Risk Factors For Rapid Progression Research Articles

Progression of aortic stenosis in patients with diabetes mellitus type 2 compared with matched controls

Abstract Background Degenerative aortic stenosis (AS) and diabetes mellitus type 2 (DM) increase with age1,2 and their prevalence is expected to rise. Patients with DM have a higher risk to develop AS3 and the pathophysiological process leading from a normal aortic valve to AS involves factors associated with DM. AS develops over years, but it can evolve more rapidly. There is insufficient knowledge about risk factors for rapid progression in AS and monitoring strategies among patients at high risk for rapid progression. The aim of this project is to evaluate the AS progression towards combined outcome (incident heart failure, death, need for intervention) in patients with type 2 DM compared with matched controls. Methods From the Swedish National Diabetes Register (NDR) we identified all patients with type 2 DM between 01-01-2001- 31-12-2019 and for each patient 5 controls (matched for age, sex, region) from the Swedish Total Population Register. Afterwards we identified a cohort of individuals with AS from these two groups, by linking the NDR with the National Patient Register. The outcomes were: all- cause and cardiovascular mortality, and combined outcome (mortality, hospitalization for heart failure (HF) or aortic valve replacement (AVR)). We used Kaplan Meier survival curves to detect differences in all-cause mortality, cardiovascular mortality, time until AVR and combined outcome between cases and controls. Cox proportional hazards model adjusted for sex, age, obesity, renal failure, hyperparathyroidism, hypertension, hyperlipidemia was used to study the risk difference between the cases and controls for the combined outcome. Results We identified 16 144 individuals with type 2 DM and AS and 31 206 matched controls. The individuals with type 2 DM were predominately men (59% vs 53%), younger (mean age 70.6 vs 71.9), and had more comorbidities. In unadjusted analysis they were hospitalized for HF more often (8.2% vs 6.8%) and more often underwent AVR (surgically) (22.0% vs 19.0%) or transcatheter(6.6% vs 5.0%). Patients with AS and DM had higher all-cause and cardiovascular mortality and faster progression towards death, AVR or hospitalization for HF (see figure 1, A, B, C). The progression to AVR was significant, although the difference was small and not clinically relevant (plot D). In the adjusted model, the patients with AS and DM had 13% higher hazard to have the combined outcome compared with controls (see figure 2). Sex (female), hypertension and hyperlipidemia lowered the hazard for the combined event, while obesity, hyperparathyroidism and renal failure increased the hazard for the combined event. Conclusions Patients with concomitant AS and DM seem to have faster progression towards death (both all-cause and cardiovascular), and heart failure hospitalization or AVR compared with patients with AS without DM. Therefore, it might be appropriate to be more active regarding follow-up and intervention in these patients.Kaplan Meirer curvesForest plot for adjusted Cox model

Several factors that predict the outcome of large B-cell lymphoma patients who relapse/progress after chimeric antigen receptor (CAR) T-cell therapy can be identified before cell administration.

The aim of this study was to analyse the outcomes of patients with large B-cell lymphoma (LBCL) treated with chimeric antigen receptor T-cell therapy (CAR-Tx), with a focus on outcomes after CAR T-cell failure, and to define the risk factors for rapid progression and further treatment. We analysed 107 patients with LBCL from the Czech Republic and Slovakia who were treated in ≥3rd-line with tisagenlecleucel or axicabtagene ciloleucel between 2019 and 2022. The overall response rate (ORR) was 60%, with a 50% complete response (CR) rate. The median progression-free survival (PFS) and overall survival (OS) were 4.3 and 26.4 months, respectively. Sixty-three patients (59%) were refractory or relapsed after CAR-Tx. Of these patients, 39 received radiotherapy or systemic therapy, with an ORR of 22% (CR 8%). The median follow-up of surviving patients in whom treatment failed was 10.6 months. Several factors predicting further treatment administration and outcomes were present even before CAR-Tx. Risk factors for not receiving further therapy after CAR-Tx failure were high lactate dehydrogenase (LDH) levels before apheresis, extranodal involvement (EN), high ferritin levels before lymphodepletion (LD) and ECOG PS >1 at R/P. The median OS-2 (from R/P after CAR-Tx) was 6.7 months (6-month 57.9%) for treated patients and 0.4 months (6-month 4.2%) for untreated patients (p < 0.001). The median PFS-2 (from R/P after CAR-Tx) was 3.2 months (6-month 28.5%) for treated patients. The risk factors for a shorter PFS-2 (n = 39) included: CRP > limit of the normal range (LNR) before LD, albumin < LNR and ECOG PS > 1 at R/P. All these factors, together with LDH > LNR before LD and EN involvement at R/P, predicted OS-2 for treated patients. Our findings allow better stratification of CAR-Tx candidates and stress the need for a proactive approach (earlier restaging, intervention after partial remission achievement).

#1790 Metformin versus standard of care in slowing progression of autosomal dominant polycystic kidney disease and correlation with total kidney volume

Abstract Background and Aims Autosomal dominant kidney disease (ADPKD) is the most common monogenic disorder leading to renal failure with very limited therapeutic options. Apart from lifestyle modifications and control of hypertension, tolvaptan is the only Food and Drug Administration (FDA) approved disease modifying drug. Although, it has proven therapeutic benefit in slowing disease progression in high risk Mayo Class (Mayo Class 1C-E), the aquaretic potential, potential hepatotoxicity and the cost limits its widespread use especially in resource constrained country. Metformin has been shown to be effective in ADPKD in preclinical studies and is also well tolerated by the general population. We planned this study to assess the efficacy and safety of metformin in non diabetic ADPKD patients. Method Our study is a prospective, randomized controlled, open labelled clinical trial of 52 non diabetic adults 18 to 60 years of age with typical ADPKD, estimated glomerular filtration rate (eGFR) &amp;gt; 45 ml/min/m2 and no risk factors of rapid progression. Participants were randomized in a 1:1 ratio by a computer-generated random number table into Metformin + standard of care group (Metformin arm) and standard of care group (Placebo arm). Primary outcome of the study was to evaluate the effects of metformin versus placebo arm on the percentage and absolute change in eGFR over 6-month period. Secondary outcomes were to study the effect of metformin versus placebo arm on the percentage and absolute change in height adjusted total kidney volume (htTKV ml/m) at 6 months, to evaluate the effect of baseline plasma copeptin levels with percentage change in htTKV and eGFR over 6 months, to evaluate metformin tolerability, to evaluate the effects of metformin versus placebo on the changes in body weight, BMI, blood pressure and urine protein excretion at 6 months period. Results Mean (SD) age of the cohort was 37.15 (10.16) years with half of them being females. The mean (SD) baseline htTKV and eGFR was 335.67 (153.3) ml/m and 100.23 (25.95) ml/min/m2. Clinical exome sequencing was available in 9 (17.3%) patients of which two third had PKD1 mutation. Baseline characteristics were distributed equally across randomized groups. Baseline proteinuria was significantly higher in the Metformin arm (p = 0.014). The eGFR difference and percentage change in eGFR was not different between the groups at 6 months (p = 0.535, 0.483). There was no statistically significant difference in htTKV difference and percentage change in htTKV at 6 months between the groups although increase in htTKV was numerically smaller in the metformin group (p = 0.769, 0.805). Blood pressure, weight, body mass index (BMI) and proteinuria also did not differ between two groups. Half of the cohort tolerated the maximum dose of metformin. Around 2/3rd patients reported adverse effects most commonly asthenia. There was no lactic acidosis or significant gastrointestinal side effects as assessed by gastrointestinal rating scale (GSRS) scale. Baseline copeptin levels did not correlate with eGFR or htTKV difference at 6 months. Conclusion Metformin appears to be safe and tolerable in non diabetic ADPKD patients over 6 months. However larger clinical trials are needed to conclude regarding the efficacy in terms of eGFR decline or htTKV progression.

#2068 Factors affecting disease progression in individuals with heterozygous COL4A3/COL4A4 pathogenic variants

Abstract Background and Aims Individuals with heterozygous pathogenic variants in COL4A3/COL4A4 or also known as autosomal dominant Alport syndrome (ADAS) are increasingly diagnosed and show a wide spectrum of disease. Factors contributing to these different outcomes are not well understood. Here we study a cohort of patients with pathogenic (P) or likely pathogenic (LP) variants in COL4A3/COL4A4 with slow and rapid progression to evaluate risk factors associated with the condition. Method A retrospective observational multicenter study was performed in a cohort of individuals with heterozygous P and LP in COL4A3/COL4A4. Criteria were established to classify patients into rapid (RP) and slow progression (SP) (Fig. 1). In this study, we compared both cohorts and identified risk factors of rapid progression using T-score for numeric variables or Chi square for categoric variables. For the numerical variables that were correlated with RP, a cut-off point was established fitting the data with a regression curve. Further analyses are ongoing. Results A total of 374 patients were studied, the progression of the disease was classified in 135 individuals: 82 with RP (60.7%) and 53 SP (39.3%). The remaining patients couldn't be classified due to age or missing data during follow-up. The mean age at diagnosis of classified patients was 46.61 years (SD 17.46), with 65% being women. Genetic variant distribution was COL4A3 38%, COL4A4 58%, and digenic 4%. At diagnosis, 72% of patients had albuminuria or proteinuria (mean age of diagnosis: 50 years). Among these, 52.7% had ACR or PCR greater than 300 or 500 mg/gCr, with mean ACR at 445.92 mg/gCr (SD 587.54, max 2240 mg/g) and mean PCR at 968.38 (SD 1422, max 10633). 94% individuals had hematuria (mean age at diagnosis: 36.27 years). Forty-nine patients (36%) had CKD G-5, with a mean age of diagnosis of 53.08 years (SD 12.42). The mean eGFR was 67.56 (SD 30.56 ml/min). Results of kidney biopsy were available for 51 patients. 73 individuals had hypertension (HTN) with a mean age at diagnosis of 46.30 years (SD 13.81). A total of 82 patients responded to personal habits questionnaire. With all the variables studied, a total of 4 main variables were associated with RP. Conclusion The main variables associated with a worse outcome in individuals with heterozygous pathogenic variants in COL4A3/COL4A4 is the presence of albuminuria/proteinuria, HTN, age at diagnosis of HTN and age at diagnosis of the disease. Smoking has also been associated with a worse outcome when an exposure time over 11.8 years. More studies are still needed to understand the reasons for the huge phenotypic variability of this condition.

The utility of serum neutrophil gelatinase-associated lipocalin level on predicting autosomal dominant polycystic kidney disease progression.

We focused on neutrophil gelatinase-associated lipocalin (NGAL) and autosomal dominant polycystic kidney disease (ADPKD) progression. ADPKD patients with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 were included. Serum NGAL level and NGAL to eGFR ratio (NGR), height-adjusted total kidney volume (hTKV) were assessed initially. Patients were followed-up for 5 years. Sixty one patients were enrolled and initial eGFR was 73.6 (48.9-101.5) ml/min/1.73m2. EGFR declined by 3.7 mL/min/1.73m2 per year. Thirty four patients (55.7%) exhibited rapid progression. Rapid progression group had lower serum NGAL levels (p < 0.001) and higher hTKV (p < 0.001). Lower serum NGAL level was a risk factor for rapid progression (p < 0.001). NGR was not associated with rapid progression. Serum NGAL level was predictive in for rapid progression ROC analysis (cut-off <10.62 ng/mL). Relatively lower serum NGAL levels can predict worse outcomes in ADPKD and can provide risk stratification in patients with ADPKD.

Impact of demographic factors, comorbidities, and co‐medication on progression and survival in a large Chinese ALS cohort

AbstractObjectiveTo clarify the impact of specific risk/protective factors on the disease progression and survival in a large population of Chinese sporadic ALS (sALS) patients.MethodsWe investigated a cohort of 937 sALS patients prospectively. Uni‐ and multivariate regression analysis were performed to analyze the influence of demographic factors, comorbidities and medication on the progression and survival of ALS.ResultsOur results showed younger age of onset (p &lt; 0.05), long diagnostic delay (p &lt; 0.001) and intake of riluzole (p &lt; 0.001) were significantly related to low progression rate and long survival time. History of smoking (p &lt; 0.05) and bulbar onset (p &lt; 0.001) were risk factors for rapid progression and poor prognosis. Baseline ALSFRS‐R score (p &lt; 0.001) and total MRC score (p &lt; 0.05) were positively related to mean survival time of included patients. Neither comorbidities nor intake of antihypertensive drugs, antidiabetics, and statins as dependent variables showed considerable influence on ALS progression or survival.ConclusionOur study revealed early onset and long diagnostic delay were indicators of slow progression and long survival. Smoking and bulbar onset were risk factors for shorter survival times and abstaining from smoking was beneficial to patients with ALS in improving median survival time. Long‐term intake of riluzole should be recommended for affordable patients.

Prognostic utility of rhythmic components in 24-h ambulatory blood pressure monitoring for the risk stratification of chronic kidney disease patients with cardiovascular co-morbidity

Chronic kidney disease (CKD) represents a significant global burden. Hypertension is a modifiable risk factor for rapid progression of CKD. We extend the risk stratification by introducing the non-parametric determination of rhythmic components in 24-h profiles of ambulatory blood pressure monitoring (ABPM) in the Chronic Renal Insufficiency Cohort (CRIC) and the African American Study for Kidney Disease and Hypertension (AASK) cohort using Cox proportional hazards models. We find that rhythmic profiling of BP through JTK_CYCLE analysis identifies subgroups of CRIC participants that were more likely to die due to cardiovascular causes. While our fully adjusted model shows a trend towards a significant association between absent cyclic components and cardiovascular death in the full CRIC cohort (HR: 1.71,95% CI: 0.99–2.97, p = 0.056), CRIC participants with a history of cardiovascular disease (CVD) and absent cyclic components in their BP profile had at any time a 3.4-times higher risk of cardiovascular death than CVD patients with cyclic components present in their BP profile (HR: 3.37, 95% CI: 1.45–7.87, p = 0.005). This increased risk was not explained by the dipping or non-dipping pattern in ABPM. Due to the large differences in patient characteristics, the results do not replicate in the AASK cohort. This study suggests rhythmic blood pressure components as a potential novel biomarker to unmask excess risk among CKD patients with prior cardiovascular disease.

Development and Validation of a Clinic Machine Learning Classifier for the Prediction of Risk Stratifications of Prostate Cancer Bone Metastasis Progression to Castration Resistance.

To explore the predictive factors and predictive model construction for the progression of prostate cancer bone metastasis to castration resistance. Clinical data of 286 patients diagnosed with prostate cancer with bone metastasis, initially treated with endocrine therapy, and progressing to metastatic castration resistant prostate cancer (mCRPC) were collected. By comparing the differences in various factors between different groups with fast and slow occurrence of castration-resistant prostate cancer (CRPC). Kaplan-Meier survival analysis and COX multivariate risk proportional regression model were used to compare the differences in the time to progression to CRPC in different groups. The COX multivariate risk proportional regression model was used to evaluate the impact of candidate factors on the time to progression to CRPC and establish a predictive model. The accuracy of the model was then tested using receiver operating characteristic (ROC) curves and decision curve analysis (DCA). The median time for 286 mCRPC patients to progress to CRPC was 17 (9.5-28.0) months. Multivariate analysis showed that the lowest value of PSA (PSA nadir), the time when PSA dropped to its lowest value (timePSA), and the number of BM, and LDH were independent risk factors for rapid progression to CRPC. Based on the four independent risk factors mentioned above, a prediction model was established, with the optimal prediction model being a random forest with area under curve (AUC) of 0.946[95% CI: 0.901-0.991] and 0.927[95% CI: 0.864-0.990] in the training and validation cohort, respectively. After endocrine therapy, the PSA nadir, timePSA, the number of BM, and LDH are the main risk factors for rapid progression to mCRPC in patients with prostate cancer bone metastases. Establishing a CRPC prediction model is helpful for early clinical intervention decision-making.

Cape York Kidney Care: service description and baseline characteristics of a client-centred multidisciplinary specialist kidney health service in remote Australia

BackgroundChronic Kidney disease (CKD) is over-represented amongst First Nation people with more than triple the rate of CKD in those aged 15 years and over. The impact of colonisation, including harmful experiences of health practices and research, has contributed to these health inequities. Cape York Kidney Care (CYKC) has been created as an unique service which provides specialist care that aims to centre the client within a multidisciplinary team that is integrated within the primary care setting of the remote health clinics in six communities in western Cape York, Australia. This research aims to describe the Cape York Kidney Care service delivery model, and baseline service data, including aggregated client health measures.MethodsThe model of care is described in detail. Review of the first 12 months of service provision has been undertaken with client demographic and clinical profile baseline data collected including kidney health measures. Participants are adults (> 18 years if age) with CKD grades 1–5. This data has been de-identified and aggregated.ResultsCYKC reviewed 204 individuals, with 182 not previously been reviewed by specialist kidney health services. Three quarters of clients identified as Aboriginal. The average age was 55 with a high level of comorbidity, with majority having a history of hypertension and Type 2 diabetes (average Hba1c 8.2%). Just under one third had cardiovascular disease. A large proportion of people had either Grade 2 CKD (32%) or Grade 3 CKD (~ 30%), and over half had severely increased albuminuria (A3), with Type 2 diabetes being the predominant presumed cause of CKD. Most clients did not meet evidence-based targets for diabetes, blood pressure or lipids and half were self-reported smokers. The proportion of clients reviewed represents 6.2% of the adult population in the participating First Nation communities.ConclusionThe CYKC model was able to target those clients at high risk of progression and increase the number of people with chronic kidney disease reviewed by specialist kidney services within community. Baseline data demonstrated a high burden of chronic disease that subsequently will increase risk of CKD progression and cardiovascular disease. People were seen to have more severe disease at younger ages, with a substantial number demonstrating risk factors for rapid progression of kidney disease including poorly controlled Type 2 diabetes and severely increased albuminuria. Further evaluation concerning implementation challenges, consumer and community satisfaction, and health outcomes is required.

#4609 ASSOCIATION BETWEEN THE SERUM CREATININE-TO-CYSTATIN-C RATIO AND RAPID PROGRESSION OF CHRONIC KIDNEY DISEASE

Abstract Background and Aims Chronic Kidney Disease (CKD) is a common and progressive condition that affects a significant portion of the global population. It is a leading cause of death and requires timely evaluation and monitoring to ensure proper management. Cystatin C has been shown to be an effective marker of kidney function and a predictive marker of CKD progression. However, there is limited research evaluating the relationship between the serum creatinine-to-cystatin-C (Cr/cysC) ratio and the rapid progression of CKD. This study aims to investigate the effectiveness of the Cr/cysC ratio in predicting rapid progression of CKD. Method A retrospective study was conducted on 1,104 patients with CKD who were treated at the Nephrology Outpatient Clinic of Hanyang University Guri Hospital between December 2020 and November 2022. Eligible patients had at least two simultaneous measurements of serum creatinine and cystatin C, with a minimum interval of 6 months. The definition of rapid progression of CKD was a decrease in creatinine-based estimated glomerular filtration rate (eGFR) of more than 4 mL/min/1.73 m2 over a 1-year period or initiation of renal replacement therapy (RRT). In addition, considering the short duration of the study, initiation of RRT was considered as a secondary outcome only in CKD stages 3b, 4, and 5. Results The study population consisted of patients with CKD stages 1 to 5, with a mean age of 69.7 years and 57.7% of the population being male. The mean baseline body mass index was 25.8 kg/ m2, and the mean initial eGFR was 46.7 mL/min/1.73 m2. 38.4% of the total patients showed rapid progression of CKD. The analysis showed that a lower Cr/cysC ratio was significantly associated with an increased risk of rapid progression of CKD (OR: 0.812, 95% CI: 0.761-0.867, p&amp;lt;0.001). After adjusting for age, sex, body mass index, and initial eGFR, a lower Cr/cysC ratio remained a significant risk factor for rapid progression of CKD (OR: 0.760, 95% CI: 0.685-0.844, p&amp;lt;0.001). The initiation of RRT increased with the advancement of CKD stage, with 11 patients with CKD stage 3b, 30 patients with CKD stage 4, and 41 patients with CKD stage 5 initiating dialysis treatment. After adjusting for all variables, the OR was 0.774 (95% CI: 0.667-0.898, p = 0.001), indicating that as the Cr/cysC ratio increased, the progression of dialysis significantly decreased by 22.6%. Conclusion In this study, a lower Cr/cysC ratio was significantly associated with an increased risk of rapid progression of CKD and initiation of RRT. The results of this study suggest that monitoring the Cr/cysC ratio may provide valuable information for the management of CKD patients.

#4613 PREVALENCE OF DKD RAPID PROGRESSION IN TYPE 2 DIABETES IN A DEVELOPING COUNTRY AND ITS CLINICAL PREDICTORS: A SINGLE CENTERED RETROSPECTIVE STUDY

Abstract Background and Aims A significant proportion of diabetic kidney patients experience a rapid decline in GFR, leading to ESRD within months. Although there is a large number of studies on DKD, at present, there is a lack of well-controlled long follow-up studies to assess the burden of rapid progression, distinguishing the clinical profile of rapid progressors from non-progressors and its predictors. Identifying independent risk factors that contribute specifically to rapid progression is essential to prevent end-stage renal disease. Here we conducted a retrospective, hospital-based cohort study aimed to assess the prevalence, clinical profile, and clinical predictors for the rapid progression of DKD in type 2 DM. Method Type 2 DKD patients attending tertiary care hospital in South India were involved between January 2018 and 2022. CKD5 and those without minimum 6 months follow-up were excluded. Patients were followed up for 3.5 years. A sustained decline of eGFR &amp;gt;10 mL/1.73 m2/year was defined as rapid progressors. Patients were categorized into rapid and non-rapid progressors. Clinical profiles, micro-macrovascular complications, cardiovascular events, and other risk factors for rapid progression were studied. Data were analyzed using SPSS22 Results In a median follow-up of 3.5 years, 220(61.3%) were rapidly progressed with median eGFR decline 12ml/1.73 m2/year(IQR 8.5-19.3), and 139(38.7%) were non-rapid progressors with median eGFR decline 1.6ml/1.73 m2(IQR-0-3.3).The baseline characteristics were given in Table 1. The presence of hypertension, proteinuria, diabetic retinopathy, and cardiovascular events (p-0.01) was higher in rapid progressors than non-progressors.On logistic regression analysis, independent predictors of rapid progression were proteinuria (OR4.7;95%CI(2.24-9.88); P = .001), diabetic retinopathy(OR 0.24; 95% CI(0.11-0.52); P = .001), and AKI episodes(OR 2.18;95% CI (1.28-3.71); P = .003) (Table 2). Conclusion The majority of type 2 DKD patients in our setting are rapid progressors. The higher degree of baseline proteinuria, presence of diabetic retinopathy, and AKI episodes were found independently associated with clinical predictors of progression.

PS-BPC11-4: LOW SOLUBLE KLOTHO IS ASSOCIATED WITH RESISTANT HYPERTENSION IN CKD: FROM THE KNOW-CKD STUDY

Objective: Apparent treatment-resistant hypertension (ATRH) is highly prevalent in chronic kidney disease (CKD) and is a risk factor for rapid progression of CKD. Soluble klotho is an extracellular domain of klotho released into the circulation. Although soluble klotho is known to be a risk factor for hypertension, the association between soluble klotho and ATRH is unknown. The aim of this study is to evaluate the association of soluble klotho with ATRH in CKD. Design and method: In this cross-sectional study, we analyzed 1,737 predialysis CKD patients enrolled in the prospective Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD). Apparent treatment-resistant hypertension was defined as systolic blood pressure &gt; = 140 mm Hg or diastolic blood pressure &gt; = 90 mm Hg with concurrent use of three antihypertensive medication classes or use of four or more antihypertensive medication classes regardless of blood pressure level. Serum klotho levels were measured using an enzyme-linked immunosorbent assay. Participants were divided into quartiles. Results: Among study subjects, 303 patients (17.4%) had ATRH. Prevalence of ATRH were 21.9%, 18.9%, 18.2% and 10.8% for the 1st to 4th quartiles of soluble klotho, respectively (p for trend &lt; 0.001). The adjusted OR [95% CI] of 1st to 3th quartile of soluble klotho in reference to 4th quartile were 2.01 (1.32–3.06), 1.59 (1.04–2.42) and 1.69 (1.11–2.57). Conclusions: Soluble klotho level was inversely associated with the presence of ATRH in Korean predialysis CKD patients. This relationship was independent of various cardiovascular risk factors.

Abstract 12076: Longitudinal Echocardiographic Analysis of Aortic Valve Stenosis Progression

Introduction: Despite its high prevalence, the rate of progression of aortic valve stenosis (AS) remains incompletely characterized and assumed to be constant across the spectrum of AS severity. Previous studies involve limited number of patients, short follow-up, and focused on more severe stages of AS. Hypothesis: The annual rate of AS progression as defined by aortic valve mean gradient (AVMG) increases in magnitude as AS class severity increases. Methods: The study cohort included adult patients with native AS from the MGH echocardiography database from 1990 to 2020. Patients were included if AVMG was reported in at least two echocardiograms in mild, moderate, or severe AS stages. Generalized linear mixed models were employed to simultaneously model fixed effects and random effects stratified by AS severity grade. Multivariable models included age, sex, race, dyslipidemia, DM2, kidney disease, LVEF, moderate/severe AI, and AV morphology. A linear model identified risk factors for rapid progression in severe AS. Results: In 8,848 patients with 29,513 echocardiograms, baseline mean gradient for mild, moderate, and severe AS was 7.0, 20.9, and 43.0 mmHg, respectively. The annual rate of progression in mild, moderate, and severe AS was found to be 0.3, 1.0, and 4.0 mmHg/year. Female gender and white race increased the rate of AVMG by 0.57mmHg/year and 1.05mmHg/year. Conclusions: The progression of AS accelerates with worsening severity of AS. The rate of AVMG progression in severe AS is similar to historically accepted values, but rates are slower for mild and moderate AS. Female gender and white race may be associated with faster progression in severe AS.

Abstract 11827: A Case of Rapidly Progressive Aortic Valve Stenosis Secondary to Chronic Hypercalcemia

Introduction: Moderate hypercalcemia may be well-tolerated, but rapid calcium deposition to the aortic valve may have life-threatening consequences. Clinical case: We present a case of a 77-year-old female with a history of retroperitoneal liposarcoma complicated by hypercalcemia. The patient had had recurrent hypercalcemia for the past 6 months, ranging from 12-14 mg/dL. She complained of 4 weeks of progressive dyspnea and orthopnea. Physical exam showed jugular venous distension and bilateral pitting edema. A transthoracic echocardiogram (TTE) showed critical aortic stenosis (AS) with a valve area of 0.4 cm2, peak velocity of 6 m/s, and a mean gradient of 90 mmHg (Figure 1). Her last TTE just 9 months prior showed mildly thickened aortic valve leaflets without evidence of stenosis with a valve area of 2.2 cm2, peak velocity of 1.4 m/s, and mean gradient of 4 mmHg (Figure 2). Discussion: The most common cause of AS is age-related calcification. However, the role of hypercalcemia in AS has not been well-defined. Typically, the valve area is expected to decline by 0.1cm2 per year. Surprisingly, our patient’s valve area decreased from 2.2 cm2 to 0.4 cm2 in just 9 months. Rapid decline is usually associated with typical cardiovascular risk factors, however, studies have begun to recognize hypercalcemia as a potential risk factor for rapid progression. In our case, we believe our patient suffered from rapidly progressive AS secondary to chronic hypercalcemia due to malignancy. Conclusions: The severity of AS should be closely monitored in hypercalcemia and further studies are warranted to develop strategies for secondary prevention.

Body weight loss and glycemic control on the outcomes of patients with NAFLD. The role of new antidiabetic agents

Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide affecting a third of adults and 12% of children in Western countries. In around 50–60%% of cases, NAFLD and type 2 diabetes mellitus (T2DM) coexist and act synergistically to increase the risk of adverse hepatic and extra-hepatic outcomes. T2DM is a strong risk factor for rapid progression of NAFLD to nonalcoholic steatohepatitis (NASH), cirrhosis or hepatocellular carcinoma (HCC), which have become frequent indications of liver transplantation.The pathophysiology of NAFLD is complex and its relationship with T2DM is bidirectional, where lipotoxicity and insulin resistance (IR), act as the strongest pillars.To date, no pharmacological treatment has been approved for NAFLD. However, there is an intense research with numerous drugs focused on reversing inflammation and liver fibrosis through modulation of molecular targets without good results.It has been known for some time that weight reduction >10% is associated to histological improvement of NAFLD. Recently, glycemic control has been shown to induce similar results. Diet and physical exercise for weight reduction have limitations, so alternative methods (pharmacologic, endoscopic or surgical) may be required. Currently, new antidiabetic drugs inducing weight loss, have been recently approved for the treatment of obesity. Nevertheless, their therapeutic effects on NAFLD have not been extensively studied.We will review here, recently published data on the effects of weight loss and glycemic control on the histological and metabolic parameters of NAFLD and recent published data on therapeutic studies of NAFLD with new antidiabetic drugs.

MO265: Patients with Alport Syndrome from the Radar Registry: A Natural History Study

Abstract BACKGROUND AND AIMS Alport Syndrome (AS) is the second most common genetic kidney disease and results from mutations in COL4A3, A4 or A5 genes. It is characterized by glomerulonephritis, CKD, hearing loss, and ocular lens defects. Estimated incidence is ∼ 1 in 50 000 live births with prevalence of 1 in 5000–10 000. About 80% patients reach ESKD by age 35 years. The UK Alport Registry, part of the National Registry of Rare Kidney Diseases (RaDaR), performs on-going collection of longitudinal data of AS patients. The aims of this study were to characterize demographic and lab data of AS patients and determine the proportion of AS patients at risk for rapid kidney function decline. METHOD Eligible patients had a clinical, histological or genetic diagnosis of ‘Alport syndrome’ or ‘thin basement membrane nephropathy’ by their physician and provided informed consent. Some data were entered manually, but most routine test results were collected by automatic link between RaDaR and renal IT systems. eGFR was calculated using CKD-EPI Cr equation without race adjustment (2021) or Schwartz equation for subjects ≤16 years of age at time of Cr measurement. For eGFR slope calculations, a minimum of four measurements over at least 2 years were required to be included in this analysis; subjects were censored if they reached ESKD, defined as maintenance dialysis, transplant, or ≥ 2 consecutive eGFR measurements of &amp;lt;15 mL/min/1.73 m2. Data are presented as percentages for categorical variables and mean ± SD for continuous variables. RESULTS Between 4 January 2013 and 29 November 2021, 887 patients were recruited. See Table 1 for summary of data stratified by age groups. Overall, 52% male versus 48% female, and in those with genotyping data, 54% had X-linked AS with a mean age of 25.8 years at diagnosis and a mean age of proteinuria onset of 29.6 years. Clinically meaningful Stage 2 CKD was already present at time of diagnosis (mean eGFR 72.7 mL/min/1.73 m2) in many of those ≥ 18 years of age. A total of 43% of this AS cohort have reached ESKD, at a mean age of 32.8 years. While 37% were on ACEi and 20% on ARB medications, only 4% were on dual RAAS blockade therapy. About 50% had documentation of eGFR loss ≥4 mL/min/1.73 m2 per year, 29% had UPCR &amp;gt; 2 g/g, and 50% of those age ≥ 18 years had reached ESKD. The proportion of patients with ≥1 risk factor for rapid progression of kidney failure (defined as eGFR decline ≥ 4 mL/min/1.73 m2 per year, UPCR &amp;gt; 2 g/g, UACR &amp;gt; 1 g/g or male 18–23 yrs with eGFR &amp;lt; 90 mL/min/1.73 m2 based on ATHENA natural history study) was 41%. CONCLUSION Demographic and genetic characteristics of AS patients in the RaDaR registry are generally comparable with previously reported data. Approximately 50% had eGFR decline ≥ 4 mL/min/1.73 m2 per year and 41% of patients had exhibited ≥ 1 risk factor for future rapid progression of kidney disease. Results should be interpreted with caution, however, in light of the considerable amount of missing data in a number of the analyses. On-going data collection in this open cohort should allow for further insights on the natural history over time as well as identify AS patients for potential enrollment into clinical trials.

Predicting Factors for Rapid Progressive Chronic Kidney Disease in Primary Glomerular Disease Patients with Moderate-to-Severe Stage.

Objective To investigate the predictive factors associated with rapid progressive chronic kidney disease (CKD) in patients with primary glomerular disease (PGD). Methods Baseline data, clinical biochemistry, laboratory data, and imaging data were collected from 112 PGD patients in CKD stages 3 and 4 who were hospitalized at the Third Xiangya Hospital. Patients were divided into rapid progression group (Group R) and no rapid progression group (NR) according to the definition of rapid progression of CKD. Results The age, systolic blood pressure (SBP), serum β2-microglobulin (sβ2-MG), urinary α1-microglobulin (uα1-MG), and cardiothoracic ratio (CTR) of the R group were significantly higher than the NR group. However, the size of the kidney, high-dense lipoprotein (HDL), hemoglobin (Hb), and hematocrit of the R group were significantly lower than the NR group (P < 0.05). Binary logistic regression analysis showed that baseline CTR, SBP, size of the kidney, and HDL were independent risk factors for rapid progression of PGD. At the end of follow-up, CTR and SBP of group R were higher than the NR group, and the size of the kidney and HDL of group R were lower than the NR group. Conclusion Increased baseline CTR and SBP and decreased baseline HDL and renal volume could be the predictors of rapid progression in patients of PGD at the CKD stages 3 and 4.

Trajectories and risk factors of dementia progression: a memory clinic cohort followed up to 3 years from diagnosis.

Patients with dementia follow different trajectories of progression. We aimed to investigate which factors at the time of diagnosis could predict trajectory group membership. Longitudinal observational study. Specialized memory clinic, Oslo University Hospital in Norway. Patients assessed at the memory clinic, between 12 January 2009 and 31 July 2016, who were registered in the Norwegian Registry of persons assessed for cognitive symptoms (NorCog) and diagnosed with dementia after the baseline examination period (n = 442). The patients were followed up to 3 years, with an average of 3.5 examinations. Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), the Consortium to Establish a Registry of Alzheimer's disease (CERAD) 10-item word list delayed recall, the Clock Drawing Test, (CDT) Trail Making Test A (TMT-A), and Neuropsychiatric Inventory Questionnaire (NPI-Q). Based on changes in scores on the CDR-SB, we used group-based trajectory modeling (GBTM) to explore the presence of trajectory groups. Multinomial logistic regression was used to explore whether a set of baseline variables could predict trajectory group membership. Three trajectory groups were identified, one with a slow progression rate and two with more-rapid progression. Rapid progression was associated with older age, lower cognitive function (MMSE and TMT-A), and more-pronounced neuropsychiatric symptoms (NPI-Q) at the time of diagnosis. Our findings demonstrate the heterogeneity of dementia progression and describe risk factors for rapid progression, emphasizing the need for individual follow-up regimes. For future intervention studies, our results may guide the selection of patients.

Rapid progression of carotid stenosis was rare in a large integrated healthcare system during an eight-year period

ObjectiveFew studies have evaluated the rapid progression of carotid stenosis on a large scale. We created a custom software algorithm to analyze an electronic medical record database to examine the natural progression of carotid stenosis, identify a subset of patients with rapid progression, and evaluate the specific patient risk factors associated with this rapid progression. MethodsPatients in a large integrated healthcare system who had undergone two or more carotid ultrasound scans from August 2010 to August 2018 were identified. We did not distinguish between those with an established carotid stenosis diagnosis and those with a screening ultrasound scan. We used our novel algorithm to extract data from their carotid ultrasound reports. The degrees of carotid stenosis were categorized as follows: level 1, 0% to 39%; level 2, 40% to 59%; level 3, 60% to 79%; level 4, 80% to 99%; and level 5, complete occlusion. The primary endpoint was rapid vs slow progression of carotid stenosis, with rapid progression defined as an increase of two or more levels within any 18-month period of the study, regardless of the date of the initial ultrasound scan. The association of the demographic and clinical characteristics with rapid progression was assessed by univariable and multivariable logistic regression. ResultsFrom a cohort of 4.4 million patients, we identified 4982 patients with two or more carotid ultrasound scans and a median follow-up period of 13.1 months (range, 0.1-93.7 months). Of the 4982 patients, 879 (17.6%) had shown progression of carotid stenosis. Only 116 patients (2.3%) had had progression to level 4 (80%-99% stenosis) from any starting level during a median of 11.5 months. A total of 180 patients (3.6%) were identified as experiencing rapid progression during a median follow-up of 9.9 months. The final multivariable analysis showed that younger age (P < .01), white race (P = .02), lower body mass index (P = .01), a diagnosis of peripheral arterial disease (P = .03), and a diagnosis of transient ischemic attack (P < .01) were associated with rapid progression. ConclusionsUsing a novel algorithm to extract data from >4 million patient records, we found that rapid progression of carotid stenosis appears to be rare. Although 17.6% of patients showed any degree of progression, only 3.6% had experienced rapid progression. Among those with any disease progression, 20.5% had experienced rapid progression. Although the overall incidence of rapid progression was low, patients with any progression might warrant close follow-up, especially if they have the associated risk factors for rapid progression. The custom software algorithm might be a powerful tool for creating and evaluating large datasets.

P1037EFFECT OF VITAMIN D SUPPLEMENTATION ON PROTEINURIA, LIPID STATUS, GLICOREGULATION, C-REACTIVE PROTEIN, VEGF-A, TGF-BETA1 AND NEPHRIN IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Abstract Background and Aims: Vitamin D insufficiency/deficiency is often present in patients with Type-2 diabetes mellitus and could present a risk factor for rapid progression of diabetic nephropathy and higher incidence of cardiovascular events. The aim of this study was to examine the influence of vitamin D supplementation on glucoregulation, inflammation, cholesterol, triglycerides, albuminuria and biomarkers of renal injury – nephrin, VEGF-A and TGF- β1 in patients with Type-2 diabetes mellitus and vitamin D insufficiency/deficiency. Method: We included 90 patients with Type-2 diabetes mellitus and vitamin D insufficiency/deficiency in this prospective, cohort study. Patients are divided in 3 equal groups: 30 patients with normal albuminuria, 30 with microalbuminuria and 30 with macroalbuminuria. Therapy included 6 months of supplementation with cholecalciferol drops: first 2 months with 20000 IU twice weekly, than if vitamin D level remained below normal range, we procedeed with same dose next 4 months. If the level of vitamin D normalized, we proceeded with 5000 IU twice weekly. At the beginning and at the end of the study we measured levels of albumin, hemoglobin, serum iron, urea, creatinine, fasting blood glucose, hemoglobin A1c, calcium, phosphorus, total cholesterol, triglycerides, C-reactive protein, intact parathyroid hormone, and urine analysis: 24-hour urine protein, albumin/creatinine ratio and creatinine clearance. Biomarkers are measured in serum and urine. Levels of calcium, phosphorus and vitamin D are also checked 2 months after beginning of therapy due to possible correction of cholecalciferol dose. Results are analysed according to the vitamin D level at the beginning and at the end of the study. Results: The lowest level of vitamin D, before therapy, is found in patients with macroalbuminuria, while at the end of the study we found significantly higher level of vitamin D in all three groups. After 6 months of therapy we found significant decrease of 24-hour urine protein, total cholesterol, triglycerides, hemoglobin A1c and VEGF-A in urine, in all three groups, and C-reactive protein in patients with normal albuminuria and microalbuminuria, nephrin in urine in patients with microalbuminuria and TGF- β1 in urine in patients with macroalbuminuria. Conclusion: vitamin D supplementation with high-dose cholecalciferol in patients with Type-2 diabetes mellitus (with or without albuminuria) decreases C-reactive protein, hemoglobin A1c, total cholesterol, triglycerides in serum, and albumin/creatinine ratio, 24-hour urine protein, VEGF-A, TGF- β1 and nephrin in urine.