Exclusion of Polymorphisms in Carnosinase Genes (CNDP1 and CNDP2) as a Cause of Diabetic Nephropathy in Type 1 Diabetes: Results of Large Case-Control and Follow-Up Studies

OBJECTIVES— Recently, an association was found between diabetic nephropathy and the D18S880 microsatellite, located in the carnosinase gene (CNDP1) on chromosome 18q. Alleles of this microsatellite encode for a variable number of leucine residues (from four to seven) in the leader peptide of the carnosinase precursor. The frequency of subjects homozygous for the five leucines was higher in control subjects than in case subjects in studies focusing on type 2 diabetic patients. To test whether this finding can be extended to type 1 diabetic patients, we carried out a comprehensive study on association between diabetic nephropathy and the D18S880 microsatellite and 21 additional SNPs that tagged the genomic region containing CNDP1 and CNDP2

Transcriptome Analysis of Proximal Tubular Cells (HK-2) Exposed to Urines of Type 1 Diabetes Patients at Risk of Early Progressive Renal Function Decline

Background: In patients with Type 1 Diabetes (T1D) who develop microalbuminuria, progressive decline in glomerular filtration rate (GFR) may be initiated by leakage into the urine of toxic proteins (txUPs). This study tested this hypothesis. Methods: After archiving baseline urine, we followed T1D patients with microalbuminuria for 8–12 years to distinguish those in whom GFR declined (Decliners) and those in whom it remained stable (Non-decliners). Human proximal tubular cells (HK-2 cells) were grown in serum-free medium enriched with pooled urines from Decliners or Non-decliners. We determined genome-wide expression profiles in extracted mRNA. Results: The two pooled urines induced differential expression of 312 genes. In terms of gene ontology, molecular functions of the 119 up-regulated genes were enriched for protein binding and peptidase inhibitor activities. Their biologic processes were enriched for defense response, responses to other organisms, regulation of cellular processes, or response to stress or stimulus, and programmed cell death. The 195 down-regulated genes were disproportionately represented in molecular functions of cation binding, hydrolase activity, and DNA binding. They were disproportionately represented in biological processes for regulation of metabolic processes, nucleic acid metabolic processes, cellular response to stress and macromolecule biosynthesis. The set of up-regulated genes in HK-2 cells overlaps significantly with sets of over-expressed genes in tubular and interstitial compartments of kidney biopsies from patients with advanced DN (33 genes in one study and 25 in the other compared with 10.3 expected by chance, p<$10^{−9}$ and p<$10^{−4}$, respectively). The overlap included genes encoding chemokines and cytokines. Overlap of down-regulated genes was no more than expected by chance. Conclusions: Molecular processes in tubules and interstitium seen in advanced diabetic nephropathy can be induced in vitro by exposure to urine from patients with minimal microalbuminuria who subsequently developed progressive renal function decline, presumably due to putative txUPs

Związek między polimorfizmem insercyjno-delecyjnym genu enzymu konwertazy angiotensyny I i obecnością zmian miażdżycowych w tętnicach wieńcowych u pacjentów ze zwężeniem zastawki aortalnej

Wstęp: Celem pracy była ocena zależności między polimorfizmem insercyjno-delecyjnym genu konwertazy angiotensyny (ACE) a częstością występowania istotnych zmian miażdżycowych w tętnicach wieńcowych u pacjentów z istotnym zwężeniem zastawki aortalnej. Materiał i metody: Badano 392 pacjentów (159 kobiet i 233 mężczyzn) w średnim wieku 61 &plusmn; 10 lat z izolowanym zwężeniem zastawki aortalnej. U wszystkich pacjentów przed operacją wymiany zastawki aortalnej wykonano koronarografię oraz oznaczono warianty polimorfizmu genu ACE. Za istotne przyjęto zwężenie tętnicy wieńcowej > 70% (lub > 50-procentową zmianę w pniu lewej tętnicy wieńcowej). Wyniki: Istotne zmiany miażdżycowe w tętnicach wieńcowych stwierdzono u 95 badanych - u 30 kobiet (19%) i 65 mężczyzn (28%). Istotne zwężenia odnotowano u 14% kobiet z genotypem II, u 20% z genotypem DI i u 21% pacjentek z genotypem DD. U mężczyzn istotne zwężenia obserwowano u 38% pacjentów z genotypem II, u 25% z genotypem DI i u 22% badanych z genotypem DD. Znamiennie częstsze istotne zwężenia stwierdzono wśród mężczyzn z genotypem II (p < 0,05). W grupie kobiet różnice nie były istotne statystycznie. Wnioski: U pacjentów ze zwężeniem zastawki aortalnej zależność między polimorfizmem I/D genu ACE a występowaniem istotnych zmian miażdżycowych tętnic wieńcowych jest różna u kobiet i mężczyzn. U kobiet zaobserwowano tendencję do częstszego występowania istotnych zmian miażdżycowych w tętnicach wieńcowych u pacjentek z allelem D, natomiast u mężczyzn zmiany takie zanotowano istotnie częściej u homozygot II. (Folia Cardiol. 2003; 10: 161&#8211;168

Związek między polimorfizmem insercyjno-delecyjnym genu enzymu konwertazy angiotensyny I i obecnością zmian miażdżycowych w tętnicach wieńcowych u pacjentów ze zwężeniem zastawki aortalnej

Wstęp: Celem pracy była ocena zależności między polimorfizmem insercyjno-delecyjnym genu konwertazy angiotensyny (ACE) a częstością występowania istotnych zmian miażdżycowych w tętnicach wieńcowych u pacjentów z istotnym zwężeniem zastawki aortalnej. Materiał i metody: Badano 392 pacjentów (159 kobiet i 233 mężczyzn) w średnim wieku 61 &plusmn; 10 lat z izolowanym zwężeniem zastawki aortalnej. U wszystkich pacjentów przed operacją wymiany zastawki aortalnej wykonano koronarografię oraz oznaczono warianty polimorfizmu genu ACE. Za istotne przyjęto zwężenie tętnicy wieńcowej > 70% (lub > 50-procentową zmianę w pniu lewej tętnicy wieńcowej). Wyniki: Istotne zmiany miażdżycowe w tętnicach wieńcowych stwierdzono u 95 badanych - u 30 kobiet (19%) i 65 mężczyzn (28%). Istotne zwężenia odnotowano u 14% kobiet z genotypem II, u 20% z genotypem DI i u 21% pacjentek z genotypem DD. U mężczyzn istotne zwężenia obserwowano u 38% pacjentów z genotypem II, u 25% z genotypem DI i u 22% badanych z genotypem DD. Znamiennie częstsze istotne zwężenia stwierdzono wśród mężczyzn z genotypem II (p < 0,05). W grupie kobiet różnice nie były istotne statystycznie. Wnioski: U pacjentów ze zwężeniem zastawki aortalnej zależność między polimorfizmem I/D genu ACE a występowaniem istotnych zmian miażdżycowych tętnic wieńcowych jest różna u kobiet i mężczyzn. U kobiet zaobserwowano tendencję do częstszego występowania istotnych zmian miażdżycowych w tętnicach wieńcowych u pacjentek z allelem D, natomiast u mężczyzn zmiany takie zanotowano istotnie częściej u homozygot II. (Folia Cardiol. 2003; 10: 161&#8211;168

Temporal trends of transcatheter aortic valve implantation in a high-volume academic center over 10 years

Background: Indications for transcatheter aortic valve implantation (TAVI) have gradually expanded since its introduction.Aims: The aim was to analyze temporal trends in TAVI characteristics based on the experience of a high-volume academic center over the period of 10 years.Methods: Five hundred and six consecutive (n = 506) patients with 1-year follow-up were divided into early (G1, years 2010–2013, n = 130), intermediate (G2, 2014–2016, n = 164) and recent (G3, 2017–2019, n = 212) experience groups.Results: Patient’s age remained constant over time (mean [SD]; G1 = 79.1 [7.1] years vs G2 = 79.1 [7.1] years vs G3 = 79.7 [6.6] years, P = 0.73) but surgical risk in G3 was lower (log Euroscore, median [IQR]: G1 = 14.0 [8.4–20.2] vs G2 = 12.0 [7.0–22.2] vs G3 = 5.1 [3.5–8.5]; P &lt;0.001). Major/life-threatening bleeding (G1 = 26.9% vs G2 = 12.8% vs G3 = 9.4%; P &lt;0.001), major vascular complications (G1 = 15.4% vs G2 = 8.5% vs G3 = 5.7%; P = 0.02) and moderate/severe paravalvular leak (G1 = 16.2% vs G2 = 11% vs G3 = 7.5%; P = 0.046) were decreasing with time. There was a significant drop in all-cause 1-year mortality in G3 (G1 = 20% vs G2 = 17.7% vs G3 = 9.1%; log rank = 0.01).Conclusions: The age of TAVI recipients remained unchanged over the last decade. Decreasing surgical risk coupled with improvements in procedural technique and care resulted in fewer periprocedural complications and better 1-year survival

Long-term outcomes and quality of life following implementation of dedicated mitral valve Heart Team decisions for patients with severe mitral valve regurgitation in tertiary cardiovascular care center

Background: This study was purposed to investigate which treatment strategy was associated with the most favourable prognosis for patients with severe mitral regurgitation (MR) following Heart Team (HT)-decisions implementation. Methods: In this retrospective study, long-term outcomes of patients with severe MR qualified after HT discussion to: optimal medical treatment (OMT) alone, OMT and MitraClip (MC) procedure or OMT and mitral valve replacement (MVR) were evaluated. The primary endpoint was defined as cardiovascular (CV) death and the secondary endpoints included all-cause mortality, myocardial infarctions (MI), strokes, hospitalizations for heart failure exacerbation and CV events during a mean (standard deviation [SD]) follow-up of 29 (15) months. Results: From 2016 to 2019, 176 HT meetings were held and a total of 157 participants (mean age [SD] = 71.0 [9.2], 63.7% male) with severe MR and completely implemented HT decisions (OMT, MC or MVR for 53, 58 and 46 patients, respectively) were included into final analysis. Comparing OMT, MC and MVR groups statistically significant differences between the implemented procedures and occurrence of primary and secondary endpoints with the most frequent in OMT-group were observed (p &lt; 0.05). However, for interventional strategy MC was non-inferior to MVR for all endpoints (p &gt; 0.05). General health status assessed at the end of follow-up were significantly the lowest for MVR, then for MC and the highest for OMT-group (p &lt; 0.01). Conclusions: In the present study it was demonstrated that after careful HT evaluation of patients with severe MR at high risk of surgery, percutaneous strategy (MC) can be considered as equivalent to surgical treatment (MVR) with non-inferior outcomes

Genome-Wide Association Scan for Diabetic Nephropathy Susceptibility Genes in Type 1 Diabetes

OBJECTIVE—Despite extensive evidence for genetic susceptibility to diabetic nephropathy, the identification of susceptibility genes and their variants has had limited success. To search for genes that contribute to diabetic nephropathy, a genome-wide association scan was implemented on the Genetics of Kidneys in Diabetes collection. RESEARCH DESIGN AND METHODS—We genotyped 360,000 single nucleotide polymorphisms (SNPs) in 820 case subjects (284 with proteinuria and 536 with end-stage renal disease) and 885 control subjects with type 1 diabetes. Confirmation of implicated SNPs was sought in 1,304 participants of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term, prospective investigation of the development of diabetes- associated complications. RESULTS—A total of 13 SNPs located in four genomic loci were associated with diabetic nephropathy with P1105. The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR]1.45, P5.0107). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR 1.36, P3.1106). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR]1.33, P0.02, and HR1.32, P 0.01, respectively). We demonstrated expression of both FRMD3 and CARS in human kidney. CONCLUSIONS—We identified genetic associations for susceptibility to diabetic nephropathy at two novel candidate loci near the FRMD3 and CARS genes. Their identification implicates previously unsuspected pathways in the pathogenesis of this important late complication of type 1 diabetes

A disease haplotype for advanced nephropathy in type 2 diabetes at the ACE locus

Previous investigations of the ACE gene as a susceptibility factor for diabetic nephropathy have primarily focused on its insertion/deletion (Ins/Del) polymorphism. In a departure from these earlier studies, we used three tagging markers (A-5466C, T-3892C, and Ins/Del) at the ACE locus to test for disease haplotype associations. A case-control study design was used where case subjects were type 2 diabetic patients with advanced diabetic nephropathy, as indicated by the presence of proteinuria or chronic renal failure/end-stage renal disease, while control subjects were normoalbuminuric, despite >6 years of diabetes. None of the individual markers showed significant disease association when considered on their own. However, haplotype analyses revealed a near doubling in the prevalence of the A.T.D risk haplotype in case subjects (0.136) compared with control subjects (0.075) (P =3D 0.009), thus providing first evidence for a disease haplotype for advanced diabetic nephropathy at the ACE locus