Biological ageing and the human genome.

Age is a crucial prognostic factor across clinical specialities with significant implications for medical practice. Increasingly, "biological age" is being used as a more relevant age marker in a clinical context and is heavily integrated into the medical use of AI. This review describes the current knowledge about molecular biological and genetic aging-related changes associated with the genome and epigenome, used for biological age determination. It explores the potential causes of these changes and provides an update on treatment status and "rejuvenation" of these genome-related factors.

Does hydration status influence kidney volume in autosomal dominant polycystic kidney disease?

Autosomal dominant polycystic kidney disease (ADPKD) is a progressive kidney disease where the size of the kidneys is correlated to the stage of kidney failure. Total kidney volume (TKV) is used as a prognostic marker to determine disease stage, progression, and possible effect of treatment. It has been shown that water restriction is associated with reduced kidney volume in healthy subjects. The aim of this study was to evaluate the relationship between TKV and hydration status in ADPKD patients. 40 ADPKD patients with chronic kidney disease stage 1 - 3 were randomized to either 3 hours of water restriction (n = 21) or 1 hour of water loading (n = 19; intake: 20 mL/kg). The patients had a mean age of 38 years (19 - 73) and mean plasma creatinine level of 91 (54 - 178) µmol/L. Magnetic resonance imaging of the kidneys was performed before and after intervention, and TKV was measured using the ellipsoid formula. Water restriction resulted in an insignificant 0.67% increase in TKV (median: 1.48, interquartile range (IQR): 6.1, range: -1. - 4.5). Water loading resulted in an insignificant 2.67% increase in TKV (median: 3.18, IQR: 11.4, range: -3.6 - 7.8). Interestingly, a 7.09% increase in right-kidney volume was found after water loading (median: 5.58, IQR: 9.4 range: 1.9 - 11.3, p < 0.05), whereas the left-kidney volume showed an insignificant decrease of 0.18% after water loading (median: -1.65, IQR: 18.0, range: -12.5 - 5.5). We found in ADPKD patients that neither short-term water restriction nor acute water loading had significant effects, suggesting that the use of TKV for disease staging is independent of hydration level in these patients.

[Personalised medicine requires a paradigm shift in the concept of evidence].

Personalised medicine via a central biobank will require the introduction of a paradigm shift navigating by detecting pattern and correlation, instead of evidence of limited use in our complex environment. Accordingly, to make sense, population-wide data comprising "deep phenotype" including genetics, must be submitted to evaluation by "machine intelligence", based on "unsupervised learning" - the algorithm concomitantly improving its power with increasing mass of data. A system not based on deductive logic cannot be checked by logic but must be taken on face value.

A model to predict disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD): the ADPKD Outcomes Model.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the leading inheritable cause of end-stage renal disease (ESRD); however, the natural course of disease progression is heterogeneous between patients. This study aimed to develop a natural history model of ADPKD that predicted progression rates and long-term outcomes in patients with differing baseline characteristics. METHODS: The ADPKD Outcomes Model (ADPKD-OM) was developed using available patient-level data from the placebo arm of the Tolvaptan Efficacy and Safety in Management of ADPKD and its Outcomes Study (TEMPO 3:4; ClinicalTrials.gov identifier NCT00428948). Multivariable regression equations estimating annual rates of ADPKD progression, in terms of total kidney volume (TKV) and estimated glomerular filtration rate, formed the basis of the lifetime patient-level simulation model. Outputs of the ADPKD-OM were compared against external data sources to validate model accuracy and generalisability to other ADPKD patient populations, then used to predict long-term outcomes in a cohort matched to the overall TEMPO 3:4 study population. RESULTS: A cohort with baseline patient characteristics consistent with TEMPO 3:4 was predicted to reach ESRD at a mean age of 52 years. Most patients (85%) were predicted to reach ESRD by the age of 65 years, with many progressing to ESRD earlier in life (18, 36 and 56% by the age of 45, 50 and 55 years, respectively). Consistent with previous research and clinical opinion, analyses supported the selection of baseline TKV as a prognostic factor for ADPKD progression, and demonstrated its value as a strong predictor of future ESRD risk. Validation exercises and illustrative analyses confirmed the ability of the ADPKD-OM to accurately predict disease progression towards ESRD across a range of clinically-relevant patient profiles. CONCLUSIONS: The ADPKD-OM represents a robust tool to predict natural disease progression and long-term outcomes in ADPKD patients, based on readily available and/or measurable clinical characteristics. In conjunction with clinical judgement, it has the potential to support decision-making in research and clinical practice.

[Autosomal dominant polycystic kidney disease].

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder which causes end stage renal disease. In Denmark, estimated 5,000 patients are living with the disease. Most of the patients are in regular contact with physicians due to the progression of kidney failure causing hypertension as well as cyst infections, back pain, abdominal distension and other symptoms caused by the enlarged kidneys. In this article we describe the clinical presentation, the genetics, the pathophysiology and the current and future treatment modalities of the disease.

[Molecular genetic screening for polycystic kidney disease can be an important diagnostic tool]. / Molekylærgenetisk screening for polycystisk nyresygdom kan være et vigtigt diagnostisk redskab.

Autosomal dominant polycystic kidney disease (ADPKD) is associated with mutation in the PKD1- or PKD2-gene. We present two cases with an atypical presentation of ADPKD. Molecular genetic screening of PKD1 and PKD2 confirmed the diagnoses. Screening of PKD1 and PKD2 has become an important diagnostic tool.

Renal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe: prevalence and survival--an analysis of data from the ERA-EDTA Registry.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the fourth most common renal disease requiring renal replacement therapy (RRT). Still, there are few epidemiological data on the prevalence of, and survival on RRT for ADPKD. METHODS: This study used data from the ERA-EDTA Registry on RRT prevalence and survival on RRT in 12 European countries with 208 million inhabitants. We studied four 5-year periods (1991-2010). Survival analysis was performed by the Kaplan-Meier method and by Cox proportional hazards regression. RESULTS: From the first to the last study period, the prevalence of RRT for ADPKD increased from 56.8 to 91.1 per million population (pmp). The percentage of prevalent RRT patients with ADPKD remained fairly stable at 9.8%. Two-year survival of ADPKD patients on RRT (adjusted for age, sex and country) increased significantly from 89.0 to 92.8%, and was higher than for non-ADPKD subjects. Improved survival was noted for all RRT modalities: haemodialysis [adjusted hazard ratio for mortality during the last versus first time period 0.75 (95% confidence interval 0.61-0.91), peritoneal dialysis 0.55 (0.38-0.80) and transplantation 0.52 (0.32-0.74)]. Cardiovascular mortality as a proportion of total mortality on RRT decreased more in ADPKD patients (from 53 to 29%), than in non-ADPKD patients (from 44 to 35%). Of note, the incidence rate of RRT for ADPKD remained relatively stable at 7.6 versus 8.3 pmp from the first to the last study period, which will be discussed in detail in a separate study. CONCLUSIONS: In ADPKD patients on RRT, survival has improved markedly, especially due to a decrease in cardiovascular mortality. This has led to a considerable increase in the number of ADPKD patients being treated with RRT.

Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of end-stage kidney failure, but is often identified early and therefore amenable to timely treatment. Interventions known to postpone the need for renal replacement therapy (RRT) in non-ADPKD patients have also been tested in ADPKD patients, but with inconclusive results. To help resolve this we determined changes in RRT incidence rates as an indicator for increasing effective renoprotection over time in ADPKD. We analyzed data from the European Renal Association-European Dialyses and Transplant Association Registry on 315,444 patients starting RRT in 12 European countries between 1991 and 2010, grouped into four 5-year periods. Of them, 20,596 were due to ADPKD. Between the first and last period the mean age at onset of RRT increased from 56.6 to 58.0 years. The age- and gender-adjusted incidence rate of RRT for ADPKD increased slightly over the four periods from 7.6 to 8.3 per million population. No change over time was found in the incidence of RRT for ADPKD up to age 50, whereas in recent time periods the incidence in patients above the age of 70 clearly increased. Among countries there was a significant positive association between RRT take-on rates for non-ADPKD kidney disease and ADPKD. Thus, the increased age at onset of RRT is most likely due to an increased access for elderly ADPKD patients or lower competing risk prior to the start of RRT rather than the consequence of effective emerging renoprotective treatments for ADPKD.

Low birth weight is associated with earlier onset of end-stage renal disease in Danish patients with autosomal dominant polycystic kidney disease.

Low-birth-weight individuals have a higher risk of hypertension and end-stage renal disease (ESRD). Here we investigated whether low birth weight was associated with earlier onset of ESRD in patients with autosomal dominant polycystic kidney disease (ADPKD). In collaboration with all Danish departments of nephrology, 307 of 357 patients with ADPKD and ESRD born and living in Denmark were recruited. We were able to analyze complete data of 284 patients obtained from both hospital medical files and midwife protocols in the Danish State Archives. Multivariable linear regression adjusted for birth weight, adult height, mean arterial pressure, gender, birth decade, and type of antihypertensive treatment showed that for every kilogram increase in birth weight, the age at onset of ESRD significantly increased by 1.7 years. Male gender and increased mean arterial pressure were both associated with earlier onset of ESRD. Patients treated with renin-angiotensin system blockade or calcium channel blockers during follow-up had significantly later onset of ESRD by 4.3 years and 2.1 years, respectively. Treatment with beta-blockade or a diuretic was not associated with the age at onset of ESRD. Thus, low birth weight may contribute to considerable phenotypic variability in the progression of renal disease between individuals with ADPKD.

Changes in causes of death and risk of cancer in Danish patients with autosomal dominant polycystic kidney disease and end-stage renal disease.

BACKGROUND: With the improved prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD), causes of death and the risk of cancer might have changed. This was investigated in a Danish population with ADPKD and end-stage renal disease (ESRD) between 1 January 1993 and 31 December 2008. METHODS: Data were retrieved from three Danish national registries and a total of 823 patients were identified of which 431 had died during the study period. The 16 years were divided into two 8-year periods and the causes of death were divided into six categories: cancer, cardiovascular, cerebrovascular, infection, other and unknown. RESULTS: Cardiovascular disease was the major cause of death. A multivariate competing risk model comparing the two 8-year periods, adjusted for age at ESRD, gender and treatment modality, showed that deaths from cardiovascular disease decreased by 35% [hazard ratios (HR) 0.65, P=0.008] and deaths from cerebrovascular disease decreased by 69% (HR 0.31, P=0.0003) from the first to the second time period. There were no significant changes between the time periods in death from cancer, infection, other or unknown. From the first to the second 8-year interval, the prevalence of cancer increased by 35% (P=0.0002) while the cancer incidence was stable. CONCLUSIONS: In Danish patients with ADPKD and ESRD, there was a significant reduction in cardiovascular and cerebrovascular deaths from 1993 to 2008. The prevalence of cancer increased without significant change in cancer incidence or deaths from cancer.

Improved prognosis in patients with autosomal dominant polycystic kidney disease in Denmark.

BACKGROUND AND OBJECTIVES: The introduction of new therapies, including agents that block the renin-angiotensin system, may have affected progression of autosomal dominant polycystic kidney disease (ADPKD). We investigated whether the age when reaching ESRD and survival during renal replacement therapy in Danish patients with ADPKD changed from January 1, 1990, through December 31, 2007. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: According to the Danish National Registry on Regular Dialysis and Transplantation, 693 patients with ADPKD reached ESRD in the study period. The 18 years were divided into three consecutive 6-year intervals. RESULTS: The incidence of reaching ESRD for patients with ADPKD increased from 6.45 per million people in 1990 through 1995 to 7.59 per million people in 2002 through 2007, and the mean age at onset of ESRD increased by 4.7 years. The age-adjusted male-to-female ratio for onset of ESRD changed from 1.6 to 1.1, indicating a trend toward similar progression in both genders. From onset of ESRD, a Cox regression analysis to compare the first and second 6-year intervals, adjusted for age, gender, and treatment modality, showed that patient survival improved by 38%. Although NS, a similar trend was found during the second and third time intervals. CONCLUSIONS: This study demonstrates that in Danish patients with ADPKD, the prognosis had significantly improved during the study period. Furthermore, the results indicate that male gender may be losing its importance as a risk factor for progression in ADPKD.

Estimating glomerular filtration rate using the new CKD-EPI equation and other equations in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: No studies have compared the performance of equations for estimating glomerular filtration rate (GFR) in patients with autosomal dominant polycystic kidney disease (ADPKD), where the declining GFR typically is followed for many years or even decades. This was the purpose of the present investigation. METHODS: 101 ADPKD patients with chronic kidney disease stages 1-5 were recruited and GFR was measured with the (51)Cr-EDTA clearance method, and estimated with the Modification of Diet in Renal Disease Study (MDRD) equation with 4 variables, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Cockcroft-Gault equation adjusted for body surface area and the MDRD equation with cystatin C. Performance was evaluated by mean bias, precision and accuracy. RESULTS: The MDRD equation with cystatin C had 97% of GFR estimates within 30% of measured GFR (accuracy). Both the CKD-EPI and Cockcroft-Gault equations had an accuracy of 90% whereas the MDRD equation had an accuracy of 83%. This difference of accuracy was especially marked with GFR >60 ml/min/1.73 m(2). CONCLUSION: For estimating GFR in ADPKD patients the MDRD equation with cystatin C incorporated had the best performance. The CKD-EPI or the Cockcroft-Gault equations showed better performance compared to the 4-variable MDRD equation.