Albuminuria reduction: the holy grail for kidney protection.

Increased urinary excretion of albumin or total protein has become firmly established as a risk predictor for progression of chronic kidney disease. Observational analyses have raised a strong hypothesis that albuminuria reduction should be a clinical treatment target. Bakris et al. report further exploration of albuminuria-lowering capabilities of intensified renin-angiotensin system inhibition in a randomized clinical trial that included patients at high cardiovascular risk, most of whom appeared to have diabetic kidney disease.

Diabetic nephropathy: implications for renal and cardiovascular outcomes.

Diabetic nephropathy is a disease entity that is becoming more prevalent in the developed world. Its effect on individuals and society is profound, both in terms of cost and on patient health, especially in relation to associated cardiovascular disease. This review is an analysis of the most recent data available on diabetic nephropathy and its clinical applications to patient care. Using Medline search for relevant data from 1983 to the present, it focuses on clinical strategies that are employed to help curtail the progressive nature of this disease. Current strategies, including glycemic control, blood pressure treatment, inhibition of the renin/angiotensin system, nutrition, and hyperlipidemia, are discussed in relation to the relevant clinical data. Current clinical markers and possible future treatments are also discussed in the context of aiming to improve clinical outcomes in patients who are affected.

Ischemic nephropathy.

Ischemic nephropathy is a major cause of chronic renal failure in people over 50 years of age. In addition, renal artery stenosis is associated with increased mortality, particularly if renal or cardiac function is compromised. The diagnosis is made both by clinical characteristics and imaging studies. At present, duplex Doppler ultrasound and magnetic resonance angiography appear to be the most promising non-invasive screening tests. Although data from controlled trials are lacking, revascularization is the mainstay of therapy for ischemic nephropathy. Advances in percutaneous interventions now allow revascularization to be offered to many patients, including those who are poor surgical candidates. The role of medical therapies (statins, angiotensin-converting enzyme inhibitors, intensive control of blood pressure) and how to best utilize revascularization (which patients and when) remain to be defined.

Urinary albumin and insulin as predictors of coronary artery disease: An angiographic study.

Microalbuminuria has been associated with cardiovascular risk factors, events, and mortality. It also clusters with hyperinsulinemia and the metabolic syndrome. How urinary albumin excretion and the fasting serum insulin level relate to coronary artery disease (CAD) has not been previously determined. In 308 patients undergoing elective coronary angiography, the albumin to creatinine ratio was measured in urine from an early morning void. The fasting serum insulin level was also determined. CAD was assessed by angiography. Urinary albumin excretion was 28 +/- 5 mg/g (mean +/- SE) in patients with CAD and 10 +/- 1 mg/g in those without CAD (P < 0.001). Fasting serum insulin levels were also greater in patients with CAD compared with those without CAD; 20 +/- 3 and 13 +/- 1 microU/mL, respectively (P = 0.016). Urinary albumin excretion and fasting serum insulin levels increased progressively with severity of CAD. In patients without diabetes (n = 255), significant relationships of urinary albumin excretion and the fasting serum insulin levels to CAD were observed, but they were more pronounced when patients with diabetes (n = 53) were included. In multiple regression analysis, the odds ratios for severe CAD were 2.2 (95% confidence interval, 1.1 to 4.5) for microalbuminuria and 2. 2 (95% confidence interval, 1.3 to 3.8) for hyperinsulinemia. In summary, urinary albumin excretion and the fasting serum insulin levels were directly related to angiographic evidence of CAD. Microalbuminuria and hyperinsulinemia predict a significantly elevated risk for coronary atherosclerosis.

Endovascular stents for renal artery revascularization.

Revascularization cures or attenuates the clinical manifestations of renal artery stenosis (hypertension, ischemic nephropathy, pulmonary edema, angina, and congestive heart failure). Traditional approaches have been sub-optimal due to low rates of success and long-term patency after angioplasty, and to relatively high rates of perioperative morbidity and mortality. Endovascular stent placement is an alternative interventional method for renal artery revascularization. Technical success rates are excellent, and the impact on clinical outcomes (blood pressure, renal function, and cardiac complications) is promising.

Treatment of atherosclerotic ostial renal artery stenosis with the intravascular stent.

Traditional approaches to revascularization for atherosclerotic ostial renal artery stenosis (RAS) have been suboptimal because of the invasiveness and relatively high perioperative morbidity and mortality of surgery and the low rates of success and long-term patency with percutaneous renal angioplasty (PTRA). We report our 5-year (1991 to 1996) experience with the intravascular stent (Palmaz stent; Johnson & Johnson, Miami Lakes, FL) for the treatment of ostial RAS in 129 patients (63 men, 66 women) and 148 arteries. The mean age of the patients was 71+/-10 years; 98% were hypertensive and 57% had renal dysfunction. Angiographic characteristics of RAS were unilateral in 78%, bilateral in 15%, and single kidney in 7%. The technical success rates were 98% for stent versus 11% for PTRA in the ostial location. The stent restenosis rate (angiographic) was 14% at 8+/-5 months. Systolic and diastolic blood pressures were as follows: baseline, 158+/-3 and 84+/-2 mm Hg; 6 months, 149+/-3 and 81+/-2 mm Hg; 12 months, 149+/-3 and 79+/-2 mm Hg; and 24 months, 135+/-3 and 79+/-2 mm Hg. Follow-up values were significantly lower than baseline (P < 0.05). The number of medications for hypertension initially decreased from 2.2+/-0.1 at baseline to 1.6+/-0.1 and 1.8+/-0.1 at 1 and 3 months, respectively (P < 0.05). By 6 months, however, the number of medications had increased and was not significantly different from before stent placement. Renal function was stable in the group as a whole: Cockroft-Gault creatinine clearance (C-G CrCl) at baseline was 40+/-2 mL/min; at 6 months, 36+/-3 mL/min; at 12 months, 39+/-3 mL/min; and at 24 months, 39+/-4 mL/min. When stratified by degree of renal function, values were similarly stable. Patients with a baseline serum creatinine level of 2 mg/dL or less had C-G CrCl values as follows: baseline, 53+/-3 mg/dL; 6 months, 43+/-4 mg/dL; 12 months, 46+/-4 mg/dL; and 24 months, 52+/-5 mg/dL. Those with a baseline serum creatinine level greater than 2 mg/dL had C-G CrCl values as follows: baseline, 26+/-2 mg/dL; 6 months, 31+/-4 mg/dL; 12 months, 32+/-6 mg/dL; and 24 months, 23+/-3 mg/dL. Of eight patients who were dialysis dependent, four (50%) recovered renal function with a mean serum creatinine level of 2.3+/-0.5 mg/dL at 15+/-6 months (range, 9 to 24 months). Stent placement for the treatment of atherosclerotic ostial RAS has a high success rate and a low rate of restenosis. Control of hypertension improves in most patients. Renal function stabilizes or improves in the majority of patients, even those with severe renal failure. These favorable outcomes are maintained long term.

Increased lipoprotein(a) concentrations in chronic renal failure.

Subjects with chronic renal failure have a greatly increased risk of coronary heart disease and dyslipidemia. Relatively few studies have examined the relationship of chronic renal failure to lipoprotein (Lp)(a) concentrations, an important risk factor for coronary heart disease. Diabetic subjects have been reported to have both increased Lp(a) concentrations and an increased risk of renal failure, thereby possibly confounding the Lp(a)-renal failure association. The association between Lp(a) and chronic renal failure in 359 control subjects and 111 subjects with renal failure was examined. Lp(a) (in milligrams per deciliter) was elevated in subjects with chronic renal failure, regardless of ethnicity (Mexican Americans, 19.8 +/- 2.7 versus 14.1 +/- 1.3; P = 0.03; non-Hispanic white patients, 24.9 +/- 3.0 versus 16.3 +/- 1.2; P = 0.006;). These differences persisted after adjustment for diabetes and ethnicity (P < 0.001). The type of treatment for chronic renal failure (diet, hemodialysis, or peritoneal dialysis) did not have an effect on Lp(a) concentrations. Lp(a) levels were not correlated with the level of creatinine in subjects with chronic renal failure. Thus, the elevation of Lp(a) levels in renal failure must occur early in renal failure, or alternatively, elevated Lp(a) levels may promote progression to chronic renal failure. These results indicate that Lp(a) concentrations are increased in chronic renal failure and may increase the risk for coronary heart disease in these subjects.

Effect of insulin therapy on renal hemodynamic response to amino acids and renal hypertrophy in non-insulin-dependent diabetes.

Since renal hemodynamic disturbances are important in renal injury and are exacerbated by elevated plasma amino acid concentrations in insulin-dependent diabetes, we measured glomerular filtration rate (GFR) and renal plasma flow (RPF) after an overnight fast and during amino acid infusion in 12 patients with NIDDM and nine normal subjects. In the diabetic patients (plasma glucose 12.4 +/- 0.6 mmol/liter), the fasting GFR (113 +/- 6 vs. 98 +/- 7 ml/min.1.73 m2 in normal subjects, P = 0.056) and RPF (635 +/- 37 vs. 540 +/- 20 ml/min.1.73 m2 in normal subjects, P less than 0.05) were increased. After amino acid infusion, the increase in GFR (159 +/- 7 vs. 121 +/- 6 ml/min.1.73 m2 in normal subjects, P less than 0.05) and RPF (970 +/- 51 vs. 700 +/- 18 ml/min.1.73 m2 in normal subjects, P less than 0.05) were augmented. Insulin infusion for 36 hours did not change these responses. After three weeks of insulin therapy (plasma glucose 5.9 +/- 0.2 mmol/liter), the amino acid-stimulated GFR (143 +/- 5 ml/min.1.73 m2) and RPF (836 +/- 30 ml/min.1.73 m2) declined (P less than 0.05), while the fasting values remained unchanged. The right kidney volume was measured by ultrasonography and found to decrease after three weeks of insulin therapy from 188 +/- 12 to 165 +/- 9 ml/1.73 m2 (P less than 0.05). However, both values were greater than that in the normal subjects, 124 +/- 13 ml/1.73 m2 (P less than 0.01). Glomerular hyperfiltration and hyperperfusion became augmented during hyperaminoacidemia in our NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of change of lipoprotein (a) concentration with improved glycemic control in subjects with type II diabetes.

Recently, lipoprotein (a) [Lp(a)] has been identified as a major risk factor for coronary heart disease. No data are available on the effect of improved metabolic control on plasma Lp(a) concentrations in subjects with type II diabetes mellitus, a group at high risk for coronary heart disease. We examined the effects of improved metabolic control on plasma lipid and lipoproteins and Lp(a) concentrations in 12 subjects before and after 21 days of tight metabolic control. Glycosylated hemoglobin declined from 8.9% to 6.9% (P less than .002). Lp(a) increased slightly from 21.4 to 25.8 mg/dL (P = .119) with improved metabolic control. There were no significant differences in total, low-density, or high-density cholesterol values, although the decline in triglyceride concentrations was statistically significant. The distribution of apolipoprotein (a) [apo (a)] isoforms in subjects with type II diabetes mellitus was not unusual and the apo (a) isoform patterns did not change with improved metabolic control. Although the number of subjects was small, there was no decline in Lp(a) concentrations with improved control and thus the effect of glycemic control on Lp(a) concentrations may be much smaller in type II than in type I diabetes. These results suggest that diabetic subjects with elevated Lp(a) concentrations should have intensive management of conventional cardiovascular risk factors such as high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), and blood pressure.

Altered renal calcium handling in hypercalcemia of malignancy.

It has been controversial whether increased renal tubular calcium reabsorption contributes to hypercalcemia in patients with malignancies. Moreover, whether this abnormality is associated with volume depletion, a parathyroid hormone-like effect, or other mechanisms has not been clarified. Eight consecutive patients with hypercalcemia due to a variety of tumor types were studied in detail. The glomerular filtration rate (iothalamate clearance) was reduced in all patients (0.98 +/- 0.10 (mean +/- SE) mL/s.1.73 m2; P less than 0.001) compared with normal controls (N = 9) (1.93 +/- 0.08 mL/s.1.73 m2), but it was similar to that in controls matched for renal insufficiency (N = 6) (1.15 +/- 0.05 mL/s.1.73 m2). During hypercalcemia produced by calcium infusion, urinary calcium excretion (millimoles of calcium per liter of glomerular filtrate) was increased in controls with renal insufficiency compared to those with normal renal function (P = 0.028). In all patients with hypercalcemia of malignancy, urinary calcium excretion was decreased compared with controls with renal insufficiency, but it was low in only five of eight patients compared with normal controls. Extracellular fluid volume (iothalamate volume of distribution) was not decreased in any patient, and urinary cAMP and/or plasma parathyroid hormone-like bioactivity were increased in six of eight patients. After treatment with an inhibitor of bone resorption, aminopropylidene 1,1 diphosphonate, abnormal renal calcium handling was not detected if the serum calcium normalized. It was concluded that increased renal tubular calcium reabsorption was consistently present in patients with hypercalcemia of malignancy compared with controls matched for renal insufficiency, but the proportion with the abnormality was underestimated if normal controls were used.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of strict glycemic control on renal hemodynamic response to amino acids and renal enlargement in insulin-dependent diabetes mellitus.

BACKGROUND: Many patients with insulin-dependent diabetes mellitus have an increase in the glomerular filtration rate and renal enlargement early in the course of their disease. Both these changes may be risk factors for the later development of diabetic nephropathy. Their cause is not known, but they could be due to augmented renal responses to the increase in plasma amino acid concentrations that occurs when dietary protein intake is high, a factor known to increase glomerular filtration and renal blood flow in normal subjects. METHODS: We measured the glomerular filtration rate and renal plasma flow after an overnight fast and during an infusion of amino acids in 12 patients with insulin-dependent diabetes mellitus and 9 normal subjects. The diabetic patients were studied when they were hyperglycemic, when they were euglycemic after an insulin infusion for 36 hours, and after intensive insulin therapy for 3 weeks. Kidney volume was measured by ultrasonography before and after the period of intensive insulin therapy. RESULTS: The glomerular filtration rate and renal plasma flow were normal after fasting when the patients were hyperglycemic (mean [+/- SE] fasting plasma glucose level, 11.5 +/- 0.7 mmol per liter). After the amino acid infusion, these values increased more in the patients (glomerular filtration rate, 2.65 +/- 0.07 ml per second per 1.73 m2 of body-surface area; renal plasma flow, 13.30 +/- 0.68 ml per second per 1.73 m2; P less than 0.05 for both) than in the normal subjects (2.25 +/- 0.08 and 11.20 +/- 0.65 ml per second per 1.73 m2, respectively). The 36-hour infusion of insulin in the diabetic patients did not alter the glomerular filtration rate or renal plasma flow either before or during the amino acid infusion. After three weeks of intensive insulin therapy (fasting plasma glucose level, 5.3 +/- 0.2 mmol per liter), the glomerular filtration rate and renal plasma flow after the amino acid infusion (2.33 +/- 0.03 and 11.30 +/- 0.43 ml per second per 1.73 m2, respectively) were similar to those in the normal subjects. The kidney volumes in the normal subjects and the patients with diabetes were 219 +/- 14 and 312 +/- 14 ml per 1.73 m2, respectively (P less than 0.01); the volume decreased to 267 +/- 22 ml per 1.73 m2 (P less than 0.001) in the diabetic patients after three weeks of intensive insulin therapy, which was not significantly different from the volume in the normal subjects (P = 0.1). CONCLUSIONS: Conventionally treated diabetic patients who have normal renal function while fasting have augmented renal hemodynamic responses to increased plasma amino acid concentrations. The concomitant decrease in these hemodynamic responses and in kidney size with strict glycemic control suggests that these phenomena are related and influenced by the metabolic state.

Decrease of lipoprotein(a) with improved glycemic control in IDDM subjects.

OBJECTIVE: Recently, lipoprotein(a) [Lp(a)] has been identified as a major risk factor for coronary heart disease. There are few data available on the influence of metabolic control on plasma Lp(a) concentrations in subjects with insulin-dependent diabetes mellitus (IDDM), a group at high risk for coronary heart disease. RESEARCH DESIGN AND METHODS: We examined the effects of improved metabolic control on plasma lipid and lipoproteins and Lp(a) concentrations in 12 subjects before and after 21 days of tight metabolic control. RESULTS: Glycosylated hemoglobin declined from 8.4 to 6.9% (P less than 0.001), and Lp(a) declined from 29.7 to 27.1 mg/dl (P = 0.022). There were no significant differences in total, low-density lipoprotein, or high-density lipoprotein cholesterol, although the decline in triglyceride concentrations were borderline statistically significant. The distribution of apolipoprotein(a) isoforms in IDDM patients was not unusual, and the apolipoprotein(a) isoform phenotypes did not change with improved metabolic control. Lp(a) concentrations were also significantly higher than in a population-based control group of nondiabetic subjects from the San Antonio Heart Study. CONCLUSIONS: Although the number of subjects was small and the degree of improvement in metabolic control was modest, the results suggest that improved metabolic control may decrease the risk of coronary heart disease mediated by Lp(a) in IDDM.