Summary Autosomal dominant polycystic kidney disease is the most common inherited kidney disease and accounts for 7–10% of all patients on renal replacement therapy worldwide. Although first reported ...500 years ago, this disorder is still regarded as untreatable and its pathogenesis is poorly understood despite much study. During the past 40 years, however, remarkable advances have transformed our understanding of how the disease develops and have led to rapid changes in diagnosis, prognosis, and treatment, especially during the past decade. This Review will summarise the key findings, highlight recent developments, and look ahead to the changes in clinical practice that will likely arise from the adoption of a new management framework for this major kidney disease.
Hypertension affects over 1.2 billion individuals worldwide and has become the most critical and expensive public health problem. Hypertension is a multifactorial disease involving environmental and ...genetic factors together with risk-conferring behaviors. The cause of the disease is identified in ∼10% of the cases (secondary hypertension), but in 90% of the cases no etiology is found (primary or essential hypertension). For this reason, a better understanding of the mechanisms controlling blood pressure in normal and hypertensive patients is the aim of very active experimental and clinical research. In this article, we review the importance of the renin-angiotensin-aldosterone system (RAAS) for the control of blood pressure, focusing on the evolution of the system and its critical importance for adaptation of vertebrates to a terrestrial and dry environment. The evolution of blood pressure control during the evolution of primates, hominins, and humans is discussed, together with the role of common genetic factors and the possible causes of the current hypertension pandemic in the light of evolutionary medicine.
The Current State of Peritoneal Dialysis Mehrotra, Rajnish; Devuyst, Olivier; Davies, Simon J ...
Journal of the American Society of Nephrology,
11/2016, Letnik:
27, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Technical innovations in peritoneal dialysis (PD), now used widely for the long-term treatment of ESRD, have significantly reduced therapy-related complications, allowing patients to be maintained on ...PD for longer periods. Indeed, the survival rate for patients treated with PD is now equivalent to that with in-center hemodialysis. In parallel, changes in public policy have spurred an unprecedented expansion in the use of PD in many parts of the world. Meanwhile, our improved understanding of the molecular mechanisms involved in solute and water transport across the peritoneum and of the pathobiology of structural and functional changes in the peritoneum with long-term PD has provided new targets for improving efficiency and for intervention. As with hemodialysis, almost half of all deaths on PD occur because of cardiovascular events, and there is great interest in identifying modality-specific factors contributing to these events. Notably, tremendous progress has been made in developing interventions that substantially reduce the risk of PD-related peritonitis. Yet the gains have been unequal among individual centers, primarily because of unequal clinical application of knowledge gained from research. The work to date has further highlighted the areas in need of innovation as we continue to strive to improve the health and outcomes of patients treated with PD.
Uromodulin: Roles in Health and Disease Schaeffer, Céline; Devuyst, Olivier; Rampoldi, Luca
Annual review of physiology,
02/2021, Letnik:
83, Številka:
1
Journal Article
Recenzirano
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Uromodulin, a protein exclusively produced by the kidney, is the most abundant urinary protein in physiological conditions. Already described several decades ago, uromodulin has gained the spotlight ...in recent years, since the discovery that mutations in its encoding gene
UMOD
cause a renal Mendelian disease (autosomal dominant tubulointerstitial kidney disease) and that common polymorphisms are associated with multifactorial disorders, such as chronic kidney disease, hypertension, and cardiovascular diseases. Moreover, variations in uromodulin levels in urine and or blood reflect kidney functioning mass and are of prognostic value for renal function, cardiovascular events, and overall mortality. The clinical relevance of uromodulin reflects its multifunctional nature, playing a role in renal ion transport and immunomodulation, in protection against urinary tract infections and renal stones, and possibly as a systemic antioxidant. Here, we discuss the multifaceted roles of this protein in kidney physiology and its translational relevance.
In the past decade, kidney disease diagnosed with objective measures of kidney damage and function has been recognised as a major public health burden. The population prevalence of chronic kidney ...disease exceeds 10%, and is more than 50% in high-risk subpopulations. Independent of age, sex, ethnic group, and comorbidity, strong, graded, and consistent associations exist between clinical prognosis and two hallmarks of chronic kidney disease: reduced glomerular filtration rate and increased urinary albumin excretion. Furthermore, an acute reduction in glomerular filtration rate is a risk factor for adverse clinical outcomes and the development and progression of chronic kidney disease. An increasing amount of evidence suggests that the kidneys are not only target organs of many diseases but also can strikingly aggravate or start systemic pathophysiological processes through their complex functions and effects on body homoeostasis. Risk of kidney disease has a notable genetic component, and identified genes have provided new insights into relevant abnormalities in renal structure and function and essential homoeostatic processes. Collaboration across general and specialised health-care professionals is needed to fully address the challenge of prevention of acute and chronic kidney disease and improve outcomes.
Key points
The reabsorptive activity of renal proximal tubule cells is mediated by receptor‐mediated endocytosis and polarized transport systems that reflect final cell differentiation.
...Loss‐of‐function mutations of the endosomal chloride–proton exchanger ClC‐5 (Dent's disease) cause a major trafficking defect in proximal tubule cells, associated with lysosomal dysfunction, oxidative stress and dedifferentiation/proliferation.
A similar but milder defect is associated with mutations in CFTR (cystic fibrosis transmembrane conductance regulator).
Vesicular chloride transport appears to be important for the integrity of the endolysosomal pathway in epithelial cells.
The epithelial cells lining the proximal tubules of the kidney reabsorb a large amount of filtered ions and solutes owing to receptor‐mediated endocytosis and polarized transport systems that reflect final cell differentiation. Dedifferentiation of proximal tubule cells and dysfunction of receptor‐mediated endocytosis characterize Dent's disease, a rare disorder caused by inactivating mutations in the CLCN5 gene that encodes the endosomal chloride–proton exchanger, ClC‐5. The disease is characterized by a massive urinary loss of solutes (renal Fanconi syndrome), with severe metabolic complications and progressive renal failure. Investigations of mutations affecting the gating of ClC‐5 revealed that the proximal tubule dysfunction may occur despite normal endosomal acidification. In addition to defective endocytosis, proximal tubule cells lacking ClC‐5 show a trafficking defect in apical receptors and transporters, as well as lysosomal dysfunction and typical features of dedifferentiation, proliferation and oxidative stress. A similar but milder defect is observed in mouse models with defective CFTR, a chloride channel that is also expressed in the endosomes of proximal tubule cells. These data suggest a major role for endosomal chloride transport in the maintenance of epithelial differentiation and reabsorption capacity of the renal proximal tubule.
Uromodulin (Tamm–Horsfall protein) is the most abundant protein excreted in the urine under physiological conditions. It is exclusively produced in the kidney and secreted into the urine via ...proteolytic cleavage. Its biological function is still not fully understood. Uromodulin has been linked to water/electrolyte balance and to kidney innate immunity. Also, studies in knockout mice demonstrated that it has a protective role against urinary tract infections and renal stone formation. Mutations in the gene encoding uromodulin lead to rare autosomal dominant diseases, collectively referred to as uromodulin-associated kidney diseases. They are characterized by progressive tubulointerstitial damage, impaired urinary concentrating ability, hyperuricemia, renal cysts, and progressive renal failure. Novel in vivo studies point at intracellular accumulation of mutant uromodulin as a key primary event in the disease pathogenesis. Recently, genome-wide association studies identified uromodulin as a risk factor for chronic kidney disease (CKD) and hypertension, and suggested that the level of uromodulin in the urine could represent a useful biomarker for the development of CKD. In this review, we summarize these recent investigations, ranging from invalidation studies in mouse to Mendelian disorders and genome-wide associations, which led to a rediscovery of uromodulin and boosted the scientific and clinical interest for this long discovered molecule.
Lowe syndrome is an X-linked disease that is characterized by congenital cataracts, central hypotonia, intellectual disability and renal Fanconi syndrome. The disease is caused by mutations in OCRL, ...which encodes an inositol polyphosphate 5-phosphatase (OCRL) that acts on phosphoinositides - quantitatively minor constituents of cell membranes that are nonetheless pivotal regulators of intracellular trafficking. In this Review we summarize the considerable progress made over the past decade in understanding the cellular roles of OCRL in regulating phosphoinositide balance along the endolysosomal pathway, a fundamental system for the reabsorption of proteins and solutes by proximal tubular cells. We discuss how studies of OCRL have led to important discoveries about the basic mechanisms of membrane trafficking and describe the key features and limitations of the currently available animal models of Lowe syndrome. Mutations in OCRL can also give rise to a milder pathology, Dent disease 2, which is characterized by renal Fanconi syndrome in the absence of extrarenal pathologies. Understanding how mutations in OCRL give rise to two clinical entities with differing extrarenal manifestations represents an opportunity to identify molecular pathways that could be targeted to develop treatments for these conditions.
Little is known about the molecular changes that take place in the kidney during the aging process. In order to better understand these changes, we measured mRNA and protein levels in genetically ...diverse mice at different ages. We observed distinctive change in mRNA and protein levels as a function of age. Changes in both mRNA and protein are associated with increased immune infiltration and decreases in mitochondrial function. Proteins show a greater extent of change and reveal changes in a wide array of biological processes including unique, organ-specific features of aging in kidney. Most importantly, we observed functionally important age-related changes in protein that occur in the absence of corresponding changes in mRNA. Our findings suggest that mRNA profiling alone provides an incomplete picture of molecular aging in the kidney and that examination of changes in proteins is essential to understand aging processes that are not transcriptionally regulated.
The Pathophysiology of the Peritoneal Membrane DEVUYST, Olivier; MARGETTS, Peter J; TOPLEY, Nicholas
Journal of the American Society of Nephrology,
07/2010, Letnik:
21, Številka:
7
Journal Article
Recenzirano
Odprti dostop
The development of peritoneal dialysis (PD) as a successful therapy has and still depends on experimental models to test and understand critical pieces of pathophysiology. To date, the majority of ...studies performed in rat and rabbit models derive mechanistic insights primarily on the basis of interventional pharmacologic agents, blocking antibodies, or transient expression systems. Because body size no longer limits the performance of in vivo studies of PD, genetic mouse models are increasingly available to investigate the molecular and pathophysiologic mechanisms of the peritoneal membrane. We illustrate in this review how these investigations are catching up with other areas of biomedical research and provide direct evidence for understanding transport and ultrafiltration, responses to infection, and structural changes including fibrosis and angiogenesis. These studies are relevant to mechanisms responsible not only for the major complications of PD but also for endothelial biology, host defense, inflammation, and tissue repair processes.
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