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Elevated arterial pressure enhances the risk for cardiovascular (CV) events in patients with diabetic nephropathy. The optimal BP and the component of the elevated BP that affect the risk have not been defined. A post hoc analysis was performed to assess the impact of achieved systolic, diastolic, and pulse pressures on CV outcomes in 1590 adults who had overt diabetic nephropathy and were enrolled in the Irbesartan Diabetic Nephropathy Trial (IDNT) and had a baseline serum creatinine above the normal range, up to 266 micromol/L (3.0 mg/dL), 24-h urine protein >900 mg/d, and at least 6 mo of follow-up. Patients were randomized to irbesartan, amlodipine, or placebo, with other antihypertensive agents to a BP goal of < or =135/85 mmHg. Progressively lower achieved systolic BP (SBP) to 120 mmHg predicted a decrease in CV mortality and congestive heart failure (CHF) but not myocardial infarctions (MI). A SBP below this threshold was associated with increased risk for CV deaths and CHF events. Achieved diastolic BP <85 mmHg was associated with a trend to increase in all-cause mortality, significant increase in MI, but decreased risk for strokes. Increased pulse pressure predicted increased all-cause mortality, CV mortality, MI, and CHF. It is concluded that achieved SBP approaching 120 mmHg and diastolic BP of 85 mmHg are associated with the best protection against CV events in these patients. BP < or =120/85 may be associated with an increase in CV events.

Individuals with type 2 diabetes and nephropathy represent a particularly high-risk group for both adverse cardiac as well as renal events. Using the Irbesartan in Diabetic Nephropathy Trial (IDNT) cohort, our objective was to determine baseline characteristics of individuals with type 2 diabetic nephropathy and hypertension predictive for cardiac events. IDNT identified 1715 individuals with type 2 diabetic nephropathy and hypertension having serum creatinine of 1.0 to 3.0 mg/dL and urinary albumin excretion rates > or = 900 mg/day. A cardiovascular (CV) composite was used consisting of CV death, nonfatal MI, hospitalization for heart failure, stroke, amputation, and coronary and peripheral revascularization. Using multivariable Cox regression analysis, 41 baseline characteristics determined a priori were analyzed for their potential relationship to risk of experiencing a CV event. Of the 1715 individuals, 518 (30.2%) had at least one of the CV composite end points. Older age, male gender, longer duration of diabetes, history of cardiovascular disease, history of CHF, high urinary albumin:creatinine ratio, and low serum albumin were strong predictors for CV events; of these, prior history of CVD (RR 2.00, 95% CI 1.63-2.45; P < 0.0001) and high urinary albumin:creatinine ratio (RR 1.29 per natural log unit, 95% CI 1.13-1.48; P = 0.0002) at baseline were highly predictive for cardiovascular events. In conclusion, among individuals with hypertension and diabetic nephropathy, both the degree of albuminuria and lower serum albumin levels provide additional prognostic information concerning cardiovascular risk, in addition to traditional coronary risk factors.

During the Irbesartan Diabetic Nephropathy Trial, 1,387 participants with type 2 diabetes mellitus, hypertension, and nephropathy underwent serial electrocardiograms for the identification of Q-wave myocardial infarction (MI). During a mean follow-up of 2.5 years, 14 of 99 first nonfatal MIs in this group were clinically unrecognized, accounting for 14% of all first nonfatal MIs.

Background: Patients with diabetes have increased risk for adverse cardiovascular events. Angiotensin-converting enzyme inhibitors are protective in type 1 diabetes. However, no definitive studies have examined the use of angiotensin-receptor blockers in patients with type 2 diabetes and overt nephropathy. The primary outcomes of the Irbesartan Diabetic Nephropathy Trial were doubling of serum creatinine levels, end-stage renal disease, and death from any cause., Objective: To compare rates of cardiovascular events among patients with type 2 diabetic nephropathy who received conventional antihypertensive therapy with an angiotensin-receptor blocker (irbesartan) or a calcium-channel blocker (amlodipine), or placebo., Design: Randomized double-blind, placebo-controlled trial with a median follow-up of 2.6 years. A time event analysis was used., Setting: 209 centers in the Americas, Europe, Israel, and Australasia., Participants: 1715 adults with type 2 diabetic nephropathy and hypertension; serum creatinine levels of 89 micromol/L (1.0 mg/dL) to 266 micromol/L (3.0 mg/dL) in women and 106 micromol/L (1.2 mg/dL) to 266 micromol/L (3.0 mg/dL) in men; and urinary protein excretion rates of at least 900 mg/d., Intervention: Treatment with irbesartan, amlodipine, or placebo., Measurements: Time to cardiovascular death, myocardial infarction, congestive heart failure, strokes, and coronary revascularization., Results: The three groups were not statistically different in the composite of cardiovascular events. Among the components of the composite, there was a trend toward a decrease in strokes in patients receiving amlodipine versus those receiving placebo (hazard ratio, 0.65 [95% CI, 0.35 to 1.22]; P = 0.18). Likewise, patients receiving amlodipine had a significantly lower rate of myocardial infarction when compared with placebo recipients (hazard ratio, 0.58 [CI, 0.37 to 0.92]; P = 0.02). In contrast, patients receiving irbesartan had a significantly lower incidence of congestive heart failure when compared with placebo recipients (hazard ratio, 0.72 [CI, 0.52 to 1.00]; P = 0.048) or amlodipine recipients (hazard ratio, 0.65 [CI, 0.48 to 0.87]; P = 0.004)., Conclusion: The composite cardiovascular event rate did not differ in patients with type 2 diabetes and overt nephropathy treated with irbesartan, amlodipine, or placebo in addition to conventional antihypertensive therapy.

The renal medulla contains more mRNA of the inducible isoform of nitric oxide synthase (iNOS) than the cortex, which may be important in preventing ischaemic injury, since blood flow and tissue oxygen tension are normally low in this region. We examined the effects of the bacterial endotoxin E. coli lipopolysaccharide (LPS) on renal function and regional expression of iNOS in male Sprague-Dawley rats. In six rats, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were 0.95 +/- 0.09 ml min(-1) g(-1) and 3.36 +/- 0.20 ml min(-1) g(-1), respectively, and decreased significantly to 0.35 +/- 0.09 and 1.74 +/- 0.54 ml min(-1) g(-1), respectively, 1 h after administration of LPS. In an additional seven rats, GFR and ERPF were 0.91 +/- 0.07 and 2.97 +/- 0.30 ml min(-1) g(-1), respectively, 18 h after LPS administration; these values were similar to those in control rats. In all rats, arterial pressure was stable throughout all study periods. In control rats, immunoblot analysis revealed expression of the iNOS protein in the cortex and more pronounced expression in the medulla. In rats studied 18 h after LPS treatment, there was a striking increase in the iNOS expression in the outer medulla. Immunohistochemical examination in the LPS-treated rats showed limited iNOS immunostaining in the cortex, localised to the vascular endothelium and macula densa; however, intense and widespread staining was noted in the tubular and vascular structures of the outer medulla. These findings demonstrated a differential constitutive expression of iNOS protein in different regions of the rat kidney, and marked augmentation of iNOS expression in the outer medulla by LPS.

Purpose: In the early stage of unilateral ureteral obstruction total renal blood flow increases but medullary blood flow decreases, exacerbating medullary tissue hypoxia. We examined the expression of inducible nitric oxide synthase, a product of a hypoxia sensitive gene, in the cortex and medulla in dogs with unilateral ureteral obstruction for 21 hours., Materials and Methods: Hemodynamic and clearance experiments were performed after release of ureteral obstruction in 6 dogs with unilateral ureteral obstruction, followed by Western blot analysis of nitric oxide synthase and immunohistochemistry., Results: Ureteral obstruction raised mean ureteral pressure plus or minus standard error to 35.0 +/- 7.2 mm. Hg. In dogs with unilateral ureteral obstruction mean renal blood flow was 116 +/- 10 ml. per minute, lower than the 213 +/- 22 ml. per minute in sham operated dogs (p <0.01). After unilateral ureteral obstruction release the mean glomerular filtration rate was 9.5 +/- 2.1 ml. per minute, lower than the 27.3 +/- 1.8 ml. per minute in the contralateral unobstructed kidney (p <0.01). Western blot analysis showed that mean nitric oxide synthase/beta-actin in the cortex of the obstructed kidney was 0.04 +/- 0.01 densitometry units, lower than 0.11 +/- 0.02 densitometry units in the unobstructed contralateral kidney (p <0.05). In contrast, mean nitric oxide synthase/beta-actin in the medulla of the obstructed kidney was 1.29 +/- 0.33 densitometry units, greater than the 0.34 +/- 0.03 densitometry units in the unobstructed kidney (p <0.05). Immunohistochemistry revealed that the increased expression of nitric oxide synthase protein was localized to the endothelium of the vasa recta., Conclusions: Unilateral ureteral obstruction enhances nitric oxide synthase expression in the medulla but not in the cortex. This increased expression in the medulla may be the result of increased medullary hypoxia in unilateral ureteral obstruction, possibly contributing to medullary hyperemia after unilateral ureteral obstruction release.

We report a 28-year-old male who presented with a clinical picture compatible with idiopathic polymyositis and nephrotic-range proteinuria. Muscle biopsy confirmed the diagnosis of polymyositis and a diagnostic renal biopsy demonstrated IgM mesangial glomerulonephritis. Following a short-course of prednisone, both the myositis and proteinuria resolved. Glomerulonephritis associated with idiopathic polymyositis is rare; however, since it appeared to respond to corticosteroid therapy concomitant with the improvement in the myositis, it was likely an associated immunological complication.

Idiopathic focal segmental glomerulosclerosis (FSGS) is a common cause of glomerular disease. Although previous case reports suggesting a familial form of the disease exist in the literature, its significance has not been emphasized. We report on our experience with nine cases in four families, as well as a review of the literature, and provide evidence that a familial form of FSGS might represent a distinct genotypic and phenotypic subset of idiopathic FSGS.

The aging process in man leads to some loss of kidney mass and function. The kidney produces epidermal growth factor (EGF), a polypeptide involved in the repairing process of epithelial cells. Human urine contains high concentrations of EGF, derived from its production in the kidney. It is not known if aging alters urinary EGF production in humans. This study investigates the possibility of decreased urinary EGF in elderly people. Urine samples were collected from 70 healthy subjects of various ages and measured for EGF by the technique of radioimmunoassay. The studied urine samples were divided into five age groups (3 to 10, 11 to 20, 21 to 60, 61 to 70, and 71 to 80 years). Urinary EGF (corrected for the urine creatinine concentration and measured as ng per mg creatinine) was highest in the two youngest groups, 78.5 +/- 14.3 and 76.2 +/- 18.8 (mean +/- standard error of the mean), respectively, and decreased with age so that the lowest urinary EGF was observed in the oldest group (27.0 +/- 8.8 ng per mg creatinine). In addition, a significant inverse relationship exists between urinary EGFD in all 79 subjects and their respective age (P < 0.001). These findings show that normal values of urinary EGF should take age into account. The reduced production of EGF by the kidney in the elderly may have functional significance in retarding the repair process in the kidney.

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.

High-dose trimethoprim-sulfamethoxazole (TMP-SMX) causes hyperkalemia, thought to result from TMP-induced blockade of amiloride-sensitive Na(+)-channels in the distal nephron. The present study was performed in anesthetized dogs to determine if increasing distal sodium delivery affects this antikaliuretic effect. In Group 1, intrarenal infusion of vehicle did not alter renal function. In Group 2, i.v. infusion of amiloride led to diuresis, natriuresis and antikaliuresis associated with a reduction of the transtubular potassium gradient (TTKG) in both kidneys. Intrarenal infusion of TMP (0.2 mg/kg/min) into the left kidney did not further alter these parameters. In groups 3 and 4, intrarenal infusion of TMP caused an ipsilateral diuresis, natriuresis, antikaliuresis and a reduction in (TTKG) without affecting the contralateral kidney. The TMP infusion was followed by furosemide (20 mg i.v.) in group 3 and acute saline loading in group 4. Despite continuous TMP infusion, both furosemide and saline loading reversed the antikaliuretic effect of TMP in the ipsilateral kidney and was associated with a similar kaliuresis, diuresis, natriuresis and decrease in urine osmolality in both kidneys. The TTKG following furosemide or saline loading increased in the ipsilateral kidney and decreased in the contralateral kidney. In all groups the systemic and renal hemodynamics remained unchanged. These results suggest that acute administration of TMP inhibits the amiloride-sensitive Na(+)-channel and K+ secretion in the distal nephron. Maneuvers that increase distal Na+ delivery can abrogate TMP's antikaliuretic effect due, in part, to an increase of the low TTKG observed with TMP.

The Modification of Diet in Renal Disease Study was a multicenter trial of the effect of protein restriction and strict blood pressure control on the progression rate of chronic renal failure of multiple causes. At the first baseline visit, 1,795 screened patients with renal disease had blood pressure measured, antihypertensive medications recorded, glomerular filtration rate (GFR) determined by 125I-iothalamate clearance, a nutritional assessment, and a 24-hour urine collection to determine sodium and potassium levels. A total of 1,494 patients in this cohort were classified as hypertensive (83%) and the remainder (301 patients) as nonhypertensive. Ninety-one percent of the hypertensive subjects were on treatment, 54% being controlled to a blood pressure of < or = 140/90 mm Hg. To better understand the factors that contribute to the development of hypertension in chronic renal disease, some determinants of the prevalence of hypertension in this cohort were investigated. Compared with normotensive subjects, hypertensive patients were older (51.2 +/- 12.7 years v 46.6 +/- 13.1 years [mean +/- SD]), had a higher body mass index (BMI; 27.5 +/- 4.7 kg/m2 v 25.4 +/- 4.2 kg/m2), and had a lower GFR (37.8 +/- 19.6 mL/min/1.73 m2 v 50.1 +/- 25 mL/min/1.73 m2). All these differences were significant (P < 0.01). The prevalence of hypertension was significantly higher for men than for women (86% v 80%; P = 0.001), and for blacks than for whites (93% v 81%; P < 0.001). The prevalence of hypertension was higher in subjects with glomerular disease than in those with tubulointerstitial disease (85% v 62.6%; P < 0.001). The prevalence of hypertension varied inversely with GFR (from 66% at a GFR of 83 mL/min/1.73 m2 to 95% at a GFR of 12 mL/min/1.73 m2). The prevalence of hypertension varied directly with BMI (from 70% with a BMI at the 10th percentile to 94% with a BMI at the 97th percentile). This relationship was independent of GFR. Multiple logistic regression analysis showed five predictors in decreasing order of significance as determined by chi-square values: GFR, 83.2; BMI, 36.7; black race, 19.9; increasing age, 14.5 (all P < 0.001); and male gender, 5.1 (P = 0.024). Salt intake was not a determinant of blood pressure status. These results confirm previous reports indicating that hypertension in renal disease is determined by the level of renal function. For the first time, three factors known to predict blood pressure levels in populations with normal renal function were also shown to be determinants of blood pressure in renal disease: BMI, black race, and age. In addition, the data suggest that hypertension is inadequately treated in more than half of patients with chronic renal disease in the United States.

Ascites in hemodialysis patients has been reported in association with systemic diseases, such as cirrhosis or congestive heart failure, and as an idiopathic form. Regardless of the etiology, these patients often are refractory to treatment with intradialytic ultrafiltration because of recurrent hypotensive episodes. In this report we describe the hemodynamic effects of peritoneovenous shunts (PVSs) in three hemodialysis patients with ascites refractory to conventional treatment. One patient had idiopathic ascites and the other two had associated liver disease. Patients were monitored for lowest blood pressure, number of intradialytic hypotensive episodes, number of grams of albumin infused to treat hypotensive episodes, interdialytic weight gain, and hemodynamic stability (defined as the difference between the predialysis mean arterial pressure and the lowest intradialytic mean arterial pressure). In all three patients the hemodynamic parameters stabilized after PVS placement despite equal or greater ultrafiltration during dialysis (due to a significant increase in the lowest measured intradialytic blood pressure). The total number of hypotensive episodes decreased from 219 prior to PVS placement to zero after shunt placement. The need for albumin infusion during hemodialysis (for blood pressure support) decreased (significantly in two patients), as did the volume of ascites in all three patients. One patient required PVS replacement secondary to infection, which was the only complication. We believe that refractory ascites in end-stage renal disease patients can be successfully treated by placement of a PVS, which often results in relief of the ascites and significant improvement in intradialytic hemodynamic stability.

Endothelins (ET) possess both vasodilatory and vasoconstrictive properties. The renal actions of ET-1 and ET-3, as well as in vivo interactions of these two isopeptides with the prostaglandin and endothelium-derived relaxation factor/nitric oxide systems were studied in anesthetized dogs. The ETs were infused intrarenally at doses not affecting systemic hemodynamics. Both ET-1 and ET-3 induced an early transient renal vasodilation, followed by a prolonged vasoconstriction. Inhibition of nitric oxide synthase with NG-monomethyl-L-arginine completely abolished the renal vasodilation induced by either ET-1 or ET-3 and enhanced the vasoconstriction. Endothelin-1 was associated with an increase in the renal release of prostacyclin, while urinary thromboxane A2 was increased after ET-3 administration. Inhibition of cyclooxygenase (with indomethacin) augmented the renal vasoconstriction induced by ET-1, but inhibition of cyclooxygenase (with meclofenamate) abolished the ET-3-evoked vasoconstriction. Endothelin-1 showed little effects on urinary water and sodium excretion; however, ET-3 displayed significant diuretic and natriuretic effects, which were inhibited by nitric oxide synthase inhibition. These findings suggest that these two isopeptides activate the endothelial endothelium-derived relaxation factor/nitric oxide system, which elicits early renal vasodilation, whereas direct effects on the vascular smooth muscle leads to vasoconstriction. Endothelin-3 causes diuresis and natriuresis, possibly by inducing release of nitric oxide in medullary collecting duct cells.

Acquired cystic kidney disease occurs in over 74% of patients with ESRD on hemodialysis for more than 4 yr. A variety of complications have been associated with these cysts including bleeding, lithiasis, infection, obstruction, and malignant transformation. An ESRD patient who developed accelerating hypertension secondary to an acute perinephric hematoma due to a bleeding-acquired renal cyst is described. The hypertension, which was refractory to aggressive drug therapy, was controlled only after the involved kidney was removed, after the demonstration of an elevated ipsilateral renal vein renin level. This is the first case reported in which worsening hypertension, apparently due to the "Page Kidney," developed as a complication of perinephric bleeding in an ESRD patient with acquired cystic kidney disease.

Objective: To determine the effect of trimethoprimsulfamethoxazole (Tmp-Smx) on serum potassium concentration., Design: Retrospective cohort study., Setting: An urban teaching hospital., Patients: Fifty-one persons hospitalized for symptomatic infection with human immunodeficiency virus (HIV). Twenty-five patients who were taking high-dose Tmp-Smx (trimethoprim 20 mg/kg per day; sulfamethoxazole, 100 mg/kg per day) for Pneumocystis carinii pneumonia were the study group. Twenty-six patients who had not received the drug were the control group. Patients who received potassium supplements, those taking medications known to alter potassium homeostasis or renal function, or those with a serum creatinine level more than 186 mumol/L were excluded., Measurements and Main Results: Serum potassium concentration in the study group was 4.1 +/- 0.1 mmol/L (mean +/- SE) and increased by 1.1 mmol/L (Cl, 0.8 to 1.5 mmol/L) (P < 0.0001) 9.8 +/- 0.5 days after starting Tmp-Smx therapy. Patients followed longitudinally showed a progressive increase in serum potassium levels during therapy and a progressive decline after discontinuing Tmp-Smx. Blood urea nitrogen and serum creatinine levels increased mildly from 4.3 +/- 0.5 mmol/L and 85 +/- 6 mumol/L to 6.4 +/- 0.7 mmol/L and 113 +/- 8 mumol/L, respectively. The serum potassium level in the control group was 4.3 +/- 0.1 mmol/L and remained unchanged during hospitalization., Conclusions: High-dose Tmp-Smx therapy used for the treatment of P. carinii pneumonia in HIV-infected patients leads to an increase in the serum potassium concentration and may result in life-threatening hyperkalemia. Patients receiving high doses of Tmp-Smx require close monitoring of their serum potassium concentration, particularly 7 to 10 days after the start of therapy.

The hyperlipidemia of the nephrotic syndrome is characterized by an elevation of total cholesterol (TC) and low-density lipoprotein cholesterol (LDLC), with a normal or low high-density lipoprotein cholesterol (HDLC), and an increase in triglycerides (TGs) later in the course of the disease. If sustained, this lipid profile probably places these patients at increased risk for cardiovascular disease. Despite extensive trials of diet and drug therapy in patients with primary hyperlipidemias, few such trials exist in patients with the nephrotic syndrome. We conducted a randomized, prospective, double-blind, placebo-controlled trial to investigate the efficacy and safety of pravastatin, the newest cholesterol synthesis inhibitor, in the treatment of the hyperlipidemia of the nephrotic syndrome. After dietary modification was implemented, 13 patients received pravastatin and eight received placebo. All patients were maintained on a low-fat, low-cholesterol diet for the duration of the trial (24 weeks). The dose of pravastatin was increased from the initial 20 mg/d to 40 mg/d at week 10 or 18 if TC remained elevated (> 50th percentile). A bile acid sequestrant was added at week 18 if TC remained elevated and if the patient was already receiving the maximal pravastatin dosage. Dietary modification did not significantly change the lipid profile. Pravastatin (20 mg/d) reduced TC by 22% from a baseline of 301 +/- 28 mg/dL (P < 0.05) and LDLC by 28% from a baseline of 222 +/- 28 mg/dL (P < 0.05). When used at 40 mg/d (in six patients) no further change in the lipid profile was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Thrombosis is the most common complication of arteriovenous (A-V) access, resulting in malfunction or total failure. We describe the first use of the thrombolytic agent tissue plasminogen activator (t-PA) to declot the A-V access in 15 hemodialysis patients (14 A-V grafts and one fistula). The t-PA was infused directly into the A-V access in 10-mg doses, at 2-hour intervals, to a maximum of 30 mg. As determined by angiography, t-PA infusion resulted in a dramatic decrease in clot volume in all cases and complete lysis, with return of bruit and thrill, in 10 patients. Eight of the 10 were able to be treated with hemodialysis via the A-V access the following day. In these patients, angiography demonstrated stenosis at the venous end of the A-V access in eight of nine A-V grafts (the one fistula did not have a venous stenosis). Three patients reclotted within 24 hours, and one had bleeding 5 days later after dialysis requiring compression of the A-V access, which resulted in reclotting. Five patients had functioning A-V grafts 1 to 15 months after t-PA treatment (with angioplasty of the venous stenosis required in three of these), and one patient was lost to follow-up. All five patients in whom t-PA infusion was only partially successful had venous stenosis. One patient died before surgery (unrelated to t-PA). Thus, venous stenosis was present in 13 of 15 A-V accesses studied, the highest incidence reported to date.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of verapamil on papillary plasma flow (PPF) and Na+ excretion were studied in anesthetized chronic caval dogs with low cardiac output and Na+ retention. Infusion of verapamil into the left renal artery (5 and 10 micrograms.kg-1.min-1) caused a dose-dependent ipsilateral increase in renal blood flow and Na+ excretion (from 10 +/- 2 to 171 +/- 32 and 225 +/- 35 mu eq/min, respectively). PPF in the left kidney was 26.6 +/- 4.4 and was significantly greater than that measured in the contralateral kidney (13.3 +/- 2.4 ml.min-1.100 g-1) (P < 0.01). The natriuresis occurred independent of changes in cardiac output and peripheral vascular resistance. In a separate group of caval dogs in which stimulation of the renin-angiotensin and adrenergic systems was intensified with a tighter caval constriction, verapamil failed to induce renal vasodilation or natriuresis and PPF was not altered. Despite the disparate hemodynamic responses, verapamil stimulated renal production of both renin and prostaglandin E2 in both groups of caval dogs. We conclude that the ability of verapamil to induce papillary vasodilation may contribute to the natriuresis seen in the caval dog, in which the site of Na+ retention includes the loop of Henle.

Creation of an aortocaval fistula (ACF) in dogs induces salt and water retention, activation of the renin-angiotensin and adrenergic nervous systems and renal papillary ischemia associated with high levels of circulating atrial natriuretic peptide (ANP). The effects of intrarenal ANP (1.2 micrograms/min) infusion on systemic and renal hemodynamics, renal excretory function, renal output of renin and norepinephrine (NE) and papillary plasma flow (PPF) were studied in both normal and ACF dogs. ANP did not alter systemic hemodynamics in either group, but led to a significant increase in renal blood flow (RBF), glomerular filtration rate (GFR), urine flow rate (V), sodium excretion (UNaV) and fractional excretion of sodium (FENa), and a significant decrease in renal vascular resistance (RVR) and urine osmolality (UOsm) in normal dogs. GFR, RBF, RVR, V, UNaV, FENa and UOsm remained unchanged, however, in ACF dogs. In ACF dogs, both renal renin and NE output were significantly greater during baseline and remained significantly greater following ANP infusion, associated with a significantly lower PPF compared with normal dogs. These data suggest that ACF dogs are resistant to the renal effects of ANP, which can neither mitigate the hormonal mediators of sodium retention nor reverse the papillary ischemia observed in this model.

The incidence of end-stage renal disease among hypertensive patients is increasing. Early recognition of renal insufficiency is critically important, since reversible causes of renal failure, such as urinary tract obstruction and renal artery stenosis, may be identified and corrected. Control of hypertension slows the progression of renal failure. Once renal failure develops, special attention must be given to diet and drug therapy.

A clinic for patients with "resistant" hypertension was established and patients were followed by one physician, nurse, and secretary. The records of 105 randomly chosen patients out of 700 were reviewed. In 86 of 105 (82%), diastolic blood pressure was controlled (less than 90 mm Hg) (group I), but in 19 patients, after 54 +/- 6 (mean +/- standard error) months, it remained greater than 90 mm Hg (group II) with substantial improvement in 53% (10 of 19 patients). The two groups were similar in age (57 +/- 1 vs 54 +/- 3 years), race (84% vs 74% blacks), and sex (75% vs 86% female). The entry blood pressures in groups I and II were similar, 170 +/- 3/101 +/- 1 and 167 +/- 6/105 +/- 3 mm Hg, respectively. Last visit blood pressure was 130 +/- 1/79 +/- 1 in group I, lower than 156 +/- 5/94 +/- 2 in group II (p less than 0.05). At entry into the clinic and at the last visit, dosing and type of medications were similar in both groups. Although patient visits averaged 6.7/yr in both groups, patients in group II missed 1.7 +/- 0.3 compared with 0.9 +/- 0.1 visits/year for group I (p less than 0.01). Group II patients were also less compliant with medications, primarily because of psychosocial problems. Medications, however, were more available to this group, since 16 of 19 (84%) were Medicaid recipients, compared with 46 of 86 (53%) in group I (p less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

The renal actions of endothelin were examined by infusing it intrarenally in anesthetized dogs at 4 ng.min-1.kg-1 without affecting arterial blood pressure or cardiac output. Endothelin infusion caused a transient and significant increase in renal blood flow (RBF) by 13 +/- 2%, followed by large decreases in RBF and glomerular filtration rate (GFR; by 26 +/- 2 and 23 +/- 7%, respectively) but did not alter urine flow rate or absolute sodium excretion. After endothelin infusion, renal venous and arterial plasma 6-ketoprostaglandin F1 alpha increased from 250 +/- 58 and 117 +/- 31 to 1,044 +/- 249 and 617 +/- 211 pg/ml, respectively, and its renal output increased from 339 +/- 99 to 963 +/- 202 pg.min-1.g-1 (P less than 0.01 for all). The renal prostacyclin synthesis was augmented by endothelin without stimulating the renal renin release or norepinephrine output. Inhibition of prostaglandin synthesis with indomethacin partially prevented the early renal vasodilation induced by endothelin, which then caused a more pronounced decline in RBF and GFR (by 65 +/- 7 and 54 +/- 8%, respectively). With suppression of prostacyclin synthesis, inhibition of renin release by endothelin was observed. Thus the vasoconstrictive effects of endothelin on renal hemodynamics are significantly modified by its ability to enhance production of vasodilators, including prostacyclin.

From January 1, 1986 through June 30, 1989, 320 maintenance hemodialysis patients treated at The Brookdale Hospital Medical Center were tested for the presence of antibody to the human immunodeficiency virus (HIV) using the enzyme-linked immunosorbent assay (ELISA) and Western blot assays. Thirty-nine patients (12%) tested positive for HIV antibody (HIV+) with both the ELISA and Western blot, 24 (62%) of whom were known intravenous drug abusers (IVDA). Of the remaining non-IVDA patients, unanticipated HIV+ results were found in 10 (25%). Thirty-four (87%) of the 39 HIV+ patients were asymptomatic at the start of the study, while two had acquired immunodeficiency syndrome (AIDS) and three others, AIDS-related complex (ARC). Four patients subsequently developed AIDS 20 +/- 4.9 weeks (range, 12 to 32) after testing, three of whom initially had ARC. One patient developed ARC 7 months after testing. Sixteen HIV+ patients died, including five of the six with AIDS, one with ARC, and two others from Mycobacterium tuberculosis. The eight other deaths were from causes unrelated to HIV disease and occurred 12 +/- 2.3 months (range, 1 to 24) after testing. Two HIV+ patients were lost to follow-up. Twenty-one HIV+ patients (54%) are alive and 20 (51%) asymptomatic 15 +/- 2.4 months (range, 1 to 42) after HIV testing. Thus, despite HIV positivity, 28 patients (72%) had an asymptomatic period lasting 14 +/- 1.9 months (range, 1 to 42). Seventy-two of the 281 HIV-negative (HIV-) patients died during the study. None of the HIV- patients manifested ARC or AIDS, confirming that there was no false-negative HIV test.(ABSTRACT TRUNCATED AT 250 WORDS)

It is now becoming apparent that the medullary circulation in the kidney can be regulated separately from overall renal blood flow. This characteristic of the medullary circulation plays an important role in the kidney's ability to excrete a dilute or concentrated urine in concert with changes in water and sodium transport in the distal nephron secondary to the action of vasopressin, prostaglandins, the renal nerves, and other hormones without significant other renal hemodynamic changes. There is strong evidence that renal autocoids such as angiotensin II and prostaglandins uniquely affect regional blood flow in the inner medulla because of the special structure and organization of the microvasculature in this region. There is also evidence that this regional blood flow is in part regulated by circulating hormones, such as vasopressin and atrial natriuretic peptide, which are released in response to changes in extracellular fluid volume or osmolality. In addition, data are emerging to suggest that the kallikrein-kinin system, acetylcholine, the renal nerves and adenosine participate in this regulation. In addition to the role of the medullary circulation in the urinary concentrating operation, there are data to suggest that the medullary circulation either directly (by changes in physical forces) or indirectly (by regulating medullary toxicity) may influence sodium excretion in a variety of conditions. In this regard, activation of the renin-angiotensin system locally reduces blood flow in the papilla which may be necessary before sodium retention is fully expressed in salt retaining states. Future research looking at the microvasculature of the medulla and papilla and those factors that control the contractility of these vessels are necessary before a clearer picture emerges. Nevertheless, from the data already available it seems reasonable to suggest that the medullary circulation may be as important to kidney function during physiological and pathophysiological states as is the cortical circulation.

With better understanding of the pathophysiology of uremia, the development of more efficient dialysis techniques and more portable machinery, a larger number of patients on maintenance dialysis are not stable enough to undertake travel to places where a regular hemodialysis center may not be availabel or to travel on a ship for a relatively long period of time. Ten stable patients were taken on a 7 day cruise utilizing the relatively lightweight and portable REDY Dialysis System. The medical team consisted of 2 nurses, 2 technicians and 1 physician. The ship's infirmary was converted to a 4 bed hemodialysis unit. Complications were minimal and easily handled by the medical staff.

We tested a once-a-day antihypertensive regimen using minoxidil, nadolol, and a diuretic in 55 patients with resistant hypertension. Forty-seven patients had evidence of end-organ damage. Twelve had mild renal insufficiency (serum creatinine concentration, 2.5 +/- 0.3 mg/dL). In 34 patients, treatment with nadolol and a diuretic was started with minoxidil added one to four weeks later. In the remainder, minoxidil, nadolol, and a diuretic were begun simultaneously because of severe hypertension. Initial supine and standing blood pressure (BP) in the 55 patients were 186 +/- 4/111 +/- 2 and 180 +/- 4/108 +/- 2 mm Hg, respectively. After 7 +/- 1 weeks, BP was controlled in 46 patients (84%) with the supine and standing BP reduced to 140 +/- 3/80 +/- 1 and 134 +/- 3/80 +/- 1, respectively. In six patients, BP was controlled but intolerable side effects occurred, making the regimen therapeutically successful in 40 patients (73%). The BP remained controlled during a follow-up of 43 +/- 5 weeks. In 31 patients, BPs measured 24 hours after the last dose were not different from random measurements. Mean serum creatinine levels remained stable in the 12 patients with renal insufficiency.

Although the hemodynamic effects of diuretics have been studied extensively, their effects on inner medullary blood flow remain unknown. In the present study, renal hemodynamics, including papillary plasma flow measured by the albumin accumulation technique, and associated alterations in papillary tissue solute content were determined in anesthetized, hydropenic dogs and during euvolemic diuresis induced by furosemide (3 mg/kg plus 2 mg/kg per hr, iv), ethacrynic acid (3 mg/kg plus 2 mg/kg per hr, iv) or chlorothiazide (10 mg/kg plus 10 mg/kg per hr, iv). Renal blood flow increased significantly after furosemide and ethacrynic acid and decreased significantly after chlorothiazide. Sixty minutes after diuretic administration, papillary plasma flow was 10.8 +/- 1.0 (mean +/- SE) in six furosemide- and 11.3 +/- 2.6 ml/min per 100 g in six ethacrynic acid-treated dogs, both significantly lower than in eight normal or eight chlorothiazide-treated dogs [26.4 +/- 2.6 and 26.7 +/- 2.7 ml/min per 100 g, respectively (P less than 0.01)]. A similarly low papillary plasma flow was also noted 10 minutes after diuretic administration in five furosemide and four ethacrynic acid dogs (13.6 +/- 2.3 and 13.4 +/- 1.8 ml/min per 100 g, respectively). In furosemide and ethacrynic acid dogs, papillary osmolality and sodium content were significantly lower than those in normal or chlorothiazide dogs. In normal and chlorothiazide dogs, papillary sodium content was similar, with a significantly reduced papillary osmolality in the latter. At the time papillary plasma flow was measured, extracellular fluid volume was similar among the four groups of dogs; however, plasma renin activity increased significantly in furosemide and ethacrynic acid dogs (P less than 0.01) and remained unchanged in normal and chlorothiazide dogs. Furthermore, papillary plasma flow was restored to normal (25.3 +/- 3.9 ml/min per 100 g) in five dogs in which furosemide was infused during angiotensin II blockage with saralasin, despite a similar diuresis and natriuresis as the other furosemide group. These data demonstrate that after administration of furosemide, ethacrynic acid and chlorothiazide, regulation of papillary plasma flow is independent of renal blood flow, and suggest that angiotensin II may play a role in the reduced papillary plasma flow in furosemide and ethacrynic acid dogs.

One hundred patients participated in a double-blind, randomized study to compare the antihypertensive efficacy of sustained-release nifedipine and propranolol in hypertensive patients whose diastolic blood pressure exceeded 95 mm Hg while receiving diuretic therapy. Nifedipine (mean dose, 79.6 mg per day) decreased blood pressure by 11.4/10.5 mm Hg; propranolol (mean dose, 198.4 mg per day) decreased blood pressure by 13.5/10.3 mm Hg. Reduction of diastolic blood pressure to below 90 mm Hg was achieved in 63 percent of nifedipine-treated patients and in 57 percent of propranolol-treated patients. Nifedipine therapy was associated with an increase in high-density lipoprotein cholesterol levels and a decrease in serum triglyceride levels. In contrast, propranolol therapy was associated with a decrease in high-density lipoprotein cholesterol levels and an increase in serum triglyceride levels. Nifedipine is as effective as propranolol in the treatment of patients with mild to moderate hypertension whose blood pressure is inadequately controlled by diuretic therapy.

The effects of chronic salt depletion on medullary hemodynamics remain unknown. In the present study, sodium excretion, renal hemodynamics including papillary plasma flow, measured by the albumin-accumulation technique, and papillary tissue solute content were determined during hydropenia in 13 anesthetized sodium-replete and 10 sodium-depleted dogs. Salt depletion induced a significant rise in plasma renin activity and aldosterone without potassium depletion. Mean arterial pressure, GFR, and renal blood flow were similar in sodium-depleted and sodium-replete dogs. Despite a similar distribution of cortical blood flow (measured by the microsphere method) in the two groups, papillary plasma flow was markedly reduced in sodium-depleted dogs (8.8 +/- 1.7 vs. 22.8 +/- 1.9 ml X min-1 X 100 g-1 in sodium-replete dogs), associated with a significant decrease in renal sodium excretion. Furthermore, papillary osmolality and sodium concentration were significantly greater in sodium-depleted dogs. Ultrastructure examination revealed smooth muscle cells surrounding the efferent arterioles and pericytes with contractile potential encircling descending vasa recta. These results suggest that included in the complex hemodynamic adjustment to chronic sodium depletion is a significant reduction in inner medullary blood flow that may be important in maintaining enhanced papillary solute concentration. In addition, the anatomy of the medullary vasculature is compatible with regional regulation of medullary blood flow.

In 20 patients with severe hypertension, rapid oral clonidine titration was employed for control of blood pressure, with 0.2 mg as the initial dose followed by 0.2 or 0.1 mg at one hour and then 0.1 mg/hour, for a total dose of 0.8 mg. All 20 patients had a successful response, defined as a decrease in mean arterial pressure (MAP) of 30 mm Hg or more or attainment of a diastolic pressure of 100 mm Hg or lower. Baseline MAP was 160 +/- 4 (SEM) mm Hg (212 +/- 7/134 +/- 3) and decreased to 120 +/- 3 mm Hg (151 +/- 5/104 +/- 3). The mean dose was 0.32 +/- 0.02 mg, and mean response time 1.8 +/- 0.2 hours. Side effects were minimal, except for one patient who died of a cerebral infarct, which developed after the blood pressure was lowered with clonidine. Eighteen patients were treated in our emergency room; 14 were sent home after rapid titration. In ten who returned for a follow-up visit three to seven days later, blood pressure was reasonably well controlled, with clonidine and a diuretic only. Rapid oral clonidine titration can be effectively and, for the most part, safely used for treating severe hypertension even in an ambulatory setting. As with any other hypotensive drug, we recommended proceeding with caution, particularly in patients with symptomatic arteriosclerotic disease.

Sudden onset of congestive heart failure due to development of a femoral arteriovenous fistula in a hemodialysis patient is reported as a complication of repeated femoral vein catheterization for access. Closure of the fistula led to disappearance of signs and symptoms of congestive heart failure.

Metastatic pulmonary calcification, a well-known complication in patients with chronic disease, has been demonstrated postmortem in patients with a negative chest X-ray. Recently, scintigrams with bone-seeking radionuclides have been used to detect such subclinical pulmonary calcium deposits. We describe 23 patients on maintenance hemodialysis with no evidence of pulmonary calcification on chest X-ray who were prospectively studied by lung scanning with a bone-seeking radionuclide and pulmonary function testing. Of the 23 patients, 14 (61%) had a positive technetium-99m diphosphonate (99mTc-DP) scan (group 1). These patients were on dialysis 38 +/- 5 months compared with 12 +/- 4 months in 9 patients with a negative scan (group 2) (P less than 0.01). Age, sex, blood pressure, hematocrit, serum calcium, phosphorous, bicarbonate, magnesium, and calcium X phosphorus product, as well as parathyroid hormone level did not differ between the two groups. Of 10 group-1 patients tested, 7 had abnormal pulmonary diffusion capacity compared with non in 5 group-2 patients tested (P = 0.014). Histologic examination of the lung in 1 group-1 patients who expired revealed calcification (amorphous on X-ray diffraction), whereas none was found in 1 group-2 patients autopsied. These observations suggest that in patients on maintenance hemodialysis, pulmonary scanning with 99mTc-DP is a sensitive method for detecting pulmonary metastatic calcification, which may be associated with an abnormality in pulmonary diffusion capacity.

It has been suggested that the establishment of a tubular fluid to plasma chloride gradient in the late proximal tubule by the reabsorption of bicarbonate (and other anions) in the early proximal tubule is responsible for a significant part of sodium chloride and water reabsorption in the proximal tubule. In the present study the effects of acetazolamide on proximal tubule water and electrolyte excretion were examined in 6 normal dogs and 10 chronic ammonium chloride-loaded dogs during distal blockade produced by ethacrynic acid and chlorothiazide administration. During distal blockade control urine/plasma osmolality and urine/plasma sodium were close to unity in all experiments. Urine/plasma chloride and urine/plasma bicarbonate were 1.21+/-0.02 and 0.75+/-0.07 in normal and 1.24+/-0.01 and 0.04+/-0.01 in acidotic dogs, respectively. After the administration of acetazolamide (20 mg/kg i.v.), there was a significant increase in urine flow, absolute and fractional excretion of sodium, bicarbonate, and chloride in all animals. Associated with these effects, urine/plasma osmolality and urine/plasma sodium remained unchanged but urine/plasma chloride decreased significantly to 1.15+/-0.01 in normal and to 1.19+/-0.01 in acidotic dogs. In acidotic dogs there was a significant correlation between the increase in bicarbonate, sodium, or chloride excretion after acetazolamide and the plasma bicarbonate level (range 6.8-12.5 meq/liter). These data demonstrate a significant effect of acetazolamide on bicarbonate, sodium, and chloride reabsorption in the proximal tubule even in the face of severe acidosis. Moreover, the data suggest that the decrease in chloride reabsorption (and accompanying sodium) after acetazolamide is related to the decrease in bicarbonate reabsorption and the associated decrease in the transtubular chloride gradient.

Uteroplacental ischemia is associated with uterine renin release in pregnant nephrectomized rabbits. In the present study, uterine and renal renin release after uteroplacental ischemia were investigated in 10 Australian white rabbits at 24 to 28 days' gestation. Pentobarbital was administered, and both uterine arteries were ligated close to their origins. Blood samples were taken for plasma renin activity (PRA) determinations from the femoral artery, uterine vein, and right renal vein before ligation and at 30 and 60 minutes after ligation. Mean arterial blood pressure (MAP) was monitored throughout. In five additional pregnant rabbits renal blood flow (RBF) was measured with an electromagnetic flowmeter. The preligation uterine vein-artery PRA difference was not significant (1.9 +/- 1.1 ng/ml/hr). Postligation uterine vein-artery PRA was 11.4 +/- 3.2 at 30 minutes and 6.6 +/- 1.9 ng/ml/hr at 90 minutes (p less than 0.02). Preligation renal vein-artery PRA was 32.3 +/- 10.5 ng/ml/hr (p less than 0.02) and did not change significantly after ligation. MAP remained stable and RBF was unchanged after uterine artery ligation. These observations confirm the finding that the kidney is the primary source of renin in the normal pregnant rabbit and demonstrate that following acute uteroplacental ischemia there is significant uterine renin release even when the kidneys are intact.