Donald E. Wesson

Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy

In most patients with hypertensive nephropathy and low glomerular filtration rate (GFR), the kidney function progressively declines despite the adequate control of the hypertension with angiotensin-converting enzyme inhibition. Previously we found that 2 years of oral sodium citrate slowed GFR decline in patients whose estimated GFR (eGFR) was very low (mean 33 ml/min). This treatment also slowed GFR decline in an animal model of surgically reduced nephron mass. Here, we tested if daily oral sodium bicarbonate slowed GFR decline in patients with hypertensive nephropathy with reduced but relatively preserved eGFR (mean 75 ml/min) in a 5-year, prospective, randomized, placebo-controlled, and blinded interventional study. Patients matched for age, ethnicity, albuminuria, and eGFR received daily placebo or equimolar sodium chloride or bicarbonate while maintaining antihypertensive regimens (including angiotensin-converting enzyme inhibition) aiming for their recommended blood pressure targets. After 5 years, the rate of eGFR decline, estimated using plasma cystatin C, was slower and eGFR was higher in patients given sodium bicarbonate than in those given placebo or sodium chloride. Thus, our study shows that in hypertensive nephropathy, daily sodium bicarbonate is an effective kidney protective adjunct to blood pressure control along with angiotensin-converting enzyme inhibition.

Amelioration of metabolic acidosis in patients with low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR

Metabolic acidosis often accompanies low glomerular filtration rate and induces secretion of endothelin, which in turn might mediate kidney injury. Here we tested whether treatment of metabolic acidosis in patients with low glomerular filtration rate reduced the progression of kidney disease. Fifty-nine patients with hypertensive nephropathy and metabolic acidosis had their blood pressure reduced with regimens that included angiotensin-converting enzyme inhibition. Thirty patients were then prescribed sodium citrate, and the remaining 29, unable or unwilling to take sodium citrate, served as controls. All were followed for 24 months with maintenance of their blood pressure reduction. Urine endothelin-1 excretion, a surrogate of kidney endothelin production, and N-acetyl-beta-D-glucosaminidase, a marker of kidney tubulointerstitial injury, were each significantly lower, while the rate of estimated glomerular filtration rate decline was significantly slower. The estimated glomerular filtration rate was statistically higher after 24 months of sodium citrate treatment compared to the control group. Hence it appears that sodium citrate is an effective kidney-protective adjunct to blood pressure reduction and angiotensin-converting enzyme inhibition.

Cigarette smoking is associated with augmented progression of renal insufficiency in severe essential hypertension

Hypertension-associated renal disease is a major cause of end-stage renal disease (ESRD) in the United States, but its risk factors remain incompletely defined. Identification and correction of amendable ESRD risk factors among patients with essential hypertension could reduce ESRD prevalence. Patients referred by their primary care physician for hypertension management to an academic nephrology clinic during calendar year 1995 were followed up prospectively. Studied patients had no evidence of secondary hypertension, diabetes, or primary renal disease. All were treated pharmacologically toward a target mean blood pressure (MBP) of 100 mm Hg or less. The course of renal function during follow-up was assessed as the slope of the reciprocal of plasma creatinine concentration (1/P(cr)) plotted against months of follow-up and as the change in calculated glomerular filtration rate (GFR) in milliliters per minute per month. The following patient characteristics were prospectively examined as possible predictive factors for altered renal function: age, sex, ethnicity, initial MBP, initial P(cr) level, initial level of urine protein excretion, and smoking status. Fifty-three patients were enrolled, and follow-up data were available for 51 patients after a mean follow-up of 35.5 months. Despite MBP reduction from 126.8 +/- 1.3 to 96.5 +/- 1.1 mm Hg (P < 0.0001), P(cr) level increased from 1.5 +/- 0.1 to 1.9 +/- 0. 2 mg/dL (P < 0.01). Multivariate regression analysis showed that smoking, greater initial P(cr) level, and black ethnicity were the only examined parameters that independently predicted both a decrease in the 1/P(cr) slope and calculated GFR with at least 95% confidence. Smoking was by far the most powerful of the examined factors, with initial P(cr) and ethnicity being much less predictive. These studies show for the first time that smoking is an independent risk factor for renal function decline in patients with severe essential hypertension.

A Comparison of Treating Metabolic Acidosis in CKD Stage 4 Hypertensive Kidney Disease with Fruits and Vegetables or Sodium Bicarbonate

BACKGROUND AND OBJECTIVES Current guidelines recommend Na(+)-based alkali for CKD with metabolic acidosis and plasma total CO2 (PTCO2) < 22 mM. Because diets in industrialized societies are typically acid-producing, we compared base-producing fruits and vegetables with oral NaHCO3 (HCO3) regarding the primary outcome of follow-up estimated GFR (eGFR) and secondary outcomes of improved metabolic acidosis and reduced urine indices of kidney injury. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Individuals with stage 4 (eGFR, 15-29 ml/min per 1.73 m(2)) CKD due to hypertensive nephropathy, had a PTCO2 level < 22 mM, and were receiving angiotensin-converting enzyme inhibition were randomly assigned to 1 year of daily oral NaHCO3 at 1.0 mEq/kg per day (n=35) or fruits and vegetables dosed to reduce dietary acid by half (n=36). RESULTS Plasma cystatin C-calculated eGFR did not differ at baseline and 1 year between groups. One-year PTCO2 was higher than baseline in the HCO3 group (21.2±1.3 versus 19.5±1.5 mM; P<0.01) and the fruits and vegetables group (19.9±1.7 versus 19.3±1.9 mM; P<0.01), consistent with improved metabolic acidosis, and was higher in the HCO3 than the fruits and vegetable group (P<0.001). One-year urine indices of kidney injury were lower than baseline in both groups. Plasma [K(+)] did not increase in either group. CONCLUSIONS One year of fruits and vegetables or NaHCO3 in individuals with stage 4 CKD yielded eGFR that was not different, was associated with higher-than-baseline PTCO2, and was associated with lower-than-baseline urine indices of kidney injury. The data indicate that fruits and vegetables improve metabolic acidosis and reduce kidney injury in stage 4 CKD without producing hyperkalemia.

Dietary acid reduction with fruits and vegetables or bicarbonate attenuates kidney injury in patients with a moderately reduced glomerular filtration rate due to hypertensive nephropathy

The neutralization of dietary acid with sodium bicarbonate decreases kidney injury and slows the decline of the glomerular filtration rate (GFR) in animals and patients with chronic kidney disease. The sodium intake, however, could be problematic in patients with reduced GFR. As alkali-induced dietary protein decreased kidney injury in animals, we compared the efficacy of alkali-inducing fruits and vegetables with oral sodium bicarbonate to diminish kidney injury in patients with hypertensive nephropathy at stage 1 or 2 estimated GFR. All patients were evaluated 30 days after no intervention; daily oral sodium bicarbonate; or fruits and vegetables in amounts calculated to reduce dietary acid by half. All patients had 6 months of antihypertensive control by angiotensin-converting enzyme inhibition before and during these studies, and otherwise ate ad lib. Indices of kidney injury were not changed in the stage 1 group. By contrast, each treatment of stage 2 patients decreased urinary albumin, N-acetyl β-D-glucosaminidase, and transforming growth factor β from the controls to a similar extent. Thus, a reduction in dietary acid decreased kidney injury in patients with moderately reduced eGFR due to hypertensive nephropathy and that with fruits and vegetables was comparable to sodium bicarbonate. Fruits and vegetables appear to be an effective kidney protective adjunct to blood pressure reduction and angiotensin-converting enzyme inhibition in hypertensive and possibly other nephropathies.

Acid retention accompanies reduced GFR in humans and increases plasma levels of endothelin and aldosterone

Dietary alkali slows GFR decline in humans with a moderately reduced glomerular filtration rate (GFR) despite the absence of metabolic acidosis. Similarly, dietary alkali slows GFR decline in animals with 2/3 nephrectomy (Nx), a chronic kidney disease (CKD) model without metabolic acidosis in which GFR decline is mediated by acid (H(+)) retention through endothelin (ET) and mineralocorticoid receptors. To gain insight as to whether this mechanism might mediate GFR decline in humans, we explored whether macroalbuminuric subjects with moderately reduced (CKD stage 2 = 60-90 ml/min; CKD 2) compared with normal estimated GFR (> 90 ml/min; CKD 1), each without metabolic acidosis, have H(+) retention that increases plasma levels of ET-1 and aldosterone. Baseline plasma ET and aldosterone concentrations were each higher in CKD 2 than CKD 1. Baseline dietary H(+) and urine net acid excretion (NAE) were not different between groups, but an acute oral NaHCO₃ bolus reduced urine NAE less (i.e., postbolus urine NAE was higher) in CKD 2 than CKD 1, consistent with greater H(+) retention in CKD 2 subjects. Thirty days of oral NaHCO₃ reduced H(+) retention in CKD 2 but not CKD 1 subjects and reduced plasma ET and aldosterone in both groups but to levels that remained higher in CKD 2 for each. Subjects with CKD stage 2 eGFR and no metabolic acidosis nevertheless have H(+) retention that increases plasma ET and aldosterone levels, factors that might mediate subsequent GFR decline and other untoward vascular effects.

Acid retention during kidney failure induces endothelin and aldosterone production which lead to progressive GFR decline, a situation ameliorated by alkali diet

Rats with 5/6 nephrectomy have metabolic acidosis with a progressive decline in the glomerular filtration rate (GFR) ameliorated by endothelin and aldosterone antagonists and by dietary alkali. Interestingly, rats with 2/3 nephrectomy have no metabolic acidosis yet have a progressive GFR decline induced by acid retention and ameliorated by dietary alkali. Because patients without metabolic acidosis but with a moderately reduced GFR have a progressive GFR decline, ameliorated by oral sodium bicarbonate, we used rats with 2/3 nephrectomy to model these patients. Kidney acid content, endothelin-1, and aldosterone (measured by microdialysis) were higher in the rats with 2/3 nephrectomy than those with a sham operation despite no differences in plasma acid-base parameters. The GFR of the former but not the latter was lower at 25 than at 1 week after nephrectomy. Endothelin and aldosterone antagonism improved the preservation of GFR; however, this remained lower at week 24 than at week 1. By contrast, the GFR at weeks 24 and 1 was not different if the rats were given dietary alkali to normalize the kidney acid content. Antagonist of endothelin and aldosterone yielded no added GFR benefit. Thus, our study shows that (1) the decline in GFR in 2/3 nephrectomy is mediated by acid retention-induced kidney endothelin and aldosterone production; (2) receptor antagonism and dietary alkali are not additive; and (3) dietary alkali better preserves GFR than both endothelin and aldosterone receptor antagonism.

Increased Oxidative Stress Following Acute and Chronic High Altitude Exposure

The generation of reactive oxygen species is typically associated with hyperoxia and ischemia reperfusion. Recent evidence has suggested that increased oxidative stress may occur with hypoxia. We hypothesized that oxidative stress would be increased in subjects exposed to high altitude hypoxia. We studied 28 control subjects living in Lima, Peru (sea level), at baseline and following 48 h exposure to high altitude (4300 m). To assess the effects of chronic altitude exposure, we studied 25 adult males resident in Cerro de Pasco, Peru (altitude 4300 m). We also studied 27 subjects living in Cerro de Pasco who develop excessive erythrocytosis (hematocrit > 65%) and chronic mountain sickness. Acute high altitude exposure led to increased urinary F(2)-isoprostane, 8-iso PGF(2 alpha) (1.31 +/- 0.8 microg/g creatinine versus 2.15 +/- 1.1, p = 0.001) and plasma total glutathione (1.29 +/- 0.10 micromol versus 1.37 +/- 0.09, p = 0.002), with a trend to increased plasma thiobarbituric acid reactive substance (TBARS) (59.7 +/- 36 pmol/mg protein versus 63.8 +/- 27, p = NS). High altitude residents had significantly elevated levels of urinary 8-iso PGF(2 alpha) (1.3 +/- 0.8 microg/g creatinine versus 4.1 +/- 3.4, p = 0.007), plasma TBARS (59.7 +/- 36 pmol/mg protein versus 85 +/- 28, p = 0.008), and plasma total glutathione (1.29 +/- 0.10 micromol versus 1.55 +/- 0.19, p < 0.0001) compared to sea level. High altitude residents with excessive erythrocytosis had higher levels of oxidative stress compared to high altitude residents with normal hematological adaptation. In conclusion, oxidative stress is increased following both acute exposure to high altitude without exercise and with chronic residence at high altitude.

Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate

Alkali therapy of metabolic acidosis in patients with chronic kidney disease (CKD) with plasma total CO2 (TCO2) below 22 mmol/l per KDOQI guidelines appears to preserve estimated glomerular filtration rate (eGFR). Since angiotensin II mediates GFR decline in partial nephrectomy models of CKD and even mild metabolic acidosis increases kidney angiotensin II in animals, alkali treatment of CKD-related metabolic acidosis in patients with plasma TCO2 over 22 mmol/l might preserve GFR through reduced kidney angiotensin II. To test this, we randomized 108 patients with stage 3 CKD and plasma TCO2 22-24 mmol/l to Usual Care or interventions designed to reduce dietary acid by 50% using sodium bicarbonate or base-producing fruits and vegetables. All were treated to achieve a systolic blood pressure below 130 mm Hg with regimens including angiotensin converting enzyme inhibition and followed for 3 years. Plasma TCO2 decreased in Usual Care but increased with bicarbonate or fruits and vegetables. By contrast, urine excretion of angiotensinogen, an index of kidney angiotensin II, increased in Usual Care but decreased with bicarbonate or fruits and vegetables. Creatinine-calculated and cystatin C-calculated eGFR decreased in all groups, but loss was less at 3 years with bicarbonate or fruits and vegetables than Usual Care. Thus, dietary alkali treatment of metabolic acidosis in CKD that is less severe than that for which KDOQI recommends therapy reduces kidney angiotensin II activity and preserves eGFR.

Cigarette smoking exacerbates and its cessation ameliorates renal injury in type 2 diabetes.

Background: Patients with type 2 diabetes and macroalbuminuria generally experience progressive glomerular filtration rate (GFR) decline despite angiotensin‐converting enzyme inhibition (ACEI) and blood pressure (BP) control but this therapy generally stabilizes GFR in those without macroalbuminuria. Cigarette smoking exacerbates GFR decline in patients with type 2 diabetes and macroalbuminuria despite ACEI and BP control; whether this therapy prevents nephropathy progression in nonmacroalbuminuric type 2 diabetic smokers is unknown. Methods: We determined the course of urine excretion of indices of renal injury that distinguished patients with type 2 diabetes with and without macroalbuminuria but with normal plasma creatinine who were prospectively followed 6 months while receiving ACEI and BP control. We compared this course in nonsmokers and smokers with normo‐, micro‐, and macroalbuminuria (n = 157) and in response to smoking cessation in a separate cohort (n = 80) with microalbuminuria. Results: Urine excretion of transforming growth factor &bgr;‐1 (UTGF&bgr;V) increased in macroalbuminuric but not in nonmacroalbuminuric nonsmokers and UTGF&bgr;V rate was higher in smokers than nonsmokers within each albuminuria group. In the separate microalbuminuric cohort, the rate of UTGF&bgr;V change for quitting smokers was not different from nonsmokers (0.093 versus −0.123 ng/g of creatine/week, P = not significant) but that for nonquitting smokers (0.970) was higher than nonsmokers (P = 0.017). Conclusions: Patients with type 2 diabetes who are at high risk compared with low risk for nephropathy progression have progressive renal injury as measured by increasing UTGF&bgr;V. Cigarette smoking exacerbates renal injury in type 2 diabetes despite BP control and ACEI, but its cessation in those with microalbuminuria ameliorates the progressive renal injury caused by continued smoking.