Nephron Glomerular Filtration Rate Research Articles

Relationship between cortical and medullary thickness and glomerular filtration rate among living kidney donors.

The relationship between the kidney cortex and medulla is not well understood in healthy populations. This study characterised the relationship between cortical/medullary thickness and measured glomerular filtration rate (GFR) in 390 living kidney donors. A positive relationship was observed between medullary, but not cortical, thickness and GFR. We propose that this reflects a correlation between juxtamedullary nephron number and GFR.

PS-BPB08-6: REGULATORY MECHANISM OF GLOMERULAR FILTRATION RATE BY THE KEAP1/NRF2 PATHWAY

The activation of the Kelch like ECH associated protein 1 (Keap1)/nuclear factor (erythroid derived 2) like 2 (Nrf2) pathway increases glomerular filtration rate (GFR) in patients with type 2 diabetes and chronic kidney disease. However, the mechanisms whereby the Keap1/Nrf2 pathway regulates GFR are unknown. C57BL/6 mice (WT), Nrf2 deficient mice, and Nrf2 activated Keap1 knockdown mice were compared, and RTA dh404 (CDDO dhTFEA) was used as a Nrf2 activator. Glomerular hemodynamics and the permeability of glomeruli to macromolecules were evaluated using laser Doppler techniques and in vivo imaging. Calcium influx and the rearrangement of the actin cytoskeleton in response to angiotensin II, H2O2, the Nrf2 activator dh404, and transient receptor potential cation channel, subfamily C (TRPC) channel inhibitors were evaluated in podocytes. Finally, the effects of a TRPC6 inhibitor on GFR were investigated in vivo. Pharmacological and genetic Keap1/Nrf2 activation increased renal blood flow (p < 0.05), glomerular volume (p < 0.05), and GFR (p < 0.05), but did not alter afferent or efferent arteriolar diameter or glomerular permeability. Calcium influx into podocytes through TRPC channels in response to angiotensin II or H2O2 was suppressed by Keap1/Nrf2 activation. TRPC inhibitors and dh404 reduced the activation of the small GTPase(RhoA)/Rho associated kinase 1/LIM domain kinase 1/cofilin pathway and the subsequent actin rearrangement induced by angiotensin II or H2O2. Treatment with a TRPC6 inhibitor increased single nephron GFR in WT mice. In conclusion, the Keap1/Nrf2 pathway regulates GFR through changes in ultrafiltration via intracellular calcium signaling and cellular contractility, mediated through TRPC activity, in glomerular cells.

Obesity Facts and Their Influence on Renal Function Across the Life Span

Obesity is a chronic disease, with a rapidly increasing prevalence worldwide. Body mass index (BMI) provides the most useful population-level measure of overweight and obesity. For adults, overweight is defined as a BMI (Kg/m2) ≥ 25, and obesity as a BMI ≥ 30, for non-Asians and ≥ 27.5 for Asians. Abdominal obesity can be defined as a waist circumference equal to or higher than 102 cm for men and ≥88 cm for women. The definition of children and adolescents BMI changes with age and sex. Obesity may be exogenous or endogenous obesity, the latter is multifactorial and predominantly manifested during childhood. Presently, overweight and obesity are linked to more deaths worldwide than underweight. The total kidney glomerular filtration rate (GFR) is determined by the sum of nephrons and the GFR within each nephron or single nephron GFR. In clinical practice, GFR is more frequently calculated by GFR estimating equations based upon the plasma levels of creatinine, cystatin C, or both. The measured value of plasma creatinine is strongly influenced by non-GFR factors, by its tubular and gastrointestinal secretion, and by the problems associated with the lack of standardization of creatinine's laboratory assay discrediting it as an ideal GFR biomarker. Unlike creatinine, cystatin C plasma levels are mainly determined by GFR. Obesity may affect the kidney, via development of systemic arterial hypertension and/or diabetes mellitus, or directly, by ectopic accumulation of adipose tissue in the kidney. As obesity is a clinical condition associated with altered body composition, creatinine may not be the ideal biomarker for GFR measurement in obese individuals.

A new analysis approach for single nephron GFR in intravital microscopy of mice

Background: Intravital microscopy is an emerging technique in life science with applications in kidney research. Longitudinal observation of (patho-)physiological processes in living mice is possible in the smallest functional unit of the kidney, a single nephron (sn). In particular, effects on glomerular filtration rate (GFR) - a key parameter of renal function - can be assessed. Methods: After intravenous injection of a freely filtered, non-resorbable, fluorescent dye in C57BL/6 mice, a time series was captured by multiphoton microsopy. Filtration was observed from the glomerular capillaries to the proximal tubule (PT) and the tubular signal intensity shift was analyzed to calculate the snGFR. Results: Previously described methods for snGFR analysis relied on two manually defined measurement points in the PT and the tubular volume was merely estimated in 2D images. We present an extended image processing workflow by adding continuous measurement of intensity along the PT in every frame of the time series using ImageJ. Automatic modelling of actual PT volume in a 3D dataset replaced 2D volume estimation. Subsequent data analysis in R, with a calculation of intensity shifts in every frame and normalization against tubular volume, allowed exact assessment of snGFR by linear regression. Repeated analysis of image data obtained in healthy mice showed a striking increase of reproducibility by reduction of user interaction. Conclusions: These improvements in image processing and data analysis maximize the reliability of a sophisticated intravital microscopy technique for the precise assessment of snGFR, a highly relevant predictor of kidney function.

A new analysis approach for single nephron GFR in intravital microscopy of mice.

Background: Intravital microscopy is an emerging technique in life science with applications in kidney research. Longitudinal observation of (patho-)physiological processes in living mice is possible in the smallest functional unit of the kidney, a single nephron (sn). In particular, effects on glomerular filtration rate (GFR) - a key parameter of renal function - can be assessed. Methods: After intravenous injection of a freely filtered, non-resorbable, fluorescent dye in C57BL/6 mice, a time series was captured by multiphoton microsopy. Filtration was observed from the glomerular capillaries to the proximal tubule (PT) and the tubular signal intensity shift was analyzed to calculate the snGFR. Results: Previously described methods for snGFR analysis relied on two manually defined measurement points in the PT and the tubular volume was merely estimated in 2D images. We present an extended image processing workflow by adding continuous measurement of intensity along the PT in every frame of the time series using ImageJ. Automatic modelling of actual PT volume in a 3D dataset replaced 2D volume estimation. Subsequent data analysis in R, with a calculation of intensity shifts in every frame and normalization against tubular volume, allowed exact assessment of snGFR by linear regression. Repeated analysis of image data obtained in healthy mice showed a striking increase of reproducibility by reduction of user interaction. Conclusions: These improvements in image processing and data analysis maximize the reliability of a sophisticated intravital microscopy technique for the precise assessment of snGFR, a highly relevant predictor of kidney function.

A new analysis approach for single nephron GFR in intravital microscopy of mice

Background: Intravital microscopy is an emerging technique in life science with applications in kidney research. Longitudinal observation of (patho-)physiological processes in living mice is possible in the smallest functional unit of the kidney, a single nephron (sn). In particular, effects on glomerular filtration rate (GFR) - a key parameter of renal function - can be assessed. Methods: After intravenous injection of a freely filtered, non-resorbable, fluorescent dye in C57BL/6 mice, a time series was captured by multiphoton microsopy. Filtration was observed from the glomerular capillaries to the proximal tubule (PT) and the tubular signal intensity shift was analyzed to calculate the snGFR. Results: Previously described methods for snGFR analysis relied on two manually defined measurement points in the PT and the tubular volume was merely estimated in 2D images. We present an extended image processing workflow by adding continuous measurement of intensity along the PT in every frame of the time series using ImageJ. Automatic modelling of actual PT volume in a 3D dataset replaced 2D volume estimation. Subsequent data analysis in R, with a calculation of intensity shifts in every frame and normalization against tubular volume, allowed exact assessment of snGFR by linear regression. Repeated analysis of image data obtained in healthy mice showed a striking increase of reproducibility by reduction of user interaction. Conclusions: These improvements in image processing and data analysis maximize the reliability of a sophisticated intravital microscopy technique for the precise assessment of snGFR, a highly relevant predictor of kidney function.

A new analysis approach for single nephron GFR in intravital microscopy of mice

Background: Intravital microscopy is an emerging technique in life science with applications in kidney research. Longitudinal observation of (patho-)physiological processes in living mice is possible in the smallest functional unit of the kidney, a single nephron (sn). In particular, effects on glomerular filtration rate (GFR) - a key parameter of renal function - can be assessed. Methods: After intravenous injection of C57BL/6 mice with a freely filtered, non-resorbable, fluorescent dye a time series was captured by multiphoton microsopy. Filtration was observed from the glomerular capillaries to the proximal tubule (PT) and the tubular signal intensity shift was analyzed to calculate the snGFR. Results: Previous methods for this analysis relied on two manually defined measurement points in the PT and the tubular volume was merely estimated in 2D images. We extended the workflow in FIJI by adding continuous measurement of intensity along the PT in every frame of the time series. Automatic modelling of actual PT volume in a 3D dataset replaced 2D volume estimation. Subsequent data analysis in R, with a calculation of intensity shifts in every frame and normalization against tubular volume, allowed exact assessment of snGFR by linear regression. Repeated analysis of image data obtained in healthy mice showed a striking increase of reproducibility by reduction of user interaction. Conclusions: These improvements maximize the reliability of a sophisticated intravital microscopy technique for the precise assessment of snGFR, a highly relevant predictor of kidney function.

Renal functional reserve: from physiological phenomenon to clinical biomarker and beyond.

Glomerular filtration rate (GFR) is acutely increased following a high-protein meal or systemic infusion of amino acids. The mechanisms underlying this renal functional response remain to be fully elucidated. Nevertheless, they appear to culminate in preglomerular vasodilation. Inhibition of the tubuloglomerular feedback signal appears critical. However, nitric oxide, vasodilator prostaglandins, and glucagon also appear important. The increase in GFR during amino acid infusion reveals a "renal reserve," which can be utilized when the physiological demand for single nephron GFR increases. This has led to the concept that in subclinical renal disease, before basal GFR begins to reduce, renal functional reserve can be recruited in a manner that preserves renal function. The extension of this concept is that once a decline in basal GFR can be detected, renal disease is already well progressed. This concept likely applies both in the contexts of chronic kidney disease and acute kidney injury. Critically, its corollary is that deficits in renal functional reserve have the potential to provide early detection of renal dysfunction before basal GFR is reduced. There is growing evidence that the renal response to infusion of amino acids can be used to identify patients at risk of developing either chronic kidney disease or acute kidney injury and as a treatment target for acute kidney injury. However, large multicenter clinical trials are required to test these propositions. A renewed effort to understand the renal physiology underlying the response to amino acid infusion is also warranted.

Chronic sodium bicarbonate may promote metabolic dysregulation in a rodent model of CKD

Chronic kidney disease (CKD) has no cure, and few treatment options targeted at slowing the decline in glomerular filtration rate (GFR). Several small clinical trials have indicated that oral sodium bicarbonate (NaHCO3) targets and slows the decline in GFR in CKD. The reported beneficial effects of NaHCO3 in this setting have led to its now common use clinically. It’s known however, that chronic alkali ingestion can promote potassium (K+) wasting, and that K+ depletion has been linked with metabolic dysregulation. Further, CKD patients who are supplemented chronically with oral NaHCO3 display significantly decreased plasma K+ levels relative to control treated counterparts, although these decreases in plasma K+ remain within normal range. No study has investigated the metabolic impacts of chronic NaHCO3 treatment and K+ wasting in CKD. To this end, we tested the hypothesis that in the setting of high tubular flow, chronic NaHCO3 ingestion would promote K+ wasting and metabolic dysfunction. In order to test our hypothesis, 9 male, 8 wk old Sprague Dawley (SD) rats underwent a 2/3 nephrectomy (Nx) and telemetry implantation. The 2/3 Nx is a model of reduced renal mass that has increased single nephron GFR in the absence of metabolic acidosis, similar to most human patients with CKD. Following 4 weeks of recovery, animals were given either 0.1M NaHCO3 (Bicarb, n=3), 0.1M NaCl (Vehicle, n=3) or 0.2M NH4Cl‐NaHCO3 (AC/B, n=3) in the drinking water for 12 weeks. Following 9 weeks of drinking water treatment, we observed a significantly higher hemoglobin A1c in our bicarb treated group compared to vehicle and AC/B treated groups (Bicarb 4.6 ± 0.1 vs Veh 4.2 ± 0.3 vs AC/B 4.2 ± 0.2; One‐way ANOVA, p=0.05). Following another 3 weeks of drinking water treatment, we performed blood gas measurements to assess plasma K+. In contrast to our hypothesis we observed the highest levels of plasma K+ in our bicarb treated animals compared to our vehicle or AC/B groups (Bicarb 5.18 ± 0.28 vs Veh 4.48 ± 0.66 vs AC/B 4.5 ± 0.21; One‐way ANOVA, p=0.16). Our data show that oral NaHCO3 could worsen blood glucose control in the setting of high tubular flow. Additionally, plasma K+ may not be a reliable measure for assessment of K+ status in CKD patients supplemented with NaHCO3. As the majority of K+ is stored intracellularly, further studies characterizing the effect of chronic alkali ingestion on total body K+ are warranted to assess the impact of NaHCO3 on K+ depletion in this patient population.Support or Funding InformationNIH PO1H134604 and DK099548

In-vivo techniques for determining nephron number.

Many studies have suggested low nephron endowment at birth contributes to the risk of developing hypertension and chronic kidney disease (CKD) later in life. Loss of nephrons with age and disease is largely a subclinical process. New technologies are needed to count nephrons as glomerular filtration rate (GFR) is a poor surrogate for nephron number. Cortical volume, glomerular density, and percent globally sclerotic glomeruli are imperfect surrogates for nephron number. The disector-fractionator method is the most accurate method to count nephrons but is limited to autopsy settings. Glomerular density combined with kidney imaging and ultrafiltration coefficient-based methods require a kidney biopsy, and have been applied in living humans (kidney donors). Low nephron number predicts a higher postdonation urine albumin. Contrast-enhanced MRI has detected glomeruli without a biopsy, but so far, not in living humans. Currently, there is no accurate and well tolerated method for determining nephron number in living humans. A clinically useful method may allow GFR to be replaced by its more relevant determinants: nephron number and single nephron GFR. This could revolutionize nephrology by separating the measurement of chronic disease (nephron loss) from more reversible hemodynamic effects (nephron hyperfiltration/hypofiltration).

Impaired SIRT1 activity leads to diminution in glomerular endowment without accelerating age-associated GFR decline.

Glomerular filtration rate (GFR) declines with age such that the prevalence of chronic kidney disease is much higher in the elderly. SIRT1 is the leading member of the sirtuin family of NAD +‐dependent lysine deacetylases that mediate the health span extending properties of caloric restriction. Since reduction in energy intake has also been shown to decrease age‐related kidney disease in rodents, we hypothesized that a diminution in SIRT1 activity would accelerate the GFR decline and structural injury with age. To test this hypothesis, we compared changes in the kidney structure and function in control mice and mice that carry a point mutation at a conserved histidine (H355Y) of SIRT1 that renders the enzyme catalytically inactive. Taking advantage of this mouse model along with the disector/fractionator technique for glomerular counting and direct measurements of GFR by inulin clearance, we assessed the impact of SIRT1 inactivity on kidney aging. At 14 months of age, SIRT1 catalytically inactive (Sirt1 Y/Y) mice had lower GFRs and fewer glomeruli than their wild‐type (Sirt1 +/+) counterparts. This was not, however, due to either accelerated GFR decline or increased glomerulosclerosis and loss, but rather to reduced glomerular endowment in Sirt1 Y/Y mice. Moreover, the compensatory glomerular hypertrophy and elevated single nephron GFR that customarily accompany reduction in nephron number were absent in Sirt1 Y/Y mice. These findings suggest a role for SIRT1 not only in determining nephron endowment but also in orchestrating the response to it.

A mathematical model of the rat nephron: glucose transport

Mathematical models of the proximal tubule (PT), loop of Henle (LOH), and distal nephron have been combined to simulate transport by rat renal tubules. The ensemble is composed of 24,000 superficial (SF) nephrons and 12,000 juxtamedullary (JM) nephrons in 5 classes (according to LOH length); all coalesce into 7,200 connecting tubules (CNT). Medullary interstitial solute concentrations are specified. The model equations require that each nephron glomerular filtration rate (GFR) satisfies a tubuloglomerular feedback (TGF) relationship, and each initial hydrostatic pressure yields a common CNT pressure; that common CNT pressure is determined from an overall distal hydraulic resistance to flow. By virtue of the greater GFR for JM nephrons, fluid delivery to SF and JM tubules is comparable. Glucose reabsorption is restricted to the PT, cotransported with one Na in the convoluted tubule (SGLT2), and two Na in the straight tubule (SGLT1). Increasing ambient glucose from 5 to 10 mM increases proximal Na reabsorption and decreases distal delivery. This is mitigated by a TGF-mediated increase in GFR, and may thus be an etiology for TGF-mediated glomerular hyperfiltration. With SGLT2 inhibition by 95%, the model predicts that under normoglycemic conditions about 60% of filtered glucose will still be reabsorbed, so that profound glycosuria is not to be expected. Compared with glucose-driven osmotic diuresis, SGLT2 inhibition provokes greater natriuresis. When hyperglycemia is superimposed on SGLT2 inhibition, the model suggests that natriuresis may be severe, reflecting synergy of a proximal diuretic and osmotic diuresis. In sum, the model captures TGF-mediated diabetic hyperfiltration and predicts glomerular protection with SGLT2 inhibition.

Nephron filtration rate and proximal tubular fluid reabsorption in the Akita mouse model of type I diabetes mellitus

An increase of glomerular filtration rate (hyperfiltration) is an early functional change associated with type I or type II diabetes mellitus in patients and animal models. The causes underlying glomerular hyperfiltration are not entirely clear. There is evidence from studies in the streptozotocin model of diabetes in rats that an increase of proximal tubular reabsorption results in the withdrawal of a vasoconstrictor input exerted by the tubuloglomerular feedback (TGF) mechanism. In the present study, we have used micropuncture to assess single nephron function in wild type (WT) mice and in two strains of type I diabetic Ins2+/- mice in either a C57Bl/6 (Akita) or an A1AR-/- background (Akita/A1AR-/-) in which TGF is non-functional. Kidney glomerular filtration rate (GFR) of anesthetized mice was increased by 25% in Akita mice and by 52% in Akita/A1AR-/-, but did not differ between genotypes when corrected for kidney weight. Single nephron GFR (SNGFR) measured by end-proximal fluid collections averaged 11.8 ± 1 nl/min (n=17), 13.05 ± 1.1 nl/min (n=23; p=0.27), and 15.4 ± 0.84 nl/min (n=26; p=0.009 compared to WT; p=0.09 compared to Akita) in WT, Akita, and Akita/A1AR-/- mice respectively. Proximal tubular fluid reabsorption was not different between WT and diabetic mice and correlated with SNGFR in all genotypes. We conclude that glomerular hyperfiltration is a primary event in the Akita model of type I diabetes, perhaps driven by an increased filtering surface area, and that it is ameliorated by TGF to the extent that this regulatory system is functional.

Independent two-photon measurements of albumin GSC give low values

Independent two-photon measurements of albumin GSC give low values

Ornithine decarboxylase inhibitor eliminates hyperresponsiveness of the early diabetic proximal tubule to dietary salt

Heightened sensitivity of the diabetic proximal tubule to dietary salt leads to a paradoxical effect of salt on glomerular filtration rate (GFR) via tubuloglomerular feedback. Diabetic hyperfiltration is a feedback response to growth and hyperreabsorption by the proximal tubule. The present studies were performed to determine whether growth and hyperfunction of the proximal tubule are essential for its hyperresponsiveness to dietary salt and, hence, to the paradoxical effect of dietary salt on GFR. Micropuncture was performed in four groups of inactin-anesthetized Wistar rats after 10 days of streptozotocin diabetes drinking tap water or 1% NaCl. Kidney growth was suppressed with ornithine decarboxylase (ODC) inhibitor, DFMO (200 mg.kg(-1).day(-1)), or placebo. Single nephron GFR (SNGFR) was manipulated by perfusing Henle's loop so that proximal reabsorption (Jprox) could be expressed as a function of SNGFR in each nephron, dissociating primary effects on the tubule from the effects of glomerulotubular balance. Alone, DFMO or high salt reduced SNGFR and suppressed Jprox independent of SNGFR. Suppression of Jprox was eliminated and SNGFR increased when high salt was given to rats receiving DFMO. ODC is necessary for hyperresponsiveness of the proximal tubule to dietary salt and for the paradoxical effect of dietary salt on GFR in early diabetes. This coupling of effects adds to the body of evidence that feedback from the proximal tubule is the principal governor of glomerular filtration in early diabetes.

L-arginine-induced glomerular hyperfiltration response: the roles of insulin and ANG II

Infusion of L-arginine produces an increase in glomerular filtration via kidney vasodilation, correlating with increased kidney excretion of nitric oxide (NO) metabolites, but the specific underlying mechanisms are unknown. We utilized clearance and micropuncture techniques to examine the whole kidney glomerular filtration rate (GFR) and single nephron GFR (SNGFR) responses to 1) L-arginine (ARG), 2) ARG+octreotide (OCT) to block insulin release, 3) ARG+OCT+insulin (INS) infusion to duplicate ARG-induced insulin levels, and 4) losartan (LOS), an angiotensin AT-1 receptor blocker, +ARG+OCT. ARG infusion increased GFR, while increasing insulin levels. OCT coinfusion prevented this increase in GFR, but with insulin infusion to duplicate ARG induced rise in insulin, the GFR response was restored. Identical insulin levels in the absence of ARG had no effect on GFR. In contrast to ARG infusion alone, coinfusion of OCT with ARG reduced proximal tubular fractional and absolute reabsorption potentially activating tubuloglomerular feedback. Losartan infusion, in addition to ARG and OCT (LOS+ARG+OCT), restored the increase in both SNGFR and proximal tubular reabsorption, without increasing insulin levels. In conclusion, 1) hyperfiltration responses to ARG require the concurrent, modest, permissive increase in insulin; 2) inhibition of insulin release after ARG reduces proximal reabsorption and prevents the hyperfiltration response; and 3) inhibition of ANG II activity restores the hyperfiltration response, maintains parallel increases in proximal reabsorption, and overrides the arginine/octreotide actions.

Making sense of the sensor: Mysteries of the macula densa

Increases in luminal NaCl concentration at the macula densa (MD), the sensing element, activate tubuloglomerular feedback (TGF). MD cell volume increases when increments are isosmotic and shrinks if osmolality increases. This interesting finding introduces additional complexity to the role of the MD in TGF.

Ecto-5′-nucleotidase (cd73)-dependent and -independent generation of adenosine participates in the mediation of tubuloglomerular feedback in vivo

Tubuloglomerular feedback (TGF) describes a sequence of events linking salt concentrations in tubular fluid at the macula densa to the vascular tone of the afferent arteriole and thus to the glomerular filtration rate (GFR) of the same nephron. The signal transduction pathways of TGF remain incompletely understood, but both ATP release from macula densa cells and local formation of adenosine were suggested to be involved in the process. To test the role of extracellular formation of adenosine by ecto-5'-nucleotidase (cd73) in TGF, in regulation of GFR, and in tubular reabsorption, renal clearance and micropunture experiments were performed in cd73 wild-type (cd73(+/+)) and knockout mice (cd73(-/-)). The cd73(-/-) mice presented normal mean arterial blood pressure, but modestly lower whole kidney and single nephron GFR (SNGFR). Fractional reabsorption of Na(+) and K(+) up to the late proximal tubule, distal tubule, as well as urine were not significantly different between cd73(-/-) and cd73(+/+) mice. Lack of cd73 resulted in a diminished TGF response, as indicated by smaller changes of stop-flow pressure in response to increasing loop of Henle perfusion from 0 to 25 nl/min, smaller differences in SNGFR determined from paired proximal and distal tubular collections, and by smaller fractional changes of distal SNGFR in response to adding 6 nl/min of artificial tubular fluid to free-flowing proximal tubules. The TGF response in cd73(+/+) mice and the residual TGF response in cd73(-/-) mice were completely inhibited by adenosine A(1)-receptor blockade. The results suggest that extracellular formation of adenosine by ecto-5'-nucleotidase (cd73) is dispensable for normal fluid, Na(+), or K(+) reabsorption along the nephron, but contributes to the regulation of GFR. Adenosine generated by both ecto-5'-nucleotidase (cd73)-dependent and -independent mechanisms participates in the mediation of TGF in vivo.

Effect of acute iNOS inhibition on glomerular function in tubulointerstitial nephritis

Tubulointerstitial nephritis (TIN) is characterized by progressive inflammatory infiltrate of the renal interstitium, induction of cortical tubular inducible nitric oxide synthase (iNOS) and reductions in glomerular filtration rate (GFR). These studies were designed to examine the changes in glomerular hemodynamics 7 and 21 days after induction of TIN and to evaluate the effect of acute iNOS blockade on glomerular function in the early stages of this model. TIN was induced by immunizing Brown Norway rats with renal tubular antigen in complete Freund's adjuvant (RTA/CFA). Control rats were immunized with CFA alone. Micropuncture and morphologic studies were performed 7 and 21 days after immunization. Histology revealed minimal peritubular and interstitial inflammation in the RTA/CFA group one week after immunization while extensive interstitial inflammation with few preserved superficial nephron was observed three weeks after RTA/CFA immunization. Micropuncture studies on day 7 in the RTA/CFA group revealed a significant reduction in single nephron GFR due to a profound reduction in nephron plasma flow and in the ultrafiltration coefficient. Studies performed on day 21 revealed that single nephron GFR (SNGFR), nephron plasma flow (SNPF) and the ultrafiltration coefficient had returned to the normal baseline value despite the severe reduction in GFR. To assess the role of increased nitric oxide production secondary to iNOS induction on the glomerular hemodynamic changes observed in the early stages of the disease, the iNOS blocker (l-N(6)-iminoethyl lysine, L-NIL) was administered IV (1 mg/h) in RTA/CFA rats and CFA rats. L-NIL had no effect in CFA rats but produced significant increases in GFR, SNGFR and SNPF in RTA/CFA rats. These results demonstrate that TIN is associated with a progressive reduction in GFR, which is likely the result of functional vasoconstriction and decreases in the ultrafiltration coefficient in the early stages of the disease and on a significant reduction in the number of functioning nephron in the later stages. Induction of iNOS with increased NO production actively participates in the functional changes observed in the early stages of the disease most likely by inhibiting normal endothelial NOS activity.

Effects of the angiotensin converting enzyme inhibitor benazepril in cats with induced renal insufficiency.

To determine effects of the angiotensin converting enzyme inhibitor benazepril in cats with induced renal insufficiency. 32 cats. Renal mass was surgically reduced, and cats were assigned to 1 of 4 eight-cat groups. Group 1 received placebo, whereas groups 2, 3, and 4 received benazepril hydrochloride orally once daily for approximately 6.5 months at the following doses: group 2, 0.25 to 0.50 mg/kg of body weight; group 3, 0.50 to 1.00 mg/kg; and group 4, 1.00 to 2.00 mg/kg. Arterial blood pressures, glomerular filtration rate (GFR), and renal plasma flow were determined before treatment and during the treatment period. Other determinants of renal hemodynamics were measured by use of micropuncture techniques. Renal biopsy specimens were examined microscopically. Compared with cats that received placebo, mean systolic arterial blood pressure was significantly less and GFR significantly greater in cats that received benazepril. Glomerular capillary pressure and the ratio of efferent to afferent arteriolar vascular resistance were also significantly less in treated cats. However, histologic differences in renal specimens were not detected. Treatment with benazepril sustained single nephron GFR in remnant nephrons of cats with induced renal insufficiency. Administration of benazepril was also associated with a small but significant reduction in degree of systemic hypertension and an increase in whole kidney GFR. Benazepril may be an effective treatment to slow the rate of progression of renal failure in cats with renal disease.