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Autosomal-dominant polycystic kidney disease (ADPKD) affects up to 12 million individuals and is the fourth most common cause for renal replacement therapy worldwide. There have been many recent advances in the understanding of its molecular genetics and biology, and in the diagnosis and management of its manifestations. Yet, diagnosis, evaluation, prevention, and treatment vary widely and there are no broadly accepted practice guidelines. Barriers to translation of basic science breakthroughs to clinical care exist, with considerable heterogeneity across countries. The Kidney Disease: Improving Global Outcomes Controversies Conference on ADPKD brought together a panel of multidisciplinary clinical expertise and engaged patients to identify areas of consensus, gaps in knowledge, and research and health-care priorities related to diagnosis; monitoring of kidney disease progression; management of hypertension, renal function decline and complications; end-stage renal disease; extrarenal complications; and practical integrated patient support. These are summarized in this review.

Amirali Masoumi, Berenice Reed-Gitomer, Catherine Kelleher, Mir Reza Bekheirnia, Robert W SchrierDepartment of Medicine, Health Sciences Center, University of Colorado School of Medicine, Denver, CO 80262, USAAbstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent life- threatening, hereditary disease. ADPKD is more common than sickle cell anemia, cystic fibrosis, muscular dystrophy, hemophilia, Down’s syndrome, and Huntington’s disease combined. ADPKD is a multisystemic disorder characterized by the progressive development of renal cysts and marked renal enlargement. Structural and functional renal deterioration occurs in ADPKD patients and is the fourth leading cause of end-stage renal disease (ESRD) in adults. Aside from the renal manifestations, extrarenal structural abnormalities, such as liver cysts, cardiovascular abnormalities, and intracranial aneurysms may lead to morbidity and mortality. Recent studies have identified prognostic factors for progressive renal impairment including gender, race, age, proteinuria, hematuria, hypertension and increased left ventricular mass index (LVMI). Early diagnosis and better understanding of the pathophysiology of the disease provides the opportunity to aggressivly treat hypertension with renin-angiotensin-aldosterone system inhibitors and thereby potentially reduce LVMI, prevent cardiovascular morbidity and mortality and slow progression of the renal disease.Keywords: hypertension, liver cysts, renal pain, left ventricular hypertrophy, cerebral aneurysms

Using a rat model of in vivo renal ischemia and one of gentamicin-induced nephrotoxicity as well as the freshly isolated preparation of rat proximal tubules, it was found that adenosine triphosphate levels of rat kidney cortex improves for 3-6 hours after anoxia but then subsequently declines with continued reperfusion; that calcium accumulates in mitochondria in vivo during reflow; that in vitro mitochondria return to normal buffering capacity soon after reflow begins but thereafter this capacity is lost. Finally, endoplasmic reticulum are better preserved as calcium transporting vessicles than are mitochondria and gentamicin in vivo induces early, and increases in an intracellular calcium compartment or pool even before functional and morphologic injury is seen. Keywords: Acute renal failure; norepinephrine; verapamil; nifedipine; mannitol.

Freshly isolated rat proximal tubules and cultured rabbit tubules exposed to anoxia (100% N2) die during reoxygenation unless pH is lowered or verapamil, nifedipine, trifluoropirazine of W-7 are administered. Thus, cell death and injury from increased calcium influx or calcium-calmodulin interactions are prevented. In addition, we have determined that various methods of lowering tissue ATP does not appear to compromise the baseline or subsequent recovery of cellular function after ischemia. Using NMR technology we have also followed renal tissue metabolism during and after hypotensive shock. The efficacy of various treatment protocols in shock will be evaluated in the coming year. Acute renal failure, Rabbits/rats, Calcium Fluxes, Adenine necleotides, Tissue calcium, Morphology, Lactate dehydrogenase, Atriopeptin III, Phosphate, Calcium.

Verapamil infused into the renal artery at low doses that do not influence contralateral renal function nor systemic hemodynamics prevents or attenuates markedly the severity of ischemic (norepineprine-induced) acute renal failure in the dog. When given before norepinephrine, glomerular filtration rate returns to normal at 24 hours and cellular morphology is nearly normal. When given for 2 hour after norepinephrine, glomerular filtration rate returns to 50% of normal at 24 hours. Mannitol given intravenously for 30 minutes prior to norepinephrine prevents mitochondrial respiratory depressin and improves glomerular filtration rate to 50-75% normal at 24 hours. Keywords: Kidney diseases; Calcium; Verapamil; Nifedipine; Mannitols; ATP synthesis; Vasodilation; Diuretics.

This research into the pathogenesis of acute renal failure identified that warm ischemia is followed by a very low glomerular filtration rate, due initially to vasoconstriction (low glomerular pressure) and later to tubular obstruction. Impermeant solutes such as mannitol and polyethylene glycol improve renal hemodynamics, reduce cell swelling (which attends ischemia), and wash out tubular debris thereby reducing tubular obstruction. Verapamil and nifedipine will, on the other hand, accomplish similar effects: reducing vascular and golmerular abnormalities by minimizing calcium influx induced vasoconstriction and reducing the degree of calcium induced cell death. Glomerular filtration is improved markedly after ischemia by either of these maneuvers. Keywords: Dogs/rats mitochondria; ATP; Norepinephrine; Calcium; Verapamil; Nifedipine; Mannitol; Kidney diseases; Kidney failure.

Calcium channel blockers (CCB) including verapamil, nifedipine and emopamil, and calmodulin antagonists W-7 and trifluoperazine administered 1) in vivo, 2) in the isolated perfused kidney, 3) to isolated proximal tubules, or 4) to cultured tubules prevent or greatly attenuate O2 deprivation injury. Although the absolute decrease in adenosine triphosphate (ATP) and total adenine nucleotides that occurs in O2 deprivation injury is well known, this does not appear to be the sole or primary cause of injury since similar decreases can be achieved with glycerol or fructose and no injury is seen. However, the preservation of cellular ATP seen with fructose diphosphate treatment and the rapid return of ATP and adenine nucleotide levels to near normal is important in enhancing the recovery of renal function. Finally, verapamil and possibly other CCB may exert their effect on hypoxic tissue by reducing Ca uptake. The cellular accumulation of Ca during reoxygenation still is the most prevalent mediator of injury since blockade of this event with CCB, calmodulin binding drugs or low media Ca can all attenuate cell death. AP-III also exerts powerful protective effects on GFR in the intact rat previously exposed to a period of ischemia. The isolated perfused rat kidney was used to evaluate the protective effect of AP- III and, as in the intact rat, the principal effect was on improving GFR. Based on these impressive experimental results, we have begun studies in patients to evaluate the efficacy of using AP-III and calcium entry blockers to prevent ischemic (and other forms of) acute renal failure.

Several in vitro studies on the isolated perfused kidney (IPK) and renal tubules freshly isolated from the rate were performed to evaluate the mechanism of oxygen deprivation injury and protection. Emopamil, a calcium channel blocker, prevented both warm and cold ischemia in the IPK. Cold perfusion alone is also of benefit and can be enhanced by verapamil. Atrial peptide III (the atrial natriuretic factor; ANF) exerts protection to the IPK from renal ischemia injury as well as in the whole animal. Using NMR, the protection appears to involve preservation of adenine nucleotides and prevention of intracellular acidosis. Furthermore, fructose diphosphate is also protective possibly by providing glycolytic intermediates. The tubule studies were characterized by technical improvements in preparative and incubation techniques and development of methods to ensure anoxic injury and its sequelae. Keywords: Acute renal failures, Hypoxia, Nuclear magnetic resonance.