KAPLAN INTERNAL MEDICINE PDF
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Medical Books PDF The only official lecture notes provided by Kaplan Medical, USMLE Step 2 CK Lecture Notes The set includes: Internal Medicine . This publication is not intended for use in clinical practice or the delivery of medical care. To the fullest extent of the law, neither the Publisher nor the Editors . USMLE Step 2 CK Lecture Notes Internal Medicine by Kaplan Medical - The only official Kaplan Lecture Notes for USMLE Step 2 CK cover the.
Histological hallmarks of progressive loss of renal function include infiltration of the kidney with inflammatory cells, activation and proliferation of fibroblasts, excessive production and deposition of extracellular matrix components, and rarefaction of tubular capillaries, finally resulting in irreversible tubulointerstitial fibrosis and atrophy 3 , 4.
Traditionally, research has focused on the activation of deleterious factors and pathways that drive CKD progression. We have previously consolidated a set of proteins with renoprotective potential based on scientific literature 6.
Other factors are currently investigated in clinical trials in the context of diabetes and kidney disease such as the hepatocyte growth factor HGF or proopiomelanocortin POMC encoding among others for the polypeptide hormone adrenocorticotropin. Proteins are, therefore, included in the set of renoprotective factors and hold the potential to serve as drug targets, biomarkers, or drugs themselves in the context of kidney disease.
Identification of biomarkers most often focuses on molecules with damaging properties being elevated in the diseased state. A systematic evaluation of the association of disease progression with renoprotective factors has not been conducted so far to our knowledge.
In this study, we investigated a set of renoprotective factors on the transcriptome level and determined their association with disease outcome in a discovery cohort of 63 CKD patients in the search for novel therapeutic targets.
The most promising candidate, DCXR, was further investigated on a functional level making use of human and in vitro transcriptomics data sets.
Results In the current study, we investigated proteins with renoprotective potential based on findings from the literature. Clinical drivers of disease progression in the CKD discovery cohort. A retrospective cohort of 63 patients with various CKD diagnoses and available follow-up data was used as the discovery cohort to evaluate the association of renoprotective factors with CKD progression.
Twenty-four of the sixty-three CKD patients developed end-stage renal disease ESRD — defined as the need for dialysis or renal transplantation — or experienced a 2-fold increase of serum creatinine and were therefore categorized as the progressive group. The median follow-up time was 6.
At biopsy, patients in the progressive group, as compared with the group of stable patients, were older 56 years versus 41 years on average and also had lower eGFR The percentage of male patients was also higher in the progressive group Table 1. The list of patient IDs and group assignment is available in Supplemental Table 1. Association of renoprotective factors with disease outcome in the CKD discovery cohort.
All 6 proteins were also significantly associated with outcomes in Kaplan-Meier analysis when grouping patients into tertiles based on marker expression levels Figure 1. Figure 1 Association of renoprotective factors with disease outcome in the discovery cohort. Kaplan-Meier plots for the 6 renoprotective factors showing significant associations with disease outcome log-rank test. UPCR did not show a marked correlation to any of the other parameters under study. Significant positive and negative correlations after multiple testing corrections are highlighted in shades of red and blue, respectively.
Nonsignificant correlations are displayed with a white background. Median DCXR expression across all 63 samples is indicated by a dotted horizontal line. Diagnoses are sorted in descending order based on median DCXR expression levels. B DCXR expression levels across the different histological parameters.
We observed an overall trend of lower DCXR values being present in samples with a higher degree of histological damage. DCXR is predominantly expressed in the tubulointerstitium.
In order to determine the levels of DCXR transcript and protein abundance in the different renal compartments, we assessed DCXR abundance in 3 gene expression data sets as well as data from the Human Protein Atlas.
Figure 4 DCXR expression in renal tissue. B DCXR protein abundance is also restricted to renal tubular cells. This is in line with data from the Human Protein Atlas indicating that DCXR is abundant on the protein level in tubulointerstitium, whereas, almost no protein is found in the glomeruli Figure 4B.
DCXR also showed enriched mRNA expression patterns in human proximal tubular cells in comparison with other cell types based on data from a high-resolution single-cell RNA-seq data set, as shown in Figure 4C. A significant downregulation of DCXR in diseased samples could be observed in all 3 cohorts under study.
DCXR expression was found to be significantly downregulated in an independent CKD cohort A and 2 DN cohorts B and C , as compared with healthy control subjects, when reanalyzing independent transcriptomics data sets. P values are based on t tests. The P value in the Kaplan-Meier analysis is based on the log-rank test statistics.
All tested parameters except sex were significantly associated with disease outcome. The hazard ratio for DCXR was 0. Association of DCXR with members of the formation of xylulosephosphate pathway and the dicarbonyl stress detoxification cascade. DCXR is member of the formation of xylulosephosphate pathway.
Figure 8 DCXR in the formation of xylulosephosphate pathway and the link to dicarbonyl stress detoxification. Schematic representations of the formation of xylulosephosphate pathway and key players in detoxification of dicarbonyl stress.
Correlation coefficients to DCXR based on mRNA gene expression in the 4 renal tubular transcriptomics data sets used in this study are provided for key pathway members. Significant positive and negative correlations are highlighted in red and blue, respectively.
We furthermore determined correlations of DCXR expression with key enzymes involved in dicarbonyl stress detoxification. We investigated the effect of the sodium glucose cotransporter-2 SGLT2 inhibitor canagliflozin on DCXR expression in human renal proximal tubular cells HK2 that have been stimulated with high glucose.
The authors of this study have determined gene expression profiles in 2 renal proximal tubular cells RPTECs studying the effect of the 2 SGLT2 inhibitors canagliflozin and empagliflozin. DCXR expression levels increased 1. Diamonds indicate group mean expression values. Discussion This is, to our knowledge, the first study reporting on the association with disease progression of the renoprotective factor DCXR in the context of human CKD.
A number of clinical parameters has been reported to be associated with the course of disease development in CKD patients, including impaired renal function itself, hypertension, as well as the degree of proteinuria 9 — Other risk factors associated with a worse prognosis are presence of cardiovascular disease or diabetes, black race, or being male Our discovery cohort of 63 CKD patients seems to be representative, with significant associations to disease outcome observed for sex, baseline eGFR, and type of diagnosis.
We decided to investigate this rather heterogeneous CKD patient population with different CKD diagnoses represented to increase our chances of detecting common renoprotective mechanisms and factors of general utility. In addition to clinical parameters, a number of molecular biomarkers have been discovered, with the majority being elevated in the diseased state 13 — In this work, we were particularly interested in molecules with renoprotective properties instead of damaging potential.
Of a previously published set of proteins with renoprotective potential 6 , 6 are identified as predictors of CKD outcome in our discovery cohort. The focus of all further analyses and validation in the current study were subsequently on the sixth renoprotective factor, namely DCXR, for which no human data in the context of CKD disease progression is available.
DCXR is a member of the formation of xylulosephosphate pathway with the main function of converting L-xylulose to xylitol.
Deficiency in DCXR is linked to pentosuria, a condition characterized by high L-xylulose levels in urine We found strong positive correlations of tubular DCXR expression to other members of the formation of xylulosephosphate pathway in our study.
Based on these data and consolidated literature information, we speculate that DCXR might offer a complementary way of counterbalancing dicarbonyl stress in human renal tubular cells Figure Tubular DCXR converts L-xylulose to xylitol with high urinary L-xylulose levels being characteristic for the benign condition of pentosuria.
The first clinical trials NCT testing GLO1 inducers in the context of diabetes and associated vascular complications have already shown promising results 33 , Induction of DCXR might, therefore, provide an alternative way of counterbalancing dicarbonyl stress to reduce generation of AGEs with a final beneficial effect on kidney function.
The major driver of this significant association with disease outcome, in both the discovery and the validation cohorts, are patients in the first tertile of DCXR expression levels, i. The most significant association was found in the group of FSGS patients the largest subgroup with 68 subjects.
FSGS is one of the disease entities showing a large variance in the outcome parameter. The smaller sample sizes for the MN patient subgroup, as well as for the patient subgroup with other diseases, may have weakened the association with disease outcome. The association of DCXR expression with clinical outcome and histological damage suggests that DCXR is a marker mechanistically linked to renal damage and may, therefore, serve as a novel molecule for therapeutic intervention.
DCXR was also found to be negatively associated with cortical interstitial fractional volume by Nair and colleagues In addition, calcineurin inhibitor treatment after renal transplantation had a detrimental effect on DCXR gene expression based on a microarray study by Maluf and colleagues DCXR protein concentration was also found to be upregulated around 2-fold in glomerular tissue from patients with diabetes mellitus who were being protected from development of diabetic kidney disease Very recently, DCXR was found in a proteomics study in a rat model to be downregulated in rat myocardium during development of type 2 diabetes SGLT2 inhibitors delay kidney function decline and have beneficial effect on cardiovascular outcome, although the exact underlying mechanisms are not fully understood 40 — Leon Gordis.
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Kaplan Medical. USMLE Step 2 CK Lecture Notes Internal Medicine
Continue shopping Checkout Continue shopping. Chi ama i libri sceglie Kobo e inMondadori. Internal Medicine Back to Nonfiction. download the eBook Price: Choose Store. Updated annually by Kaplan's all-star faculty. Highly illustrated.Echocardiogram is et diagnostic, treatment is surgical repair. Neonatology 7th Edition. Any change that occurs requires complete re-evaluation, including rechecking that there has not been a change in the ABCs. Embeds 0 No embeds. Based on these data and consolidated literature information, we speculate that DCXR might offer a complementary way of counterbalancing dicarbonyl stress in human renal tubular cells Figure Successfully reported this slideshow.
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