749 Clinical profile and outcome of patients with Anderson–Fabry disease followed at a multidisciplinary cardiomyopathy centre

Aims Anderson–Fabry disease (AFD) is a rare genetic lysosomal storage disorder which often goes unnoticed until the onset of symptoms requires aggressive treatment. Prompt diagnosis remains crucial. Dedicated centres may offer a remarkable opportunity to develop early detection strategies and prompt appropriate multidisciplinary management. To describe the long-term outcomes of patients diagnosed with AFD followed at a national Cardiomyopathy Referral Center according to phenotype (clinical involvement vs. sub-clinical involvement). Methods and results Consecutive patients visited at our Cardiomyopathy Unit from 1989 to 2020 with >1-year follow-up were retrospectively reviewed. Clinical involvement was defined by the presence of one among left ventricular hypertrophy (LVH)>15 mm, presence of conduction blocks or cardiac implantable electronic devices (CIED), atrial fibrillation, kidney disease (glomerular filtration rate <60 ml/min/m2, dialysis or kidney transplant), stroke or transient ischaemic attack (TIA). Disease progression was defined by either de novo CIED implantation, de novo LVH > 15mm or increased IVS, de novo Stroke/TIA, or progression of kidney disease. Overall, 110 were diagnosed with AFD [first via α galactosidase (αGAL) activity and then confirmed via genetic exam], and 86 (78%) with >1-year follow-up were selected. Clinical involvement was present in 60 (70%) patients. Age at diagnosis was similar between patients with clinical and subclinical phenotype (42 ± 17 vs. 39 ± 15, P = 0.277). Patients manifesting clinical involvement compatible with AFD were more frequently men [N = 25 (42%) vs. 4 (15%), P = 0.025] and probands (P = 0.01). Overall, one organ involvement was present in 31 (52%) patients, two organ involvement in 24 (40%) patients, and three organs in 5 (8%). A total of 46 (77%) patients were referred for enzyme replacement therapy (ERT): 52% received agalsidase α, 26% agalsidase β, and 22% migalastat. Among those with a clinical involvement not on ERT, nine (15%) were scheduled for ERT initiation, three (5%) were considered old for ERT, one (1.5%) refused ERT, and one (1.5%) had an allergic reaction to ERT. At 7 (3–12) years follow-up, both study cohorts manifested signs and symptoms of disease progression, although its incidence was higher in patients with clinical involvement [N = 28 (47%, 4.7%/year) vs. N = 4 (15%, 1.5%/year), in clinical vs. subclinical involvement, respectively, P = 0.01]. The main causes for diseases progression were increase in LVH (28%), de novo LVH (13%), progression of kidney disease (7%), and CIED implantation (5%). All patients with disease progression in the subclinical involvement group had been diagnosed with family screening; among these, two were men and one had a late onset phenotype. Three developed LVH > 15mm and one kidney disease. Conclusions Clinical involvement in AFD is frequent irrespective of age at diagnosis, being present in more than 1-in-2 patients at baseline. Prompt referral to dedicated centres is warranted for appropriate care as disease may progress in both patients with and without initial clinical involvement despite optimal medical management.

Calcium Signaling Mediates Cell Death and Crosstalk with Autophagy in Kidney Disease

The kidney is an important organ for the maintenance of Ca2+ homeostasis in the body. However, disruption of Ca2+ homeostasis will cause a series of kidney diseases, such as acute kidney injury (AKI), chronic kidney disease (CKD), renal ischemia/reperfusion (I/R) injury, autosomal dominant polycystic kidney disease (ADPKD), podocytopathy, and diabetic nephropathy. During the progression of kidney disease, Ca2+ signaling plays key roles in various cell activities such as necrosis, apoptosis, eryptosis and autophagy. Importantly, there are complex Ca2+ flux networks between the endoplasmic reticulum (ER), mitochondria and lysosomes which regulate intracellular Ca2+ signaling in renal cells and contribute to kidney disease. In addition, Ca2+ signaling also links the crosstalk between various cell deaths and autophagy under the stress of heavy metals or high glucose. In this regard, we present a review of Ca2+ signaling in cell death and crosstalk with autophagy and its potential as a therapeutic target for the development of new and efficient drugs against kidney diseases.

Abstract 16932: Primary Hyperaldosteronism And Resistant Hypertension In Pregnancy

Case Presentation: A 42-year-old woman with history of primary hyperaldosteronism (PA), IDDM and chronic kidney disease stage 3b (baseline Cr 2.5 mg/dl) presented at 10 weeks gestation with uncontrolled hypertension during pregnancy. Given prior difficulties conceiving and lack of discussions surrounding pregnancy risks, preconception counseling had not been done. She was taking carvedilol, spironolactone, and furosemide at pregnancy diagnosis. Given unclear safety profile in pregnancy, her spironolactone was discontinued. Her regimen was uptitrated to nifedipine 90 mmHg, carvedilol 50mg BID, hydralazine 50mg TID and furosemide 80mg BID. At 18 weeks gestation, she was readmitted with severe range hypertension and fluid overload unresponsive to escalating diuretic dosing. Due to poor urine output and creatinine to 5.5 mg/dl, she was initiated on dialysis. Her fetus was diagnosed with severe intrauterine growth restriction (IUGR) and umbilical doppler noted reversal of umbilical artery end-diastolic flow indicating severely elevated arterial resistance (Figure). During admission, she developed resistant hypertension requiring nicardipine and esmolol drips and severe headache, concerning for superimposed preeclampsia (SIPE). At 25 weeks gestation, she was taken for urgent c-section. Given extreme prematurity and growth restriction, her newborn baby passed away shortly after delivery. Discussion: This case highlights complications which arise from PA and antepartum persistent hypertension including progression of kidney disease, heart failure, IUGR, SIPE, and preterm delivery. It further highlights unique challenges using targeted therapies of mineralocorticoid receptor antagonists in PA in pregnancy. This information is crucial as PA is an increasingly recognized cause of resistant hypertension in young adults. Both PA and preeclampsia involve pathophysiologic mechanisms in the RAAS pathway and deserve further attention and research.

Functional Reserve of the Kidney

The exploration of the normal limits of physiological responses and how these responses are lost when the kidney is injured are rarely used in clinical practice. However, the difference between "resting" and the "stressed" responses identify an adaptive reactiveness that is diminished before baseline function is impaired. This functional reserve is important in the evaluation of prognosis and progression of kidney disease. Here we discuss stress tests that examine protein-induced hyperfiltration, proximal tubular secretion, urea-selective concentration defects and acid retention. We discuss diseases in which these tests have been used to diagnose subclinical injury. The study and follow-up of abnormal functional reserve may add considerable understanding to the natural history of chronic kidney disease.

Clinical and genetic characterization of a cohort of proteinuric patients with biallelic CUBN variants

Background Proteinuria is a well-known risk factor for progressive kidney impairment. Recently, C-terminal cubilin (CUBN) variants have been associated with isolated proteinuria without progression of kidney disease. Methods Genetic testing of 347 families with proteinuria of suspected monogenic cause was performed by next-generation sequencing of a custom-designed kidney disease gene panel. Families with CUBN biallelic proteinuria-causing variants were studied at the clinical, genetic, laboratory, and pathologic levels. Results Twelve families (15 patients) bearing homozygous or compound heterozygous proteinuria-causing variants in the C-terminal CUBN gene were identified, representing 3.5% of the total cohort. We identified 14 different sequence variants, five of which were novel. The median age at diagnosis of proteinuria was 4 years (range 9 months to 44 years), and in most cases proteinuria was detected incidentally. Thirteen patients had moderate-severe proteinuria at diagnosis without nephrotic syndrome. These patients showed lack of response to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, normal kidney biopsy, and preservation of normal kidney function over time. The two remaining patients presented a more severe phenotype, likely caused by associated comorbidities. Conclusions Identification of C-terminal pathogenic CUBN variants is diagnostic of an entity characterized by glomerular proteinuria, normal kidney histology, and lack of response to ACEi/ARB treatment. This study adds evidence and increases awareness about albuminuria caused by C-terminal variants in the CUBN gene, which is a benign condition usually diagnosed in childhood with preserved renal function until adulthood.

Serum Uric Acid and Kidney Disease Measures Independently Predict Cardiovascular and Total Mortality: The Uric Acid Right for Heart Health (URRAH) Project

Background: Serum uric acid predicts the onset and progression of kidney disease, and the occurrence of cardiovascular and all-cause mortality. Nevertheless, it is unclear which is the appropriate definition of hyperuricemia in presence of chronic kidney disease (CKD). Our goal was to study the independent impact of uric acid and CKD on mortality.Methods: We retrospectively investigated 21,963 patients from the URRAH study database. Hyperuricemia was defined on the basis of outcome specific cut-offs separately identified by ROC curves according to eGFR strata. The primary endpoints were cardiovascular and all-cause mortality.Results: After a mean follow-up of 9.8 year, there were 1,582 (7.20%) cardiovascular events and 3,130 (14.25%) deaths for all causes. The incidence of cardiovascular and all-cause mortality increased in parallel with reduction of eGFR strata and with progressively higher uric acid quartiles. During 215,618 person-years of follow-up, the incidence rate for cardiovascular mortality, stratified based on eGFR (>90, between 60 and 90 and <60 ml/min) was significantly higher in patients with hyperuricemia and albuminuria (3.8, 22.1 and 19.1, respectively) as compared to those with only one risk factor or none (0.4, 2.8 and 3.1, respectively). Serum uric acid and eGFR significantly interact in determining cardiovascular and all-cause mortality. For each SUA increase of 1 mg/dl the risk for mortality increased by 10% even after adjustment for potential confounding factors included eGFR and the presence of albuminuria.Conclusions: hyperuricemia is a risk factor for cardiovascular and all-cause mortality additively to eGFR strata and albuminuria, in patients at cardiovascular risk.

Chronic Kidney Disease: Role of Diet for a Reduction in the Severity of the Disease

Chronic kidney disease affects ~37 million adults in the US, and it is often undiagnosed due to a lack of apparent symptoms in early stages. Chronic kidney disease (CKD) interferes with the body’s physiological and biological mechanisms, such as fluid electrolyte and pH balance, blood pressure regulation, excretion of toxins and waste, vitamin D metabolism, and hormonal regulation. Many CKD patients are at risk of hyperkalemia, hyperphosphatemia, chronic metabolic acidosis, bone deterioration, blood pressure abnormalities, and edema. These risks may be minimized, and the disease’s progression may be slowed through careful monitoring of protein, phosphorus, potassium, sodium, and calcium, relieving symptoms experienced by CKD patients. In this review, the current Kidney Disease Outcomes Quality Initiative (KDOQI) recommendations are highlighted, reflecting the 2020 update, including explanations for the pathophysiology behind the recommendations. The Dietary Approaches to Stop Hypertension, the Mediterranean diet, and the whole foods plant-based diet are currently being examined for their potential role in delaying CKD progression. Biological explanations for why the whole foods plant-based diet may benefit CKD patients compared to diets that include animal products are examined. Strong evidence continues to support the importance of diet meeting the daily requirement in the prevention and progression of kidney disease, and medical nutrition therapy with a registered dietitian is a critical aspect in medical intervention for CKD.