Physiologic adaptations of the tubuloglomerular feedback system

The maintenance of volume homeostasis is sufficiently important to mammalian terrestrial life that a large amount of evolutionary energy has been expended in the development of multiple control systems, each involved in regulating the volume and composition of internal body fluids. The kidney, which participates in most of these systems, has evolved physiologic attributes which enhance the efficiency of volume regulation. Perhaps the most fundamental of these attributes is a close coordination between the processes of glomerular filtration and tubular reabsorption. Such coordination is required to prevent the amplification of small fluctuations in glomerular filtration rate into large fluctuations in total body salt and water content.It was first suggested by Homer Smith that reabsorption of fluid from the nephron should increase as the delivery of tubular fluid into that segment increases [1]. When applied to the proximal tubule, this principle of flow-dependent transport has come to be referred to as “glomerulotubular balance” [2, 3]. Glomerulotubular balance depends upon intrinsic properties of the proximal nephron including the affinities and densities of various solute transporters and the differential permeabilities of the nephron to various solutes and water, and upon the trans-epithelial concentration gradients of these solutes [4–6]. By definition, glomerulotubular balance describes the functional dependence of tubular reabsorption on glomerular filtration rate independently of other neuro-humoral effectors of tubular transport. However, since glomerulotubular balance is a substrate-driven process, it cannot accomplish an increment in proximal tubular reabsorption which exceeds an increment in delivered load. Therefore, in the absence of effectors other than glomerulotubular balance the volume of fluid entering the distal nephron must be a monotonically increasing function of GFR [7].How then, may the kidney avert an unintentional diuresis should the hemodynamic forces favoring glomerular filtration combine to overwhelm the reabsorptive capacity of the nephron? In 1937 Goormaghtigh suggested that the juxtaglomerular apparatus might participate in the maintenance of volume homeostasis by generating some sort of signal in response to changes in the composition of distal tubular fluid [8]. The peculiar anatomic arrangement of the nephron would facilitate transmission of this signal to the upstream glomerulus and lead to alterations in the physiologic determinants of glomerular filtration. This hypothesis has been refined over the past three decades as substantial experimental data have accrued to support the existence of an operational system of tubuloglomerular feedback (TGF) [9]. Contemporary models of the TGF system, by analogy to negative feedback-driven control systems in engineering control theory, divide the system into three component processes [10]. The first of these components is a parameter which the system is designed to regulate, in this case, the rate at which tubular fluid transits the late proximal nephron or VLP. The second component includes the macula densa and surrounding interstitium which serve to detect differences between the current value of VLP and some internal set-point, and translate this information into an output command. The third component, or effector limb, of the TGF system is constituted by the contractile glomerular mesangium and glomerular arterioles which respond to the aforementioned output command by altering nephron filtration rate (SNGFR) to keep VLP in line with the system's internal set-point. When TGF is allowed to function as a closed-loop system [7], as is the case in vivo, its presence is, by nature, undetectable. However, when late proximal flow is uncoupled from nephron filtration by artificial microperfusion of the late proximal tubule, a dependence of SNGFR on VLP can be defined [11]. This relationship is referred to as the “TGF function”, or “gain” of the TGF system [7, 10]. This TGF function specifies a continuum of points in the VLP-SNGFR plane at which the nephron may operate. The actual operating point of the system exists at the point in this plane where the TGF and glomerulotubular balance functions intersect (Fig. 1).The TGF function may vary in response to the changing needs of the organism, both with regard to volume homeostasis and renal function. The altering of TGF under conditions of pregnancy, loss of renal mass, and a variety of other pathophysiologic conditions suggests that the juxtaglomerular apparatus is involved in events pertinent not merely to volume regulation but to overall renal growth and function

A single nephron model of acute tubular injury: Role of tubuloglomerular feedback

A single nephron model of acute tubular injury: Role of tubuloglomerular feedback. A single nephron model of nephrotoxic tubular injury was established to examine the mechanism whereby acute tubular damage contributes to reductions in nephron filtration rate (SNGFR). Acute microperfusion of 0.5ng of uranyl nitrate (UN) into the early proximal tubule produced a significant reduction (16 to 30%) in SNGFR measured in both distal and proximal tubules of the same nephron and a decrease in absolute proximal reabsorption. Microperfused inulin was retained in the tubule suggesting this finding reflected a true reduction in SNGFR. Concurrent infusion of high dose furosemide (2 × 10-4M) and bumetanide (2 × 10-5M), but not low dose furosemide (2 × 10-5M), prevented the UN induced reduction in SNGFR. High dose furosemide begun after UN perfusion also prevented reduction in SNGFR. Continuous direct measurement of glomerular capillary hydrostatic pressure revealed no change. Distal intratubular Na+ and CI- concentration increased significantly after UN perfusion. Activation of tubuloglomerular feedback mechanisms best explains the reduction in glomerular ultrafiltration that is characteristic of nephrotoxic forms of tubular injury

Nephroprotection by SGLT2 Inhibition: Back to the Future?

The introduction of sodium/glucose cotransporter 2 inhibitors (SGLT2i) has opened new perspectives for the management of diabetic population at risk of or with chronic kidney disease (CKD). More important, recent, large real-world studies have repositioned the nephroprotective efficacy of SGLT2i emerged from randomized trials within the frame of effectiveness. Furthermore, the salutary effects of these agents may extend to the nondiabetic population according to the positive results of current studies. Nevertheless, the clear benefits of these agents on the prevention of organ damage contrast with their unexpected, limited use in clinical practice. One potential barrier is the acute decline in glomerular filtration rate (GFR) commonly observed at the beginning of treatment. This phenomenon is reminiscent of the early response to the traditional nephroprotective interventions, namely blood pressure lowering, dietary protein and salt restriction and the inhibition of the renin-angiotensin system. Under this perspective, the "check-mark" sign observed in the GFR trajectory over the first weeks of SGT2i therapy should renew interest on the very basic goal of CKD treatment, i.e., alleviate hyperfiltration in viable nephrons in order to prolong their function

Proteinuria and nocturnal blood pressure dipping in hypertensive children and adolescents

BackgroundThe absence of nocturnal blood pressure dipping is associated with adverse cardiovascular outcomes in adults, and proteinuria is a risk factor for non-dipping in this population. Risk factors for non-dipping in children are largely unknown.MethodsWe retrospectively identified patients aged 5-19 years who underwent 24-h ambulatory blood pressure monitoring (ABPM) from August 2018 to January 2019 and had a spot urine protein-to-creatinine ratio (PCR) within 1 year of their ABPM. Dipping was defined as ≥10% reduction in systolic and diastolic blood pressure from day to night. Multivariable logistic and linear regression models evaluated the association of proteinuria with non-dipping.ResultsAmong 77 children identified, 27 (35.1%) were non-dippers. Each two-fold higher urine PCR was associated with 38% higher odds of non-dipping, after adjusting for body mass index (BMI). Higher urine PCR was also associated with a lower diastolic dipping percentage by 1.33 (95% confidence interval 0.31-2.34), after adjusting for BMI, age, and estimated glomerular filtration rate.ConclusionsLimitations of this study include its retrospective design and the time lapse between urine PCR and ABPM. Proteinuria appears to be associated with blood pressure non-dipping in children. This finding needs to be confirmed in prospective studies.ImpactOur study demonstrates the association of proteinuria with non-dipping of blood pressure in children. This association has been explored in adults, but to our knowledge, this is the first time it is evaluated in children referred for evaluation of elevated blood pressure. Non-dipping is a modifiable risk factor for kidney function decline and cardiovascular disease in adulthood, and thus early identification in children is important. The association between proteinuria and non-dipping in children will allow us to more readily identify those at risk, with a future focus on interventions to modify blood pressure dipping patterns

Sex Differences in the Progression of CKD Among OlderPatients: Pooled Analysis of 4 Cohort Studies

Rationale & Objective:Data for the associationof sex with chronic kidney disease (CKD) pro-gression are conflicting, a relationship this studysought to examine.Study Design:Pooled analysis of 4 Italianobservational cohort studies.Setting & Participants:1,311 older men and1,024 older women with estimated glomerularfiltration rate (eGFR)0.5 g/d (P=0.04).Limitations:Residual confounding; only whiteswere included.Conclusions:Excess renal risk in men may, atleast in part, be related to higher levels of pro-teinuria in men compared with women

Variations in 24-Hour BP Profiles in Cohorts of Patients with Kidney Disease around the World

Background and objectives: Ambulatory BP is increasingly recognized as a better measure of the risk for adverse outcomes related to hypertension, an important comorbidity in patients with CKD. Varying definitions of white-coat and masked hypertension have made it difficult to evaluate differences in prevalence of these BP patterns across CKD cohorts. Design, setting, participants, & measurements: The International Database of Ambulatory BP in Renal Patients collaborative group established a large database of demographic, clinical, and ambulatory BP data from patients with CKD from cohorts in Italy, Spain, the Chronic Renal Insufficiency Cohort (CRIC) and the African American Study of Kidney Disease and Hypertension Cohort Study (AASK) in the United States, and the CKD Japan Cohort (CKD-JAC). Participants (n=7518) with CKD were included in the present analyses. Cutoffs for defining controlled BP were 140/90 mm Hg for clinic and 130/80 mm Hg for 24-hour ambulatory BP. Results: Among those with controlled clinic BP, compared with CKD-JAC, AASK participants were more likely to have masked hypertension (prevalence ratio [PR], 1.21; 95% confidence interval [95% CI], 1.04 to 1.41) whereas CRIC (PR, 0.82; 0.72 to 0.94), Italian (PR, 0.73; 0.56 to 0.95), and Spanish participants (PR, 0.75; 0.64 to 0.88) were less likely. Among those with elevated clinic BP, AASK participants were more likely to have sustained hypertension (PR, 1.22; 95% CI, 1.13 to 1.32) whereas Italian (PR, 0.78; 0.70 to 0.87) and Spanish participants (PR, 0.89; 0.82 to 0.96) were less likely, although CRIC participants had similar prevalence as CKD-JAC. Prevalence of masked and sustained hypertension was elevated in males, patients with diabetes, participants on four or more antihypertensives, and those with moderate-to-severe proteinuria. Conclusions: In a large, multinational database, the prevalence of masked and sustained hypertension varied across cohorts independent of important comorbidities.Sin financiación6.243 JCR (2018) Q1, 7/70 Urology & Nephrology2.950 SJR (2018) Q1, 4/91 Critical Care and Intensive Care Medicine, 14/106 Epidemiology, 4/66 Nephrology, 3/43 TransplantationNo data IDR 2018UE