Molecular Targets of Novel Therapeutics for Diabetic Kidney Disease: A New Era of Nephroprotection.

Diabetic kidney disease (DKD) is a chronic microvascular complication in patients with diabetes mellitus (DM) and the leading cause of end-stage kidney disease (ESKD). Although glomerulosclerosis, tubular injury and interstitial fibrosis are typical damages of DKD, the interplay of different processes (metabolic factors, oxidative stress, inflammatory pathway, fibrotic signaling, and hemodynamic mechanisms) appears to drive the onset and progression of DKD. A growing understanding of the pathogenetic mechanisms, and the development of new therapeutics, is opening the way for a new era of nephroprotection based on precision-medicine approaches. This review summarizes the therapeutic options linked to specific molecular mechanisms of DKD, including renin-angiotensin-aldosterone system blockers, SGLT2 inhibitors, mineralocorticoid receptor antagonists, glucagon-like peptide-1 receptor agonists, endothelin receptor antagonists, and aldosterone synthase inhibitors. In a new era of nephroprotection, these drugs, as pillars of personalized medicine, can improve renal outcomes and enhance the quality of life for individuals with DKD.

Chyloperitoneum in Peritoneal Dialysis Secondary to Calcium Channel Blocker Use: Case Series and Literature Review.

Chyloperitoneum (chylous ascites) is a rare complication of peritoneal dialysis (PD). Its causes may be traumatic and nontraumatic, associated with neoplastic disease, autoimmune disease, retroperitoneal fibrosis, or rarely calcium antagonist use. We describe six cases of chyloperitoneum occurring in patients on PD as a sequel to calcium channel blocker use. The dialysis modality was automated PD (two patients) and continuous ambulatory PD (the rest of the patients). The duration of PD ranged from a few days to 8 years. All patients had a cloudy peritoneal dialysate, characterized by a negative leukocyte count and sterile culture tests for common germs and fungi. Except for in one case, the cloudy peritoneal dialysate appeared shortly after the initiation of calcium channel blockers (manidipine, n = 2; lercanidipine, n = 4), and cleared up within 24-72 h after withdrawal of the drug. In one case in which treatment with manidipine was resumed, peritoneal dialysate clouding reappeared. Though turbidity of PD effluent is due in most cases to infectious peritonitis, there are other differential causes including chyloperitoneum. Although uncommon, chyloperitoneum in these patients may be secondary to the use of calcium channel blockers. Being aware of this association can lead to prompt resolution by suspension of the potentially offending drug, avoiding stressful situations for the patient such as hospitalization and invasive diagnostic procedures.

[Does clinical methodology yet exist?] / Metodologia in clinica: esiste ancora?

Up to 1968, clinical methodology was considered a central step in construction of Medical procedure. Later, after specialization or high specialization introduction, it totally disappeared. The results is the absence of any epistemological knowledge in the construction of diagnosis, based on two main theory: inductivism and hypothetico-deductivism. Both start from the point that diagnostic theory can be developed in close touch with experiment and observation. The inductive theory builds up the diagnosis on the multiple observations, while the deductive theory formulates the diagnosis from the bright idea which inspires the doctor who then has to check his theory by observation. The difference between two approaches to diagnosis is based on the tabula rasa of inductive physician and tabula plena of deductive physician. Without a methodology knowledge, the new doctors are lacking of proper correct approach to right diagnosis and therapy and rarely use academic tools to deepen it in clinical work. We consider many epistemology clinical aspects related to science and medical practice. In addition, we point out the attention to some cases on the basis of new inductive and deductive theories, in order to have respect for patients and doctors dignity.

Microalbuminuria and uric acid in healthy subjects.

BACKGROUND: Microalbuminuria has been linked to cardiovascular (CV) risk in patients with diabetes or hypertension, and in an unselected general population; serum uric acid (UA) is emerging as a novel risk factor for CV disease. The aim of our study was to evaluate the prevalence of excess microalbuminuria and its relation to established CV risk factors and serum UA in healthy subjects. METHODS: We screened 900 healthy blood donors (age range, 20-65 years; 747 men, 153 women), and measured total, HDL and LDL cholesterol, blood glucose, serum and urinary creatinine, serum UA, blood pressure (BP) and microalbuminuria (urinary albumin/creatinine ratio, ACR). The Framingham risk score was also calculated. RESULTS: After excluding 52 participants, we found that in 848 participants (702 men, 146 women) the overall prevalence of excess ACR, using a 30 mg/g creatinine cutoff, was 9.3% (9.7% of men, 7.5% of women, p=0.16); adopting a gender-dependent cutoff, we found that the overall prevalence was 13.6% (15.1% of men, 6.2% of women, p<0.01). ACR was highly correlated to diastolic (r=0.88, p<0.001) and systolic (r=0.74, p<0.001) BP, and also--though not as strongly--to serum UA (r=0.38, p<0.001). In a stepwise multiple regression model, systolic and diastolic BP, total cholesterol, serum creatinine and UA were segregated as independent predictors of microalbuminuria (model R=0.91, R square=0.83). Correlation of serum UA to ACR remained significant, albeit attenuated (r=0.09, p=0.02), after adjustment for serum creatinine, total cholesterol, systolic and diastolic BP. CONCLUSIONS: The results of our study show ACR to be abnormal in a significant proportion of seemingly healthy subjects, and serum UA to be an independent predictor of microalbuminuria.

Association between extracellular water, left ventricular mass and hypertension in haemodialysis patients.

BACKGROUND: Hypertension and left ventricular hypertrophy (LVH) are present in the majority of patients undergoing haemodialysis (HD). These two pathologies persist after dialysis onset, and pharmacological therapy is often required for adequate control of blood pressure (BP). Although fluid overload is a determinant of hypertension, clinical assessment of this parameter remains difficult and unsatisfactory. Bioimpedance analysis (BIA) spectroscopy and the relative determination of extracellular water (ECW%) may provide a simple and inexpensive tool for investigating fluid overload. We studied 110 patients on thrice-weekly HD to determine whether ECW body content correlates with hypertension and LVH in this patient population. METHODS: Hypertension was determined according to the WHO criteria (office BP >/= 140/90 and/or the use of antihypertensive therapy). Twenty-four hour BP monitoring and echocardiography were performed on midweek inter-HD days. Blood chemistries, dialysis dose (spKt/V) and bioimpedance were analysed on midweek HD days. RESULTS: Hypertension was present in 74.5% of patients. There were no differences for age, spKt/V, haemoglobin, serum creatinine and residual renal function between normotensive and hypertensive patients. Twenty-four hour systolic BP (SBP), 24 h diastolic BP and 24 h pulse pressure were higher in hypertensive patients, in spite of antihypertensive therapy. LVH was present in 61.8% of patients. BIA revealed that ECW% was increased in LVH+ patients (LVH+ = 47.5 +/- 7.9%, LVH- = 42.4 +/- 6.2%, P = 0.01) and in hypertensive patients compared with normotensives (46.5 +/- 7.7% vs 43 +/- 7.2%, P = 0.02). Dry body weights and inter-HD body weight increases did not differ between hypertensive and normotensive patients nor between patients with or without LVH. ECW was correlated with SBP (r = 0.35, P < 0.01) and with left ventricular mass index (LVMi(g/sqm)) (r = 0.49, P < 0.001). A stepwise multiple linear regression model revealed that LVMi(g/sqm) was significantly correlated with ECW%, SBP and male gender (r = 0.65, P < 0.001). CONCLUSIONS: LVH and hypertension are present in a majority of HD patients and they are closely correlated with one another. We found associations between fluid load, measured by BIA and expressed as ECW, and BP and LVM.

Calcium urolithiasis, blood pressure and salt intake.

OBJECTIVES: To determine whether stone-formers have higher BP than controls drawn from the general population and matched for age, sex and ethnic origin and to compare the relationship between sodium and calcium excretion in the two groups. PATIENTS AND METHODS: Thirty-six patients [mean (+/-standard deviation, SD) = 49.0 +/- 11.7 years; range 27-70 years] with kidney or ureteric stones and 108 controls (mean age of 49.6 +/- 6.8 years; range 39-61 years), matched for gender, ethnic origin and age group were studied. Patients and controls underwent physical measurements, a venous blood sample and they were asked to collect a 24-h urine sample for sodium, potassium, calcium and creatinine. RESULTS: Stone-formers were significantly heavier and had higher BP than age-, sex- and ethnic-matched population controls. Whilst the difference in systolic BP was independent of the difference in body mass index [16.8 mmHg (7.2-26.4 mmHg), p = 0.001), the difference in diastolic BP was attenuated after adjustment for body mass [1.8 (-3.4 to 7.1), p = 0.49]. Stone-formers passed less urine than controls [-438 ml/day (95% CI -852 to -25), p = 0.038]. They had higher urinary calcium than controls [+3.7 mmol/day (2.8-4.6 mmol/day), p < 0.001], even when expressed as ratio to creatinine [+0.20 (0.11-0.29), p < 0.001]. Sodium excretion was positively associated with urinary calcium in both stone-formers and in controls. The slopes were comparable (0.92 vs 0.98 mmol Ca/100 mmol Na) so that for any level of sodium excretion (or salt intake), stone-formers had a higher calcium excretion than controls. CONCLUSIONS: In stone-formers, the BP is higher than in controls. Stone-formers excrete more calcium than controls do. In stone-formers and controls, the relationship between urinary sodium and calcium is similar. Since this relationship results from an effect of sodium on calcium, a reduction in salt intake may be a useful method of reducing urinary calcium excretion in stone-formers. However, the "relative" hypercalciuria seen in stone-formers is independent of salt intake and may well reflect an underlying genetic predisposition.

Inflammation, infection and cardiovascular events in chronic hemodialysis patients: a prospective study.

BACKGROUND: Cardiovascular (CV) disease is the leading cause of morbidity and mortality in chronic hemodialysis (HD) patients. Inflammation is a potent risk factor for CV disease in the general population. Recent evidence suggests infection, particularly with agents such as Chlamydia pneumoniae (C.pneumoniae) and Helicobacter pylori (H.pylori), as a source of sustained inflammation. Our study tested the hypothesis that C-reactive protein (CRP) and positive serology for antibodies to C.pneumoniae and H.pylori can be associated with the occurrence of new CV events in chronic HD patients. METHODS: We evaluated 76 chronic HD patients (33 women and 43 men, aged 60.5+/-17.3 years) by measuring baseline CRP levels as well as the titres of antibodies (IgG and IgA) to C.pneumoniae and(IgG) to H.pylori. In addition, risk factors such as hypertension, smoking, diabetes, cholesterol levels and albumin were assessed at baseline. The incidence of new CV events (myocardial infarction and ischemic stroke) was recorded during a 36-month follow-up period. The effect of prognostic factors was evaluated by logistic regression analysis. RESULTS: The incidence of CV events was significantly higher in patients seropositive for C.pneumoniae antibodies than in those seronegative (16.1 vs. 4.3 events/100 patient-years, p=0.017, risk ratio 3.76), whereas it did not differ for H.pylori (12.2 vs. 11.7 events/100 patient-years,p=0.91, risk ratio 1.04). Logistic regression analysis showed C.pneumoniae seropositivity (odds ratio 10.11, p=0.04) and CRP levels (odds ratio 1.78, p=0.03) to be independent predictors of the occurrence of CV events. CONCLUSIONS: CRP levels and C.pneumoniae antibodies, but not H.pylori antibodies, were predictors of CV morbidity in the chronic HD patients studied.

Theories and controversies on urine formation.

The theories of urine formation developed in the wake of progressing scientific knowledge in renal anatomy and physiology. From the philosophical theories which for a long time swung between vitalism and mechanism, the "scientific revolution" gave a great impulse to morpho/functional unit of kidney. Bowman's secretory hypothesis, as an expression of the vitalistic based theory, describes for the first time many features of the nephron and its blood supply. New insight into the inevitable errors of Bowman led Ludwig to develop the filtration-reabsorption theory, which based its scientific approach on the emerging physics and chemistry theories. The Heidenhain's secretory hypothesis which does not admit the physical filtration in Ludwig's sense, nor the hydrostatic pressure of the blood, even though incomplete and in some part without unequivocal experimental evidence, adds a fragment to the right theory of the urine formation and heralds the modern approach to the renal function of the 20th century.