Publications by authors named "Enrique Morales"

94 Publications

Immunosuppression minimization in kidney transplant recipients hospitalized for COVID-19.

Clin Kidney J 2021 Apr 29;14(4):1229-1235. Epub 2021 Jan 29.

Department of Nephrology, University Hospital "12 de Octubre", Madrid, Spain.

Background: Immunosuppressed patients such as kidney transplant recipients (KTs) have increased mortality risk in the setting of coronavirus disease 2019 (COVID-19). The role and management of chronic immunosuppressive therapies during COVID-19 must be characterized.

Methods: Herein, we report the follow-up of a cohort of 47 KTs admitted at two Spanish Kidney Transplant Units, who survived COVID-19. The impact of the management of immunosuppression during COVID-19 on graft function and immunologic events was evaluated.

Results: At least one immunosuppressive agent was withdrawn in 83% of patients, with antimetabolites being the most frequent. Steroids were generally not stopped and the dose was even increased in 15% of patients as part of the treatment of COVID-19. Although immunosuppressive drugs were suspended during a median time of 17 days, no rejection episodes or donor-specific antibodies were observed up to 3 months after discharge, and no significant changes occurred in calculated panel reactive antibodies. Acute graft dysfunction was common (55%) and the severity was related to tacrolimus trough levels, which were higher in patients receiving antivirals. At the end of follow-up, all patients recovered baseline kidney function.

Conclusions: Our observational study suggests that immunosuppression in KTs hospitalized due to COVID-19 could be safely minimized.
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http://dx.doi.org/10.1093/ckj/sfab025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929031PMC
April 2021

The Forgotten Antiproteinuric Properties of Diuretics.

Am J Nephrol 2021 Jul 7:1-15. Epub 2021 Jul 7.

Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain.

Background: Although diuretics are one of the most widely used drugs by nephrologists, their antiproteinuric properties are not generally taken into consideration.

Summary: Thiazide diuretics have been shown to reduce proteinuria by >35% in several prospective controlled studies, and these values are markedly increased when combined with a low-salt diet. Thiazide-like diuretics (indapamide and chlorthalidone) have shown similar effectiveness. The antiproteinuric effect of mineralocorticoid receptor antagonists (spironolactone, eplerenone, and finerenone) has been clearly established through prospective and controlled studies, and treatment with finerenone reduces the risk of chronic kidney disease progression in type-2 diabetic patients. The efficacy of other diuretics such as amiloride, triamterene, acetazolamide, or loop diuretics has been less explored, but different investigations suggest that they might share the same antiproteinuric properties of other diuretics that should be evaluated through controlled studies. Although the inclusion of sodium-glucose cotransporter-2 inhibitors (SGLT2i) among diuretics is a controversial issue, their renoprotective and cardioprotective properties, confirmed in various landmark trials, constitute a true revolution in the treatment of patients with kidney disease. Recent subanalyses of these trials have shown that the early antiproteinuric effect induced by SGLT2i predicts long-term preservation of kidney function. Key Message: Whether the early reduction in proteinuria induced by diuretics other than finerenone and SGLT2i, as summarized in this review, also translates into long-term renoprotection requires further prospective and observational studies. In any case, it is important for the clinician to be aware of the antiproteinuric properties of drugs so often used in daily clinical practice.
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http://dx.doi.org/10.1159/000517020DOI Listing
July 2021

Management of Chronic Hyperkalemia in Patients With Chronic Kidney Disease: An Old Problem With News Options.

Front Med (Lausanne) 2021 4;8:653634. Epub 2021 Jun 4.

Nephrology Department, Complejo Hospitalario de Navarra, Pamplona, Spain.

Hyperkalemia is one of the main electrolyte disorders in patients with chronic kidney disease (CKD). The prevalence of hyperkalemia increases as the Glomerular Filtration Rate (GFR) declines. Although chronic hyperkalemia is not a medical emergency, it can have negative consequences for the adequate cardio-renal management in the medium and long term. Hyperkalemia is common in patients on renin-angiotensin-aldosterone system inhibitors (RAASi) or Mineralocorticoid Receptor Antagonists (MRAs) and can affect treatment optimization for hypertension, diabetes mellitus, heart failure (HF), and CKD. Mortality rates are higher with suboptimal dosing among patients with CKD, diabetes or HF compared with full RAASi dosing, and are the highest among patients who discontinue RAASis. The treatment of chronic hyperkalemia is still challenging. Therefore, in the real world, discontinuation or reduction of RAASi therapy may lead to adverse cardiorenal outcomes, and current guidelines differ with regard to recommendations on RAASi therapy to enhance cardio and reno-protective effects. Treatment options for hyperkalemia have not changed much since the introduction of the cation exchange resin over 50 years ago. Nowadays, two new potassium binders, Patiromer Sorbitex Calcium, and Sodium Zirconium Cyclosilicate (SZC) already approved by FDA and by the European Medicines Agency, have demonstrated their clinical efficacy in reducing serum potassium with a good safety profile. The use of the newer potassium binders may allow continuing and optimizing RAASi therapy in patients with hyperkalemia keeping the cardio-renal protective effect in patients with CKD and cardiovascular disease. However, further research is needed to address some questions related to potassium disorders (definition of chronic hyperkalemia, monitoring strategies, prediction score for hyperkalemia or length for treatment).
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http://dx.doi.org/10.3389/fmed.2021.653634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213200PMC
June 2021

Role of non-alcoholic fatty liver disease in the evolution of renal function in patients with diabetes mellitus.

Nephrol Dial Transplant 2021 May 13. Epub 2021 May 13.

Department of Nephrology, University Hospital "12 de Octubre", Madrid, Spain.

Background: Increasing prevalence in type 2 diabetes mellitus (T2DM) have influenced in an increasing prevalence of chronic kidney disease (CKD). Little is known about the influence of non-alcoholic fatty liver disease (NAFLD) on progression of CKD. The aim of this study was to analyse the role of NAFLD and its severity in the progression of renal function in patients with T2DM.

Methods: Retrospective and observational study, including patients with T2DM and estimated glomerular filtration rate (eGFR) >30 ml/min/1,73m2. NAFLD was defined with presence of compatible ultrasonography and/or presence of fibrosis using NAFLD score. Patients were classified in three groups according to the NAFLD score; group 1 <-1.85, group 2 -1.85 to 0.18, and group 3 > 0.18.

Results: A total of 102 patients were included (67.6% males, median age 59 [53-64] years), with median time of T2DM evolution was 70 [39-131] months. Group 3 had lower eGFR (84.8  ±  40.4 vs 71.4  ±  30.6 ml/min/1.73m2; p = 0.03) and higher proteinuria at baseline (0.56  ±  0.77 vs 1.59  ±  2.70 g/24h; p = 0.05). After a follow-up time of 75.8  ±  23.9 months, group 3 had a significant decrease in eGFR (66.6  ±  33.3 vs 36.8  ±  23.1 ml/min/1.73m2; p = <0.01), and higher risk of CKD progression (OR 7.50; CI 95% 2.76-20.35; p = <0.001) defined as decrease in > 50% eGFR.

Conclusions: The presence of NAFLD with high-risk fibrosis confers higher risk of CKD progression in patients with T2DM. Therefore, NAFLD should be a risk factor evaluated in these patients to optimise treatment.
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http://dx.doi.org/10.1093/ndt/gfab176DOI Listing
May 2021

Which Patients with Obesity Are at Risk for Renal Disease?

Nephron 2021 Mar 5:1-9. Epub 2021 Mar 5.

Department of Nephrology, University Hospital "12 de Octubre", Madrid, Spain.

Obesity-related glomerulopathy (ORG) is an increasingly recognized cause of end-stage kidney disease. The most common clinical presentation is a slowly increasing nonnephrotic proteinuria that is followed by a progressive decline of kidney function. Key histological findings are glomerulomegaly and lesions of focal and segmental glomerulosclerosis. A central pathogenic mechanism is the increased sodium reabsorption by proximal tubules that typically accompanies obesity. This causes a decrease in the offer of sodium to the macula densa in the distal nephron, which results in a vasodilation of afferent glomerular arterioles and glomerular hyperfiltration. From a clinical point of view, it is essential to differentiate focal segmental glomerulosclerosis secondary to obesity from primary glomerular processes, which requires a careful differential diagnosis. Diet-induced weight loss, bariatric surgery, and renin-angiotensin blockers are the fundamental therapeutic measures in ORG. The recently developed sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 agonist represent a significant advance in renal protection and will probably improve clinical kidney outcomes in ORG.
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http://dx.doi.org/10.1159/000513868DOI Listing
March 2021

Eculizumab in Early-Stage Pregnancy.

Kidney Int Rep 2020 Dec 10;5(12):2383-2387. Epub 2020 Oct 10.

Fetal Medicine Unit-Maternal and Child Health and Development Network, Department of Obstetrics and Gynecology, University Hospital 12 de Octubre, 12 de Octubre Research Institute, Complutense University of Madrid, Madrid, Spain.

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http://dx.doi.org/10.1016/j.ekir.2020.09.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710878PMC
December 2020

Invasive pulmonary aspergillosis associated with COVID-19 in a kidney transplant recipient.

Transpl Infect Dis 2021 Apr 29;23(2):e13501. Epub 2020 Nov 29.

Department of Nephrology, University Hospital "12 de Octubre", Madrid, Spain.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might increase the risk of invasive pulmonary aspergillosis (IPA). Although several case reports and small series have been reported in the general population, scarce information is available regarding coronavirus disease 2019 (COVID-19)-associated IPA in the setting of solid organ transplantation. We describe a case of a kidney transplant recipient with severe COVID-19 that was subsequently diagnosed with probable IPA on the basis of the repeated isolation of Aspergillus fumigatus in sputum cultures, repeatedly increased serum (1 → 3)-β-d-glucan levels, and enlarging cavitary nodules in the CT scan. The evolution was favorable after initiation of isavuconazole and nebulized liposomal amphotericin B combination therapy and the withdrawal of immunosuppression.
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http://dx.doi.org/10.1111/tid.13501DOI Listing
April 2021

Results from the IRoc-GN international registry of patients with COVID-19 and glomerular disease suggest close monitoring.

Kidney Int 2021 01 9;99(1):227-237. Epub 2020 Nov 9.

Department of Medicine, Renal Division, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address:

The effects of SARS-CoV-2 infection on individuals with immune-mediated glomerulonephritis, who are often undergoing immunosuppressive treatments, are unknown. Therefore, we created the International Registry of COVID infection in glomerulonephritis (IRoc-GN) and identified 40 patients with glomerulonephritis and COVID-19 followed in centers in North America and Europe. Detailed information on glomerulonephritis diagnosis, kidney parameters, and baseline immunosuppression prior to infection were recorded, as well as clinical presentation, laboratory values, treatment, complications, and outcomes of COVID-19. This cohort was compared to 80 COVID-positive control cases from the general population without glomerulonephritis matched for the time of infection. The majority (70%) of the patients with glomerulonephritis and all the controls were hospitalized. Patients with glomerulonephritis had significantly higher mortality (15% vs. 5%, respectively) and acute kidney injury (39% vs. 14%) than controls, while the need for kidney replacement therapy was not statistically different between the two groups. Receiving immunosuppression or renin-angiotensin-aldosterone system inhibitors at presentation did not increase the risk of death or acute kidney injury in the glomerulonephritis cohort. In the cohort with glomerulonephritis, lower serum albumin at presentation and shorter duration of glomerular disease were associated with greater risk of acute kidney injury and need for kidney replacement therapy. No differences in outcomes occurred between patients with primary glomerulonephritis versus glomerulonephritis associated with a systemic autoimmune disease (lupus or vasculitis). Thus, due to the higher mortality and risk of acute kidney injury than in the general population without glomerulonephritis, patients with glomerulonephritis and COVID-19 should be carefully monitored, especially when they present with low serum albumin levels.
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http://dx.doi.org/10.1016/j.kint.2020.10.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833801PMC
January 2021

Update on Lupus Nephritis: Looking for a New Vision.

Nephron 2021 4;145(1):1-13. Epub 2020 Nov 4.

Department of Nephrology, University Hospital "12 de Octubre", Madrid, Spain.

Lupus nephritis (LN) is one of the most common manifestations of systemic lupus erythematosus (SLE), affecting approximately 40% of patients with lupus. It represents a major risk factor for morbidity and mortality, and 10% of patients with LN will develop end-stage kidney disease (ESKD). Therefore, there are a number of areas for improvement in the field of LN such as the search for new clinical biomarkers with a more accurate correlation with lupus activity and the redefinition of the histological classification into different subgroups in order to guide a personalized treatment. Although the role of protocol repeat kidney biopsies in LN is controversial, recent publications suggest that repeat histological assessment can be useful in guiding therapeutic decisions that may yield toward precision medicine. In the last decade, LN therapy has remained largely unchanged, with a probability of achieving complete or partial remission not exceeding 60-70%. Thus, optimization of old treatment strategies and search for new agents are urgently needed in order to improve outcomes such as mortality or development of ESKD. Future trials should focus in addressing unanswered issues such as the appropriate dose and duration of immunosuppressive treatment, timing of steroid withdrawal, and drug toxicity. In addition, data are still lacking regarding pregnancy and kidney transplantation in LN and knowledge about these important areas is essential for the management of a subset of patients with SLE. In summary, several major gaps are still present in the therapeutic approach and follow-up of patients with LN. The development of new clinical trial designs will be crucial in the search to improve long-term outcomes.
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http://dx.doi.org/10.1159/000511268DOI Listing
November 2020

What is the value of repeat kidney biopsies in patients with lupus nephritis?

Lupus 2021 Jan 20;30(1):25-34. Epub 2020 Oct 20.

Department of Nephrology, University Hospital "12 de Octubre", Madrid, Spain.

Introduction: Recent studies with protocol biopsies have shown a mismatch between clinical and histological remission in lupus nephritis (LN). We aimed to evaluate histological changes in repeat kidney biopsies by clinical indication in patients with LN.

Methods: We analyzed 107 patients with LN in which a kidney biopsy was performed between 2008 and 2018. Of those, we included 26 (24.2%) who had ≥2 kidney biopsies. Classification was done according to the International Society of Nephrology/Renal Pathology Society.

Results: Mean time between biopsies was 71.5 ± 10.7 months. 73.1% of patients presented a change of class at repeat biopsy; 38.4% to a higher class and 34.6% to a lower class. A significant increase in glomerulosclerosis (% GS) (3.8% 18.7%, p = 0.006), interstitial fibrosis (3.8% 26.9%, p = 0.021), tubular atrophy (15.4% 57.7%, p = 0.001) and chronicity index (CI) (1 3, p < 0.001) was observed at repeat biopsy. Subjects who developed chronic kidney disease progression had a lower rate of complete remission at 12 months (0% vs 37.5%, p = 0.02), higher % GS at first biopsy (7.9% vs 1.2%, p = 0.02) and higher CI (4 vs 2, p = 0.006), tubular atrophy (90% vs 37.6%, p = 0.008), interstitial fibrosis (50% vs 12.5%, p = 0.036) and vascular lesions (60% vs 18.8%, p = 0.031) at second biopsy.

Conclusions: Our major finding was that patients with LN showed a significant increase in % GS, interstitial fibrosis, tubular atrophy and vascular lesions in repeat biopsies performed by clinical indication. This suggest that a second kidney biopsy may provide valuable and useful information regarding kidney disease progression.
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http://dx.doi.org/10.1177/0961203320965703DOI Listing
January 2021

A Personalized Update on IgA Nephropathy: A New Vision and New Future Challenges.

Nephron 2020 20;144(11):555-571. Epub 2020 Aug 20.

Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world among patients undergoing renal biopsy. Approximately 30% of patients with IgAN develop end-stage kidney disease 20 years after renal biopsy. It is a glomerulopathy with a very broad clinical presentation, making it difficult to stratify and treat. IgAN is characterized by dysregulation of the immune system, which causes an abnormal synthesis of IgA1 that is deglycosylated causing its mesangial deposition. IgAN pathogenesis is incompletely understood; the current multi-hit hypothesis of IgAN pathogenesis does not explain the range of glomerular inflammation and renal injury associated with mesangial IgA deposition. Although associations between IgAN and glomerular and circulating markers of complement activation are established, the mechanism of complement activation and contribution to glomerular inflammation and injury are not defined. On the other hand, the renal-gut connection can also play an important role in the pathogenesis of IgAN with possible therapeutic implications. In order to standardize the histological findings, the Oxford Classification has allowed clarifying renal lesions that confer potential risk of progression. Currently, except for the blockade of the renin-angiotensin-aldosterone system, no other therapies are available in clinical setting for the treatment of IgAN, although the range of new drugs under investigation is extensive. The incorporation in the next trials of clinical parameters such as the amount of hematuria and histological lesions may allow more personalized therapeutic approaches. To summarize, in recent years, several important efforts have taken place in the understanding of IgAN, but still, further studies are warranted to elucidate the best therapeutic strategies according to the risk to improve the prognosis of this entity.
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http://dx.doi.org/10.1159/000509997DOI Listing
August 2020

Mechanisms of Cardiovascular Disorders in Patients With Chronic Kidney Disease: A Process Related to Accelerated Senescence.

Front Cell Dev Biol 2020 20;8:185. Epub 2020 Mar 20.

Departamento Biología de Sistemas, Facultad de Medicina y Ciencias de la Salud (IRYCIS), Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.

Cardiovascular diseases (CVDs), especially those involving a systemic inflammatory process such as atherosclerosis, remain the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). CKD is a systemic condition affecting approximately 10% of the general population. The prevalence of CKD has increased over the past decades because of the aging of the population worldwide. Indeed, CVDs in patients with CKD constitute a premature form of CVD observed in the general population. Multiple studies indicate that patients with renal disease undergo accelerated aging, which precipitates the appearance of pathologies, including CVDs, usually associated with advanced age. In this review, we discuss several aspects that characterize CKD-associated CVDs, such as etiopathogenic elements that CKD patients share with the general population, changes in the cellular balance of reactive oxygen species (ROS), and the associated process of cellular senescence. Uremia-associated aging is linked with numerous changes at the cellular and molecular level. These changes are similar to those observed in the normal process of physiologic aging. We also discuss new perspectives in the study of CKD-associated CVDs and epigenetic alterations in intercellular signaling, mediated by microRNAs and/or extracellular vesicles (EVs), which promote vascular damage and subsequent development of CVD. Understanding the processes and factors involved in accelerated senescence and other abnormal intercellular signaling will identify new therapeutic targets and lead to improved methods of diagnosis and monitoring for patients with CKD-associated CVDs.
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http://dx.doi.org/10.3389/fcell.2020.00185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7099607PMC
March 2020

Kidney transplantation in the extremely elderly from extremely aged deceased donors: a kidney for each age.

Nephrol Dial Transplant 2020 04;35(4):687-696

Department of Nephrology, Hospital Universitario "12 de Octubre", Instituto de Investigación Sanitaria Hospital "12 de Octubre" (imas12), Madrid, Spain.

Background: Advances in life expectancy have led to an increase in the number of elderly people with end-stage renal disease (ESRD). Scarce information is available on the outcomes of kidney transplantation (KT) in extremely elderly patients based on an allocation policy prioritizing donor-recipient age matching.

Methods: We included recipients ≥75 years that underwent KT from similarly aged deceased donors at our institution between 2002 and 2015. Determinants of death-censored graft and patient survival were assessed by Cox regression.

Results: We included 138 recipients with a median follow-up of 38.8 months. Median (interquartile range) age of recipients and donors was 77.5 (76.3-79.7) and 77.0 years (74.7-79.0), with 22.5% of donors ≥80 years. Primary graft non-function occurred in 8.0% (11/138) of patients. Cumulative incidence rates for post-transplant infection and biopsy-proven acute rejection (BPAR) were 70.3% (97/138) and 15.2% (21/138), respectively. One- and 5-year patient survival were 82.1 and 60.1%, respectively, whereas the corresponding rates for death-censored graft survival were 95.6 and 93.1%. Infection was the leading cause of death (46.0% of fatal cases). The occurrence of BPAR was associated with lower 1-year patient survival [hazard ratio (HR) = 4.21, 95% confidence interval (CI) 1.64-10.82; P = 0.003]. Diabetic nephropathy was the only factor predicting 5-year death-censored graft survival (HR = 4.82, 95% CI 1.08-21.56; P = 0.040).

Conclusions: ESRD patients ≥75 years can access KT and remain dialysis free for their remaining lifespan by using grafts from extremely aged deceased donors, yielding encouraging results in terms of recipient and graft survival.
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http://dx.doi.org/10.1093/ndt/gfz293DOI Listing
April 2020

Complement Activation and Thrombotic Microangiopathies.

Clin J Am Soc Nephrol 2019 12 6;14(12):1719-1732. Epub 2019 Nov 6.

Department of Nephrology, Hospital Universitari Arnau de Vilanova, Lleida, Spain.

Background And Objectives: Atypical hemolytic uremic syndrome is a form of thrombotic microangiopathy caused by dysregulation of the alternative complement pathway. There is evidence showing complement activation in other thrombotic microangiopathies. The aim of this study was to evaluate complement activation in different thrombotic microangiopathies and to monitor treatment response.

Design, Setting, Participants, & Measurements: Complement activation was assessed by exposing endothelial cells to sera or activated-patient plasma-citrated plasma mixed with a control sera pool (1:1)-to analyze C5b-9 deposits by immunofluorescence. Patients with atypical hemolytic uremic syndrome (=34) at different stages of the disease, HELLP syndrome (a pregnancy complication characterized by hemolysis, elevated liver enzymes, and low platelet count) or severe preeclampsia (=10), and malignant hypertension (=5) were included.

Results: Acute phase atypical hemolytic uremic syndrome-activated plasma induced an increased C5b-9 deposition on endothelial cells. Standard and lower doses of eculizumab inhibited C5b-9 deposition in all patients with atypical hemolytic uremic syndrome, except in two who showed partial remission and clinical relapse. Significant fibrin formation was observed together with C5b-9 deposition. Results obtained using activated-plasma samples were more marked and reproducible than those obtained with sera. C5b-9 deposition was also increased with samples from patients with HELLP (all cases) and preeclampsia (90%) at disease onset. This increase was sustained in those with HELLP after 40 days, and levels normalized in patients with both HELLP and preeclampsia after 6-9 months. Complement activation in those with malignant hypertension was at control levels.

Conclusions: The proposed methodology identifies complement overactivation in patients with atypical hemolytic uremic syndrome at acute phase and in other diseases such as HELLP syndrome and preeclampsia. Moreover, it is sensitive enough to individually assess the efficiency of the C5 inhibition treatment.
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http://dx.doi.org/10.2215/CJN.05830519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895490PMC
December 2019

The estimation of GFR and the adjustment for BSA in overweight and obesity: a dreadful combination of two errors.

Int J Obes (Lond) 2020 05 22;44(5):1129-1140. Epub 2019 Oct 22.

Internal Medicine Department, Universidad de La Laguna, Instituto de Tecnologías Biomédicas, Tenerife, Spain.

Background: Obesity is an established risk factor for renal disease and for disease progression. Therefore, an accurate determination of renal function is necessary in this population. Renal function is currently evaluated by estimated glomerular filtration rate (GFR) by formulas, a procedure with a proven high variability. Moreover, the adjustment of GFR by body surface area (BSA) confounds the evaluation of renal function. However, the error of using estimated GFR adjusted by BSA has not been properly evaluated in overweight and obese subjects.

Methods: We evaluated the error of 56 creatinine- and/or cystatin-C-based equations and the adjustment of GFR by BSA in 944 subjects with overweight or obesity with or without chronic kidney disease (CKD). The error between estimated (eGFR) and measured GFR (mGFR) was evaluated with statistics of agreement: the total deviation index (TDI), the concordance correlation coefficient (CCC) and the coverage probability (cp).

Results: The error of eGFR by any equation was common and wide: TDI averaged 55%, meaning that 90% of estimations ranged from -55 to 55% of mGFR. CCC and cp averaged 0.8 and 26, respectively. This error was comparable between creatinine and cystatin-C-based formulas both in obese or overweight subjects. The error of eGFR was larger in formulas that included weight or height. The adjustment of mGFR or eGFR led to a relevant underestimation of renal function, reaching at least 10 mL/min in 25% of the cases.

Conclusions: In overweight and obese patients, formulas failed in reflecting real renal function. In addition, the adjustment for BSA led to a relevant underestimation of GFR. Both errors may have important clinical consequences. Thus, whenever possible, the use of a gold standard method to measure renal function is recommended. Moreover, the sense of indexing for BSA should be re-considered and probably abandoned.
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http://dx.doi.org/10.1038/s41366-019-0476-zDOI Listing
May 2020

Renal damage secondary to check-point inhibitors.

Nefrologia (Engl Ed) 2020 Mar - Apr;40(2):206-208. Epub 2019 Oct 12.

Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España.

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http://dx.doi.org/10.1016/j.nefro.2019.05.004DOI Listing
March 2021

Pharmacological lipid-modification therapies for prevention of ischaemic heart disease: current and future options.

Lancet 2019 Aug;394(10199):697-708

Monash Cardiovascular Research Centre, Monash University, Melbourne, VIC, Australia.

Atherosclerosis and its clinical manifestation as ischaemic heart disease remains a considerable health burden. Given that many factors contribute to ischaemic heart disease, a multifactorial approach to prevention is recommended, starting with lifestyle advice, smoking cessation, and control of known cardiovascular risk factors, such as blood pressure and lipids. Within the lipid profile, the principal target is lowering LDL cholesterol, firstly with lifestyle interventions and subsequently with pharmacological therapy. Statins are the recommended first-line pharmacological treatment. Some individuals might require further lowering of LDL cholesterol or be unable to tolerate statins. Additional therapies targeting different pathways in cholesterol metabolism are now available, ranging from small molecules taken orally, to injectable therapies. Examples include ezetimibe, which targets Niemann-Pick C1-like protein, and monoclonal antibodies that target PCSK9. Phase 3 trials have also been completed for bempedoic acid (targeting ATP-citrate lyase) and inclisiran (an interference RNA-based therapeutic targeting hepatic PCSK9 synthesis). In addition to LDL cholesterol, mendelian randomisation studies support a causal role for lipoprotein(a) and triglycerides in ischaemic heart disease. In this Series paper, we appraise currently available and emerging therapies for lowering LDL cholesterol, lipoprotein(a), and triglycerides for prevention of ischaemic heart disease.
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http://dx.doi.org/10.1016/S0140-6736(19)31950-6DOI Listing
August 2019

Severe and malignant hypertension are common in primary atypical hemolytic uremic syndrome.

Kidney Int 2019 10 31;96(4):995-1004. Epub 2019 May 31.

Department of Nephrology, University Hospital Reina Sofía, Córdoba, Spain.

Malignant hypertension is listed among the causes of secondary thrombotic microangiopathy, but pathogenic mutations in complement genes have been reported in patients with hypertension-induced thrombotic microangiopathy. Here we investigated the frequency and severity of hypertension in 55 patients with primary atypical hemolytic uremic syndrome (aHUS). A genetic analysis was performed in all patients, and funduscopic examination was performed in all the patients with Grades 2 and 3 hypertension. A cohort of 110 patients with malignant hypertension caused by diseases other than aHUS served as control. Thirty-six patients with aHUS presented Grade 2 or Grade 3 hypertension and funduscopic examination showed malignant hypertension in 19. Genetic abnormalities in complement were found in 19 patients (37% among patients with malignant hypertension). Plasmapheresis was performed in 46 patients and 26 received eculizumab. Renal and hematological responses were significantly lower after plasmapheresis (24%) than after eculizumab (81%). Renal survival was significantly higher in patients treated with eculizumab (85% at one, three and five years) compared to patients who did not receive this treatment (54%, 46% and 41%), respectively. Response to eculizumab was independent of hypertension severity and the presence of complement genetic abnormalities. Among patients with malignant hypertension caused by other diseases the prevalence of thrombotic microangiopathy was very low (5%). Thus, severe and malignant hypertension are common among patients with aHUS and eculizumab treatment leads to a higher renal survival when compared to plasmapheresis. However, thrombotic microangiopathy is uncommon among patients presenting with malignant hypertension caused by diseases other than aHUS.
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http://dx.doi.org/10.1016/j.kint.2019.05.014DOI Listing
October 2019

Relapsing polychondritis and focal segmental glomerulosclerosis: Coincidence or causality.

Nefrologia (Engl Ed) 2020 May - Jun;40(3):360-362. Epub 2019 Jul 24.

Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, Madrid. Electronic address:

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http://dx.doi.org/10.1016/j.nefro.2019.04.003DOI Listing
June 2021

New tools for recombinant protein production in Escherichia coli: A 5-year update.

Protein Sci 2019 08 1;28(8):1412-1422. Epub 2019 Jul 1.

Instituto de Biología Molecular y Celular de Rosario (IBR), CONICET. Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina.

The production of proteins in sufficient amounts is key for their study or use as biotherapeutic agents. Escherichia coli is the host of choice for recombinant protein production given its fast growth, easy manipulation, and cost-effectiveness. As such, its protein production capabilities are continuously being improved. Also, the associated tools (such as plasmids and cultivation conditions) are subject of ongoing research to optimize product yield. In this work, we review the latest advances in recombinant protein production in E. coli.
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http://dx.doi.org/10.1002/pro.3668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635841PMC
August 2019

Predicting the critical quality attributes of ibuprofen tablets via modelling of process parameters for roller compaction and tabletting.

Int J Pharm 2019 Jun 7;565:209-218. Epub 2019 May 7.

Department of Pharmaceutics and Food Technology, Complutense University of Madrid, Ramón y Cajal Square, 28040 Madrid, Spain. Electronic address:

Roller compaction is a low cost granulation process which application is sometimes limited by the granular loss of compactability and reduced drug dissolution rate. Hence, the design of a robust manufacturing process is key in order to ensure quality of tablets. In this study, for ibuprofen tablets with high drug loading (<7% excipients), the correlations between two critical process parameters (CPPs), namely roller force during granulation and compaction pressure during tabletting, and several critical quality attributes (CQAs) were investigated using a design of experiment (DoE) approach. Multivariate analysis (MVA) was utilized to identify the best regression model to predict CQAs such as disintegration, dissolution, weight uniformity, hardness, porosity and tensile strength for 200 and 600 mg ibuprofen tablets. The tabletting compaction pressure had a greater impact on the aforementioned CQAs than compactor roller force. The Principal Component Analysis (PCA) correlation loading plot showed that compaction pressure was directly related to disintegration time, tensile strength and hardness, and inversely related to both the percentage of drug dissolved and porosity. The inverse correlations were observed for the roller force applied during dry granulation. Amongst all the regression models constructed, multiple linear regression (MLR) showed the best correlation between CPPs and CQAs.
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http://dx.doi.org/10.1016/j.ijpharm.2019.05.011DOI Listing
June 2019

SGLT-2 inhibitors and GLP-1 receptor agonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease. A consensus statement by the EURECA-m and the DIABESITY working groups of the ERA-EDTA.

Nephrol Dial Transplant 2019 02;34(2):208-230

Department of Nephrology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.

Chronic kidney disease (CKD) in patients with diabetes mellitus (DM) is a major problem of public health. Currently, many of these patients experience progression of cardiovascular and renal disease, even when receiving optimal treatment. In previous years, several new drug classes for the treatment of type 2 DM have emerged, including inhibitors of renal sodium-glucose co-transporter-2 (SGLT-2) and glucagon-like peptide-1 (GLP-1) receptor agonists. Apart from reducing glycaemia, these classes were reported to have other beneficial effects for the cardiovascular and renal systems, such as weight loss and blood pressure reduction. Most importantly, in contrast to all previous studies with anti-diabetic agents, a series of recent randomized, placebo-controlled outcome trials showed that SGLT-2 inhibitors and GLP-1 receptor agonists are able to reduce cardiovascular events and all-cause mortality, as well as progression of renal disease, in patients with type 2 DM. This document presents in detail the available evidence on the cardioprotective and nephroprotective effects of SGLT-2 inhibitors and GLP-1 analogues, analyses the potential mechanisms involved in these actions and discusses their place in the treatment of patients with CKD and DM.
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http://dx.doi.org/10.1093/ndt/gfy407DOI Listing
February 2019

A novel method for removing contaminant Hsp70 molecular chaperones from recombinant proteins.

Protein Sci 2019 04 20;28(4):800-807. Epub 2019 Feb 20.

Instituto de Biología Molecular y Celular de Rosario (IBR), CONICET, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, 2000, Argentina.

The production of recombinant proteins in bacteria has increased significantly in recent years, becoming a common tool for both research and the industrial production of proteins. One of the requirements of this methodology is to obtain the desired protein without contaminants. However, this goal cannot always be readily achieved. Multiple strategies have been developed to improve the quality of the desired protein product. Nevertheless, contamination with molecular chaperones is one of the recalcitrant problems that still affects the quality of the obtained proteins. The ability of chaperones to bind to unfolded proteins or to regions where the polypeptide chain is exposed make the removal of the contamination during purification challenging to achieve. This work aimed to develop a strategy to remove contaminating DnaK, one of the homologous Hsp70 molecular chaperones found in Escherichia coli, from purified recombinant proteins. For this purpose, we developed a methodology that captures the DnaK from the contaminating proteins by co-incubation with a GST-cleanser protein that has free functional binding sites for the chaperone. The cleanser protein can then be easily removed together with the captured DnaK. Here, we demonstrated the utility of our system by decontaminating a Histidine-tagged recombinant protein in a batch process. The addition of the GST-cleanser protein in the presence of ATP-Mg eliminates the DnaK contamination substantially. Thus, our decontaminant strategy results versatile and straightforward and can be applied to proteins obtained with different expression and purifications systems as well as to small samples or large volume preparations.
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http://dx.doi.org/10.1002/pro.3574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423713PMC
April 2019

Collapsing glomerulopathy: update.

Med Clin (Barc) 2019 05 13;152(9):361-367. Epub 2018 Dec 13.

Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España.

Collapsing glomerulopathy (CG) is a rare entity as a glomerular disease. Although it has been considered as a variant of focal segmental glomerulosclerosis, the fact is that the podocyte lesions show different features with respect to the typical focal segmental glomerulosclerosis, an aspect that has been attributed to a type of podocytopathy. In CG, the podocyte lesion is typically characterised by a dysregulated podocyte phenotype, reflected by the loss of expression of mature podocyte markers. CG can be a primary disease or it can be associated with several causal factors that develop a common histopathological entity. The clinical expressiveness of CG is often characterised by the presence of a nephrotic syndrome and a rapid deterioration of the renal function than other variants of the focal segmental glomerulosclerosis. The prognosis of these patients is a rapid progression towards end-stage renal disease with poor response to treatment.
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http://dx.doi.org/10.1016/j.medcli.2018.10.021DOI Listing
May 2019

ESC Council on hypertension position document on the management of hypertensive emergencies.

Eur Heart J Cardiovasc Pharmacother 2019 01;5(1):37-46

University College London (UCL) and UCL Hospitals, London, UK.

Hypertensive emergencies are those situations where very high blood pressure (BP) values are associated with acute organ damage, and therefore, require immediate, but careful, BP reduction. The type of acute organ damage is the principal determinant of: (i) the drug of choice, (ii) the target BP, and (iii) the timeframe in which BP should be lowered. Key target organs are the heart, retina, brain, kidneys, and large arteries. Patients who lack acute hypertension-mediated end organ damage do not have a hypertensive emergency and can usually be treated with oral BP-lowering agents and usually discharged after a brief period of observation.
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http://dx.doi.org/10.1093/ehjcvp/pvy032DOI Listing
January 2019

CD19 B-Cells, a New Biomarker of Mortality in Hemodialysis Patients.

Front Immunol 2018 15;9:1221. Epub 2018 Jun 15.

Department of Nephrology, Hospital Universitario 12 de Octubre and Research Institute i+12, Madrid, Spain.

Background And Objectives: Mortality of patients on hemodialysis (HD) remains very high despite recent improvements in HD techniques. Cardiovascular (CV) complications and infections are the main causes of death. Some studies suggest that disturbances in the immune system could play a role in this disproportionate mortality, through the links of immunity with inflammation and propensity to infections. However, few studies have addressed the role of lymphocyte populations and the global and CV mortality of HD patients.

Aim: To analyze the relationship of peripheral blood lymphocyte populations (PBLP) and all-cause and CV mortality of HD patients.

Design Setting Participants And Measurements: We design a prospective observational single center study in a cohort of HD prevalent patients. PBLP were analyzed at baseline and after 1 year and patients were followed for a 5-year period. Main outcomes were all-cause and CV mortality.

Results: One hundred and four patients (51% male, mean age 64.8 ± 15 years) were included. Follow-up was 18 (7-47) months. Fifty-five patients (52.8%) died, main causes of death being CVD (40%) and infections (29.1%). Low total lymphocyte counts were found in 47 patients (45.2%), and the most frequency lymphopenias were CD19 B-cell (57.7%), CD3 (40.4%), and CD4 (36.5%). After 1 year, all determinations were lower except CD56CD16CD3 natural killer. Patient survival was significantly lower in patients with a CD19 B-cell count < 100 cells/μL at baseline as compared to patients with CD19 B-cell ≥ 100 cells/μL counts at the end of follow-up (16.5 vs 54%,  = 0.003). By multivariable analysis, age, history of CV disease, Charlson index, a KT/V < 1.2, and a CD19 B-cell count < 100 cells/μL at baseline and after 1-year were factors associated with of all-cause mortality. A CD19 B-cell count < 100 cells/μL at baseline was associated with CV mortality.

Conclusion: CD19 B-cell lymphopenia is very common among HD patients, and it could be an independent predictor of all-cause and CV mortality. More studies are needed to confirm these findings.
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http://dx.doi.org/10.3389/fimmu.2018.01221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013647PMC
August 2019

Kidney transplant from uncontrolled donation after circulatory death donors maintained by nECMO has long-term outcomes comparable to standard criteria donation after brain death.

Am J Transplant 2019 02 16;19(2):434-447. Epub 2018 Aug 16.

Department of Nephrology, Hospital Universitario "12 de Octubre", Instituto de Investigación Hospital "12 de Octubre" (imas12), Madrid, Spain.

Uncontrolled donation after circulatory death (uDCD) increases organ availability for kidney transplant (KT) with short-term outcomes similar to those obtained from donation after brain death (DBD) donors. However, heterogeneous results in the long term have been reported. We compared 10-year outcomes between 237 KT recipients from uDCD donors maintained by normothermic extracorporeal membrane oxygenation (nECMO) and 237 patients undergoing KT from standard criteria DBD donors during the same period at our institution. We further analyzed risk factors for death-censored graft survival in the uDCD group. Delayed graft function (DGF) was more common in the uDCD group (73.4% vs 46.4%; P < .01), although glomerular filtration rates at the end of follow-up were similar in the 2 groups. uDCD and DBD groups had similar rates for 10-year death-censored graft (82.1% vs 80.4%; P = .623) and recipient survival (86.2% vs 87.6%; P = .454). Donor age >50 years was associated with graft loss in the uDCD group (hazard ratio: 1.91; P = .058), whereas the occurrence of DGF showed no significant effect. uDCD KT under nECMO support resulted in similar graft function and long-term outcomes compared with KT from standard criteria DBD donors. Increased donor age could negatively affect graft survival after uDCD donation.
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http://dx.doi.org/10.1111/ajt.14991DOI Listing
February 2019