an aggressive form of focal and segmental glomerulosclerosis. Distinctive pathologic features include: 1) the "collapsing" and predominantly global pattern of glomerulosclerosis; 2) the severity of visceral epithelial cell hypertrophy and droplet formation; 3) the prominent tubular microcysts and cast formation; 4) the focal tubular degenerative features; and 5) the numerous tubuloreticular inclusions.

Renographic diagnosis of renovascular hypertension with angiotensin converting enzyme inhibition and furosemide.

Captopril renography is a powerful tool for evaluating renovascular hypertension. In this article we examine four different protocols: 99mTc-DTPA, [131I]hippuran with captopril, [131I]hippuran with enalaprilat, and 99mTc-mercaptoacetyltriglycine (MAG3). In our experience, [131I]hippuran renograms are a reliable and reproducible test in patients both with and without azotemia. Although our experience with the new 99mTc-MAG3 technique is somewhat limited, it appears that this will also be a valuable test, which additionally has several advantages over hippuran, namely, a smaller turnaround time between test and baseline study, a smaller dose of radioactivity, better images, and more accurate counts. We look forward to the future development of this technique.