Novel strategies in nephrology: what to expect from the future?

Chronic kidney disease (CKD) will become the fifth global case of death by 2040. Its largest impact is on premature mortality but the number of persons with kidney failure requiring renal replacement therapy (RRT) is also increasing dramatically. Current RRT is suboptimal due to the shortage of kidney donors and dismal outcomes associated with both hemodialysis and peritoneal dialysis. Kidney care needs a revolution. In this review, we provide an update on emerging knowledge and technologies that will allow an earlier diagnosis of CKD, addressing the current so-called blind spot (e.g. imaging and biomarkers), and improve renal replacement therapies (wearable artificial kidneys, xenotransplantation, stem cell-derived therapies, bioengineered and bio-artificial kidneys).

Anti-glomerular Basement Membrane Glomerulonephritis: A Study in Real Life.

Introduction: Anti-glomerular basement membrane (anti-GBM) disease is a severe entity with few therapeutic options including plasma exchange and immunosuppressive agents. The aim of this study was to analyze the clinical and pathological features that predict the evolution of end-stage kidney disease (ESKD) and the kidney survival in a cohort of patients with anti-GBM disease with renal involvement in real life. Methods: A retrospective multicentre observational study including 72 patients from 18 nephrology departments with biopsy-proven anti-GBM disease from 1999 to 2019 was performed. Progression to ESKD in relation to clinical and histological variables was evaluated. Results: Creatinine at admission was 8.6 (± 4) mg/dL and 61 patients (84.7%) required dialysis. Sixty-five patients (90.3%) underwent plasma exchange. Twenty-two patients (30.6%) presented pulmonary hemorrhage. Kidney survival was worse in patients with creatinine levels > 4.7 mg/dL (3 vs. 44% p < 0.01) and in patients with > 50% crescents (6 vs. 49%; p = 0.03). Dialysis dependence at admission and creatinine levels > 4.7 mg/dL remained independent significant predictors of ESKD in the multivariable analysis [HR (hazard ratio) 3.13 (1.25-7.84); HR 3 (1.01-9.14); p < 0.01]. The discrimination value for a creatinine level > 4.7 mg/dL and 50.5% crescents had an area under the curve (AUC) of 0.9 (95% CI 0.82-0.97; p < 0.001) and 0.77 (95% CI 0.56-0.98; p = 0.008), respectively. Kidney survival at 1 and 2 years was 13.5 and 11%, respectively. Patient survival at 5 years was 81%. Conclusion: In real life, patients with severe anti-GBM disease (creatinine > 4.7 mg/dL and > 50% crescents) remained with devastating renal prognosis despite plasma exchange and immunosuppressive treatment. New therapies for the treatment of this rare renal disease are urgently needed.

The nephrology crystal ball: the medium-term future.

In January 2019, the ERA-EDTA surveyed nephrologists with questions on kidney care and kidney research designed to explore comprehension of the impact of alterations to organization of renal care and of advancements in technology and knowledge of kidney disease. Eight hundred and twenty-five ERA-EDTA members, ∼13% of the whole ERA-EDTA membership, replied to an ad hoc questionnaire. More than half of the respondents argued that kidney centres will be increasingly owned by large dialysis providers, nearly a quarter of respondents felt that many medical aspects of dialysis will be increasingly overseen by non-nephrologists and a quarter (24%) also believed that the care and long-term follow-up of kidney transplant patients will be increasingly under the responsibility of transplant physicians caring for patients with any organ transplant. Nearly half of the participants (45%, n = 367) use fully electronic clinical files integrating the clinical ward, the outpatient clinics, the haemodialysis and peritoneal dialysis units, as well as transplantation. Smartphone-based self-management programmes for the care of chronic kidney disease (CKD) patients are scarcely applied (only 11% of surveyed nephrologists), but a substantial proportion of respondents (74%) are eager to know more about the potential usefulness of these apps. Finally, European nephrologists expressed a cautious optimism about the application of omic sciences to nephrology and on wearable and implantable kidneys, but their expectations for the medium term are limited.

The current role of renal biopsy in diabetic patients.

Diabetes mellitus (DM) is a worldwide health problem due to its high prevalence, incidence and impact on patient morbidity and mortality. Chronic kidney disease (CKD) is one of the most important complications of DM. The indication of renal biopsy in diabetic patients is a widely debated topic and the final decision is usually individualized. The results of renal biopsy in diabetic patients can be classified into three groups: diabetic nephropathy (DN), non-diabetic renal disease (NDRD) or DN plus NDRD (mixed forms). Renal involvement in DN has been widely studied and different pathological classifications have been proposed. Some groups demonstrated a relationship between the pathological classifications in DN and renal prognosis. However, to our knowledge renal biopsy in diabetic patients with DN has not demonstrated an impact on their survival and renal prognosis. Some recent studies suggest that non-proteinuric diabetic patients may be affected of DN. In addition, kidney biopsy in DN under new treatments may have a fundamental role in assessing renal protection or even regression of diabetic histological lesions. On the other hand, the accurate and early diagnosis and subsequent treatment of diabetic patients with NDRD has been shown to benefit both their renal and patient prognosis. Renal involvement in patients with DM is very heterogeneous. Thus, the role of renal biopsy in diabetic patients is becoming increasingly important.

Priming in word stem completion tasks: comparison with previous results in word fragment completion tasks.

This study investigates priming in an implicit word stem completion (WSC) task by analyzing the effect of linguistic stimuli characteristics on said task. A total of 305 participants performed a WSC task in two phases (study and test). The test phase included 63 unique-solution stems and 63 multiple-solution stems. Analysis revealed that priming (mean = 0.22) was stronger in the case of multiple-solution stems, indicating that they were not a homogeneous group of stimuli. Thus, further analyses were performed only for the data of the unique-solution stems. Correlations between priming and familiarity, frequency of use, and baseline completion were significant. The less familiar words, which were less frequent, had higher priming values. At the same time, the stems with lower baseline completion generated more priming. A regression analysis showed that baseline completion was the only significant predictor of priming, suggesting that the previous processing of the stimuli had a greater impact on the stimuli with low baseline performance. At the same time, baseline completion showed significant positive correlations with familiarity and frequency of use, and a negative correlation with length. When baseline completion was the dependent variable in the regression analysis, the significant variables in the regression were familiarity and length. These results were compared with those obtained in a study using word fragment completion (WFC) by Soler et al. (2009), in which the same words and procedure were employed. Analysis showed that the variables that correlated with priming were the same as in the WSC task, and that completion baseline was the variable that showed the greatest predictive power of priming. This coincidence of results obtained with WFC and WSC tasks highlights the importance of controlling the characteristics of the stimuli used when exploring the nature of priming.

Diabetic nephropathy is an independent factor associated to severe subclinical atheromatous disease.

BACKGROUND: Atheromatous disease (AD) is a risk factor for death in renal patients. Traditional CV risk factors do not predict the presence of AD in this population. The aim of this study is to analyze whether the etiology of the primary renal disease influences in the risk of having silent AD. STUDY DESIGN: Observational cross-sectional study in chronic kidney disease patients without previous cardiovascular events. SETTINGS AND PARTICIPANTS: 2436 CKD subjects without any previous CV event included in the prospective Spanish multicenter NEFRONA study. Patients were classified according to primary renal disease: diabetic nephropathy (n = 347), vascular nephropathy (n = 476), systemic/glomerular disease (n = 447), tubulointerstitial and drug toxicity nephropathy (n = 320), polycystic kidney disease (n = 238), non-filiated nephropathy (n = 406) and other causes (n = 202). PREDICTORS: B-mode and Doppler ultrasonography analysis of the carotid arteries were performed to measure intima media thickness (IMT) and the presence of plaques. Clinical and laboratory parameters related to CV risk were also determined. OUTCOMES: AD was scored according with the ultrasonography findings and the ankle-brachial index into two large groups: absence or incipient AD and severe AD. RESULTS: In multivariate regression analysis, older age (OR 1.09/year [1.088-1.108]), smoking habit (OR 2.10 [1.61-2.74]), male gender (OR 1.33 [1.09-1.64]), grade-5D of CKD (OR 2.19 [1.74-2.74]), and diabetic nephropathy (OR 2.59 [1.93-3.48]) are independent risk factors for severe AD. The prevalence of silent AD was highest for diabetic nephropathy with grade-5D of CKD (82.2%) and lowest with stages 2-3 CKD systemic/glomerular disease (36.6%). LIMITATIONS: Observational study with the potential for confounding. CONCLUSION: In CKD patients without any CV event in the background clinical history, diabetic nephropathy as primary renal disease is the most significant factor associated to severe silent AD. Furthermore, this difference was independent of other conventional risk factors for atherosclerosis and CV events.

Translational value of animal models of kidney failure.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with decreased renal function and increased mortality risk, while the therapeutic armamentarium is unsatisfactory. The availability of adequate animal models may speed up the discovery of biomarkers for disease staging and therapy individualization as well as design and testing of novel therapeutic strategies. Some longstanding animal models have failed to result in therapeutic advances in the clinical setting, such as kidney ischemia-reperfusion injury and diabetic nephropathy models. In this regard, most models for diabetic nephropathy are unsatisfactory in that they do not evolve to renal failure. Satisfactory models for additional nephropathies are needed. These include anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, IgA nephropathy, anti-phospholipase-A2-receptor (PLA2R) membranous nephropathy and Fabry nephropathy. However, recent novel models hold promise for clinical translation. Thus, the AKI to CKD translation has been modeled, in some cases with toxins of interest for human CKD such as aristolochic acid. Genetically modified mice provide models for Alport syndrome evolving to renal failure that have resulted in clinical recommendations, polycystic kidney disease models that have provided clues for the development of tolvaptan, that was recently approved for the human disease in Japan; and animal models also contributed to target C5 with eculizumab in hemolytic uremic syndrome. Some ongoing trials explore novel concepts derived from models, such TWEAK targeting as tissue protection for lupus nephritis. We now review animal models reproducing diverse, genetic and acquired, causes of AKI and CKD evolving to kidney failure and discuss the contribution to clinical translation and prospects for the future.

Short form of Spanish version of the WISC-IV for intelligence assessment in elementary school children.

In educational settings, quick assessments of intelligence are often required to screen children with potential special needs. The WISC-IV is administered individually and takes between one and two hours to complete. Given its widespread use in Spain, a short-form of the Spanish version is likely to be of use to professionals. The goal of this research was to develop a short form of the WISC-IV that can be performed in approximately half an hour. Data obtained in 100 elementary school children were analyzed following the criteria of Resnick and Entin (1971) . The results showed that the most accurate estimation of intelligence was achieved with a combination of the Vocabulary, Block Design, Letter-Number Sequencing, and Coding subtests.

High phosphate diet increases arterial blood pressure via a parathyroid hormone mediated increase of renin.

BACKGROUND: There is growing evidence suggesting that phosphate intake is associated with blood pressure levels. However, data from epidemiological studies show inconsistent results. METHOD AND RESULTS: The present study was designed to evaluate the effect of high circulating phosphorus on arterial blood pressure of healthy rats and to elucidate the potential mechanism that stands behind this effect. Animals fed a high phosphate diet for 4 weeks showed an increase in blood pressure, which returned to normal values after the addition of a phosphate binder (lanthanum carbonate) to the diet. The expression of renin in the kidney was higher, alongside an increase in plasma renin activity, angiotensin II (Ang II) levels and left ventricular hypertrophy. The addition of the phosphate binder blunted the increase in renin and Ang II levels. The levels of parathyroid hormone (PTH) were also higher in animals fed a high phosphate diet, and decreased when the phosphate binder was present in the diet. However, blood P levels remained elevated. A second group of rats underwent parathyroidectomy and received a continuous infusion of physiological levels of PTH through an implanted mini-osmotic pump. Animals fed a high phosphate diet with continuous infusion of PTH did not show an increase in blood pressure, although blood P levels were elevated. Finally, unlike with verapamil, the addition of losartan to the drinking water reverted the increase in blood pressure in rats fed a high phosphate diet. CONCLUSION: The results of this study suggest that a high phosphate diet increases arterial blood pressure through an increase in renin mediated by PTH.

Risk factors for acute kidney injury in severe rhabdomyolysis.

BACKGROUND: Acute kidney injury (AKI) is a life-threatening complication of severe rhabdomyolysis. This study was conducted to assess risk factors for AKI and to develop a risk score for early prediction. METHODS: Retrospective observational cohort study with a 9-year follow-up, carried out in an acute-care teaching-affiliated hospital. A total of 126 patients with severe rhabdomyolysis defined as serum creatine kinase (CK) > 5,000 IU/L fulfilled the inclusion criteria. Univariate and logistic regression analyses were performed to determine risk factors for AKI. Based on the values obtained for each variable, a risk score and prognostic probabilities were estimated to establish the risk for developing AKI. RESULTS: The incidence of AKI was 58%. Death during hospitalization was significantly higher among patients with AKI, compared to patients without AKI (19.2% vs 3.6%, p = 0.008). The following variables were independently associated with AKI: peak CK (odds ratio [OR] 4.9, 95%CI 1.4-16.8), hypoalbuminemia (< 33 mg/dL, [OR 5.1, 95%CI 1.4-17-7]), metabolic acidosis (OR 5.3, 95%CI 1.4-20.3), and decreased prothrombin time (OR 4.4, 95% CI 1.3-14.5). A risk score for AKI was calculated for each patient, with an OR of 1.72 (95%CI 1.45-2.04). The discrimination value of the predictive model was established by means of a ROC curve, with the area under the curve of 0.871 (p<0.001). CONCLUSIONS: The identification of independent factors associated with AKI and a risk score for early prediction of this complication in patients with severe rhabdomyolysis may be useful in clinical practice, particularly to implement early preventive measures.

Angiotensin-converting enzyme 2: enhancing the degradation of angiotensin II as a potential therapy for diabetic nephropathy.

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that degrades angiotensin II with high efficiency leading to the formation of angiotensin-(1-7). ACE2 within the kidneys is largely localized in tubular epithelial cells and in glomerular epithelial cells. Decreased glomerular expression of this enzyme coupled with increased expression of ACE has been described in diabetic kidney disease, both in mice and humans with type 2 diabetes. Moreover, both ACE2 genetic ablation and pharmacological ACE2 inhibition have been shown to increase albuminuria and promote glomerular injury. Studies using recombinant ACE2 have shown the ability of ACE2 to rapidly metabolize Ang II in vivo and form the basis for future studies to examine the potential of ACE2 amplification in the therapy of diabetic kidney disease and cardiovascular disease.

Effectiveness of the cognitive differentiation program of the integrated psychological therapy: group versus individual treatment.

The aim of the current pilot study was to compare two strategies in the application of the cognitive differentiation program of Integrated Psychological Therapy for people with schizophrenia. Twenty-six outpatients were randomly assigned to the application of the program in group sessions (CDg), or to its application in individualized sessions (CDi). The program provides cognitive exercises to promote better performance in cognition, and both groups of participants completed the same number of exercises following the same number of sessions per week. Outcomes were assessed on neuropsychological measures of attention, executive functioning and everyday memory, and everyday functioning. Effect sizes showed the absence of effects in everyday memory and social functioning, higher improvements in the CDi group in attention, and a higher improvement in the CDg condition in executive functioning. The results suggest that the program application model could be individualized, depending on patient-specific cognitive deficits.

Speech recognition and working memory capacity in young-elderly listeners: effects of hearing sensitivity.

Young normal-hearing listeners and young-elderly listeners between 55 and 65 years of age, ranging from near-normal hearing to moderate hearing loss, were compared using different speech recognition tasks (consonant recognition in quiet and in noise, and time-compressed sentences) and working memory tasks (serial word recall and digit ordering). The results showed that the group of young-elderly listeners performed worse on both the speech recognition and working memory tasks than the young listeners. However, when pure-tone audiometric thresholds were used as a covariate variable, the significant differences between groups disappeared. These results support the hypothesis that sensory decline in young-elderly listeners seems to be an important factor in explaining the decrease in speech processing and working memory capacity observed at these ages.

C-reactive protein in lymphocytic pleural effusions: a diagnostic aid in tuberculous pleuritis.

BACKGROUND: C-reactive protein (CRP) pleural fluid levels have been found to be higher in tuberculosis and parapneumonic effusions than in other causes of pleural effusion. OBJECTIVE: The aim of this study was to analyze whether CRP (a simple and inexpensive test) may be a diagnostic aid for tuberculosis in lymphocytic pleural effusions. METHODS: One hundred and forty-four patients with a lymphocytic pleural effusion (more than 50% lymphocytes in the differential white blood cell count) were included. The patients were 93 men (65%) and 51 women (35%), aged 64 +/- 18 years (mean +/- SD). The diagnoses were as follows: tuberculosis, 20; pleural effusion associated with malignancy, 69; transudates, 38; other benign exudates, 17. RESULTS: The CRP pleural fluid level was higher in tuberculous pleuritis (54 +/- 24 mg/l) than in lymphocytic effusions of other origin (21 +/- 16 mg/l; p < 0.001). High CRP levels (>or=50 mg/l) have a high specificity for tuberculosis (95%), and low levels (<30 mg/l) have a high sensitivity (95%) for excluding disease. CONCLUSIONS: CRP pleural fluid level determination is useful in the diagnostic workup of lymphocytic pleural effusions. High CRP levels are very suggestive of tuberculous pleuritis, and low CRP levels make this diagnosis unlikely.

Biochemical and cytologic characteristics of pleural effusions secondary to pulmonary embolism.

STUDY OBJECTIVES: To characterize the biochemical and cytologic constituents of pleural effusions secondary to pulmonary embolism. DESIGN: A descriptive clinical study. SETTING: A community teaching hospital with 750 beds, which acts as a tertiary referral center for several subspecialties. PATIENTS AND INTERVENTIONS: Patients with pleural effusions secondary to pulmonary embolism who underwent diagnostic thoracentesis during the last 7 years were retrospectively studied. Pleural fluid mesothelial hyperplasia was revised and compared with that found in patients with pleural effusions of different origin. RESULTS: Pleural effusions from all 60 patients with pulmonary embolism were exudates, and in 40 patients (67%) contained erythrocyte counts > 10,000/microL. A bloody appearance was not related to the use of anticoagulant therapy before thoracentesis. Polymorphonuclear leukocytes were predominant in 36 patients (60%); in 11 patients (18%), a proportion of eosinophils > 10% was found. Mesothelial hyperplasia was significantly higher in patients with pulmonary embolism than in patients in the control group (p < 0.01). CONCLUSIONS: In the absence of trauma, a bloody or eosinophilic effusion with a marked mesothelial hyperplasia should prompt a workup to rule out embolism. The finding of transudative pleural fluid chemistries in these patients should not be assumed to be secondary to embolism before ruling out other causes of transudative effusion.