diagnosis | MY SPECIAL DOCTOR

Renal failure: a widespread and very insidious chronic disease

22 February 20246 January 2024 by psalari

About 10 percent of the world’s adult population suffers from chronic renal failure (CRI), a condition, that is, characterized by reduced kidney function. Even more worrying is the increasing trend of this condition, especially due to the aging of the population: the functional decline of the kidney, in fact, is the physiological consequence of the deterioration of the organ over time, as well as dietary errors (excess salt and/or protein), the toxic effect of substances or drugs, or the impact of infectious or neoplastic events. Its epidemic dimensions, the associated high cardiovascular risk, and the high social and economic costs of dialysis and transplantation make CRI a priority area in prevention and health care planning.

The development of CRI is often asymptomatic, making early diagnosis difficult, for which periodic urine testing and determination of creatinine clearance would be advisable for all. Two simple tests costing only a few euros that would allow early interception of alterations in renal function and early introduction of therapies and, above all, changes in the patient’s lifestyle, starting with proper dietary-nutritional therapy (DNT), to slow the progression of kidney damage.

On the subject of CRI, then, one cannot overlook its psychological impact, which is related to the various factors that lead to a reduction in quality of life. To support all patients, starting with newly diagnosed patients, the “You are not alone” campaign was launched by Dr. Schär with the aim of telling, through the real experience of real patient couples, how even with chronic renal failure one can still maintain an active life and relationships, thanks to conservative therapy that combines nutritional and drug therapy, with the goal of reducing the progression of the disease.

About proper dietary nutrition therapy for patients with CRI, the guidelines of the Italian Society of Nephrology (SIN), indicate:

Reduce protein (no more than 0.7 g per day per kg of ideal body weight) and phosphorus intake.
Limit intake of potassium and sodium (table salt: no more than 2 g of salt per day added to meals).
Take in the right amount of calories each day. For adequate caloric intake, the dietitian might recommend specific supplements and low-protein foods

Chronic kidney disease, genetic analysis promises better therapeutic approaches

18 February 20246 January 2024 by Renato Torlaschi

Chronic kidney disease is often clinically silent, and conventional clinical data alone do not allow differentiation of disease subtypes, but the results of a recent study supports the use of genetic analysis to improve its diagnosis and treatment.

In clinical practice, diagnosis and monitoring of chronic kidney disease are based on clinical parameters and only rarely involve renal biopsy. However, in many cases the disease occurs in a “silent” form and is difficult to discriminate using clinical data alone.

Thus, in many individuals, the precise cause of progressive damage to the kidneys remains unknown and the diagnosis is made late, reducing the opportunity for early therapeutic intervention; moreover, few of the current treatment approaches are individualized, but according to the study published in the New England Journal of Medicine, genetic testing could help overcome these critical issues.

The authors performed exome sequencing (the set of all portions of the genome that “code” for proteins) of 3,315 patients with chronic kidney disease due to different causes and reported a 9.3 percent rate of diagnostic genetic variants, comprising 66 monogenic sites already known to be associated with kidney disorders.

“This study,” reads an editorial in Nature Reviews Nephrology. highlights the potential of genetic testing for adults with chronic kidney disease and end-stage renal disease (Esrd). Discovering the underlying genetics of different forms of kidney disease will serve to improve diagnostic accuracy and develop new approaches according to “precision medicine.” Obtaining a genetic diagnosis for a patient with chronic kidney disease could improve clinical management, including choice of therapy, and enable targeted disease surveillance. Deepening the genetic basis could also reveal new biological mechanisms associated with the disease and lead to defining new therapeutic targets that could benefit a large number of patients.”

Groopman, EE et al. Diagnostic utility of exome sequencing for kidney disease. N Engl J Med. 2019 Jan 10;380(2):142-151.

Alzheimer’s: a new blood test will allow diagnosis many years in advance

15 February 20246 January 2024 by Renato Torlaschi

Among the many critical issues related to Alzheimer’s disease, one concerns the difficulty of diagnosing it in its early stages. Although research has not yet identified a viable therapeutic approach, diagnostically the situation may soon change with the development of a blood test that scientists say can Diagnose up to 94 percent of Alzheimer’s cases 20 years earlier That the symptoms of the disease occur. The researchers in question are from Washington University in St Louis and described the test in the journal Neurology.

The disease is characterized by the increase ofbeta-amyloid plaques in the brain, associated with the accumulation of tau protein tangles, and the test proposed by the U.S. researchers relies precisely on the measurement of beta-amyloid in the blood, which would correlate with that in the brain .

The idea is not new and is a refinement of a technique already presented two years ago; it uses mass spectrometry to measure beta-amyloid-or, more precisely, the ratio between two forms of the protein, called A-β 42 and A-β 40 – and associates its blood concentration with two fundamental risk factors for developing Alzheimer’s: advanced age and the presence of a genetic variant called APOE4.

In this way, the accuracy of the test outperforms that of previous blood tests.

The team recruited 158 adults over the age of 50; all but 10 were described as cognitively normal. Each participant underwent at least one blood test and one PET scan with amyloid tracers , which is the current gold standard, and each test was labeled as amyloid positive or amyloid negative depending on the results produced.

Among experts, there is a growing consensus that in order to manage or treat Alzheimer’s, it is important to intercept it as early as possible, before symptoms begin to appear and the brain is not too damaged.

More than for a cure, which is not currently available, the test could further research. Today, to conduct clinical trials, we check people with scans, which is time-consuming and expensive, whereas with a blood test we could easily examine a large number of subjects, which would help us find treatments more quickly, with a huge potential impact.

Source: Schindler SE, Bollinger JG, et al. High-precision plasma β-amyloid 42/40 predicts current and future brain amyloidosis. Neurology. 2019 Aug 1.

Early diagnosis of breast cancer with liquid biopsy: now you can

15 February 20246 January 2024 by rosanna.feroldi

With 2.1 million new diagnoses worldwide in 2018, breast cancer is the most prevalent neoplasm in the female population globally, but also the one that can be cured best, often definitively and with nondemolishing methods, especially if it is diagnosed early, when it is still very small and not very aggressive. For this reason, regular breast self-examination and, starting at age 45-50, mammography every two years are recommended for all women to detect any minute masses that are not perceptible by touch but are already potentially risky, to be biopsied and then subjected to histological and molecular analysis to characterize them precisely and identify optimal treatment. In the near future, this already highly efficient approach may be enriched with new noninvasive diagnostic system based on the analysis of circulating tumor DNA (ctDNA), i.e., DNA fragments released into the bloodstream from aged and destroyed breast cancer cells. The ctDNA can be obtained by a simple blood draw and analyzed by an extremely precise and rapid sequencing technique called NGS (Next Generation Sequencing), aimed at detecting certain genetic mutations that are distinctively present in the DNA of breast cancer cells. The first data supporting the clinical utility of this method, termed “liquid biopsy,” come from a pilot study, coordinated by researchers at the University of Málaga (Spain), which compared the diagnostic sensitivity of the new ctDNA test before classical tissue biopsy with that of molecular analysis after classical tissue biopsy, using mutations in the PIK3CA and TP53 genes as markers. The evaluation resulted in identifying identical mutations in 8 of the 29 patients considered (27.6%): four in TP53 and five in PIK3CA. In addition, analysis with NGS on ctDNA revealed four additional genetic mutations (three in TP53 and one in PIK3CA), which had not been reported by molecular analysis of breast tissue taken by classical biopsy: which underscores the high sensitivity of “liquid biopsy” at an early stage. One of these patients had mutations in both genes under consideration. The likelihood of testing positive for markers on ctDNA examined with NGS was higher in women who were younger, had larger tumor masserella and higher imaging scores on mammography (indicative of a higher probability of actually having cancer). At the moment, the new test is still being evaluated and not available in clinical practice, but if upcoming studies confirm the performance and diagnostic sensitivity highlighted the “liquid biopsy” may soon join the classical one in the early detection of breast cancer and, perhaps, one day supplant it. In this way, women with positive mammograms, but not necessarily breast cancer, could be prevented from having their suspected breast tissue harvested for diagnostic purposes.

Source: Rodriguez BJ et al. Detection of TP53 and PIK3CA Mutations in Circulating Tumor DNA Using Next-Generation Sequencing in the Screening Process for Early Breast Cancer Diagnosis. J Clin Med 2019;8:1183-1207; doi:10.3390/jcm8081183

In hair a clue to schizophrenia, which will make early diagnoses of the condition possible

12 February 20246 January 2024 by Redazione My Special Doctor

A newly identified biomarker in human hair appears to be related to a type of schizophrenia. In addition to providing new information about the condition , the discovery could help identify it early, before symptoms arise.

It was a group of Japanese researchers, belonging to the RIKEN Center for Brain Science, who detected, in people with schizophrenia, higher than normal levels of Mpst, an enzyme responsible for the production of hydrogen sulfide in the brain. As they hypothesize in the article published in the scientific journal Embo Molecular Medicine, this abnormality is probably the result of a physiological reaction to certain stressors during the course of life, which leads to modification of the DNA.

Schizophrenia is a complex mental disorder, which includes a range of symptoms and behaviors, including hallucinations and psychosis; research suggests that it is not just one disease but as many as eight disorders with genetically distinct causes and the genetic risk factor is believed to be a major contributor to its development.

One method currently used to diagnose schizophrenia is called PPI (Prepulse inhibition) and consists of examining a person’s response to stimuli, manifested by a contraction of skeletal and facial muscles, generally classified as a defensive reaction. People who do not have schizophrenia are less likely to be startled by a loud noise if they have heard it before, while those with the condition react as if it were the first time.

In an animal model study, researchers found that the enzyme Mpst has higher expression when PPI is low; reducing the level of Mpst also helped bring PPI back to values closer to normal.

The Japanese team then examined the postmortem brains of people with schizophrenia and found that Mpst gene expression was higher than those without. In addition, Mpst levels were found to correlate with the severity of symptoms the person had experienced during his or her lifetime.

With this information, the researchers then examined the hair follicles of more than 150 people with schizophrenia and found that, even in these tissues, Mpst expression was much higher in people with the disease. Although Mpst levels are not found to be representative of all existing types of schizophrenia, their measurement could serve in many cases as a biomarker for schizophrenia before symptoms appear.

Source:

Ide M, Ohnishi T et al. Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology. EMBO Mol Med. 2019 Oct 28:e10695.

Pro-arrhythmic drugs: more attention needed

12 February 20246 January 2024 by rosanna.feroldi

Congenital long QT syndrome is a cardiac condition present from birth that essentially consists of a “repolarization defect,” that is, an electrophysiological alteration that results in a lengthening of the time required for the cells of the heart to “recharge” after contraction of the ventricles. The name of the disease comes from the fact that this increased repolarization time can be seen on the electrocardiogram (ECG) tracing as the elongation of a particular segment called precisely “QT.”

By itself, long QT syndrome gives no symptoms and for this reason is poorly diagnosed, except during electrocardiograms required for other reasons, such as preoperative examinations, pre-sports check-ups, apparently unmotivated fainting spells, or other cardiological disorders. Unfortunately, when it occurs it does so in a striking manner, with ventricular fibrillation, cardiac arrest, and sudden death. Triggering these effects can be a very intense physical exertion or emotion or a fright or sudden awakening in the middle of the night. But sometimes fatal arrhythmia can also occur during sleep.

To date, there is no real cure for long QT syndrome, but there are some steps that can help reduce the risk. Among these, a very important one concerns medications that may need to be taken throughout life for a wide variety of reasons: from antibiotics to analgesics, from antacids to antidepressants. Many commonly used drugs, in fact, tend to have a “pro-arrhythmic” action, that is, to promote transient alterations in heart rhythm. In people without long QT syndrome, this generally does not create particular problems (except perhaps some palpitation during therapy). In contrast, if a person with long QT syndrome is taking a pro-arrhythmic drug, the risk of ventricular fibrillation and sudden death are significantly increased.

For this reason, the European Society of Cardiology (ESC) guidelines dedicated to this condition have long and strongly recommended that drugs known to be pro-arrhythmic should not be prescribed to sufferers, opting, where possible, for alternative therapeutic solutions without cardiac effects. In clinical practice, however, these recommendations seem to be largely disregarded. In particular, a recent Danish study indicates that 60% of people with congenital long QT syndrome are prescribed pro-arrhythmic drugs in the years after diagnosis, even for prolonged periods.

The most prescribed “arrhythmia risk” drugs were found to be some antibiotics (such as azithromycin, clarithromycin and erythromycin; 34.1 percent), antacid proton pump inhibitors (esomeprazole, lanzoprazole, omeprazole, pantoprazole; 15.0 percent), antidepressants (citalopram, escitalopram, sertraline; 12.0 percent) and antifungals (fluconazole; 10.2 percent). Those considered in the study were less likely to be prescribed pro-arrhythmic drugs in the year following the diagnosis of congenital long QT syndrome than in the previous year, but not by much (28.4 percent vs. 23.2 percent), while in more than one-third of the cases (33.5 percent) the at-risk drug therapy was still ongoing after five years. The likelihood of prescribing risky drugs increased slightly with age and multiplied by more than 2.5 times when the same drug had been taken by the patient before (probably, on the basis of erroneous reassurance with respect to possible cardiac side effects).

Although the study did not show a correlation between pro-arrhythmic drug use and increased mortality from ventricular arrhythmia or all causes, the authors and ESC experts urge greater caution on the part of physicians when prescribing potentially high-risk drug therapies in those with congenital long QT syndrome. On the other hand, even patients with a known diagnosis should remember to always inform any specialist physicians they spontaneously visit for consultations in various clinical settings of the cardiac issue they are suffering from, to enable them to identify optimal and safe treatment strategies.

In addition, those suffering from congenital long QT syndrome should always seek advice from their physician and/or pharmacist even when it comes to choosing commonly used over-the-counter drugs that are generally considered safe and manageable: although they indeed are for most people, some of them may be contraindicated in those who are genetically predisposed to cardiac arrhythmias (this is the case, for example, with some antihistamines).

Source:

Weeke PE et al. Long-termproarrhythmic pharmacotherapy among patients with congenital longQT syndrome and risk of arrhythmia and mortality. European Heart Journal 2019;40, 3110-3117. doi:10.1093/eurheartj/ehz228(academic.oup.com/eurheartj/article/40/37/3110/5488147)