Introduction
Introduction
Autosomal Dominant Polycystic kidney disease (ADPKD) is the most common inherited kidney disorder leading to end-stage kidney disease requiring dialysis treatment or transplantation. This disease is mainly characterized by uncontrolled growth of cysts with renal parenchyma injury, compression, and fibrosis. Increases in cyst numbers and size over time cause clinical complications such as infections, bleeding, flank pain, hypertension and, ultimately, a progressive loss in renal function. Recently, major advancements have been made in the biological understanding of the cellular pathways involved in cyst growth. Yet, therapeutic management of patients with ADPKD remains confined to symptom management and disease complications such as hypertension, urinary infections and flank pain. The main aim of this Cochrane review was to summarize the benefits and harms of therapeutic interventions directed at preventing progression of ADPKD. The Cochrane review included 30 studies among about 2000 patients. Despite numerous potential treatments targeting disease pathogenesis, evidence from clinical trials is currently sparse or limited. At present there is no evidence that pharmacological interventions prevent end-stage kidney disease or mortality.
Authors
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Davide Bolignano
Davide is a nephrologist working as clinical researcher and epidemiologist at the Institute of Clinical Physiology of the Italian National Research Council (CNR) in Reggio Calabria, Italy. His fields of interest and research are the epidemiology, physiology, and pathophysiology of kidney diseases.
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Suetonia Palmer
Suetonia is a nephrologist based at the University of Otago, Christchurch in New Zealand, and who trained in New Zealand and the USA. She is an Editor and Podcast Editor for Cochrane Kidney and Transplant.
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Copyright© 2016 Cochrane Kidney and Transplant. Published by John Wiley & Sons, Ltd.
Summary
Summary
This Cochrane Kidney and Transplant review from 2015 evaluated possible benefits and harms of drugs aiming at preventing disease progression in about 2000 individuals with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Overall, there is little information yet that using specific medicines makes any difference to the number of people with polycystic kidney disease experiencing kidney failure. Each medicine has important side-effects.
Autosomal Dominant Polycystic kidney disease (ADPKD) is the most frequent genetic disorder affecting the kidney and one of the leading causes of end-stage kidney disease requiring long-term dialysis treatment or kidney transplantation worldwide. It has been estimated that, globally, over 12 million people currently live with ADPKD, of whom about 700,000 live in the USA. ADPKD accounts for about 5% of new patients starting renal replacement therapy in the USA and between 3% and 10% in Europe.
The main feature of this ADPKD is an uncontrolled growth of cysts in the renal parenchyma. Increases in cyst numbers and size over time may cause bleeding, infections, discomfort, hypertension and progressive loss in kidney function due to parenchymal compression or fibrosis.
Healthcare for people with ADPKD is currently limited to controlling associated conditions, particularly hypertension, to limit morbidity and mortality after the disease becomes symptomatic. Specific approaches to targeting disease biology (cyst growth) have not yet been validated for widespread use in clinical practice. Recent developments arising from improved mechanistic understanding of the cellular pathways involved in cyst growth have made targeting disease pathogenesis, rather than disease complications, possible.
However, although many interventions have shown promise in experimental models, few have been tested in human clinical studies and data from existing randomized trials have not previously been summarized.
The source of trials included in this review was the Cochrane Kidney and Transplant specialized register which curates all clinical trials in kidney disease. The Cochrane Kidney and Transplant team search for all possible clinical trials about treatments for kidney disease in the Cochrane library, and supplement this with physical hand-searching of journals and conference abstracts plus electronic searches of electronic medical databases.
As is standard for Cochrane reviews, two of the review authors each studied the list of possible trials in the database independently of each other to find all trials that compared any drug intervention for people with ADPKD versus any other intervention or standard treatment/placebo. The authors also collected information from the trials about patient characteristics, the quality of the studies and a list of the key patient outcomes.
In total, 30 trials involving 2039 patients with ADPKD were included in the review. These studies investigated 11 different pharmacological interventions: angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), calcium channel blockers, beta blockers, vasopressin receptor 2 antagonists, mammalian target of rapamycin (mTOR) inhibitors, somatostatin analogues, antiplatelet agents, eicosapentenoic acids, statins, and vitamin D compounds.
Unfortunately -- for most interventions -- data were available in single trials and mostly focused on surrogate outcomes such as change in kidney or cyst volumes, blood pressure, proteinuria or albuminuria. Conversely, data on key patient outcomes, such as the need to start dialysis or renal transplantation, all-cause mortality, fatal and non-fatal cardiovascular events, quality of life, and disease-related symptoms, were limited or lacking.
There was also high-level heterogeneity in the length of study follow-up and most trials were conducted within very small populations or had a cross-over design.
ACE inhibitors significantly improved diastolic blood pressure but had no effects on kidney volumes and renal function in studies conducted in children. In adult trials, these drugs were not superior to other treatments in protecting renal function or reducing albuminuria. Evidence on the benefits of vasopressin receptor 2 antagonists on renal function and cyst volumes was inconclusive and confined to a single study while these agents caused thirst and dry mouth. Similarly, mTOR inhibitors had uncertain effects on kidney function and volume while they caused soft tissue swelling, mouth ulcers, infections and diarrhea. Somatostatin analogues were associated with better kidney function and lower total kidney volume but caused diarrhea.
In summary, there is insufficient evidence that pharmacological treatments for individuals with ADPKD can be implemented in clinical practice to delay dialysis or a kidney transplant. Future trials evaluating patient-centered outcomes and enriched with subpopulations at higher risk of end-stage kidney disease are advocated.
Copyright© 2016 Cochrane Kidney and Transplant. Published by John Wiley & Sons, Ltd.
