Effectiveness and safety of the conversion to MeltDose® extended-release tacrolimus from other formulations of tacrolimus in stable kidney transplant patients: A retrospective study.

Tacrolimus is the cornerstone of immunosuppressive therapy after kidney transplantation. Its narrow therapeutic window mandates serum level strict monitoring and dose adjustments to ensure the optimal risk-benefit balance. This observational retrospective study analyzed the effectiveness and safety of conversion from twice-daily immediate-release tacrolimus (IR-Tac) or once-daily prolonged-release tacrolimus (PR-Tac) to the recent formulation once-daily MeltDose® extended-release tacrolimus (LCP-Tac) in 365 stable kidney transplant recipients. We compared kidney function three months before and three months after the conversion. Three months after conversion, the total daily dose was reduced ~35% (P < .0001), and improved bioavailability and stable serum LCP-Tac concentrations were observed. There was no increase in the number of patients requiring tacrolimus dose adjustments after conversion. Renal function was unaltered, and no cases of BPAR were reported. Reports of tremors, as collected in the clinical histories for each patient, decreased from pre-conversion (20.8%) to post-conversion (11.8%, P < .0001). LCP-Tac generated a cost reduction of 63% compared with PR-Tac. In conclusion, the conversion strategy to LCP-Tac from other tacrolimus formulations in stable kidney transplant patients showed safety and effectiveness in a real-world setting, confirming the data from RCTs. The specific pharmacokinetic properties of LCP-Tac could be potentially advantageous in patients with tacrolimus-related adverse events.

IgA Nephropathy in Elderly Patients.

BACKGROUND AND OBJECTIVES: Some studies suggest that the incidence of IgA nephropathy is increasing in older adults, but there is a lack of information about the epidemiology and behavior of the disease in that age group. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this retrospective multicentric study, we analyzed the incidence, forms of presentation, clinical and histologic characteristics, treatments received, and outcomes in a cohort of 151 patients ≥65 years old with biopsy-proven IgA nephropathy diagnosed between 1990 and 2015. The main outcome was a composite end point of kidney replacement therapy or death before kidney replacement therapy. RESULTS: We found a significant increase in the diagnosis of IgA nephropathy over time from six patients in 1990-1995 to 62 in 2011-2015 (P value for trend =0.03). After asymptomatic urinary abnormalities (84 patients; 55%), AKI was the most common form of presentation (61 patients; 40%). Within the latter, 53 (86%) patients presented with hematuria-related AKI (gross hematuria and tubular necrosis associated with erythrocyte casts as the most important lesions in kidney biopsy), and eight patients presented with crescentic IgA nephropathy. Six (4%) patients presented with nephrotic syndrome. Among hematuria-related AKI, 18 (34%) patients were receiving oral anticoagulants, and this proportion rose to 42% among the 34 patients older than 72 years old who presented with hematuria-related AKI. For the whole cohort, survival rates without the composite end point were 74%, 48%, and 26% at 1, 2, and 5 years, respectively. Age, serum creatinine at presentation, and the degree of interstitial fibrosis in kidney biopsy were risk factors significantly associated with the outcome, whereas treatment with renin-angiotensin-aldosterone blockers was associated with a lower risk. Immunosuppressive treatments were not significantly associated with the outcome. CONCLUSIONS: The diagnosis of IgA nephropathy among older adults in Spain has progressively increased in recent years, and anticoagulant therapy may be partially responsible for this trend. Prognosis was poor. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_07_16_CJASNPodcast_19_08_.mp3.

Advanced glycation end products (AGEs) estimated by skin autofluorescence are related with cardiovascular risk in renal transplant.

BACKGROUND: Advanced glycation end products (AGEs) accumulation, a measure of cumulative metabolic stress, constitute a novel pathogenic mechanism involved in aging, diabetes, cardiovascular (CVD) and chronic kidney disease (CKD). Despite removal of uremic toxins and AGEs after a successful renal transplant (RT), CVD remains the leading cause of mortality. We hypothesized that AGEs measurement by Skin Autofluorescence (SAF) might be useful even after a successful RT and thus reflect the high cardiovascular risk burden of these patients. METHODS: 189 stable RT (61% men, aged 56±13.0 years), CKD stages 1-4 and >12 months since RT were enrolled. Variables collected comprised comorbid history, medication use, smoking habit, routine biochemistry, subclinical atheromatosis by ankle-brachial-index (ABI) and allograft resistivity index (RI), 24-h ABPM, anthropometry and handgrip strength. AGEs were measured by SAF and expressed in arbitrary units (AU). Vascular age was estimated by Koetsier´s formula (SAF-0.83/0.024) and expected 10-years cardiovascular death risk was calculated with the REGICOR score. RESULTS: Mean SAF was 3.00±0.83 AU and estimated vascular age 90±34.7 years (30 years above biological age). SAF was higher among men (3.10±0.91 vs 2.81±0.66), diabetic nephropathy (3.49±0.75 vs 2.96±0.83) and steroid users (3.14±0.86 vs 2.71±0.69). We observed a positive correlation of SAF with night-systolic blood pressure (r = 0.25, p = 0.001), parathormone (r = 0.20, p<0.01), phosphate (r = 0.28, p<0.001) and negative with hemoglobin (r = -0.29, p<0.001), CKD-EPI (r = -0.32, p<0.001), albumin (r = -0.17, p<0.05), and dynamometry (r = -0.20, p<0.01). Subclinical vascular atheromatosis (ABI and RI) as well as the REGICOR scale (r = 0.35 p<0.001) were also correlated with SAF. In multivariable analysis age, gender, steroid use, serum phosphate and handgrip strength remained independently associated with SAF. CONCLUSIONS: SAF levels are elevated in RT patients and correlate with CVD risk. Besides age and male sex, our results suggest that phosphate overload, steroid use and nutritional status are important factors linking to AGEs accumulation.

Restless Legs Syndrome: An Unresolved Uremic Disorder after Renal Transplantation.

BACKGROUND: Restless legs syndrome (RLS) is a common complication of uremia that may improve after transplantation. Its frequency might not be as low as expected, as some uremic disturbances may continue even after a successful graft. Our aim was to investigate the prevalence and related conditions for RLS in renal transplant patients. METHODS: We carried out a cross-sectional, observational study. A self-administered questionnaire following the International Restless Legs Syndrome Study Group diagnostic criteria was administered to 129 patients (82 men and 47 women) aged 57 ± 12.8 years followed up for at least 1 year, with stable renal function (Cr 1.5 ± 0.54 mg/dL). Patients with probable RLS according to the screening questionnaire underwent comprehensive neurological examination to exclude RLS mimics. RESULTS: The frequency of RLS according to questionnaires was 29.5% (18 men/20 women). After neurological exam, RLS was confirmed in 19 patients providing an overall frequency of 14.8% (higher than the prevalence in the general population). A definitive diagnosis of RLS was established for 6 men (7.3%) and 13 women (27.7%), indicating a positive predictive value for the screening questionnaire of 65% for women and 33% for men. There were fewer patients under renin-angiotensin aldosterone system (RAAS) blocking treatment in the RLS group (21.1 vs. 47.3%). Women with RLS had poorer renal function (52 ± 17.5 vs. 42 ± 13.9 mL/min) and phosphate-reabsorption rate (75 ± 10.5 vs. 65 ± 9.2). There was no difference in age, comorbidities, anticalcineurin therapy, renal function, anemia and time since transplantation between transplant patients with and without RLS. CONCLUSION: The prevalence of RLS after transplantation remains high (14.8%). This condition is twice more prevalent for females. Contribution of RAAS, graft function and phosphate overload requires further investigation.

Déficit de testosterona en los pacientes en diálisis: diferencias según la técnica de diálisis / Testosterone deficiency in dialysis patients: Difference between dialysis techniques

Los varones con enfermedad renal crónica cursan a menudo con deficiencia en testosterona. Se desconoce si el déficit de testosterona que acompaña a la pérdida de función renal se asocia con el tipo de tratamiento sustitutivo de la función renal. Métodos: El estudio de corte transversal incluyó 79 varones prevalentes en diálisis, 43 en hemodiálisis (HD) y 36 en diálisis peritoneal (DP). Con una edad media de 69 años, el 31,6% eran diabéticos. Se evaluaron los niveles de testosterona endógena (inmunoluminiscencia: N 3-10,5ng/ml), marcadores nutricionales/inflamatorios, marcadores de metabolismo óseo mineral, anemia, tipo de técnica y permanencia. La composición corporal fue estimada mediante bioimpedancia vectorial y espectroscópica. Se considera déficit de testosterona cuando los niveles son inferiores a 3ng/ml. Resultados: Los niveles de testosterona medios fueron 8,81±6,61ng/ml. El 39,5% de los pacientes en HD y el 5,6% de los de DP presentaban déficit de testosterona. Los niveles de testosterona se correlacionaron directamente con el tipo de técnica, HD (rho Spearman 0,366; p < 0,001) y el tiempo de permanencia (Rho −0,412; p=0,036) en el análisis univariante y solo con la técnica de HD en el multivariante. No se encontraron otras correlaciones significativas. Conclusiones: Los niveles circulantes de testosterona en hombres en diálisis se asocian de manera independiente con la técnica de HD. Se puede concluir que, en la reducción de testosterona que acompaña de manera natural a la pérdida de masa muscular e inflamación, se asocia un nuevo factor que es la técnica dialítica. Se necesitan estudios para elucidar si la técnica per se favorece la eliminación de testosterona (AU)

Testosterone deficiency is a prevalent condition in male patients with chronic kidney disease. However, it is not known whether the type of renal replacement therapy has an impact on testosterone deficiency that accompanies loss of renal function. Methods: The cross-sectional study enrolled 79 prevalent male patients on dialysis; 43 on haemodialysis (HD) and 36 on peritoneal dialysis (PD). The median age was 69 years and 31.6% were diabetics. Endogenous testosterone levels were measured by immunoluminescence assay (normal range 3-10.5ng/ml), while nutritional/inflammatory markers, bone and mineral metabolism markers, anaemia, type of dialysis technique and time on dialysis were also assessed. Body composition was evaluated by bioimpedance vector analysis and bioimpedance spectroscopy. Testosterone deficiency was defined as levels below 3ng/ml. Results: Mean testosterone levels were 8.81±6.61ng/ml. Testosterone deficiency affected 39.5% of HD patients and only 5.6% of PD patients. In the univariate analysis, testosterone levels were directly correlated with type of dialysis technique (HD) (Rho Spearman 0.366; P<.001) and time on dialysis (Rho −0.412; P=.036) and only with the HD technique in the multivariate analysis. No other significant correlations were found. Conclusions: Circulating testosterone levels in men on dialysis were independently associated with HD technique. It can be concluded that a new factor —namely the dialysis technique— may be associated with falling testosterone levels and the associated loss of muscle mass and inflammation. Further studies are needed to establish whether the dialysis technique itself triggers testosterone elimination (AU)

Testosterone deficiency in dialysis patients: Difference between dialysis techniques. / Déficit de testosterona en los pacientes en diálisis: diferencias según la técnica de diálisis.

Testosterone deficiency is a prevalent condition in male patients with chronic kidney disease. However, it is not known whether the type of renal replacement therapy has an impact on testosterone deficiency that accompanies loss of renal function. METHODS: The cross-sectional study enrolled 79 prevalent male patients on dialysis; 43 on haemodialysis (HD) and 36 on peritoneal dialysis (PD). The median age was 69 years and 31.6% were diabetics. Endogenous testosterone levels were measured by immunoluminescence assay (normal range 3-10.5ng/ml), while nutritional/inflammatory markers, bone and mineral metabolism markers, anaemia, type of dialysis technique and time on dialysis were also assessed. Body composition was evaluated by bioimpedance vector analysis and bioimpedance spectroscopy. Testosterone deficiency was defined as levels below 3ng/ml. RESULTS: Mean testosterone levels were 8.81±6.61ng/ml. Testosterone deficiency affected 39.5% of HD patients and only 5.6% of PD patients. In the univariate analysis, testosterone levels were directly correlated with type of dialysis technique (HD) (Rho Spearman 0.366; P<.001) and time on dialysis (Rho -0.412; P=.036) and only with the HD technique in the multivariate analysis. No other significant correlations were found. CONCLUSIONS: Circulating testosterone levels in men on dialysis were independently associated with HD technique. It can be concluded that a new factor -namely the dialysis technique- may be associated with falling testosterone levels and the associated loss of muscle mass and inflammation. Further studies are needed to establish whether the dialysis technique itself triggers testosterone elimination.

Endocarditis de Libman-Sacks: una manifestación frecuentemente inadvertida / Libman-Sacks’ endocarditis: A frequently unnoticed complication

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Restless legs syndrome in non-dialysis renal patients: is it really that common?

BACKGROUND: Sleep disorders are frequent in chronic kidney disease (CKD). Among them, restless legs syndrome (RLS) may affect up to 60% of patients on dialysis, and it has been related to a poor quality of life and higher cardiovascular risk. Despite its high prevalence in advanced stages of renal disease, RLS frequency in non-dialysis CKD has not been clearly established. The aim of this study was to assess the frequency of RLS in non-dialysis CKD patients (stages 2 to 4) followed in a reference nephrology outpatient clinic. METHODS: A standardized questionnaire following the international RLS study group diagnostic criteria was self-administered by 110 patients regularly followed in the nephrology clinic. The series comprised 69 men and 41 women, aged 68 ± 13.2 years, with mean serum creatinine of 1.7 ± 0.8 mg/dL. Subsequently, patients classified as probable RLS according to the questionnaire underwent a systematic neurological examination. The presence of peripheral artery disease was evaluated by the ankle-brachial index (ABI). RESULTS: The frequency of probable RLS according to the questionnaire results was 21% (17% for men and 27% for women). However, after thorough neurological examination, the diagnosis of RLS was confirmed in only 5 patients. Therefore, the overall definitive RLS frequency was 4.5% (within the prevalence reported for the general population) and was higher among women (9.7% vs 0.2%). In the remaining cases symptoms were due to leg discomfort related with other disorders. Patients with probable and improbable RLS were not significantly different in age, ABI, diabetes, and other comorbid circumstances, except for tricyclic antidepressant prescription, which was more frequent in the probable RLS group (17% vs 2%). Renal function was better in definitive RLS patients than cases classified as probable RLS by the questionnaire but not confirmed after neurological exam. CONCLUSIONS: Although RLS can represent an early manifestation of CKD, its prevalence seems very close to that reported for the general population. Diagnostic confirmation of RLS dramatically falls after expert examination, raising the question whether, in the study of RLS cohorts, CKD has a potentially causal relationship or is a confounding factor associated with other causes of leg discomfort.

Flank pain and acute renal failure after binge drinking: a growing concern?

We describe two cases of acute renal failure (ARF) after heavy alcohol intake. Remarkable features included a few days latency period after binge drinking, acute flank pain resembling pyelonephritis, lack of rhabdomyolysis or liver injury, and concomitant intake of non-steroidal anti-inflammatory drugs (NSAIDs). Renal function improved with conservative treatment, and despite NSAIDs use, hyperkalemia was not clinically significant. Since binge drinking is common in the Western population, early recognition of this syndrome may be helpful when examining a patient with flank pain and ARF of unclear etiology.

Recognizing misplacement of a dialysis catheter in the azygos vein.

Uneventful central venous catheterization for hemodialysis patients may not always result in a correct tip position. A case of inadvertent cannulation of the azygos vein is described. Radiographic features for its early recognition are emphasized and mechanisms related with azygos unintended catheterization are discussed.

Insulin resistance and the metabolism of branched-chain amino acids in humans.

Peripheral resistance to insulin action is the major mechanism causing the metabolic syndrome and eventually type 2 diabetes mellitus. The metabolic derangement associated with insulin resistance is extensive and not restricted to carbohydrates. The branched-chain amino acids (BCAAs) are particularly responsive to the inhibitory insulin action on amino acid release by skeletal muscle and their metabolism is profoundly altered in conditions featuring insulin resistance, insulin deficiency, or both. Obesity, the metabolic syndrome and diabetes mellitus display a gradual increase in the plasma concentration of BCAAs, from the obesity-related low-grade insulin-resistant state to the severe deficiency of insulin action in diabetes ketoacidosis. Obesity-associated hyperinsulinemia succeeds in maintaining near-normal or slightly elevated plasma concentration of BCAAs, despite the insulin-resistant state. The low circulating levels of insulin and/or the deeper insulin resistance occurring in diabetes mellitus are associated with more marked elevation in the plasma concentration of BCAAs. In diabetes ketoacidosis, the increase in plasma BCAAs is striking, returning to normal when adequate metabolic control is achieved. The metabolism of BCAAs is also disturbed in other situations typically featuring insulin resistance, including kidney and liver dysfunction. However, notwithstanding the insulin-resistant state, the plasma level of BCAAs in these conditions is lower than in healthy subjects, suggesting that these organs are involved in maintaining BCAAs blood concentration. The pathogenesis of the decreased BCAAs plasma level in kidney and liver dysfunction is unclear, but a decreased afflux of these amino acids into the blood stream has been observed.

Membranous nephropathy, leiomyoma and autoimmune myasthenia: more than a coincidence?

Membranous nephropathy (MN) has been associated with several infectious, immunological and malignant conditions, but had only rarely been reported with malignant and other immune disorders in the same patient. We describe the case of a 56-year-old male with MN who was also diagnosed with a gastrointestinal stromal tumour (GIST), myasthenia gravis (MG) and thymic hyperplasia. Thus, we report here for the first time the coincidence of these conditions in the same patient. There was a recurrence of nephrotic syndrome without impairment of renal function 5 years after removal of the GIST (3 years after thymectomy). The possible basis for the relationship between these diseases is discussed, and some common genetic and immune physiopathological pathways are hypothesized.

Metabolic acidosis-induced insulin resistance and cardiovascular risk.

Microalbuminuria has been conclusively established as an independent cardiovascular risk factor, and there is evidence of an association between insulin resistance and microalbuminuria, the former preceding the latter in prospective studies. It has been demonstrated that even the slightest degree of metabolic acidosis produces insulin resistance in healthy humans. Many recent epidemiological studies link metabolic acidosis indicators with insulin resistance and systemic hypertension. The strongly acidogenic diet consumed in developed countries produces a lifetime acidotic state, exacerbated by excess body weight and aging, which may result in insulin resistance, metabolic syndrome, and type 2 diabetes, contributing to cardiovascular risk, along with genetic causes, lack of physical exercise, and other factors. Elevated fruits and vegetables consumption has been associated with lower diabetes incidence. Diseases featuring severe atheromatosis and elevated cardiovascular risk, such as diabetes mellitus and chronic kidney failure, are typically characterized by a chronic state of metabolic acidosis. Diabetic patients consume particularly acidogenic diets, and deficiency of insulin action generates ketone bodies, creating a baseline state of metabolic acidosis worsened by inadequate metabolic control, which creates a vicious circle by inducing insulin resistance. Even very slight levels of chronic kidney insufficiency are associated with increased cardiovascular risk, which may be explained at least in part by deficient acid excretory capacity of the kidney and consequent metabolic acidosis-induced insulin resistance.