A Gut–Liver–Kidney (GLK) Multi-Organ Chip for Physiologically Modeling the Renal Filtration and Reabsorption of Oral Drugs

To quantify the effect of the sodium-glucose co-transporter 2 inhibitor, empagliflozin, on renal glucose reabsorption in patients with type 2 diabetes, and to evaluate covariate effects, using a mechanistic population pharmacokinetic-pharmacodynamic (PK-PD) model. Four phase I/II trials were used for model development. Empagliflozin's PK characteristics were characterized by a two-compartmental model with sequential zero- and first-order absorption. Urinary glucose excretion (UGE) was described as dependent on renal glucose filtration and reabsorption; splay of the glucose reabsorption/excretion curves was considered. The modelling assumed that empagliflozin lowers the maximum renal glucose reabsorption capacity and, thereby, the renal threshold for glucose (RTg). Covariate effects were investigated using a full covariate modelling approach, emphasizing parameter estimation. The PK-PD model provided a reasonable description of the PK characteristics of empagliflozin and its effects on UGE across a range of renal function levels. Its parameters are consistent with reported values for renal physiology. Using this model, the effect of empagliflozin on renal glucose reabsorption was quantified. Steady-state empagliflozin doses (1, 5, 10 and 25 mg) reduced RTg from 12.5 mmol/L [95% confidence interval (CI) 12.0, 13.1] to 5.66 (95% CI 4.62, 6.72), 3.01 (95% CI 2.33, 3.69), 2.53 (95% CI 1.83, 3.14) and 2.21 (95% CI 1.47, 2.84) mg/dl, respectively. Covariate analysis showed the effect of empagliflozin on UGE was not influenced, to a clinically relevant extent, by sex, age or race. A method for characterizing renal glucose reabsorption was developed that does not require complex glucose clamp experiments. These analyses indicate that empagliflozin provided concentration-dependent RTg reductions, with 10 and 25 mg providing near-maximum RTg-lowering.

about 180 liters of filtrate are produced by the human kidneys every day, with more than 99% of the filtered salt and water being subsequently reabsorbed along the nephron. In view of this high level of renal filtration, even slight alterations in the balance between filtration and reabsorption will

Acute kidney injury occurs frequently after cardiac or major vascular surgery and is believed to be predominantly a consequence of impaired renal oxygenation. However, in patients with acute kidney injury, data on renal oxygen consumption (RVO2), renal blood flow, glomerular filtration, and renal oxygenation, i.e., the renal oxygen supply/demand relationship, are lacking and current views on renal oxygenation in the clinical situation of acute kidney injury are presumptive and largely based on experimental studies. Prospective, two-group comparative study. Cardiothoracic intensive care unit of a tertiary center. Postcardiac surgery patients with (n = 12) and without (n = 37) acute kidney injury were compared with respect to renal blood flow, glomerular filtration, RVO2, and renal oxygenation. None Data on systemic hemodynamics (pulmonary artery catheter) and renal variables were obtained during two 30-min periods. Renal blood flow was measured using two independent techniques: the renal vein thermodilution technique and the infusion clearance of paraaminohippuric acid, corrected for renal extraction of paraaminohippuric acid. The filtration fraction was measured by the renal extraction of Cr-EDTA and the renal sodium resorption was measured as the difference between filtered and excreted sodium. Renal oxygenation was estimated from the renal oxygen extraction. Cardiac index and mean arterial pressure did not differ between the two groups. In the acute kidney injury group, glomerular filtration (-57%), renal blood flow (-40%), filtration fraction (-26%), and sodium resorption (-59%) were lower, renal vascular resistance (52%) and renal oxygen extraction (68%) were higher, whereas there was no difference in renal oxygen consumption between groups. Renal oxygen consumption for one unit of reabsorbed sodium was 2.4 times higher in acute kidney injury. Renal oxygenation is severely impaired in acute kidney injury after cardiac surgery, despite the decrease in glomerular filtration and tubular workload. This was caused by a combination of renal vasoconstriction and tubular sodium resorption at a high oxygen demand.

The effect or oral glucose ingestion on renal phosphate reabsorption was studied in 13 patients with the inherited form of vitamin D-resistant rickets (VDRR) and 5 normal subjects. In contrast to the normal subjects, glycosuria developed in six VDRR patients after glucose ingestion and resulted in a further 43% decrease in renal phosphate reabsorption. This was accompanied by a 33% increase in phosphate clearance. This was not attended by differences in fasting glucose or phosphorus levels between groups, or in their respective values 1 h after glucose ingestion. Baseline renal phosphate reabsorption was less and baseline phosphate clearance was greater in those VDRR subjects who developed glycosuria. The accumulated data suggest that excessive glucose ingestion by some patients with VDRR may add an additional insult to the phosphaturia characteristic of this disorder. This, in turn, would further compromise the response of circulating phosphate to therapeutic attempts at oral phosphate supplementation, thereby reducing the efficacy of oral phosphate therapy on skeletal growth and development in this disorder.

Perfluorooctanoic acid (PFOA) exposure induces renal filtration and reabsorption disorders via down-regulation of aquaporins

To find out whether insulin-like growth factor-I (IGF-I) mimics the stimulatory effects of growth hormone (GH) on bone turnover and renal tubular phosphate reabsorption. Randomized, crossover study. University Hospital, Zürich, Switzerland. Seven young healthy male subjects. Each subject was studied three times at 2-week intervals, treated with saline 0.9% (S), IGF-I [8 micrograms kg-1 h-1] by a continuous subcutaneous infusion and finally with GH (6 U. twice daily s.c.) for 5 days. 36 h after the start of treatment, IGF-I, biochemical markers of bone turnover, calcium, calcium regulating hormones, kidney function and phosphate reabsorption were measured in serum and in 2 h urine in fasting state. Serum levels of IGF-I were 26.8 +/- 7.3 (S), 119.4 +/- 11.4 (IGF-I) (P < 0.02) and 58.4 +/- 12.9 nmol L-1 (GH) (P < 0.02), respectively. Serum osteocalcin and carboxyterminal propeptide of type I collagen (PICP) as well as the urinary deoxypyridinoline/creatinine and the calcium/ creatinine ratios were all significantly higher after IGF-I (P < 0.02) or GH (P < 0.02) than after saline treatment. PTH levels did not change in response to treatment. Total albumin-corrected calcium increased only after GH treatment (P < 0.05). The free calcitriol index rose from 2.2 +/- 0.5 x 10(-5) (S) to 2.81 +/- 0.25 x 10(-5) (IGF-I) (P < 0.03) and 2.45 +/- 0.25 x 10(-5) (GH), respectively. Serum phosphate and maximal tubular reabsorption divided by glomerular filtration rate (TmP/GFR) were significantly raised by GH (P < 0.03) but not by IGF-I as compared to saline 0.9%. (i) Similar to GH, IGF-I rapidly activates bone turnover. (ii) IGF-I does not mimic the effect of GH on renal phosphate reabsorption in spite of comparable effects on renal blood flow and glomerular filtration rate. (iii) IGF-I increases free calcitriol index in face of unchanged serum levels of calcium, phosphate and PTH, consistent with a direct stimulatory effect on 25-OHD-1a-hydroxylase.

To develop a quantitative drug-disease systems model to investigate the paradox that sodium-glucose co-transporter (SGLT)2 is responsible for >80% of proximal tubule glucose reabsorption, yet SGLT2 inhibitor treatment results in only 30% to 50% less reabsorption in patients with type 2 diabetes mellitus (T2DM). A physiologically based four-compartment model of renal glucose filtration, reabsorption and excretion via SGLT1 and SGLT2 was developed as a system of ordinary differential equations using R/IQRtools. SGLT2 inhibitor pharmacokinetics and pharmacodynamics were estimated from published concentration-time profiles in plasma and urine and from urinary glucose excretion (UGE) in healthy people and people with T2DM. The final model showed that higher renal glucose reabsorption in people with T2DM versus healthy people was associated with 54% and 28% greater transporter capacity for SGLT1 and SGLT2, respectively. Additionally, the analysis showed that UGE is highly dependent on mean plasma glucose and estimated glomerular filtration rate (eGFR) and that their consideration is critical for interpreting clinical UGE findings. Quantitative drug-disease system modelling revealed mechanistic differences in renal glucose reabsorption and UGE between healthy people and those with T2DM, and clearly showed that SGLT2 inhibition significantly increased glucose available to SGLT1 downstream in the tubule. Importantly, we found that the findings of lower than expected UGE with SGLT2 inhibition are explained by the shift to SGLT1, which recovered additional glucose (~30% of total).

Renal lithium reabsorption in man: physiologic and pharmacologic determinants.

Nectar‐feeding birds face a constant challenge in terms of water balance, experiencing water loading when feeding and potential dehydration when fasting. A growing collection of studies is revealing how species across different orders deal with this osmoregulatory challenge. To meet their high mass‐specific energy demands these birds must often deal with exceptionally high proportionate water fluxes. Birds that ingest large volumes of water may either eliminate excess water in the kidney or regulate the volume of water absorbed in the gastrointestinal tract. Across species, renal filtration during feeding periods generally does not exceed allometric predictions and is not highly responsive to water loading, but renal fractional water reabsorption varies with water load as expected. Hummingbirds (Apodiformes) absorb a constant, high proportion of ingested water across the gastrointestinal tract, while sunbirds and honeyeaters (Passeriformes) modulate intestinal water absorption, potentially avoiding significant water loads when feeding on dilute diets. Data suggest that these passerine nectarivores regulate transepithelial water flux independently of sugar absorption, opening the door to intriguing questions about how water transport is regulated in the vertebrate gastrointestinal tract. Despite reducing their intestinal water absorption, these birds show linear increases in water flux and fractional body water turnover as water intake increases, suggesting that the modulation of fractional water absorption is not sufficient to completely offset dietary water loads. Species in both orders exhibit significant diel variation in renal filtration, essentially shutting down renal filtration during overnight fasts and thus avoiding dehydration. Convergence in diet has led to the evolution of many similar traits in hummingbirds and sunbirds, but the physiological traits of these two groups that allow the processing of a watery and sugary diet may be very different.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) reduce glucose levels in diabetes by inhibiting renal glucose reabsorption in the proximal tubule (PT), resulting in urinary glucose excretion. A recent large cardiovascular outcomes trial suggested that the SGLT2i empagliflozin may also decrease risk of renal dysfunction. Because sodium (Na) and glucose reabsorption are coupled through SGLT2, it is hypothesized that the renal benefits may be derived from lowering Na reabsorption in the PT, which would lead to favorable renal hemodynamic changes. However, the quantitative contribution of SGLT2 to PT Na reabsorption, as well as the differences between healthy and diabetic subjects, and the impact of SGLT2i on PT Na reabsorption are unknown. In this study we extended an existing mathematical model of glucose dynamics to account for renal glucose filtration and excretion. We utilized this model to quantify glucose and Na reabsorption through SGLT2 in healthy, controlled, and uncontrolled diabetes and following treatment with canagliflozin. In healthy, controlled diabetic, and uncontrolled diabetic states, Na reabsorption through SGLT2 was found to be 5.7%, 11.5%, and 13.7% of total renal Na reabsorption, and 7.1% to 9.5%, 14.4% to 19.2%, and 17.1% to 22.8% of sodium reabsorption in the PT alone. The model predicted that treatment of controlled diabetes with canagliflozin returns PT Na reabsorption through SGLT2 to normal levels. The degree of increased PT Na reabsorption due to SGLT2 is likely sufficient to drive pathologic changes in renal hemodynamics, and restoration of normal Na reabsorption through SGLT2 may contribute to beneficial renal effects of SGLT2 inhibition.

Glucose homeostasis is highly controlled, and the function of the kidney plays an integral role in this process. The exquisite control of blood glucose relies, in part, on renal glucose filtration, renal glucose reabsorption, and renal gluconeogenesis. Particularly critical to maintaining glucose homeostasis is the renal reabsorption of glucose; with ~162 g of glucose filtered by the kidney per day, it is imperative that the kidney have the ability to efficiently reabsorb nearly 100% of this glucose back in the bloodstream. In this review, we focus on this central process, highlighting the renal transporters and regulators involved in both the physiology and pathophysiology of glucose reabsorption.

BackgroundApplication of idarucizumab and hemodialysis are options to reverse the action of the oral anticoagulant dabigatran in emergency situations.ObjectivesThe objectives of this study were to build and evaluate a mechanistic, whole-body physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of idarucizumab, including its effects on dabigatran plasma concentrations and blood coagulation, in healthy and renally impaired individuals, and to include the effect of hemodialysis on dabigatran exposure.MethodsThe idarucizumab model was built with the software packages PK-Sim® and MoBi® and evaluated using the full range of available clinical data. The default kidney structure in MoBi® was extended to mechanistically describe the renal reabsorption of idarucizumab and to correctly reproduce the reported fractions excreted into urine. To model the PD effects of idarucizumab on dabigatran plasma concentrations, and consequently also on blood coagulation, idarucizumab-dabigatran binding was implemented and a previously established PBPK model of dabigatran was expanded to a PBPK/PD model. The effect of hemodialysis on dabigatran was implemented by the addition of an extracorporeal dialyzer compartment with a clearance process governed by dialysate and blood flow rates.ResultsThe established idarucizumab-dabigatran-hemodialysis PBPK/PD model shows a good descriptive and predictive performance. To capture the clinical data of patients with renal impairment, both glomerular filtration and tubular reabsorption were modeled as functions of the individual creatinine clearance.ConclusionsA comprehensive and mechanistic PBPK/PD model to study dabigatran reversal has been established, which includes whole-body PBPK modeling of idarucizumab, the idarucizumab-dabigatran interaction, dabigatran hemodialysis, the pharmacodynamic effect of dabigatran on blood coagulation, and the impact of renal function in these different scenarios. The model was applied to explore different reversal scenarios for dabigatran therapy.Electronic supplementary materialThe online version of this article (10.1007/s40262-019-00857-y) contains supplementary material, which is available to authorized users.

Neuropeptide Y (NPY) is a potent vasoconstrictor peptide contained in sympathetic nerve terminals and is co-released with norepinephrine. Previous studies in the rat have suggested that NPY influences renal sodium reabsorption and renin release. However, little is known about the physiological effects of NPY on the kidney in the human. In the present study NPY was infused intravenously and directly into the renal artery of the primate Macaca fascicularis, an experimental model of the human. Intravenous NPY infusion at doses of 20-1,000 ng.kg-1.min-1 produced dose-dependent rises in renal vascular resistance with minimal changes in arterial pressure. Urine flow and sodium excretion were changed significantly only at doses of NPY that significantly reduced renal blood flow and filtration rate. Arterial plasma renin activity and renin secretion rate were not significantly altered at any dose of NPY. Intrarenal infusion of NPY at doses of 20-400 ng.kg-1.min-1 produced potent dose-dependent renal vasoconstriction with minimal changes in arterial pressure. Under these conditions sodium excretion was significantly reduced concurrent with decreases in renal blood flow and glomerular filtration rate. However, no significant changes in arterial plasma renin activity or renin secretion rate were found at any dose of NPY. These data indicate that in the nonhuman primate NPY is a potent renal vasoconstrictor agent that has variable effects on renal excretory and secretory function, which may be secondary to its vasoconstrictor actions.

Imbalance of the renal medullary oxygen supply/demand relationship can cause hypoxic medullary damage and ischaemic acute renal failure (ARF). The use of mannitol for prophylaxis/treatment of clinical ischaemic ARF is controversial and the effect of mannitol on renal oxygenation in man has not yet been investigated. We evaluated the effects of mannitol on renal oxygen consumption (RVO(2))(,) renal blood flow (RBF) and glomerular filtration rate (GFR) in postoperative patients. Prospective interventional study. University hospital cardiothoracic ICU. Ten uncomplicated mechanically ventilated and sedated postcardiac surgery patients with preoperatively normal renal function. Mannitol infusion (225 mg/kg + 75 mg/kg/h) and combined mannitol and furosemide infusion (0.25 mg/kg + 0.25 mg/kg/h). Systemic haemodynamics were evaluated by a pulmonary artery catheter. RBF and GFR were measured by the renal vein thermodilution technique and by renal extraction of (51)Cr-EDTA, respectively. Mannitol increased urine flow (60%), GFR (20%) and filtration fraction (FF) (20%) with no change in RBF. This was accompanied by an increase in renal sodium reabsorption (18%), RVO(2) (19%) and renal oxygen extraction (21%). When combined with mannitol, furosemide normalised sodium reabsorption, RVO(2), renal oxygen extraction with no change in RBF, while GFR and FF were still elevated compared to control. In patients with normal renal function, mannitol increases GFR, which increases tubular sodium load, sodium reabsorption and RVO(2) after cardiac surgery. The lack of effect on RBF, indicates that mannitol impairs the renal oxygen supply/demand relationship. Furosemide normalised renal oxygenation when combined with mannitol.

Plasma activity and excretion of pancreatic (P) amylase in the rat was found to be negligible. In contrast, the excretion rate of salivary (S) amylase was substantial and variable, depending on diuresis. P-amylase had a higher isoelectric point, a greater sieving coefficient, and a shorter half-life than S-amylase. A bolus injection of 125I-labelled enzymes was followed by the appearance of 125I-labelled enzyme- as well as protein-free 125I activity in the urine. The enzyme loss was smaller and the fraction of protein-free 125I activity higher following injection of P-amylase. The affinity of P-amylase to paraffin oil exceeded that of S-amylase in partition experiments with water and paraffin oil in vitro. It is concluded that both renal filtration and reabsorption of P-amylase exceed those of S-amylase. This might be due to the higher lipophility of P-amylase in comparison to the salivary type.