Dietary Acid Reduction and Progression of Chronic Kidney Disease

Upon completion, this project will determine if dietary acid reduction done with either fruits and vegetables (F+V) or the medication sodium bicarbonate (NaHCO3) in study participants with high blood pressure (hypertension) and initially normal kidney function but with signs of kidney injury 1) slows progression of chronic kidney disease (CKD); 2) improves indices of cardiovascular risk; and 3) better preserves acid-base status. These studies are designed to determine if the simple and comparatively inexpensive intervention of dietary acid reduction can prevent or reduce adverse outcomes in individuals with early-stage CKD.

The long-term objective of this study is to determine if the simple and comparatively inexpensive intervention of dietary acid reduction can prevent or reduce adverse outcomes in individuals with hypertension and early-stage chronic kidney disease (CKD). The specific aims of this study are to determine if dietary acid reduction done with either base-producing fruits and vegetables (F+V) in amounts calculated to reduce participant dietary acid content by half or with sodium bicarbonate (NaHCO3, 0.4 milliequivalents (mEq)/kg body weight (bw), an amount designed to match the alkali content of the prescribed F+V) in participants with initially normal kidney function but with signs of kidney injury 1) slows progression of CKD; 2) improves indices of cardiovascular risk; and 3) better preserves acid-base status. The incidence and prevalence of CKD is increasing along with increased incidence and prevalence of its adverse outcomes, including heart attack and stroke, the latter for which patients with CKD are at increased risk. Most modern diets produce acid when metabolized in the body and some studies suggest that the small amount of acid produced causes progressive and long-term injury to blood vessels in kidneys, heart, and brain, thereby increasing risk for kidney disease and its progression, heart attack and stroke. This study will recruit participants with hypertension and macroalbuminuria (urine albumin \[mg\]-to-creatinine \[g\] ratio \> 200 mg/g) but with normal estimated glomerular filtration rate (eGFR) greater than or equal to 90 ml/min/1.73 m2) to be randomized to receive dietary acid reduction done with F+V or oral NaHCO3 or to no dietary acid reduction (Usual Care). At study entry and yearly for 5 years, all participants will have 10 milliliters (ml) of blood drawn from an antecubital vein for measurement of pH, partial pressure of carbon dioxide (PCO2), total CO2 (TCO2), creatinine, cystatin-C, low-density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, Lp(a) cholesterol, sodium, potassium, chloride, and citrate. They will also have 20 ml of urine collected for measurement of creatinine, pH, TCO2, ammonium, titratable acidity, albumin, N-acetyl-D-glucosaminidase, angiotensinogen, isoprostane 8-isoprostaglandin F2 alpha (8-iso), and citrate. Body acid will be measured in participants at baseline and at 5 years during an 8-hour protocol conducted in a Texas Tech University Health Sciences Center (TTUHSC) clinic. They will be told to fast after midnight and report to the TTUHSC clinic the following morning at which time they will be given a single oral dose of sodium bicarbonate (NaHCO3, 0.5 mEq/kg) and have 1 ml of blood drawn from a needle maintained in an arm vein for protocol duration for TCO2 before and at 2, 4, and 6 hours after the dose of NaHCO3 was given and urine collected over 8 hours for TCO2, pH, ammonium, and titratable acidity. The change in blood TCO2 in response to the amount of bicarbonate retained the body (dose minus urine bicarbonate excretion) will be used to calculate participant body acid. The course of serum and urine parameters over the 5 years of follow up in those randomized to F+V or NaHCO3 compared to Usual Care will help determine the effect of dietary acid reduction on CKD progression (change in eGFR and in urine indices of kidney injury), indices of cardiovascular disease risk (change in LDL, HDL, and Lp(a) cholesterol, and change in 8-iso), and on participant acid-base status (serum acid-base parameters (pH, PCO2, bicarbonate concentration \[HCO3\], TCO2, urine citrate excretion, and body acid measurement). These studies will also determine differences in these outcomes with dietary acid reduction done with F+V or NaHCO3.

The investigators hypothesize that dietary acid reduction will 1) reduce kidney injury indicated by lower urine indices of kidney injury and slow kidney function decline indicated by slower eGFR decline rate; 2) improve indices of cardiovascular risk indicated by lower LDL, higher HDL, lower Lp(a) cholesterol, and lower 8-iso; and 3) improve acid-base status indicated by higher serum TCO2, higher urine citrate excretion, and lower body acid. The investigators additionally hypothesize that F+V will have greater benefits on indicators of parameters of cardiovascular risk than NaHCO3. Excretion of urine acid-base parameters will help determine effects of dietary acid reduction on urine acid excretion. Blood pH and PCO2 will be measured using a blood gas analysis system and blood and urine concentrations of albumin and creatinine will be measured with standard techniques. Blood and urine TCO2 will be measured as done previously using fluorimetry techniques in the PI's laboratory. Urine ammonium, titratable acidity, N-Acetyl-beta-D-glucosaminidase, angiotensinogen, isoprostane 8-isoprostaglandin F2 alpha and citrate will be measured as done previously in the laboratory of the Co-PI.

Eligibility Criteria:
Inclusion Criteria:

* Non-malignant high blood pressure or hypertension
* 18-70 years old
* Urine albumin-to-creatine ratio \> 200 mg/g creatinine
* Estimated glomerular filtration rate (eGFR) greater than or equal to 90 ml/min/1.73 m2
* Serum total CO2 (TCO2) \> 22 mmol/l
* Greater than or equal to 2 primary care visits in the preceding year
* Able to provide informed consent

Exclusion Criteria:

* Malignant hypertension or history thereof
* Primary kidney disease or findings consistent thereof such as \> 3 red blood cells per high powered field of urine or urine cellular casts
* History of diabetes or fasting glucose greater than or equal to 110 mg/dl
* History of hematologic disorders, malignancies, chronic infections, current pregnancy, history or clinical evidence of cardiovascular disease
* Peripheral edema or diagnosis associated with edema such as heart/liver failure or nephrotic syndrome
* Unable to provide consent