MO1031FROM MARCELLO MALPIGHI THROUGH JEAN REDMAN OLIVER AND JOSEP TRUETA: A CONTINUING CONTRIBUTION TO THE “BLACK BOX” CLINICAL PREDICTION MODELS IN NEPHROLOGY

Background and Aims The modern development of the black box approach in clinical nephrology is inconceivable without a logical theory of renal function and a comprehension of anatomical architecture of the kidney, in health and disease: this is the undisputed contribution offered by Malpighi, Oliver and Trueta starting from the seventeenth century. The machine learning model for the prediction of acute kidney injury, progression of renal failure and tubulointerstitial nephritis is a good example of how different knowledge about kidney are an indispensable tool for the interpretation of model itself. Method Historical data were collected from literature, textbooks, encyclopedias, scientific periodicals and laboratory experimental data concerning these three authors. Results The Italian Marcello Malpighi (1628-1694), born in Crevalcore near Bologna, was Professor of anatomy at Bologna, Pisa and Messina. The historic description of the pulmonary capillaries was made in his second epistle to Borelli published in 1661 and intitled De pulmonibus, by means of the frog as “the microscope of nature” (Fig. 1). It is the first description of capillaries in any circulation. William Harvey in De motu cordis in 1628 (year of publication the same of date of birth of Italian anatomist!) could not see the capillary vessels. This thriumphant discovery will serve for the next reconnaissance of characteristic renal rete mirabile.in the corpuscle of Malpighi, lying within the capsule of Bowman. Jean Redman Oliver (1889-1976), a pathologist born and raised in Northern California, was able to bridge the gap between the nephron and collecting system through meticulous dissections, hand drawn illustrations and experiments which underpin our current understanding of renal anatomy and physiology. In the skillful lecture “When is the kidney not a kidney?” (1949) Oliver summarizes his far-sighted vision on renal physiology and disease in the following sentence: the Kidney in health, if you will, but the Nephrons in disease. Because, the “nephron” like the “kidney” is an abstraction that must be qualified in terms of its various parts, its cellular components and the molecular mechanisms involved in each discrete activity (Fig. 2). The Catalan surgeon Josep Trueta I Raspall (1897-1977) was born in the Poblenou neighborhood of Barcelona. His impact of pioneering and visionary contribution to the changes in renal circulation for the pathogenesis of acute kidney injury was pivotal for history of renal physiology. “The kidney has two potential circulatory circulations. Blood may pass either almost exclusively through one or other of two pathways, or to a varying degree through both”. (Studies of the Renal Circulation, published in 1947). Now this diversion of blood from cortex to the less resistant medullary circulation is known with the eponym Trueta shunt. Conclusion The black box approach to the kidney diseases should be considered by practitioners as a further tool to help to inform model update in many clinical setting. The number of machine learning clinical prediction models being published is rising, as new fields of application are being explored in medicine (Fig. 3). A challenge in the clinical nephrology is to explore the “kidney machine” during each therapeutic diagnostic procedure. Always, the intriguing relationship between the set of nephrological syndromes and kidney diseases cannot disregard the precious notions the specific organization of kidney microcirculation, fruit of many scientific contributions of the work by Malpighi, Oliver and Trueta (Fig. 3).

Doppler ultrasoundgraphy capability in the evaluation of renal circulation in patients with type 2 diabetes mellitus and chronic kidney disease

The 72 patients with type 2 diabetes mellitus and chronic kidney were examined to clarify Doppler ultrasound capability in assessing the renal circulation. Hemodynamics changes in kidney tissue appeared on early stage of diabetic kidney disease. Intrarenal hemodynamics disturbances in patients with type 2 diabetes mellitus is revealed through a decrease in the minimum blood flow velocity and an increase in the intrarenal vascular resistance parameters. We found the correlation between dopplerographic indicators, kidney functions and other parameters (age, disease duration, glycated hemoglobin level), which play a pathogenetic role in diabetic kidney disease. Serum creatinine level and glomerular filtration rate were indicators of renal hemodynamic changes. Resistant index above 0,7 conventional units, pulsatility index above 1,54 conventional units, systolic diastolic ratio above 3,8 conventional units were ultrasound signs of kidney damage. Patients without standard signs of chronic kidney disease have diagnostically significant index of resistance in 72% of cases, a pulsation index in 50%, a systolic-diastolic ratio in 28%. Renal blood flow examination in right segmental artery area will be use for non-invasive diagnosis and estimation of kidney dysfunction in patients with type 2 diabetes mellitus.

Hepatorenal syndrome: pathophysiology, diagnosis, and management

ABSTRACTHepatorenal syndrome (HRS), the extreme manifestation of renal impairment in patients with cirrhosis, is characterized by reduction in renal blood flow and glomerular filtration rate. Hepatorenal syndrome is diagnosed when kidney function is reduced but evidence of intrinsic kidney disease, such as hematuria, proteinuria, or abnormal kidney ultrasonography, is absent. Unlike other causes of acute kidney injury (AKI), hepatorenal syndrome results from functional changes in the renal circulation and is potentially reversible with liver transplantation or vasoconstrictor drugs. Two forms of hepatorenal syndrome are recognized depending on the acuity and progression of kidney injury. The first represents an acute impairment of kidney function, HRS-AKI, whereas the second represents a more chronic kidney dysfunction, HRS-CKD (chronic kidney disease). In this review, we provide critical insight into the definition, pathophysiology, diagnosis, and management of hepatorenal syndrome.

Western diet induces renal artery endothelial stiffening that is dependent on the epithelial Na+ channel

Consumption of a Western diet (WD) induces central aortic stiffening that contributes to the transmittance of pulsatile blood flow to end organs, including the kidney. Our recent work supports that endothelial epithelial Na+ channel (EnNaC) expression and activation enhances aortic endothelial cell stiffening through reductions in endothelial nitric oxide (NO) synthase (eNOS) and bioavailable NO that result in inflammatory and oxidant responses and perivascular fibrosis. However, the role that EnNaC activation has on endothelial responses in the renal circulation remains unknown. We hypothesized that cell-specific deletion of the α-subunit of EnNaC would prevent WD-induced central aortic stiffness and protect the kidney from endothelial dysfunction and vascular stiffening. Twenty-eight-week-old female αEnNaC knockout and wild-type mice were fed either mouse chow or WD containing excess fat (46%), sucrose, and fructose (17.5% each). WD feeding increased fat mass, indexes of vascular stiffening in the aorta and renal artery (in vivo pulse wave velocity and ultrasound), and renal endothelial cell stiffening (ex vivo atomic force microscopy). WD further impaired aortic endothelium-dependent relaxation and renal artery compliance (pressure myography) without changes in blood pressure. WD-induced renal arterial stiffening occurred in parallel to attenuated eNOS activation, increased oxidative stress, and aortic and renal perivascular fibrosis. αEnNaC deletion prevented these abnormalities and support a novel mechanism by which WD contributes to renal arterial stiffening that is endothelium and Na+ channel dependent. These results demonstrate that cell-specific EnNaC is important in propagating pulsatility into the renal circulation, generating oxidant stress, reduced bioavailable NO, and renal vessel wall fibrosis and stiffening.

Hydrogen sulfide regulation of renal and mesenteric blood flow

Hydrogen sulfide (H2S) dilates isolated arteries, and knockout of the H2S-synthesizing enzyme cystathionine γ-lyase (CSE) increases blood pressure. However, the contributions of endogenously produced H2S to blood flow regulation in specific vascular beds are unknown. Published studies in isolated arteries show that CSE production of H2S influences vascular tone more in small mesenteric arteries than in renal arteries or the aorta. Therefore, the goal of this study was to evaluate H2S regulation of blood pressure, vascular resistance, and regional blood flows using chronically instrumented rats. We hypothesized that during whole animal CSE inhibition, vascular resistance would increase more in the mesenteric than the renal circulation. Under anesthesia, CSE inhibition [β-cyanoalanine (BCA), 30 mg/kg bolus + 5 mg·kg−1·min−1 for 20 min iv) rapidly increased mean arterial pressure (MAP) more than saline administration (%Δ: saline −1.4 ± 0.75 vs. BCA 7.1 ± 1.69, P < 0.05) but did not change resistance (MAP/flow) in either the mesenteric or renal circulation. In conscious rats, BCA infusion similarly increased MAP (%Δ: saline −0.8 ± 1.18 vs. BCA 8.2 ± 2.6, P < 0.05, n = 7) and significantly increased mesenteric resistance (saline 0.9 ± 3.1 vs. BCA 15.6 ± 6.5, P < 0.05, n = 12). The H2S donor Na2S (50 mg/kg) decreased blood pressure and mesenteric resistance ,but the fall in resistance was not significant. Inhibiting CSE for multiple days with dl-proparglycine (PAG, 50 mg·kg−1·min−1 iv bolus for 5 days) significantly increased vascular resistance in both mesenteric (ratio of day 1: saline 0.86 ± 0.033 vs. PAG 1.79 ± 0.38) and renal circulations (ratio of day 1: saline 1.26 ± 0.22 vs. 1.98 ± 0.14 PAG). These results support our hypothesis that CSE-derived H2S is an important regulator of blood pressure and vascular resistance in both mesenteric and renal circulations. Furthermore, inhalation anesthesia diminishes the effect of CSE inhibition on vascular tone. NEW & NOTEWORTHY These results suggest that CSE-derived H2S has a prominent role in regulating blood pressure and blood flow under physiological conditions, which may have been underestimated in prior studies in anesthetized subjects. Therefore, enhancing substrate availability or enzyme activity or dosing with H2S donors could be a novel therapeutic approach to treat cardiovascular diseases.