baseline characteristics of the study population - edj 2 …€¦ · goraya et al. (2014) – study...

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Goraya et al. (2014) – Study Summary

TREATMENT OF METABOLIC ACIDOSIS IN PATIENTS WITH STAGE 3 CHRONIC KIDNEY DISEASE WITH FRUITS AND VEGETABLES OR SODIUM BICARBONATE REDUCES URINE ANGIOTENSINOGEN AND PRESERVES GLOMERULAR FILTRATION RATE This was a 3-year, single-center, prospective, randomized, interventional study in 108 subjects with Stage 3 CKD (eGFR 30 – 59 mL/min/1.73m2) due to hypertensive nephropathy and with plasma total CO2 > 22 to < 24 mM. According to current treatment guidelines (KDOQI, 2000), the level of metabolic acidosis present in this patient population would not warrant alkali therapy; initiation of therapy is suggested when serum bicarbonate (plasma total CO2) falls below 22 mM. The objective of the study was to compare the effect of intervention with: 1) oral sodium bicarbonate; 2) dietary fruits and vegetables (F+V); or 3) usual care on eGFR decline, metabolic acidosis and markers of kidney injury in patients whose plasma total CO2 was above the current treatment threshold.

The primary outcome measure was the change in cysGFR after 36 months of treatment with oral sodium bicarbonate or a diet including an amount of fruits and vegetables that was designed to reduce dietary acid by 50% (achieved with an average dose of 25.2 mEq/day or 0.3 mEq/kg/day of sodium bicarbonate or 3-day food intake diaries with PRAL calculation for F+V intervention); these interventions were compared with a usual care group. Secondary outcomes were plasma crGFR, urinary albumin and urinary NAG, two urine indices whose increasing levels are associated with worsening kidney injury, and urine angiotensinogen.

The three treatment groups were well matched for demographics and baseline characteristics; study subjects had mean crGFR and cysGFR values ~42 mL/min/1.73 m2 and ~39 mL/min/1.73 m2, respectively, and mean venous total CO2 levels ~41 mM. Baseline characteristics of the study population are presented in Table 1.

BASELINE CHARACTERISTICS OF THE STUDY POPULATION

Characteristic

Treatment

Usual Care Oral Sodium Bicarbonate

Fruits and Vegetables

Number of Subjects 36 36 36 Age (years; mean ± SD) 53.9 ± 4.8 53.6 ± 5.3 53.5 ± 5.2 Gender (%) Male Female

44 54

44 54

44 54

Race / Ethnicity (%) Black White Hispanic

53 14 33

53 22 25

53 17 30

Estimated GFR (mL/min/1.73m2; mean ± SD) calculated using plasma creatinine calculated using plasma cystatin C

42.6 ± 7.6 39.5 ± 6.8

42.6 ± 7.0 39.6 ± 6.6

42.3 ± 7.1 39.4 ± 6.4

Venous Total CO2 (mM; mean ± SD) 41.4 ± 0.6 41.6 ± 0.5 41.5 ± 0.6 Venous pH (mean ± SD) 7.36 ± 0.01 7.36 ± 0.01 7.36 ± 0.01 Systolic Blood Pressure (mmHg; mean ± SD) 158.6 ± 10.6 165.1 ± 10.1 163.3 ± 11.7 Dietary PRAL (mmol/day; mean ± SD) 60.5 ± 7.7 60.2 ± 6.9 61.9 ± 7.6 Diagnosis (%) Hypertension

100

100

100

Medication Use (%) Furosemide Enalapril

100 100

100 100

100 100

Table 1: Baseline Characteristics of the Study Population (Goraya et al., 2014); GFR = glomerular filtration rate; CO2 = carbon dioxide; PRAL = Potential Renal Acid Load; SD = standard deviation


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Compared to baseline, at the end of the 3-year treatment period, plasma total CO2 was significantly higher in the patients receiving oral sodium bicarbonate (p<0.01) or fruits/vegetables (p<0.01) and significantly lower in patients who received usual care (p<0.01) (Figure 1). At the end of treatment, the 8-hour net acid excretion was significantly lower, and comparable, in the two active treatment groups (p<0.01) and remained unchanged in the usual care group (Figure 2).

Figure 1: Goraya, 2014 (originally Figure 1, left panel, in study)

Usual care = individuals without dietary intervention; Oral sodium bicarbonate = individuals given oral sodium bicarbonate at 0.3 mEq/kg lean body weight per day; Fruits and vegetables = subjects given fruits and vegetables in amounts designed to reduce potential renal acid load by half.


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Figure 2: Goraya, 2014 (originally Figure 1, right panel, in study)

Usual care = individuals without dietary intervention; Sodium bicarbonate = individuals given oral sodium bicarbonate at 0.3 mEq/kg lean body weight per day; Fruits and vegetables = subjects given fruits and vegetables in amounts designed to reduce potential renal acid load by half.


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Mean cysGFR and crGFR decreased over the 3-year treatment period in all three treatment groups, but the decrease from baseline to Year 2 and from baseline to Year 3 was significantly less in the oral sodium bicarbonate and fruits/vegetables groups than in the usual care group (p<0.05). The authors also reported that linear mixed effect models showed that the rates of eGFR decline were significantly less negative for the two active treatment groups compared to the usual care group (Figure 3).

Figure 3: Goraya, 2014 (originally Figure 3 in study)

Error bars (mean ± standard error) of plasma creatinine-calculated estimated GFR (crGFR) (left panel) and plasma cystatin C–calculated estimated GFR (cysGFR) (right panel) across four time points including baseline and 3 year follow-up.

Usual care = individuals without dietary intervention; Bicarbonate = individuals given oral sodium bicarbonate at 0.3 mEq/kg lean body weight per day; fruits and vegetables = subjects given fruits and vegetables in amounts designed to reduce potential renal acid load by half.


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Treatment with oral sodium bicarbonate and fruits/vegetables both resulted in significant decreases (p<0.05) in three markers of kidney damage over the 3-year treatment period (Figure 4). Urine albumin was assessed as a marker of general kidney injury; urine NAG is an index of kidney tubulointerstitial injury and an index of kidney injury induced by dietary acid; and urine angiotensinogen is an index of kidney angiotensin II.

Figure 4: Goraya, 2014 (originally Figure 2 in study)

Change of urine albumin (mg)-to-creatinine (g) ratio (Ualb) (left panel), N-acetyl-β-D-glucosaminidase (U)-to-creatinine (g) ratio (UNAG) (middle panel), and angiotensinogen (μg)-to-creatinine (g) ratio (UAGT) (right panel) for the three groups of CKD individuals, with eGFR 30-59 ml/min per 1.73m2 at baseline and 3-year follow-up.

Usual care = individuals without dietary intervention; Bicarbonate = individuals given oral sodium bicarbonate at 0.3 mEq/kg lean body weight per day; Fruits and Vegetables = subjects given fruits and vegetables in amounts designed to reduce potential renal acid load by half.

After 3 years, mean plasma potassium was significantly lower than baseline in the oral sodium bicarbonate group (4.19 ± 0.09 vs. 4.24 ± 0.12 mEq/L; p<0.01), but was not different from baseline in the fruits/vegetables and usual care groups. Mean systolic blood pressure was lower after treatment than at baseline in all three treatment groups due to the blood pressure reduction program specified in the protocol. After the 3-year treatment period, mean systolic blood pressure was significantly lower (p<0.05) in the fruits/vegetable group (128.3 ± 4.5 mmHg) compared to the oral sodium bicarbonate (135.7 ± 4.5 mmHg), and usual care (135.4 ± 6.2 mmHg) groups. Mean body weight decreased significantly from baseline to end-of-treatment in the usual care and the fruits/vegetable groups (-1.9 ± 2.6 kg and -4.0 ± 3.9 kg, respectively; p<0.01), but not in the oral sodium bicarbonate treatment group (-0.17 ± 2.7 kg; p=0.72).

In conclusion, this study demonstrated that acid reduction with oral sodium bicarbonate or base-inducing dietary fruits and vegetables reduced urine excretion of angiotensinogen, a marker of kidney angiotensin II levels, and preserved eGFR in patients with Stage 3 CKD due to hypertensive nephropathy. These results suggest that dietary acid reduction is kidney protective in CKD patients with plasma total CO2 higher than that for which current treatment guidelines recommend alkali therapy.


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The magnitude of the treatment effect of oral sodium bicarbonate and fruits/vegetables on plasma total CO2 was comparable in this study, in contrast to the study reported by Goraya et al., 2013, which showed a significantly greater effect from oral sodium bicarbonate. The difference between the two studies is that, while the fruits/vegetable regimen was the same, the dose of oral sodium bicarbonate was 0.3 mEq/kg/day in this study and 1.0 mEq/kg/day in the previous study. The limitations of this study are its relatively small size, its open-label design and the use of only a single study site. A summary of the design and key findings of the study is presented in Table 2.

TREATMENT OF METABOLIC ACIDOSIS IN PATIENTS WITH STAGE 3 CKD WITH FRUITS AND VEGETABLES OR SODIUM BICARBONATE REDUCES URINE ANGIOTENSINOGEN AND

PRESERVES GLOMERULAR FILTRATION RATE Study Design and Results

Study Site Texas Tech University Health Sciences Center Eligibility Criteria

Nonmalignant hypertension; eGFR 30 – 59 mL/min/1.73m2; plasma total CO2 > 22 mM and < 24 mM; macroalbuminuria; able to tolerate ACE inhibition; non-smoking; age ≥ 18 years; history of compliance with clinic visits; no diabetes or cardiovascular disease

Exclusion Criteria

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); plasma potassium level > 4.6 mEq/L; taking or inability to stop taking drugs (other than ACE inhibitors) that limit potassium excretion

Study Treatments

Oral sodium bicarbonate tablets (0.3 mEq/kg/day; 36 subjects) Fruits/vegetables in amounts to reduce dietary PRAL by 50% (36 subjects) Usual care (36 subjects)

Randomization After participation in a 6-month blood pressure reduction program, eligible subjects were matched according to age, gender, ethnicity, eGFR, urine albumin and randomized into the three treatment groups

Duration 3 years Assessments At baseline and end-of-treatment the following were assessed: systolic blood pressure;

plasma and urine creatinine, venous plasma acid-base variables; urine total CO2; urine 8-hour net acid excretion, albumin, N-acetyl-β-D-glucosaminidase (NAG) and angiotensinogen (ATG).

Primary Outcome

Cystatin C-estimated GFR (cysGFR) in response to 3 years of oral sodium bicarbonate or fruits and vegetables compared to usual care

Secondary Outcomes

Creatinine-estimated GFR (crGFR), two urinary measures of kidney injury (albumin, NAG) and urine angiotensinogen in response to 3 years of oral sodium bicarbonate or fruits and vegetables compared to usual care


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Goraya (2014) - Study Design and Results (cont.) Results Compared to baseline, at the end of the 3-year treatment period:

1. Slower decline in kidney function as measured by eGFR in the oral sodium bicarbonate and fruits/vegetables treatment groups as compared to those receiving usual care; there was no significant difference between the two active treatment groups

2. There was a significant decrease in metabolic acidosis (an increase in plasma pH and total CO2) in the oral sodium bicarbonate and fruits/vegetables treatment groups, while the usual care group showed worsening acidosis (decrease in plasma pH and total CO2); there was no significant difference between the two active treatment groups.

3. 8-hour urine net acid excretion was decreased in the oral sodium bicarbonate and fruits/vegetables groups and was unchanged in the usual care group.

4. Urine albumin, NAG and angiotensinogen all decreased more in the oral sodium bicarbonate and fruits/vegetables groups compared to the usual care group.

5. Mean plasma potassium levels were decreased in the oral sodium bicarbonate group, but unchanged in the fruits/vegetables and usual care groups.

6. All groups had lower mean systolic blood pressure, as a result of treatment with ACE inhibitors; values were lower in the fruits/vegetables group than in the oral sodium bicarbonate and usual care groups.

Table 2: Treatment of Metabolic Acidosis in Patients with Stage 3 Chronic Kidney Disease with Fruits and Vegetables or Sodium Bicarbonate Reduces Urine Angiotensinogen and Preserves Glomerular Filtration Rate (Goraya et al., 2014); CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; ACE = angiotensin converting enzyme; PRAL = potential renal acid load

Goraya N, Simoni J, Jo CH, Wesson DE: 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. Kidney Int 86(5): 1031-8, 2014.

baseline characteristics of the study population - edj 2 …€¦ · goraya et al. (2014) – study...

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