Journal of The American Society of Nephrology最新文献

Background: Chronic kidney disease (CKD) is a growing global public health issue. Physical exercise mitigates several kidney-related pathophysiological pathways, yet its impact on kidney function remains underexplored. We investigated the dose-response effect of physical exercise on kidney function preservation in older adults.

Methods: Post-hoc analysis of the Generation 100 Study, a 5-year open-label, randomized, parallel-arm clinical trial conducted from 2012 to 2018 in Trondheim, Norway. All inhabitants aged 70-77 years were invited (n=6,966). Main exclusion criteria were dementia; severe, uncontrolled cardiovascular disease or hypertension; or conditions precluding exercise. The control group (n=385) received information on national physical activity recommendations. Intervention groups underwent supervised moderate-intensity continuous training (70% of peak heart rate) for 50 minutes (n=380) twice weekly for five years or high-intensity interval training (90% of peak heart rate) for 4 minutes x4 (n=391) twice weekly for five years. The primary outcome was cystatin C-based rapid eGFR decline (>5mL/min/1.73m2 per year).

Results: A total of 1,156 participants were randomized with median (interquartile range) age 72 (3) years and eGFR 95 (20) mL/min/1.73 m2. Oxygen uptake increased by 1.8, 2.3, and 3.3 mL/kg/min in the control, moderate-intensity, and high-intensity groups. Rapid eGFR decline occurred in 117 (30%), 108 (28%), and 92 (23%) participants, respectively. Compared to controls, relative risk (RR) was 0.93 (0.75-1.16) for moderate-intensity and 0.75 (95% CI 0.59-0.95) for high-intensity, demonstrating a significant dose-response relationship (P for trend 0.02). In observational analyses, participants with decreasing moderate-vigorous activity (> -20 minute/week) had RR 1.30 (95% CI 0.93-1.83) for rapid eGFR decline, while those with increasing activity (> +20 minutes/week) had RR 0.73 (0.53-0.99) compared to stable activity after adjusting for baseline age, sex, VO2peak and eGFR.

Conclusions: High-intensity interval training significantly reduced the risk of rapid eGFR decline in older adults.

Abstract: Solutes that accumulate when the kidneys fail range in size from about 40 to 40,000 Da. Their dialytic clearance tends to decrease as their size increases. Disproportionate accumulation of large solutes has therefore long been considered a potential contributor to residual illness in dialysis patients. Early efforts focused on the removal of "middle molecules" with mass from 300 to 2000 Da. The identification of amyloidosis caused by ß2 microglobulin (ß2M) with mass 12,000 Da shifted the focus to low molecular weight proteins. High-flux dialysis and hemodiafiltration increase the clearance of these larger solutes. However non-kidney clearance and solute compartmentalization limit the extent to which their plasma levels can be lowered by increasing their clearance during treatments of standard duration. Clinical benefits of high-volume hemodiafiltration thus cannot readily be accounted for by a reduction in the levels of known large solutes. The accumulation of peptides in the original middle molecular range and the clearance of larger solutes by peritoneal dialysis has been largely neglected. There is new interest in increasing the clearance of solutes even larger than ß2M by "extended dialysis." Ongoing clinical trials will extend our knowledge of the effects of extended dialysis and hemodiafiltration. In the future we might more effectively reduce plasma large solute levels by manipulating their non-kidney clearance, which is now poorly understood. ß2M is the only large solute whose accumulation in kidney failure has been shown to have specific ill effects. Identification of the ill effects of other large solutes might prompt the development of more targeted therapies.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited nephropathy often resulting in kidney failure. It is genetically heterogeneous; along with the major genes, PKD1 and PKD2, at least 8 others have been suggested. ALG8 pathogenic variants have been associated with autosomal dominant polycystic liver disease and implicated in ADPKD, while ALG9 has been suggested as an ADPKD gene, but details of the phenotypes and penetrance are unclear.

Methods: We screened >3900 families with cystic kidneys and/or livers using global approaches to detect ALG8 or ALG9 pathogenic variants. In addition, population cohorts with sequence data (Genomics England 100kGP (100kGP), UK Biobank (UKBB), and Mayo Clinic Biobank (MCBB)), were screened for ALG8/ALG9 pathogenic variants.

Results: Multicenter screening of individuals with polycystic kidney and/or liver disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5 multiplex) families; frequencies that were ∼10x and ∼24x greater than non-polycystic kidney disease (PKD) controls. Analysis of individuals with PKD phenotypes in 100kGP, UKBB, and MCBB identified 9 ALG8 (0.39%) and 9 ALG9 (0.39%) families, an enriched frequency over controls. Two individuals had PKD1 and ALG8 pathogenic changes. Eighty-nine percent of individuals with ALG8 mutations with imaging in the entire MCBB had kidney cysts (56%, >10 cysts), with greater median kidney and liver cyst numbers than controls. For ALG9, 78% had kidney cysts (27%, >10 cysts). Individuals with ALG8 mutations typically had mild cystic kidneys with limited enlargement. Liver cysts were common (71%) with enlarged livers (>2L) found in 11/62 patients although surgical intervention was rare. The ALG9 kidney phenotype was also of mild cystic kidneys but enlarged livers were rare; for both genes chronic kidney disease or kidney failure were rare.

Conclusions: ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.

Abstract: Alport syndrome (AS) is an inherited disorder characterized by kidney disease, sensorineural hearing loss and ocular abnormalities. AS is caused by pathogenic variants in COL4A3, COL4A4 or COL4A5, which encode the α3, α4 and α5 chains of type IV collagen that forms a heterotrimer expressed in the glomerular basement membrane. Knowledge of its genetic basis has informed the development of different models in dogs, mice and rat that reflect its autosomal and X-linked inheritance patterns as well as different mutation types, including protein truncating and missense variants. A key difference between these two types is the synthesis of α3α4α5(IV), which is not made in autosomal AS (2 pathogenic variants in trans or biallelic) or males with X-linked Alport syndrome due to protein truncating variants. By contrast, α3α4α5(IV) is synthesized in AS due to missense variants. For missense variants, in vitro studies suggest that these cause impaired type IV collagen trafficking and ER stress. For protein truncating variants, knockout models suggest that persistence of an immature α1α1α2(IV) network is associated with biomechanical strain, which activates endothelin-A receptors leading to mesangial filopodia formation. Moreoever, studies suggest that activation of collagen receptors integrins and DDR1 play a role in disease propagation. In this review, we provide an overview of how these genotype-phenotype-mechanisms are key for a precision medicine-based approach in the future.

Planetary health encompasses the understanding that the long-term well-being of humanity is intrinsically linked to the health of global ecological systems. Unfortunately, current practices often overlook this principle, leading to a human-oriented (anthropocentric) worldview that has resulted in heightened greenhouse gas emissions, increased heat stress, lack of access to clean water, and pollution, threatening both the environment and health and survival of Homo sapiens and countless other species. One significant consequence of these environmental changes is the exacerbation of inflammatory and oxidative stressors, which not only contributes to common lifestyle diseases but also accelerates the aging process. We advocate for a shift away from our current anthropocentric frameworks to an approach that focuses on nature's solutions that developed from natural selection over the eons. This approach, which encompasses the field of biomimicry, may provide insights that can help protect against an inflammatory phenotype to mitigate physiological and cellular senescence and provide a buffer against environmental stressors. Gaining insights from how animals have developed ingenious approaches to combat adversity through the evolutionary process of natural selection not only provides solutions for climate change but also confronts the rising burden of lifestyle diseases that accumulate with age.