Supervised machine learning for the assessment of Chronic Kidney Disease advancement.

BACKGROUND AND OBJECTIVE: Chronic Kidney Disease (CKD) is a condition characterized by a progressive loss of kidney function over time caused by many diseases. The most effective weapons against CKD are early diagnosis and treatment, which in most of the cases can only postpone the onset of complete kidney failure. The CKD grading system is classified based on the estimated Glomerular Filtration Rate (eGFR), and it helps to stratify patients for risk, follow up and management planning. This study aims to effectively predict how soon a CKD patient will need to be dialyzed, thus allowing personalized care and strategic planning of treatment. METHODS: To accurately predict the time frame within which a CKD patient will necessarily have to be dialyzed, a computational model based on a supervised machine learning approach is developed. Many techniques, regarding both information extraction and model training phases, are compared in order to understand which approaches are most effective. The different models compared are trained on the data extracted from the Electronic Medical Records of the Vimercate Hospital. RESULTS: As final model, we propose a set of Extremely Randomized Trees classifiers considering 27 features, including creatinine level, urea, red blood cells count, eGFR trend (which is not even the most important), age and associated comorbidities. In predicting the occurrence of complete renal failure within the next year rather than later, it obtains a test accuracy of 94%, specificity of 91% and sensitivity of 96%. More and shorter time-frame intervals, up to 6 months of granularity, can be specified without relevantly worsening the model performance. CONCLUSIONS: The developed computational model provides nephrologists with a great support in predicting the patient's clinical pathway. The model promising results, coupled with the knowledge and experience of the clinicians, can effectively lead to better personalized care and strategic planning of both patient's needs and hospital resources.

A minimal model of hospital patients' dynamics in COVID-19.

Italy has been one of the countries hardest hit by the coronavirus disease (COVID-19) pandemic. While the overall policy in response to the epidemic was to a large degree centralised, the regional basis of the healthcare system represented an important factor affecting the natural dynamics of the disease induced geographic specificities. Here, we characterise the region-specific modulation of COVID dynamics with a reduced exponential model leveraging available data on sub-intensive and intensive care unit patients made available by all regional councils from the very onset of the disease. This simple model provides a rather good fit of regional patient dynamics, particularly for regions where the affected population was large, highlighting important region-specific patterns of epidemic dynamics.

Tuberous sclerosis complex: new insights into clinical and therapeutic approach.

Tuberous sclerosis complex (TSC) is a complex disease with many different clinical manifestations. Despite the common opinion that TSC is a rare condition, with a mean incidence of 1/6000 live births and a prevalence of 1/20,000, it is increasingly evident that in reality this is not true. Its clinical sequelae span a range of multiple organ systems, in particular the central nervous system, kidneys, skin and lungs. The management of TSC patients is heavily burdensome in terms of time and healthcare costs both for the families and for the healthcare system. Management options include conservative approaches, surgery, pharmacotherapy with mammalian target of rapamycin inhibitors and recently proposed options such as therapy with anti-EGFR antibody and ultrasound-guided percutaneous microwaves. So far, however, no systematically accepted strategy has been found that is both clinically and economically efficient. Thus, decisions are tailored to patients' characteristics, resource availability and clinical and technical expertise of each single center. This paper reviews the pathophysiology and the clinical (diagnostic-therapeutic) management of TSC.

Tegaderm™ CHG dressing significantly improves catheter-related infection rate in hemodialysis patients.

INTRODUCTION: Catheter-related infections are an important clinical problem in maintenance hemodialysis patients. Catheter-related bloodstream infections have a negative effect on survival, hospitalization and cost of care. Tegaderm™ chlorhexidine gluconate (CHG) dressing may be useful to reduce catheter-related infection rates. METHODS: We performed a study to assess the efficacy of Tegaderm™ CHG dressing for reducing catheter-related infections. We designed a prospective randomized cross-over study with a scheme of two treatments, Tegaderm™ CHG dressing versus standard dressing, and two periods of six months. Catheter-related infection rate was the primary outcome. We enrolled 59 prevalent hemodialysis patients. RESULTS: Catheter-related infection rate per 1000 catheter days was reduced from 1.21 in patients using standard dressing to 0.28 in patients with Tegaderm™ CHG dressing (p = 0.02). Catheter-related bloodstream infection rate per 1000 catheter days was equal to 0.09 in patients with Tegaderm™ CHG dressing versus 0.65 in patients with standard dressing (p = 0.05). Annual total healthcare costs for catheter-related bloodstream infections were estimated equal to EUR62,459 versus EUR300,399, respectively, for patients with Tegaderm™ CHG versus standard dressing. CONCLUSIONS: This is the first prospective study to show that Tegaderm™ CHG dressing significantly reduces catheter-related infection rates in hemodialysis patients.

[Internal hemodiafiltration]. / L'emodiafiltrazione interna.

Internal hemodiafiltration is a high-flux bicarbonate dialysis modality with a special filter having geometric characteristics to increase the internal filtration. Internal hemodiafiltration improves convective transport by direct filtration and back-filtration without the use of a reinfusion fluid as in on-line hemodiafiltration. The back-filtration or passive reinfusion is predictable and can be calculated with a user-friendly software program. Internal hemodiafiltration not only has good capacity for intradialytic removal of low and middle molecules (similar to on-line hemodiafiltration), but can also reduce or even stop the steady increase in uremic toxins seen in standard bicarbonate dialysis. This paper describes the most important technical characteristics and clinical results of internal hemodiafiltration.

Internal hemodiafiltration versus low-flux bicarbonate dialysis: Results from a long-term prospective study.

INTRODUCTION: About ten years ago it was discovered that changes in filter design which increase passive filtration improved dialysis efficiency. Later, these modified membranes showed similar intra-dialytic efficiency when used in on-line hemodiafiltration or in bicarbonate dialysis, called internal hemodiafiltration. AIM AND METHODS: On the basis of these previous results, we studied the long-term effects of internal hemodiafiltration, in comparison with low-flux bicarbonate dialysis. The pre-dialysis beta2-microglobulin level was chosen as the primary outcome variable. A prospective multicenter study with a cross-over scheme, 2 treatments and 3 periods, was designed. Twenty-four patients, followed in two dialysis centers, were enrolled. Many other parameters were measured every month at the first dialysis session of the week. The intra-dialytic removal of urea, beta2-microglobulin and homocysteine was also calculated. RESULTS: The removal of uremic toxins was significantly higher in internal hemodiafiltration than in low-flux bicarbonate dialysis. The pre-dialysis value of urea, phosphorus, beta2-microglobulin and homocysteine was lower during internal hemodiafiltration as compared with low-flux bicarbonate dialysis. The mean pre-dialysis value of hemoglobin was significantly higher during internal hemodiafiltration than low-flux bicarbonate dialysis, with a trend towards a significantly lower consumption of erythropoiesis stimulating agents during internal hemodiafiltration as compared with low-flux bicarbonate dialysis. CONCLUSIONS: Long-term treatment with internal hemodiafiltration improves the removal of small molecules and stops the continuous increase of middle molecules as seen in low-flux bicarbonate dialysis. Internal hemodiafiltration may substitute low-flux bicarbonate dialysis, but we need new prospective studies about long-term hard end-points.

Protective effect of vitamin B therapy on bone and cardiovascular disease.

Vitamin B deficiency causes many diseases, which may be improved by vitamin B supplementation. Homocysteine, a sulphur amino acid, is frequently increased in patients with vitamin B deficiency, chronic renal failure and metabolism disorders. Bone and cardiovascular disease is often detected in patients with renal disease or homocystinuria. This review shows the most important discoveries, including recent patents, about vitamin B therapy not only in hyperhomocysteinemic patients but also in the general population. Vitamin B supplementation may be useful to reduce bone and cardiovascular events, but until now prospective intervention studies have given uncertain results. We need well-done randomized controlled trials to verify the effects of vitamin B treatment on these hard end-points.

Some old drugs improve late primary patency rate of native arteriovenous fistulas in hemodialysis patients.

Vascular access failure causes 20% of all hospitalizations of dialysis patients. Native arteriovenous fistulas, the best type of dialysis vascular access, have a 1-year primary patency rate that is extremely variable, ranging 40-80%. Neointimal hyperplasia is the most important cause of arteriovenous fistula late primary dysfunction. In recent years the arteriovenous fistula late primary patency rate has not improved because of the increase of old uremic patients with a high number of comorbidities and the lack of new therapeutic interventions. Therefore, we performed a long-term case-control study to analyze which factors or drugs may affect native arteriovenous fistula late primary patency rate in 60 incident hemodialysis patients. The arteriovenous fistula late primary patency rate was 75.1% after 12 months, 58.5% after 24 months, and 50% after 987 days. Homocysteine levels during follow-up had a significant direct association with vascular access failure (event vs. event-free 28.5+/-1.9 vs. 22.3+/-1.2 micromol/L, p<0.01). Folate values had a trend toward an inverse relationship with arteriovenous fistula failure (event vs. event-free 11.5+/-1.2 vs. 14.6 vs. 1.1 ng/mL, p=0.06). Patients treated with folic acid and/or statin had an arteriovenous fistula late primary patency rate significantly higher than patients without folic acid and statin therapy, respectively, 81.7% vs. 66% after 1 year and 71.5% vs. 39.1% after 2 years (p=0.02). Many other factors were not associated with vascular access failure. Statin and homocysteine-lowering folic acid therapy is associated with prolonged arteriovenous fistula survival. It is important to perform randomized trials to verify our observation.

Homocysteine-lowering vitamin B treatment decreases cardiovascular events in hemodialysis patients.

In Italy, the mortality rate of hemodialysis patients is approximately 14% per year. Cardiovascular disease is the most important cause of morbidity and mortality in hemodialysis patients. High plasma homocysteine levels are commonly detected in these patients, but hyperhomocysteinemia and cardiovascular mortality are not always strictly correlated. The Dialysis Outcomes and Practice Pattern Study (DOPPS) showed a direct association between regular use of water-soluble vitamins and lower cardiovascular mortality. We recently performed a long-term prospective trial to study the effects of folic acid therapy on cardiovascular events in hemodialysis patients. We observed not only a lower rate of combined cardiovascular events in patients treated with folate, but also a direct correlation between hyperhomocysteinemia and cardiovascular morbidity. On the contrary, the distribution of deaths was similar in treated and untreated patients, because, almost certainly, sudden death is not always due to atherosclerotic events, and non-cardiovascular deaths, such as cachexia, septicemia and malignancy were characterized by low levels of homocysteine, which may be, in addition, a nutritional index similar to albumin and protein catabolic rate. As it is known that diabetic hemodialysis patients have a higher mortality rate, but lower homocysteine levels as compared to non-diabetic patients, we performed an equal allocation of diabetic patients in treated and untreated groups. We observed a similar homocysteine reduction rate in diabetic patients as compared to non-diabetic patients, and a trend towards a lower rate of composite cardiovascular events in treated diabetic patients as compared to untreated diabetic patients. To summarize, the strong relationship between homocysteine and nutritional, inflammatory markers may hide its association with cardiovascular disease. Homocysteine-lowering vitamin B therapy may lower cardiovascular events in dialysis patients. It is mandatory to perform large prospective trials to confirm our results.

Effectiveness, safety and cost-effectiveness of homeopathy in general practice - summarized health technology assessment.

INTRODUCTION: The Health Technology Assessment report on effectiveness, cost-effectiveness and appropriateness of homeopathy was compiled on behalf of the Swiss Federal Office for Public Health (BAG) within the framework of the 'Program of Evaluation of Complementary Medicine (PEK)'. MATERIALS AND METHODS: Databases accessible by Internet were systematically searched, complemented by manual search and contacts with experts, and evaluated according to internal and external validity criteria. RESULTS: Many high-quality investigations of pre-clinical basic research proved homeopathic high-potencies inducing regulative and specific changes in cells or living organisms. 20 of 22 systematic reviews detected at least a trend in favor of homeopathy. In our estimation 5 studies yielded results indicating clear evidence for homeopathic therapy. The evaluation of 29 studies in the domain 'Upper Respiratory Tract Infections/Allergic Reactions' showed a positive overall result in favor of homeopathy. 6 out of 7 controlled studies were at least equivalent to conventional medical interventions. 8 out of 16 placebo-controlled studies were significant in favor of homeopathy. Swiss regulations grant a high degree of safety due to product and training requirements for homeopathic physicians. Applied properly, classical homeopathy has few side-effects and the use of high-potencies is free of toxic effects. A general health-economic statement about homeopathy cannot be made from the available data. CONCLUSION: Taking internal and external validity criteria into account, effectiveness of homeopathy can be supported by clinical evidence and professional and adequate application be regarded as safe. Reliable statements of cost-effectiveness are not available at the moment. External and model validity will have to be taken more strongly into consideration in future studies.

Homocysteine-lowering vitamin B treatment decreases cardiovascular events in hemodialysis patients.

BACKGROUND: Dialysis patients have higher cardiovascular events rate than patients with normal renal function. Hyperhomocysteinemia, a risk factor for cardiovascular disease, is frequently detected in dialysis patients. Vitamin B supplementation lowers hyperhomocysteinemia, but it is unknown whether it reduces cardiovascular events rate. We planned a long-term study to analyze the effects of homocysteine-lowering vitamin B therapy on cardiovascular disease in hemodialysis patients. METHODS: We performed a single center open prospective trial. Patients, just on folate therapy at enrolment, were left out from randomization and maintained folate therapy according to study's protocol (group A). Patients, untreated with folic acid at recruitment, were randomly assigned to other 2 groups: patients submitted to folate supplementation according to study's protocol (group B), and untreated ones (group C). We instructed patients to take 5 mg oral daily folic acid or 5 mg every other day whether serum folate levels were up the normal high limit. We measured homocysteine, folate and vitamin B12 plasma levels at baseline and every 4 months. We chose the appearance of fatal and nonfatal cardiovascular events as end-points. RESULTS: We analyzed data of 114 patients for a median follow-up time of 871 days. Stepwise regression analysis demonstrated that baseline homocysteine levels were related to folate (coefficient: -1.02; F: 64.5), creatinine (coefficient: 0.98; F: 11.3), and C reactive protein (coefficient: -0.64; F: 4.3). Patients ended the study for the following reasons: cardiovascular morbidity (n = 44), death (n = 25), renal transplant (n = 9), moved away (n = 4). Cardiovascular events occurred in 58 of 114 patients (51%), in 26 of 63 (41%) treated patients (both group A and group B) and in 32 of 51 (63%; chi2 = 6.0; p = 0.05) untreated patients (group C). Kaplan-Meier survival analysis showed that cardiovascular events were less frequent in treated patients with low homocysteine levels (chi2 24.1; p < 0.0001). Cox regression analysis showed that cardiovascular events were explained by homocysteine, dialysis vintage, past cardiovascular accidents, and age. We noticed not only lower homocysteine levels, but also higher protein catabolic rate values in events-free patients as compared with patients with nonfatal cardiovascular events. After having divided patients into 4 subgroups according to high and low, split at median, Hcy and protein catabolic rate values, we observed in Kaplan-Meier survival curves for cardiovascular events by these subgroups that patients with low Hcy and high protein catabolic rate values showed a significant lower hazard rate than patients with high Hcy and low protein catabolic rate levels (chi2 = 21.7; p < 0.0001). CONCLUSIONS: This trial shows for the first time that homocysteine-lowering folate therapy decreases cardiovascular events in dialysis patients. It is necessary to perform large prospective studies to confirm our results.

Multifocal bilateral renal cell carcinoma and retinal angiomas in a patient with de novo von Hippel-Lindau disease: identification of a new germline mutation.

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder characterized by multifocal and bilateral renal cell carcinoma and cysts, retinal angiomas, hemangioblastoma of the central nervous system, pheochromocytoma, epididymis cystoadenoma, pancreatic cysts and/or islet cell tumors. However, phenotypic manifestations and clinical outcome are wide ranging including inter and intra-familial patterns. The VHL gene has been localized on chromosome 3 p 25-26 and more than 250 germline mutations have been described. The sensitivity of analytic techniques of VHL gene is close to 100%. It is well known that about 25% of VHL patients present de novo mutations, and first cases function as possible founders of new VHL kindreds. Herein, we report the clinical case of a 45-year-old Caucasian female patient affected by bilateral polycystic kidney disease with two renal carcinomas in both kidneys without lynphoadenopathies. She underwent ophthalmologic surgery at 19 years old because of retinal detachment due to bilateral retinal angiomatosis. Direct gene sequencing showed a deletion-insertion in exon 3, starting from nucleotide 499 of the coding sequence (c.499-504 delinstT) in a heterozygous status; it causes a frame-shift and creates a premature stop at codon 170. The genetic study of the unaffected parents and of the unaffected brother confirmed the diagnosis of de novo VHL disease with the dentification of a new germline mutation, never reported in the literature. The patient showed normal kidney function and she did not show other organ lesions or clinical manifestations of VHL disease. She was successfully submitted to renal parenchymal sparing-surgery. In conclusion, it is important to test for germline mutations in VHL patients with the involvement of one organ or a pair of organs. Once the mutation is found in the proband, all family members can be easily tested for the documented mutation. The early identification of VHL patients is very important for clinical and genetic reasons.

Chronic renal failure, dialysis, and renal transplantation in Anderson-Fabry disease.

Anderson-Fabry disease (AFd) is a rare, inherited, x-linked disease characterized by the deficiency of the lysosomal enzymatic alpha-galactosidase A activity (alpha-Gal-A). The enzyme defect leads to progressive accumulation of glycosphingolipids (GL) in all kinds of cells, tissues, organs, and body fluids. The clinical manifestations are very protean, the residual activity of alpha-Gal-A and/or different gene mutations might explain different phenotypes, but as yet these concepts have not been proven. Usually, patients with AFd show 3 clinical phases, more evident in men than in heterozygous women. The first phase (childhood and adolescence) is characterized by myalgia, arthralgia, acroparesthesia, fever, cutaneous angiokeratomas, and corneal opacities. The second phase is characterized mainly by renal involvement. In the third phase, severe renal impairment and involvement of cerebrovascular and cardiovascular systems are present. The progression to end-stage renal disease (ESRD) is common in hemizygous males (3rd-5th decade of life); usually, death occurs because of cerebral and/or cardiovascular complications in patients undergoing chronic dialysis therapies. The survival of patients with AFd in dialysis is better than in diabetic patients, but it clearly is decreased compared with uremic patients with other nephropathies, despite a lower mean age of uremia (50 versus 60 y). The outcome of kidney transplantation is similar to that found in other patients with ESRD, despite controversial issues published in the past. The use of a kidney donor with normal alpha-Gal-A activity in the control of the metabolic systemic disease is unproven. The recurrence of GL deposits in the kidney graft has been documented rarely. The definitive treatment for AFd is enzyme replacement therapy with purified alpha-Gal-A produced by a genetically engineered human cell line or Chinese hamster oocytes: relatively short-term studies have shown a significant treatment effect on clinical outcome measures.

Effective homocysteine-lowering vitamin B treatment in peritoneal dialysis patients.

BACKGROUND: Hyperhomocysteinemia, a risk factor for atherosclerosis, is frequently detected in patients with renal failure. Vitamin B supplementation reduces but rarely normalizes homocysteine (Hcy) levels in hemodialysis patients. There are no data about the effects of vitamin B therapy on Hcy levels in patients on peritoneal dialysis (PD). AIMS: We performed this trial both to observe baseline plasma Hcy levels in PD patients and to assess the effects of vitamin B therapy on Hcy levels in continuous ambulatory PD patients. METHODS: We conducted a 6-month prospective study of the effects of vitamin B therapy on plasma Hcy levels. Biochemical analyses were obtained at baseline and after every phase of treatment with folic acid, folic acid plus vitamin B12, and folic acid plus vitamin B12 plus vitamin B6. Eighteen of the 25 enrolled patients finished the study. RESULTS: Hyperhomocysteinemia was present in 83% of PD patients. We detected a trend toward a significant inverse relationship between baseline Hcy and folate levels. There were no significant correlations between baseline Hcy and vitamin B12, peritoneal membrane permeability, dialytic efficiency, or computed peritoneal Hcy clearance. We obtained an effective decrease in mean Hcy concentration from 20 to 14.8 micromol/L after folic acid and vitamin B12 treatment. We observed a further reduction in mean Hcy level to 12.8 micromol/L using the triple therapy; 72% of patients normalized their Hcy value. CONCLUSIONS: High doses of folic acid, vitamin B6, and vitamin B12 normalize Hcy values in the majority of PD patients. This treatment may be important in reducing cardiovascular morbidity and mortality.

Juvenile renal cell carcinoma as first manifestation of von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome characterized by germline mutations in the VHL tumor suppressor gene located at chromosome 3p25-26 and pleomorphic clinical picture. The major clinical manifestations include retinal angiomas, central nervous system hemangioblastomas, pheopleochromocytoma, pancreatic cysts, epididymal cystoadenomas and renal lesions. Recently, we observed a 58-year-old male patient with macrohematuria and a history of nephrectomy due to renal cell carcinoma (RCC). The patient showed retinal angiomatosis, cerebellar hemangioblastomas, multiple pancreatic cysts, right kidney with polycystic features plus two RCC. The patient's offspring, two females and one male, showed VHL lesions, such as retinal angiomatosis, cerebellar hemangioblastomas and polycystic kidney disease (PKD). The affected family members were screened for mutations in the VHL gene. Data suggested the presence of a deletion encompassing exon 1 of the VHL gene. Early diagnosis of VHL disease in patients and their relatives is important for clinical and geneticreasons. VHL disease patients have an increased incidence of malignant carcinomas and the syndrome can mimic the presentation of other cystic kidney diseases. Early diagnosis and molecular genetic testing of family members is essential to improve the clinical management of patients and to allow an accurate risk assessment in asymptomatic individuals. In conclusion, nephrologists and urologists must carefully evaluate patients with PKD and RCC to confirm or exclude VHL disease, and physicians must play a crucial role in the clinical process of therapeutical decisions and choices for VHL patients.