Polycystic Kidney Disease (PKD) Clinical Trials Network

• Ancillary Study Policies
• Background
• PKD Clinical Trials Network

Background

Polycystic kidney disease (PKD) is a serious, burdensome, and costly disease. The cystic diseases are the fourth leading cause of chronic renal failure in the nation. Our increased understanding of the underlying molecular processes that result in cyst formation and cyst growth in the kidneys is yielding improved animal models of disease. In these animal models, a number of agents have been proven to slow cyst growth, and these experimental strategies should yield potential new therapeutic approaches to the disease in man. Appropriate clinical interventions to ameliorate the course of PKD need to be developed and tested. Several previous studies have established that glomerular filtration rate (GFR) declines rather rapidly in PKD patients with renal insufficiency. Nevertheless, through much of the disease course, GFR is relatively stable, and detectable decreases in it occur relatively late in the natural history of the disease.

Current approaches to treatment of patients with PKD have not succeeded in slowing the progressive decline in GFR that frequently results in end-stage renal failure. Also, treatment of hypertension has not been definitively shown to retard loss of renal function in patients with PKD. Whether target blood pressures should be lower in these patients than in the general population is unclear.

A sizable body of data supports the effectiveness of converting enzyme inhibitors (CEIs) in slowing the progression of other renal diseases, particularly those associated with proteinuria. These agents remain the most effective strategy to prevent or delay chronic renal failure, but the effectiveness of this class of agent in PKD is not clear. However, biological evidence is compatible with the hypothesis that interruption of the renin-angiotensin-aldosterone axis might have a protective effect in PKD. Some studies in animal models support this hypothesis. Evidence for high tissue renin has been found in polycystic kidneys from human patients, and there is clinical evidence for activation of the renin-angiotensin axis in hypertensive patients with PKD.

The results of randomized, interventional clinical trials of CEI in PKD have been contradictory, although the total number of patients studied has been relatively small. Many nephrologists elect to use CEIs for blood pressure management, particularly in patients with PKD who also have some degree of proteinuria. In addition, other strategies to block this pathway include angiotensin receptor blockers and aldosterone antagonists-agents that potentially could be administered either alone or together with CEI.

PKD Clinical Trials Network

Important advances in understanding the molecular basis of autosomal dominant polycystic kidney disease (PKD)-ADPKD1 and ADPKD2-have provided investigators with new research opportunities. In 2001, the National Institute of Diabetes and Digestive and Kidney Diseases established a network of clinical centers to design and implement clinical trials of treatments that will slow the progressive loss of renal function in PKD. The network will develop and execute both pilot and feasibility trials and a large, randomized, controlled clinical trial on blockade of the renin-angiotensin axis in patients with PKD The network comprises a data-coordinating center and four participating clinical centers at Emory University, New England Medical Center, Mayo Clinic, and University of Colorado Health Sciences Center.

The first large interventional clinical trial in this network, called HALT-PKD, will be a randomized controlled trial of a blockade of the renin-angiotensin axis in patients with hypertensive PKD. The effects of the blockade on renal disease progression will be assessed by monitoring renal volume and glomerular filtration rate. HALT-PKD is currently in the protocol-planning phase. After the protocol is finalized and approved by the required clinical trial advisory review groups, patient recruitment for the trial will begin. This process will take place in the next few months.

The consortium will conduct pilot and feasibility studies and a full-scale interventional trial over a period of seven years. The trial network will implement both a large, multicenter trial examining the effect of renin-angiotensin blockade on progression of PKD and one or more pilot and feasibility studies examining innovative strategies for slowing the progression of PKD. The network will also develop a specimen bank and information data system from study samples and patient information.

Topics for pilot and feasibility studies include, but are not limited to, the following:

• Safety of new agents for treatment of PKD
• Impact of intensive blockade of the renin-angiotensin axis on potassium homeostasis in patients with PKD and renal insufficiency
• Impact of innovative interventions on surrogate markers for cyst growth or cyst growth assessed by imaging methods
• Impact of innovative interventions on possible mechanisms of cystogenesis, such as loss of heterozygosity
• Safety or effectiveness of potential interventions in special PKD populations

The NIDDK has also recently funded the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) to determine whether changes in anatomic characteristics of the kidneys of patients with autosomal-dominant PKD will be useful in providing surrogate measures for disease progression. Currently in its final year, CRISP has followed 240 patients using annual glomerular filtration rate evaluation and magnetic resonance imaging to assess changes in renal volume over time. Although data from these studies are not presently available, preliminary findings from this group over the next several years might inform the designs of clinical trials in patients with PKD in the near future.