Diuretics for Early Chronic Kidney Disease

(DOCK Trial)

Overseen By Lucile P Gregg, MD MS

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: VA Office of Research and Development

Must be taking: Diuretics

Disqualifiers: CKD stages 4-5, Dialysis, Transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 4 weeks

46 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of diuretics for early chronic kidney disease?

The research indicates that in chronic kidney disease patients, there was an increase in the prescription of diuretics when patients were followed up in renal protection clinics, suggesting that these drugs are considered beneficial in managing the condition. ^{1 2 3 4 5}

Are diuretics safe for people with chronic kidney disease?

Diuretics, including thiazide and loop types, have been used for many years and are generally safe, but they can have side effects like low sodium or potassium levels, especially in people with kidney issues. Potassium-sparing diuretics are considered safer in some cases, but all types should be used with caution and under medical supervision, particularly in those with advanced kidney disease. ^{6 7 8 9 10}

How is the drug Diuretic Augmentation unique for treating early chronic kidney disease?

Diuretic Augmentation, which includes thiazide and loop diuretics, is unique because it combines different types of diuretics to potentially enhance their effectiveness in managing early chronic kidney disease, despite concerns about their efficacy in advanced stages. This combination may offer renoprotective benefits and better blood pressure control, especially in patients with conditions like type 2 diabetic kidney disease. ^{6 8 11 12 13}

What is the purpose of this trial?

This trial is testing whether medications that help remove extra fluid from the body can improve heart health in Veterans with early-stage kidney disease and high blood pressure. By reducing fluid volume, these medications may lower blood pressure and decrease heart strain. These medications have been used to manage extra fluid buildup and control blood pressure in various conditions, including heart failure and high blood pressure, for many years.

Research Team

Lucile P Gregg, MD

Principal Investigator

Michael E. DeBakey VA Medical Center, Houston, TX

Eligibility Criteria

This trial is for Veterans with early-stage chronic kidney disease (CKD stages 1-3) who have high blood pressure. Participants must be at least 18 years old, able to give informed consent, and not on dialysis or a recipient of a kidney transplant. Those with severe heart issues, liver cirrhosis, major limb amputation, pregnancy, or certain devices like pacemakers are excluded.

Inclusion Criteria

Your blood pressure was too high at your last two doctor visits.

I have been diagnosed with mild to moderate kidney disease for at least 3 months.

Able to understand and sign informed consent after the nature of the study has been fully explained.

Exclusion Criteria

I am able to understand and give informed consent.

My kidney function is very low (stage 4-5 CKD).

I have been diagnosed with liver cirrhosis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Initiation or increase of diuretic treatment to assess changes in natriuretic peptides, symptoms, and cardiovascular parameters

4 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Diuretic Augmentation

Trial Overview The study tests whether diuretics (like hydrochlorothiazide or furosemide) can reduce fluid overload in the body and improve cardiovascular health in people with early CKD. It compares two methods of measuring fluid overload and observes changes in symptoms and short-term heart function after treatment.

Participant Groups

Group I: Diuretic augmentation Experimental Treatment 1 Intervention

The participant's blood pressure medication regimen will be altered to initiate a thiazide-type or loop diuretic in those not already prescribed a diuretic, or to increase the dose if one is already prescribed.

Diuretic Augmentation is already approved in European Union, United States, Canada, Japan, China for the following indications:

Approved in European Union as Diuretics for:

• Hypertension
• Edema
• Heart failure
• Chronic kidney disease

Approved in United States as Diuretics for:

• Hypertension
• Edema
• Heart failure
• Chronic kidney disease
• Nephrotic syndrome

Approved in Canada as Diuretics for:

• Hypertension
• Edema
• Heart failure
• Chronic kidney disease

Approved in Japan as Diuretics for:

• Hypertension
• Edema
• Heart failure

Approved in China as Diuretics for:

• Hypertension
• Edema
• Heart failure
• Chronic kidney disease

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Findings from Research

Referral to renal protection clinics significantly increased the prescription rates of cardioprotective medications, such as ACE inhibitors and beta-blockers, among 259 patients with chronic kidney disease over a follow-up period of up to 1 year.

Despite the increase in prescriptions, adherence to these medications did not improve, indicating that while more patients were prescribed cardioprotective drugs, they were not necessarily taking them as directed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The impact of renal protection clinics on prescription of and adherence to cardioprotective drug therapy in chronic kidney disease patients. Lepeytre, F., Cardinal, H., Fradette, L., et al.[2020]

This observational study of 100 dialysis patients in New Zealand aims to identify factors influencing medication adherence, using a comprehensive survey that assesses health literacy, medication knowledge, and beliefs about medications.

The findings will help develop targeted interventions to improve medication adherence in dialysis patients, which is crucial for enhancing their health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Understanding barriers to optimal medication management for those requiring long-term dialysis: rationale and design for an observational study, and a quantitative description of study variables and data. Aspden, T., Wolley, MJ., Ma, TM., et al.[2022]

A randomized controlled trial with 120 hemodialysis patients showed that monthly educational sessions from a clinical pharmacist significantly improved adherence to treatment recommendations, with a total adherence score of 1170.6 in the intervention group compared to 665.8 in the control group (p < 0.001).

The intervention not only enhanced adherence but also led to better clinical outcomes, including improved quality of life, better laboratory values for key health indicators, and fewer hospitalizations (0.54 vs. 0.78 per patient, p < 0.001).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of clinical pharmacist in enhancing hemodialysis patients' adherence and clinical outcomes: a randomized-controlled study. Alshogran, OY., Hajjar, MH., Muflih, SM., et al.[2022]

In a study of 200 hospitalized patients at Alcañiz Hospital, 46.5% experienced kidney function deterioration during their stay, highlighting a significant risk for patients with chronic kidney disease (CKD).

Despite the high incidence of CKD and kidney function deterioration, only 28% of patients with a prior CKD diagnosis had it recorded in their clinical history, and only 34% in discharge reports, indicating a need for improved documentation and awareness among healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Undiagnosed kidney disease in hospitalised patients: an opportunity for improvement. Campos Gutiérrez, B., Lou Arnal, LM., Gimeno Orna, JA., et al.[2013]

Educational and self-management interventions both showed a small to moderate positive effect on adherence to treatment in hemodialysis patients, particularly in fluid intake, diet, and drug management, based on a systematic review of randomized controlled trials.

There was no significant difference in effectiveness between educational and self-management interventions, suggesting that both approaches can be effectively utilized by healthcare professionals to improve patient adherence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the effect of educational and self-management interventions on adherence to treatment in hemodialysis patients: A systematic review and meta-analysis of randomized controlled trials. Yangöz, ŞT., Özer, Z., Boz, İ.[2021]

Chlorthalidone has been shown to effectively reduce blood pressure in patients with advanced chronic kidney disease (CKD), suggesting that thiazide diuretics can still be beneficial even at lower glomerular filtration rates (GFR).

While diuretics can have adverse effects, recent studies indicate that they do not negatively impact kidney or cardiovascular outcomes in CKD patients, and careful monitoring of electrolytes and GFR is essential for safe use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Revisiting diuretic choice in chronic kidney disease. Ali, S., Navaneethan, SD., Virani, SS., et al.[2023]

Indapamide is associated with a significant incidence of hyponatraemia (20.9%) and hypokalaemia (21.7%) in Australian patients, particularly affecting elderly individuals, especially women, who are more susceptible to these electrolyte disturbances.

Compared to other diuretics like hydrochlorothiazide and amiloride, indapamide shows a higher proportion of reports for both hyponatraemia and hypokalaemia, indicating a need for careful monitoring of electrolyte levels in patients prescribed this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyponatraemia and hypokalaemia due to indapamide. Chapman, MD., Hanrahan, R., McEwen, J., et al.[2020]

Thiazide diuretics are established as first-line treatments for hypertension and can be used alone or in combination with other medications, but their use in patients with advanced chronic kidney disease (CKD) is often avoided due to safety and efficacy concerns.

An updated review by Minutolo et al. examines the pharmacological properties and clinical trial data of thiazide diuretics in CKD patients, suggesting that these medications may still be effective and safe despite the reluctance to prescribe them in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiazides in chronic kidney disease: "back to the future". de la Espriella, R., Cobo, M., Núñez, J.[2023]

Potassium-sparing diuretics are particularly useful for cirrhotic patients with ascites, as they provide diuretic effects without the risk of potassium loss, which can be dangerous with stronger diuretics.

These drugs can enhance the effects of other diuretics and can be safely combined with medications like ACE inhibitors, making them versatile in treating conditions such as hypertension and specific syndromes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Potassium-sparing diuretics (spironolactone, triamterene, amylorid)]. Haris, A., Radó, J.[2013]

Loop diuretics are effective in increasing sodium excretion and urine output, even in patients with significantly impaired kidney function, particularly in cases of chronic renal failure and conditions like nephrotic syndrome or chronic heart failure.

While loop diuretics can help manage fluid overload in patients on dialysis, their effectiveness is limited, and high doses can lead to serious side effects such as neurological issues and muscle pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The place of loop diuretics in the treatment of acute and chronic renal failure. Russo, D., Memoli, B., Andreucci, VE.[2010]

Recent evidence suggests that thiazide diuretics, traditionally discouraged for hypertension treatment in advanced chronic kidney disease (CKD), may actually help in controlling blood pressure and promoting natriuresis in these patients.

The review highlights the pharmacology and common side effects of thiazides, indicating that they could be reconsidered as a treatment option for hypertension in advanced CKD based on emerging data.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Use of Thiazide Diuretics for the Treatment of Hypertension in Patients With Advanced Chronic Kidney Disease. Pham, NT., Owen, JG., Singh, N., et al.[2023]

In a study of 11 patients with advanced type 2 diabetic kidney disease (DKD) and severe edema, the addition of hydrochlorothiazide (HCTZ) to loop diuretics significantly reduced both blood pressure and proteinuria over a 12-month period.

The combination therapy did not adversely affect kidney function, as measured by the estimated glomerular filtration rate (eGFR), indicating that HCTZ can be safely used in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Renoprotective effects of thiazides combined with loop diuretics in patients with type 2 diabetic kidney disease. Hoshino, T., Ookawara, S., Miyazawa, H., et al.[2021]

In a study of 11,297 patients starting hemodialysis, continuing loop diuretics was linked to lower rates of hospitalization and intradialytic hypotension, suggesting a beneficial role in managing fluid balance during dialysis.

Despite these benefits, there was no significant difference in mortality rates over the first year of dialysis between those who continued loop diuretics and those who did not.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Continuation of Loop Diuretics at Hemodialysis Initiation with Clinical Outcomes. Sibbel, S., Walker, AG., Colson, C., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

The impact of renal protection clinics on prescription of and adherence to cardioprotective drug therapy in chronic kidney disease patients. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Understanding barriers to optimal medication management for those requiring long-term dialysis: rationale and design for an observational study, and a quantitative description of study variables and data. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

The role of clinical pharmacist in enhancing hemodialysis patients' adherence and clinical outcomes: a randomized-controlled study. [2022]

4. Spain pubmed.ncbi.nlm.nih.gov

Undiagnosed kidney disease in hospitalised patients: an opportunity for improvement. [2013]

5. India pubmed.ncbi.nlm.nih.gov

Comparison of the effect of educational and self-management interventions on adherence to treatment in hemodialysis patients: A systematic review and meta-analysis of randomized controlled trials. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Revisiting diuretic choice in chronic kidney disease. [2023]

7. Australia pubmed.ncbi.nlm.nih.gov

Hyponatraemia and hypokalaemia due to indapamide. [2020]

8. England pubmed.ncbi.nlm.nih.gov

Thiazides in chronic kidney disease: "back to the future". [2023]

9. Hungary pubmed.ncbi.nlm.nih.gov

[Potassium-sparing diuretics (spironolactone, triamterene, amylorid)]. [2013]

10. Germany pubmed.ncbi.nlm.nih.gov

The place of loop diuretics in the treatment of acute and chronic renal failure. [2010]

11. United States pubmed.ncbi.nlm.nih.gov

The Use of Thiazide Diuretics for the Treatment of Hypertension in Patients With Advanced Chronic Kidney Disease. [2023]

12. Japan pubmed.ncbi.nlm.nih.gov

Renoprotective effects of thiazides combined with loop diuretics in patients with type 2 diabetic kidney disease. [2021]

13. United States pubmed.ncbi.nlm.nih.gov

Association of Continuation of Loop Diuretics at Hemodialysis Initiation with Clinical Outcomes. [2023]