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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether diuretics (medications that help the body eliminate extra fluid) can improve heart health in people with early-stage chronic kidney disease (CKD). Researchers aim to determine if early treatment of volume overload (excess fluid in the body) can prevent heart problems such as heart attacks and strokes. Participants will have their current blood pressure medication adjusted to include diuretics if not already prescribed. Veterans with CKD stages 1-3 for at least three months and high blood pressure may be eligible to join. As a Phase 4 trial, this research involves an FDA-approved treatment and seeks to understand how it can benefit more patients.

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 is the safety track record for diuretic treatments?

Research has shown that the medicines being studied in this trial, thiazide and loop diuretics, are usually safe for people with kidney problems. Studies have found that these diuretics do not worsen kidney disease. They often help control high blood pressure and reduce fluid buildup in the body.

Evidence also indicates that these diuretics can be used safely even in advanced kidney disease to manage blood pressure. This suggests they are likely safe for individuals with earlier stages of kidney problems as well. However, like any medication, side effects or risks may occur, so discussing any concerns with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about diuretic augmentation for early chronic kidney disease because it offers a personalized approach to managing blood pressure. Unlike standard treatments that might not adjust for individual needs, this method tailors diuretic use by either introducing a thiazide-type or loop diuretic or increasing the dose for those already on such medication. This customized adjustment could potentially optimize blood pressure control, which is crucial for slowing kidney disease progression. By focusing on better blood pressure management, this approach might improve outcomes more effectively than current standard treatments.

What evidence suggests that diuretics might be an effective treatment for early chronic kidney disease?

Research has shown that certain water pills, such as thiazide and loop diuretics, can lower blood pressure in people with chronic kidney disease (CKD). This is crucial because high blood pressure is common in CKD and can lead to heart problems. Studies have found that these water pills reduce extra fluid in the body, benefiting heart health. By lowering blood pressure and reducing fluid, they may also slow the progression of kidney disease. The evidence supports using these water pills to manage symptoms and potentially improve long-term outcomes in CKD. Participants in this trial will undergo diuretic augmentation, which involves altering their blood pressure medication regimen to initiate or increase the dose of a thiazide-type or loop diuretic. ^{1 3 4 6 7}

Who Is on the Research Team?

Lucile P Gregg, MD

Principal Investigator

Michael E. DeBakey VA Medical Center, Houston, TX

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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Early data suggest that thiazide diuretics may be useful for alleviating polyuria caused by tolvaptan in patients with polycystic kidney disease.

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This review examines the evidence that diuretic therapy for treatment-resistant hypertension may constitute a risk factor for preventable ...