Treating Metabolic Acidosis in Chronic Kidney Disease to Prevent Adverse Kidney and Cardiovascular Outcomes

NCT06545461 | Completed

• 1 other identifier: L-INTMED-97884
• Study Type: interventional
• Target: 108
• Locations: 0 countries
• Sites: N/A

Brief Summary

Upon completion, this project will determine if treatment of metabolic acidosis in non-diabetic study participants with reduced kidney function (chronic kidney disease \[CKD\] stage 3) associated with high blood pressure (hypertension) and macroalbuminuria, the latter indicating pronounced kidney injury, using either base-producing fruits and vegetables (F+V) or standard therapy for treatment of metabolic acidosis with the medication sodium bicarbonate (NaHCO3) 1) slows progression of CKD toward end-stage renal disease \[ESRD\]; 2) improves indices of cardiovascular disease (CVD) risk; and 3) better preserves plasma acid-base parameters. These studies are designed to compare the differential effects of treating the metabolic acidosis of CKD with F+Vs or NaHCO3 on kidney outcomes, including progression to ESRD, on indices of CVD risk and on plasma acid-base parameters.

Conditions

Chronic Kidney Diseases; Cardiovascular Diseases; Hypertension

Keywords

acidosis; albuminuria; diet

Outcome Measures

Primary Outcomes (7)

• Difference in estimated glomerular filtration rate (eGFR) at follow up

  eGFR (ml/min/1.73 m2) will be calculated using measured serum creatinine and cystatin-C concentrations, age, sex, and whether or not of African American ethnicity using a standard accepted formula. eGFR will be compared among the three groups yearly up to 10 years follow up to assess chronic kidney disease (CKD) progression. Milestone assessments will be done at 3, 5, and 10 years. Higher eGFR indicates better-preserved kidney function. The investigators hypothesize that F+V or NaHCO3 will lead to better preserved (higher) eGFR.

  eGFR will be measured at baseline and yearly for 10 years

• Difference in the rate of eGFR change during follow up

  The rate of eGFR change (ml/min/1.73 m2/year) will assess CKD progression. It will be calculated by dividing the net change in eGFR between the milestone year of follow up and baseline divided by the years of follow up. The investigators hypothesize that F+V or NaHCO3 will lead to a slower rate of eGFR change, indicative of slower CKD progression.

  eGFR rate of change will be measured at 3, 5, and 10 years

• Difference in the net eGFR change during follow up

  The net eGFR change (ml/min/1.73 m2) will assess CKD progression and will be calculated by subtracting the milestone value from the baseline value. The investigators hypothesize that dietary acid reduction will lead to a smaller net eGFR change, indicative of less CKD progression.

  eGFR net change compared to baseline will be measured at 3, 5, and 10 years

• Difference in the number of participants who reach need for kidney replacement therapy (KRT)

  Differences in the number of participants who reach the need for KRT will be determined by comparing the number of participants among arms who reach the need for dialysis or kidney transplant; this is a measure of how well the interventions protect kidney health. The investigators hypothesize that the F+V or NaHCO3 arms will have fewer participants reaching KRT.

  Number of participants reaching KRT will be determined at years 3, 5, and 10 from baseline

• Difference in change in urine albumin excretion during follow up

  CKD progression will be assessed by change in the urine albumin (mg)-to-creatinine (g) ratio (UACR) in a "spot" urine. An increased UACR is indicative of kidney injury and risk for subsequent decrease of kidney function with time. A decrease in UACR is indicative of reduced kidney injury and a lower risk for decreased kidney function with time. The investigators hypothesize that F+V or NaHCO3 will lead to a lower UACR. • UACR will be compared among the three groups as follows: Value at 3,5, and 10 years Net change compared to baseline value at 3, 5, and 10 years

  UACR will be measured at baseline and yearly for 10 years

• Difference in change in urine N-acetyl-D -glucosaminidase (UNAG) excretion during follow up

  CKD progression will be assessed by change in the UNAG (Units)-to-creatinine (g) ratio in a "spot" urine. An increased UNAG/creatinine ratio is indicative of increased kidney injury. The investigators hypothesize that F+V or NaHCO3 will lead to a lower UNAG/creatinine. • UNAG/creatinine will be compared among the three groups as follows: Value at 3, 5, and 10 years Net change compared to baseline at 3, 5, and 10 years

  UNAG will be measured at baseline and yearly for 10 years

• Difference in change in urine angiotensinogen (UATG) excretion during follow up

  CKD progression will be assessed by change in the UATG (ug)-to-creatinine (g) ratio in a "spot" urine. An increased UATG/creatinine ratio is an indirect measure of kidney levels of angiotensin II and is indicative of increased kidney injury. The investigators hypothesize that F+V or NaHCO3 will lead to a lower UATG/creatinine ratio. • UATG/creatinine will be compared among the three groups as follows: Value at 3, 5, and 10 years Net change compared to baseline at 3, 5, and 10 years

  UATG will be measured at baseline and yearly for 10 years

Secondary Outcomes (8)

• Difference in change in serum LDL cholesterol level during follow up

  Serum LDL cholesterol will be measured at baseline and yearly for 10 years

• Difference in change in serum HDL cholesterol level during follow up

  Serum HDL cholesterol will be measured at baseline and yearly for 10 years

• Difference in change in serum Lp(a) cholesterol level during follow up

  Serum Lp(a) cholesterol will be measured at baseline and yearly for 10 years

• Difference in change in urine isoprostane 8-isoprostaglandin F2α excretion follow up

  Urine Isoprostane 8-isoprostaglandin F2α to creatinine ratio will be measured at baseline and yearly for 10 years.]

• Difference in change in plasma pH during follow up

  Plasma pH will be measured at baseline and yearly for 10 years

Study Arms (3)

Fruits and vegetables (F+V)

EXPERIMENTAL

36 participants with hypertension, eGFR 30-59 ml/min/m2, macroalbuminuria (albumin \[mg\] to creatinine \[g\] ratio \> 200 mg/g) and PTCO2 \>22 but \<24 mM will receive a prescribed amount of F+Vs designed to reduce dietary acid intake by half. The chosen level of metabolic acidosis does not warrant alkali treatment by current guidelines with standard therapy, oral NaHCO3. Because macroalbuminuria places them at increased risk for worsening kidney function and development of CVD, they will receive oral enalapril (minimum 5 mg daily) and oral atorvastatin (minimum 10 mg daily). They will otherwise receive standard medical care and followed annually for 10 years.

Other: Fruits and Vegetables (F+V)

NaHCO3 (HCO3)

EXPERIMENTAL

36 participants with hypertension, eGFR 30-59 ml/min/m2, macroalbuminuria (albumin \[mg\] to creatinine \[g\] ratio \> 200 mg/g) and PTCO2 \>22 but \<24 mM will receive sodium bicarbonate (NaHCO3) dosed to match the alkali intake of the F+V given to the F+V group. Because macroalbuminuria places them at increased risk for worsening of their kidney function and for development of CVD, they will receive oral enalapril (minimum 5 mg daily) and oral atorvastatin (minimum 10 mg daily). They will otherwise receive standard care and followed annually for 10 years.

Other: Sodium Bicarbonate (NaHCO3)

Usual Care (UC)

ACTIVE COMPARATOR

36 participants with hypertension, eGFR 30-59 ml/min/m2, macroalbuminuria (albumin \[mg\] to creatinine \[g\] ratio \> 200 mg/g) and PTCO2 \>22 but \<24 mM will receive no additional alkali (neither F+V or NaHCO3). The chosen level of metabolic acidosis does not warrant alkali treatment by current guidelines with standard therapy with oral NaHCO3. Because their macroalbuminuria places them at increased risk for worsening of their kidney function and for subsequent development of CVD, they will receive oral enalapril (minimum 5 mg daily) and oral atorvastatin (minimum 10 mg daily). They will otherwise receive standard care and followed annually for 10 years.

Other: Usual Care

Interventions

Fruits and Vegetables (F+V) OTHER

Participants will receive a prescribed amount of F+V designed to reduce their dietary acid intake by half. This typically amounts to 2-4 cups daily of F+V provided in weekly allotments. Amount provided will be that calculated for the participant multiplied times number of household members to assure participants eat the prescribed amount and do not share with household members.

Fruits and vegetables (F+V)

Sodium Bicarbonate (NaHCO3) OTHER

Participants will receive 0.3 mEq/kg bw/day NaHCO3 tablets to match the alkali provided by F+V given to F+V participants. This will be provided as 650 mg NaHCO3 tablets for an average of 4-5 tablets/day in two divided oral doses.

NaHCO3 (HCO3)

Usual Care OTHER

Participants will receive standard medical care but no additional alkali (F+V nor NaHCO3).

Usual Care (UC)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Non-malignant high blood pressure or hypertension
• yrs old
• urine albumin-to-creatine ratio \> 200 mg/g creatinine
• estimated glomerular filtration rate (eGFR) 30 to 59 ml/min/1.73 m2
• Plasma total CO2 (PTCO2) \> 22 but \< 24 mmol/l
• able to tolerate angiotensin converting enzyme \[ACE\] inhibition drug therapy because guidelines recommend it for patients with albuminuric CKD
• non-smoking
• greater than or equal to 2 primary care visits in the preceding year, indicating compliance
• Able to provide informed consent.

You may not qualify if:

• 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 CVD
• peripheral edema or diagnosis associated with edema such as heart/liver failure or nephrotic syndrome because of the sodium load that accompanies NaHCO3 therapy
• baseline plasma potassium concentration \> 4.6 mmol/l to reduce the risk for hyperkalemia in those participants randomized to F+Vs which increases dietary potassium intake
• taking, or unable to stop taking, drugs other than ACE inhibitors that limit urine potassium excretion
• Unable to provide informed consent.

Sponsors & Collaborators

• University of Texas at Austin: lead

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Cardiovascular Diseases; Hypertension; Acidosis; Albuminuria

Interventions

Fruit; Vegetables; Sodium Bicarbonate

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Vascular Diseases; Acid-Base Imbalance; Metabolic Diseases; Nutritional and Metabolic Diseases; Proteinuria; Urination Disorders; Urological Manifestations; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Food; Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages; Bicarbonates; Carbonates; Carbonic Acid; Carbon Compounds, Inorganic; Inorganic Chemicals; Sodium Compounds

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: None (Open label)
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: prospective, randomized parallel three-arm design

Study Record Dates

• First Submitted: August 5, 2024
• First Posted: August 9, 2024
• Study Start: June 22, 1998
• Primary Completion: October 25, 2006
• Study Completion: October 30, 2016
• Last Updated: August 9, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Within 90 days and for 30 days
• Access Criteria: Other medical science investigators