BASELINE CHARACTERISTICS OF THE STUDY POPULATION

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Marian Hutchinson
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1 Study Summary DAILY ORAL SODIUM BICARBONATE PRESERVES GLOMERULAR FILTRATION RATE BY SLOWING ITS DECLINE IN EARLY HYPERTENSIVE NEPHROPATHY This was a 5-year, single-center, prospective, randomized, placebo-controlled, blinded interventional study of daily oral sodium bicarbonate, vs. sodium chloride and placebo in 120 subjects with macroalbuminuric hypertensive nephropathy and Stage 2 CKD (egfr ml/min/1.73m 2 ). The primary outcome measure was reduction in the rate of egfr decline in the sodium bicarbonate group compared to the placebo and sodium chloride groups. After 5-years treatment, the plasma cystatin C level was measured, and GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, since cysgfr more accurately estimates GFR above 60 ml/min. Secondary outcomes were the change from baseline to end of treatment in: 1) urine ET-1 excretion, a surrogate of kidney endothelin production that mediates progressive kidney injury in experimental CKD models; and 2) urine NAG and urine albumin excretion, two markers of kidney injury. This study was conducted to determine if alkali therapy was beneficial for patients with early-stage hypertensive nephropathy, i.e., relatively preserved egfr and no overt metabolic acidosis (plasma total CO 2 > 24.5 mm). Subjects were matched according to age (± 2 years), egfr (± 2 ml/min), albuminuria (± 10%) and ethnicity (Black, White, Hispanic) and randomized into one of three treatment groups: oral sodium bicarbonate tablets (0.5 meq/kg lean body weight per day; 40 subjects); oral sodium chloride tablets (0.5 meq/kg lean body weight per day; 40 subjects); or oral placebo (sucrose) tablets (40 subjects). At study entry, subjects were treated for hypertension with ACE inhibitors to control their blood pressure. The three treatment groups were well matched for demographics and baseline characteristics; study subjects had mean crgfr and cysgfr values ~75 ml/min and ~73 ml/min, respectively, and mean venous total CO 2 levels ~26 mm. Baseline characteristics of the Mahajan et al. study population are presented in Table 1. BASELINE CHARACTERISTICS OF THE STUDY POPULATION Treatment Characteristic Placebo Sodium Chloride Sodium Bicarbonate Number of Subjects Age (years; mean ± SD) 51.3 ± ± ± 8.2 Gender (%) Male Female Race / Ethnicity (%) Black White Hispanic Estimated GFR (ml/min; mean ± SD) calculated using plasma creatinine calculated using plasma cystatin C ± ± ± ± ± ± 6.0 Venous Total CO 2 (mm; mean ± SD) 26.0 ± ± ± 0.7 Systolic Blood Pressure (mmhg; mean ± SD) ± ± ± 12.6 Dietary PRAL (meq; mean ± SD) 60.4 ± ± ± 17.7 Diagnosis (%) Hypertension Medication Use (%) ACE inhibitor Table 1: Baseline Characteristics of the Study Population (Goraya et al., 2014); GFR = glomerular filtration rate; CO2 = carbon dioxide; PRAL = Potential Renal Acid Load; ACE = angiotensin-converting-enzyme; SD = standard deviation

2 At the end of the 5-year treatment period, systolic blood pressure was lower in all groups due to ACE inhibitor therapy. Eight-hour net urine acid excretion was significantly lower in the oral sodium bicarbonate treatment group at the end of the treatment period, compared to the two control groups, consistent with alkali ingestion. Venous total CO 2 levels did not change significantly in any treatment group. This result was expected because of the relatively preserved renal function in the test subjects, the essentially normal level of venous total CO 2 and the ability to spill excess bicarbonate under these conditions to avoid induction of alkalosis. Please refer to Table 2 for the observed 5-year results. Pcr (mg/dl) crgfr (ml/min) Pcys (mg/l) cysgfr (ml/min) SBP (mm Hg) VTCO 2 (mm) Ualb (mg/g cr) UNAG (U/g cr) UET (ng/g cr) 8 h NAE (meq) Urine Na + Excretion (meq/g cr) Urine K + Excretion (meq/g cr) OBSERVED 5-YEAR VALUES FOR THE THREE GROUPS Renal Function and Associated Parameters After 5 Years of Treatment Placebo NaCl NaHCO 3 Overall P-value P-value for NaCl vs Placebo P-value for NaHCO 3 vs Placebo P-value for NaHCO 3 vs NaCl 1.12 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 0.81 < < ± ± ± 5.4 < ± ± ± ± ± ± Table 2: Renal Function and Associated Parameters Before & After 5 Years of Treatment, (originally Table 3 in study) NaCit = sodium citrate group; no-nacit = control (no treatment) group. Pcr = plasma creatinine; crgfr = estimated glomerular filtration rate (egfr) calculated using Pcr; Pcys = plasma cystatin C; cysgfr = egfr calculated using Pcys; SBP = systolic blood pressure; VTCO2 = venous total CO2; Ualb = urine albumin-to-creatinine ratio; UNAG = urine N- acetyl-β-d-glucosaminidase-to-creatinine ratio, UET = urine endothelin-1-to-creatinine ratio; NAE = net acid excretion; cr = creatinine. Comparisons using linear mixed models demonstrated that the rate of egfr decline was significantly lower in the oral sodium bicarbonate treatment group compared the sodium chloride treatment group and the placebo group. The 5-year rate comparison between sodium bicarbonate treatment, sodium chloride treatment and placebo was ± 0.19 vs ± 0.19 (p=0.029) and ± 0.19 ml/min/year (p=0.014) when egfr was calculated using plasma creatinine values, and ± 0.20 vs ± 0.20 (p=0.003) and ± 0.20 ml/min/year (p=0.0003) when egfr was calculated using cystatin C values (Figure 1). 2

3 Figure 1: Mahajan, 2010 (originally Figure 2 in study) Trajectories of glomerular filtration rate (GFR) estimated from plasma creatinine (crgfr) and plasma cystatin C (cysgfr) in subjects taking placebo, sodium chloride, or sodium bicarbonate for 5 years, estimated using linear mixed models. 3

4 In addition to slowing renal decline, treatment with oral sodium bicarbonate also ameliorated kidney ET production, as measured by urine ET-1 (Figure 2), and ameliorated kidney tubulointerstitial injury, as measured by urine NAG (Figure 3). Figure 2: Mahajan, 2010 (originally Figure 5 in study) Trajectories for urine endothelin-1 (UET)-to-creatinine ratio in estimated glomerular filtration rate (egfr) subjects taking placebo, sodium chloride, or sodium bicarbonate estimated using linear mixed models. 4

Figure 3: Mahajan, 2010 (originally Figure 4 in study) Trajectories for urine NAG to creatinine ratio (UNAG) in subjects taking placebo, sodium chloride or sodium bicarbonate for 5 years estimated

5 Figure 3: Mahajan, 2010 (originally Figure 4 in study) Trajectories for urine NAG to creatinine ratio (UNAG) in subjects taking placebo, sodium chloride or sodium bicarbonate for 5 years estimated using linear mixed models. NAG = N-acetyl-β-D-glucosaminidase. Urine potassium, but not urine sodium was significantly higher at 5 years in the sodium bicarbonate treatment group compared to the controls (p=0.0005). This likely results from the net sodium resulting from sodium bicarbonate administration. Sodium uptake is balanced by potassium excretion, first into the extracellular space, then out into the urine. Urine albumin at 5 years was significantly lower in the oral sodium bicarbonate group than in the placebo group (p=0.026), but not significantly different than the sodium chloride group (p=0.187). This study demonstrated that alkali therapy slowed the rate of GFR decline in early-stage hypertensive nephropathy patients with reduced but relatively preserved egfr and normal serum bicarbonate. It also reduced kidney ET-1 production and slowed the trajectory of urine NAG, a marker of kidney tubulointerstitial injury. 5

6 The limitations of this study are its relatively small size and the use of only a single study site. A summary of the design and major findings of the Mahajan, 2010 study is presented in Table 3. Study Site Eligibility Criteria Exclusion Criteria Study Treatments Randomization Duration Assessments Primary Outcome Secondary Outcomes Results DAILY ORAL SODIUM BICARBONATE PRESERVES GLOMERULAR FILTRATION RATE BY SLOWING ITS DECLINE IN EARLY HYPERTENSIVE NEPHROPATHY Study Design and Results Texas Tech University Health Sciences Center Nonmalignant hypertension; macroalbuminuria (> 200 but < 2000 mg/g creatinine); crgfr 60 but < 90 ml/min; age 18 years and able to give consent; 2 clinical visits showing compliance Known primary kidney disease or findings consistent thereof; history of diabetes or fasting blood glucose 110 mg/dl; history of malignancy; chronic infection; pregnancy; clinical evidence of cardiovascular disease; peripheral edema or diagnoses associated with edema (i.e., heart failure); smoking or oral tobacco use within 1 year of recruitment; history of noncompliance Oral sodium bicarbonate tablets (0.5 meq/kg lean body weight per day; 40 subjects) Oral sodium chloride tablets (0.5 meq/kg lean body weight per day; 40 subjects) Oral placebo (sucrose) tablets (40 subjects) Eligible subjects were matched according to age (± 2 years), egfr (± 2 ml/min), albuminuria (± 10%) and ethnicity (Black, White, Hispanic) and randomized into the three treatment groups 5 years At yearly clinic visits the following were assessed: serum and urine creatinine, urine endothelin-1 (ET-1), urine albumin, urine N-acetyl-β-D-glucosaminidase (NAG), urine sodium, urine potassium, 8-hour urine net acid excretion, plasma cystatin C, venous plasma/blood ph, pco 2 (from which total CO 2 was calculated) and blood pressure Reduction in the rate of egfr decline Change from baseline to end of treatment in (1) urine ET-1 excretion, a surrogate of kidney endothelin production that mediates progressive kidney injury in experimental CKD models, and (2) urine NAG and urine albumin excretion, two markers of kidney injury At the end of the 5-year treatment period, the group of patients receiving oral sodium bicarbonate had: 1. Slower decline in kidney function as measured by egfr as compared to those receiving placebo or sodium chloride 2. Significant decreases urine ET-1 excretion, where this parameter increased or remained at baseline level in the two control groups 3. A slower trajectory of urine NAG 4. Relatively stable urine albumin, compared to increased values in the two control groups 5. Lower urine 8-hour net acid excretion, which was significantly lower than the values observed in the two control groups 6. Higher urine potassium levels, which was significantly lower than the values observed in the two control groups 7. No change in urine sodium or total venous CO 2 8. Lower systolic blood pressure, as a result of treatment with ACE inhibitors, that was not different than in the two control groups. Table 2: Daily Oral Sodium Bicarbonate Preserves Glomerular Filtration Rate by Slowing its Decline in Early Hypertensive Nephropathy () ACE = angiotensin converting enzyme; CKD = chronic kidney disease; crgfr = creatinine estimated glomerular filtration rate Mahajan A, Simoni J, Sheather SJ, Broglio KR, Rajab MH, Wesson DE: Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy. Kidney Int 78(3): 303-9,

BASELINE CHARACTERISTICS OF THE STUDY POPULATION

BASELINE CHARACTERISTICS OF THE STUDY POPULATION COMPARISON OF TREATING METABOLIC ACIDOSIS IN CKD STAGE 4 HYPERTENSIVE KIDNEY DISEASE WITH FRUITS & VEGETABLES OR SODIUM BICARBONATE This was a 1-year, single-center, prospective, randomized, interventional