Demographic, clinical characteristics and cardiovascular disease burden in a Portuguese cohort of older chronic kidney disease patients / Dados demográficos, características clínicas e peso da doença cardiovascular em uma coorte portuguesa de pacientes idosos com doença renal crônica

ABSTRACT Introduction: Chronic kidney disease (CKD) is an independent risk factor for several unfavorable outcomes including cardiovascular disease (CVD), particularly in the elderly, who represent the most rapidly growing segment of the end-stage kidney disease (ESKD) population. Portugal has the highest European unadjusted incidence and prevalence rates of ESKD. In 2012, we started to follow a cohort of elderly CKD patients, we describe their baseline characteristics, risk profile, and cardiovascular disease burden. Methods: All CKD patients aged 65 years and older referred to our department during 2012 were enrolled. Baseline data included: demographic, CKD stage, medication, comorbid conditions. Estimated glomerular filtration rate (eGFR) was calculated by the CKD-EPI formula. Results: A total of 416 patients, 50% referred by primary care physicians, aged 77 ± 7 years, 52% male, with a median eGFR of 32 mL/min/1.73m2 participated in the study. Fifty percent had diabetes (DM), 85% dyslipidemia, 96% hypertension; 26% were current/former smokers, and 24% had a body mass index > 30 kg/m2. The prevalence of CVD was 62% and higher in stage 4-5 patients; in diabetics, it gradually increased with CKD progression (stage 3a < stage 3b < stage 4-5) (39, 58, 82%; p < 0.001). Conclusions: At baseline, our CKD elderly cohort had a higher burden of CVD. The prevalence of CVD was greater than in other European CKD cohorts. Lower level of eGFR was associated with a greater burden of CVD and was more pronounced in diabetics, highlighting the importance of strategically targeting cardiovascular risk reduction in these patients.

RESUMO Introdução: Doença renal crônica (DRC) é fator de risco independente para vários desfechos desfavoráveis, incluindo doença cardiovascular (DCV), particularmente em idosos, o segmento de crescimento mais rápido da população com doença renal terminal (DRT). Portugal tem a maior incidência europeia não-ajustada e a maior prevalência de DRT. Neste artigo caracterizamos uma coorte de idosos com DRC, referenciados para a nefrologia, com particular ênfase para o risco e carga de doença cardiovascular. Métodos: Foram incluídos todos os pacientes com DRC com 65 anos ou mais encaminhados ao nosso departamento em 2012. Os dados basais incluíram: demografia, estágio da DRC, medicação e comorbidades. A taxa de filtração glomerular (TFGe) foi calculada pela fórmula CKD-EPI. Resultados: Metade dos 416 pacientes incluídos foram encaminhados por médicos da atenção primária; sua idade era 77 ± 7 anos; 52% eram homens; a TFGe mediana era de 32 mL /min/1,73 m2. Metade tinha diabetes (DM), 85% dislipidemia, 96% hipertensão; 26% eram fumantes atuais/ antigos; 24% tinham índice de massa corporal > 30 kg/m2. A prevalência de DCV foi de 62%, sendo maior entre pacientes nos estágios 4-5; em diabéticos, aumentou gradualmente com a progressão da DRC (estágio 3a < estágio 3b < estágio 4-5) (39%, 58%, 82%; p < 0,001). Conclusões: A coorte de idosos com DRC apresentava inicialmente maior carga de DCV. A prevalência de DCV foi maior que em outras coortes europeias com DRC. Níveis menores de TFGe foram associados a carga maior de DCV e foram mais pronunciados entre diabéticos, destacando a importância de objetivar estrategicamente a redução do risco cardiovascular nesses pacientes.

Unrecognized Fibrinogen A α-Chain Amyloidosis: Results From Targeted Genetic Testing.

BACKGROUND: Fibrinogen A α-chain (AFib) amyloidosis results from autosomal-dominant mutations in the gene encoding AFib (FGA). Patients with this disorder typically present with proteinuria. Isolated cases of AFib amyloidosis, carrying the FGA p.Glu545Val variant, were identified in the district of Braga, in northwest Portugal. This observation led us to hypothesize that this disorder might be an unrecognized cause of kidney disease in that region and prompted us to carry out targeted genetic testing for the p.Glu545Val variant in the local hemodialysis population and family members of identified cases. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 3 groups of participants: (1) kidney biopsy registry, n=4; (2) hemodialysis facility, n=122 of 267 patients; and (3) genetically at-risk individuals; n=69 of 167 family members. OUTCOMES: Kidney disease, kidney disease progression, and survival. RESULTS: The p.Glu545Val variant was identified in all 4 patients of the biopsy registry, 12 of 122 (9.8%) hemodialysis patients tested, and 34 of 69 (49%) relatives tested. These 50 cases belonged to 13 unrelated families with kidney disease or amyloidosis identified in 61% of probands. 35 individuals presented with hypertension at a mean of 51.0±10.4 years. Of these, 30 developed kidney disease at a mean of 56.7±12.0 years, and 21 initiated dialysis therapy at a mean of 61.4±11.3 years. Heart, liver, spleen, colon, and ileum were involved along the progression of the disease. Kidney disease was formerly attributed to hypertension in 25% of patients with AFib amyloidosis undergoing hemodialysis. LIMITATIONS: Retrospective data collection for patients with amyloidosis previously diagnosed. CONCLUSIONS: AFib amyloidosis appears to be an under-recognized disorder in Braga, Portugal, where we found a high frequency of the FGA p.Glu545Val variant. Due to the nonspecific nature of its major clinical features, the diagnosis of AFib amyloidosis should have a high index of suspicion, particularly in populations in which hypertension is prevalent.

Liver transplantation in transthyretin amyloidosis: Characteristics and management related to kidney disease.

Orthotopic liver transplantation (LT) was implemented as the inaugural disease-modifying therapy for hereditary transthyretin (ATTR) amyloidosis, a systemic amyloidosis mainly affecting the peripheral nervous system and heart. The first approach to pharmacologic therapy was focused on the stabilization of the TTR tetramer; following that new advent LT was assumed as the second step of treatment, for those patients whose neuropathy becomes worse after a course of pharmacologic therapy. The renal disease has been ignored in hereditary ATTR amyloidosis. The low level of proteinuria or slight renal impairment does not suppose such a heavy glomerular and vascular amyloid deposition. Moreover, severity of renal deposits does not consistently parallel that of myelinated nerve fiber loss. These are pitfalls that limit the success of LT and suggest troublesome criteria for pharmacological therapy or LT. An algorithm of evaluation concerning renal disease and treatment options is presented and some bridges-to-decision are exposed. In stage 4 or 5 kidney disease, the approach remains to deliver combined or sequential liver-kidney transplantation in eligible patients. However, in the majority, hemodialysis is the only option even in the presence of a well-functioning liver graft. In this review, we highlight useful information to aid the transplant hepatologist in the clinical practice.

A triple-biomarker approach for the detection of delayed graft function after kidney transplantation using serum creatinine, cystatin C, and malondialdehyde.

INTRODUCTION: Serum creatinine (SCr) alone does not allow for the early diagnosis of delayed graft function (DGF) following kidney transplantation (KTx). OBJECTIVE, DESIGN AND METHODS: The diagnostic utility of urinary neutrophil gelatinase-associated lipocalin (uNGAL), serum leptin, malondialdehyde (MD.A), and cystatin C (CysC) for the early detection of DGF was previously evaluated by our group in a prospective cohort study of 40 consecutive adults undergoing KTx. Because no single biomarker achieved adequate sensitivity or specificity for practical purposes, this study was designed to evaluate the combined use of new markers with SCr. Urine and blood samples were collected 8-to-12h after KTx (day-1). Logistic regression was used to combine the biomarkers, and receiver operating characteristic curves and areas under the curve (AUC-ROC) were generated. RESULTS: Eighteen recipients developed DGF (dialysis requirement during the first post-transplant week). On day-1, the AUC for SCr to predict DGF was 0.73, 0.88 for uNGAL, 0.90 for MDA, 0.76 for leptin, and 0.91 for CysC. Adding new biomarkers to SCr enhanced the performance of DGF prediction, and the best combination was achieved with SCr, MDA, and CysC (AUC=0.96, sensitivity=100%; specificity=86%). CONCLUSION: A combination of graft damage biomarkers outperformed SCr in the early diagnosis of DGF, and the best performance was achieved by a triple-marker approach, using SCr, MDA, and CysC.

Homozygosity for the E526V Mutation in Fibrinogen A Alpha-Chain Amyloidosis: The First Report.

Systemic hereditary amyloidoses are autosomal dominant diseases associated with mutations in genes encoding ten different proteins. The clinical phenotype has implications on therapeutic approach, but it is commonly variable and largely dependent on the type of mutation. Except for rare cases involving gelsolin or transthyretin, patients are heterozygous for the amyloidogenic variants. Here we describe the first patient identified worldwide as homozygous for a nephropathic amyloidosis, involving the fibrinogen variant associated with the fibrinogen alpha-chain E526V (p.Glu545Val) mutation. In 1989, a 44-year-old woman presented with hypertension, hepatosplenomegaly, nephrotic syndrome, and renal failure. She started hemodialysis in 1990 and 6 years later underwent isolated kidney transplantation from a deceased donor. Graft function and clinical status were unremarkable for 16 years, despite progressively increased left ventricular mass on echocardiography. In 2012, 4 months before death, she deteriorated rapidly with severe heart failure, precipitated by Clostridium difficile colitis and urosepsis. Affected family members developed nephropathy, on average, nearly three decades later, which may be explained by the gene dosage effects on the phenotype of E526V (p.Glu545Val) fibrinogen A alpha-chain amyloidosis.

Liver transplantation in transthyretin amyloidosis: issues and challenges.

Hereditary transthyretin amyloidosis (ATTR) is a rare worldwide autosomal dominant disease caused by the systemic deposition of an amyloidogenic variant of transthyretin (TTR), which is usually derived from a single amino acid substitution in the TTR gene. More than 100 mutations have been described, with V30M being the most prevalent. Each variant has a different involvement, although peripheral neuropathy and cardiomyopathy are the most common. Orthotopic liver transplantation (OLT) was implemented as the inaugural disease-modifying therapy because the liver produces the circulating unstable TTR. In this review, we focus on the results and long-term outcomes of OLT for ATTR after more than 2063 procedures and 23 years of experience. After successful OLT, neuropathy and organ impairment are not usually reversed, and in some cases, the disease progresses. The overall 5-year survival rate is approximately 100% for V30M patients and 59% for non-ATTR V30M patients. Cardiac-related death and septicemia are the main causes of mortality. Lower survival is related to malnutrition, a longer duration of disease, cardiomyopathy, and a later onset (particularly for males). Deposits, which are composed of a mixture of truncated and full-length TTR (type A) fibrils, have been associated with posttransplant myocardial dysfunction. A higher incidence of early hepatic artery thrombosis of the graft has also been documented for these patients. Liver-kidney/heart transplantation is an alternative for patients with advanced renal disease or heart failure. The sequential procedure, in which ATTR livers are reused in patients with liver disease, reveals that neuropathy in the recipient may appear as soon as 6 years after OLT, and ATTR deposits may appear even earlier. Long-term results of trials with amyloid protein stabilizers or disrupters, silencing RNA, and antisense oligonucleotides will highlight the value and limitations of liver transplantation.

Oxidative stress in kidney transplantation: malondialdehyde is an early predictive marker of graft dysfunction.

BACKGROUND: Oxidative stress is one of the most important components of the ischemia-reperfusion process after kidney transplantation (KTx) and increases with graft dysfunction. METHODS: This prospective study was conducted on 40 consecutive KTx recipients to evaluate time-dependent changes in oxidative stress-related parameters within the first week after KTx and to assess their performance in predicting delayed graft function (DGF=dialysis requirement during initial posttransplant week) and graft function at 1 year. Blood samples were collected before (day 0) and after KTx (days 1, 2, 4, and 7). Total antioxidant capacity, plasma levels of malondialdehyde (MDA), and activities of glutathione peroxidase, glutathione reductase and superoxide dismutase were measured. Multivariable linear mixed and linear regression models, receiver-operating characteristic (ROC), and areas under ROC curves (AUC-ROC) were used. RESULTS: At all time points after KTx, mean MDA levels were significantly higher in patients developing DGF (n=18). Shortly after KTx (8-12 hr), MDA values were higher in DGF recipients (on average, +0.16 µmol/L) and increased further on following day, contrasting with prompt functioning recipients. Day 1 MDA levels accurately predicted DGF (AUC-ROC=0.90), with a performance higher than SCr (AUC-ROC=0.73) and similar to cystatin C (AUC-ROC=0.91). Multivariable analysis revealed that MDA levels on day 7 represented an independent predictor of 1-year graft function. Antioxidant enzyme activities were not significantly changed during the study period and were not predictors of 1-year graft function. CONCLUSIONS: Increased MDA levels on day 1 after KTx might be an early prognostic indicator of DGF, and levels on day 7 might represent a useful predictor of 1-year graft function.

Neutrophil gelatinase-associated lipocalin in kidney transplantation is an early marker of graft dysfunction and is associated with one-year renal function.

Urinary neutrophil gelatinase-associated lipocalin (uNGAL) has been suggested as potential early marker of delayed graft function (DGF) following kidney transplantation (KTx). We conducted a prospective study in 40 consecutive KTx recipients to evaluate serial changes of uNGAL within the first week after KTx and assess its performance in predicting DGF (dialysis requirement during initial posttransplant week) and graft function throughout first year. Urine samples were collected on post-KTx days 0, 1, 2, 4, and 7. Linear mixed and multivariable regression models, receiver-operating characteristic (ROC), and areas under ROC curves were used. At all-time points, mean uNGAL levels were significantly higher in patients developing DGF (n = 18). Shortly after KTx (3-6 h), uNGAL values were higher in DGF recipients (on average +242 ng/mL, considering mean dialysis time of 4.1 years) and rose further in following days, contrasting with prompt function recipients. Day-1 uNGAL levels accurately predicted DGF (AUC-ROC = 0.93), with a performance higher than serum creatinine (AUC-ROC = 0.76), and similar to cystatin C (AUC-ROC = 0.95). Multivariable analyses revealed that uNGAL levels at days 4 and 7 were strongly associated with one-year serum creatinine. Urinary NGAL is an early marker of graft injury and is independently associated with dialysis requirement within one week after KTx and one-year graft function.

Solid organ transplantation for non-TTR hereditary amyloidosis: report from the 1st International Workshop on the Hereditary Renal Amyloidoses.

Fibrinogen A α-chain (AFib) and apolipoprotein AI (AApoAI) amyloidosis due to variants in the AFib and ApoAI genes are the most common types of hereditary amyloidosis in Europe and the United States. Liver is the exclusive source of the aberrant amyloidogenic protein in AFib and responsible for supplying approximately half of the circulating variant ApoAI. Nephrotic syndrome and renal impairment due to renal amyloidosis are common disease manifestations; however, recent research provides evidence to support a more diverse and systemic disease phenotype, which in turn has implications in the management of the hereditary amyloidoses with solid organ transplantation and, in particular, liver transplantation.

Transthyretin amyloidosis and the kidney.

The amyloidoses are protein-misfolding disorders associated with progressive organ dysfunction. Immunoglobulin light chain is the most common, amyloid A the longest recognized, and transthyretin-associated amyloidosis (ATTR) the most frequent inherited systemic form. Although ATTR, an autosomal-dominant disease, is associated with at least 100 different transthyretin (TTR) mutations, the single amino-acid substitution of methionine for valine at position 30 is the most common mutation. Each variant has a different organ involvement, although clinical differences attributed to environmental and genetic factors exist within the same mutation. Peripheral neuropathy and cardiomyopathy are broadly described, and insights into disease reveal that kidney impairment and proteinuria are also clinical features. This review combines clinical and laboratory findings of renal involvement from the main geographic regions of disease occurrence and for different mutations of TTR. Fifteen nephropathic variants have been described, but the TTR V30M mutation is the best documented. Nephropathy affects patients with late-onset neuropathy, low penetrance in the family, and cardiac dysrhythmias. Microalbuminuria can be the disorder's first presentation, even before the onset of neuropathy. Amyloid renal deposits commonly occur, even in the absence of urinary abnormalities. The experience with renal replacement therapy is based on hemodialysis, which is associated with poor survival. Because TTR is synthesized mainly in the liver, liver transplantation has been considered an acceptable treatment; simultaneous liver-kidney transplantation is recommended to avoid recurrence of nephropathy. In addition, the kidney-safety profile of new drugs in development may soon be available.

Renal transplantation in AA amyloidosis associated with Whipple's disease.

Whipple's disease (WD) is a chronic infection caused by Thropheryma whipplei that usually manifests with intestinal, articular, pulmonary, neurological and cardiac abnormalities. Rarely, WD has been associated with renal AA amyloidosis.We report a 50 year-old male with nephrotic syndrome and renal failure whose renal biopsy revealed extensive AA amyloidosis. Amyloid was not found in other organs, namely in gastrointestinal tract and bone marrow. There was no evidence of chronic inflammatory disease, and despite detailed investigation, the diagnosis of the underlying disease remained obscure. Eight months after referral he started peritoneal dialysis. Three years later he developed anorexia, weight loss, anemia, and recurrent attacks of non-bloody diarrhea. A biopsy of the small intestine showed typical histological findings of WD and PCR was positive for T. whipplei. He was treated with ceftriaxone followed by co-trimoxazole, with remission of complaints and histological features. Three years later the patient underwent successful cadaveric kidney transplantation. In this case, AA amyloidosis preceded the manifestations of WD. To the best of our knowledge, this is the first report of kidney transplantation in a patient with amyloidosis due to WD. Recurrence of amyloidosis in renal graft is not expected.

Long-term treatment of anemia with recombinant human erythropoietin in familial amyloidosis TTR V30M.

Familial amyloidosis or familial amyloid polyneuropathy (FAP) TTR V30M is a hereditary disease presented, in most cases, as a sensorimotor and autonomic neuropathy. Normocytic and normochromic anaemia was found in 24.8% of symptomatic FAP patients associated to lower serum erythropoietin (Epo) levels. Erythropoietin has been reported as efficient in anaemia correction in this disease. To evaluate the tolerance and efficacy of this treatment, a retrospective longitudinal study with 24 patients was undertaken. Patients were followed for at least 6 months. Haemoglobin, hematocrit, iron status, serum creatinine and urea and r-HuEPO doses were monitored, at 0, 3 months, 6 months and at the end of the follow-up. Long-term use of r-HuEPO proved to be efficient in the treatment of anaemia in familial amyloidosis TTR V30M and, despite the disease progression, no resistance cases to this treatment were observed. Positive side effects, like improvement on orthostatic hypotension symptoms and well-being sensation, contributing to confirm erythropoietin as a drug of choice to treat anaemia in amyloidosis TTR V30M.