GFR estimation is complicated by a high incidence of non-steady-state serum creatinine concentrations at the emergency department.

BACKGROUND: Acquiring a reliable estimate of glomerular filtration rate (eGFR) at the emergency department (ED) is important for clinical management and for dosing renally excreted drugs. However, renal function formulas such as CKD-EPI can give biased results when serum creatinine (SCr) is not in steady-state because the assumption that urinary creatinine excretion is constant is then invalid. We assessed the extent of this by analysing variability in SCr in patients who visited the ED of a tertiary care centre. METHODS: Data from ED visits at the University Medical Centre Utrecht, the Netherlands between 2012 and 2019 were extracted from the Utrecht Patient Oriented Database. Three measurement time points were defined for each visit: last SCr measurement before visit as baseline (SCr-BL), first measurement during visit (SCr-ED) and a subsequent measurement between 6 and 24 hours during admission (SCr-H1). Non-steady-state SCr was defined as exceeding the Reference Change Value (RCV), with 15% decrease or 18% increase between successive SCr measurements. Exceeding the RCV was deemed as a significant change. RESULTS: Of visits where SCr-BL and SCr-ED were measured (N = 47,540), 28.0% showed significant change in SCr. Of 17,928 visits admitted to the hospital with a SCr-H1 after SCr-ED, 27,7% showed significant change. More than half (55%) of the patients with SCr values available at all three timepoints (11,054) showed at least one significant change in SCr over time. CONCLUSION: One third of ED visits preceded and/or followed by creatinine measurement show non-stable serum creatinine concentration. At the ED automatically calculated eGFR should therefore be interpreted with great caution when assessing kidney function.

Defining the variety of cell types in developing and adult human kidneys by single-cell RNA sequencing.

The kidney is among the most complex organs in terms of the variety of cell types. The cellular complexity of human kidneys is not fully unraveled and this challenge is further complicated by the existence of multiple progenitor pools and differentiation pathways. Researchers disagree on the variety of renal cell types due to a lack of research providing a comprehensive picture and the challenge to translate findings between species. To find an answer to the number of human renal cell types, we discuss research that used single-cell RNA sequencing on developing and adult human kidney tissue and compares these findings to the literature of the pre-single-cell RNA sequencing era. We find that these publications show major steps towards the discovery of novel cell types and intermediate cell stages as well as complex molecular signatures and lineage pathways throughout development. The variety of cell types remains variable in the single-cell literature, which is due to the limitations of the technique. Nevertheless, our analysis approaches an accumulated number of 41 identified cell populations of renal lineage and 32 of non-renal lineage in the adult kidney, and there is certainly much more to discover. There is still a need for a consensus on a variety of definitions and standards in single-cell RNA sequencing research, such as the definition of what is a cell type. Nevertheless, this early-stage research already proves to be of significant impact for both clinical and regenerative medicine, and shows potential to enhance the generation of sophisticated in vitro kidney tissue.

Exenatide twice-daily does not affect renal function or albuminuria compared to titrated insulin glargine in patients with type 2 diabetes mellitus: A post-hoc analysis of a 52-week randomised trial.

AIMS: To compare the effects of long-term treatment with the GLP-1RA exenatide twice-daily versus titrated insulin glargine (iGlar) on renal function and albuminuria in type 2 diabetes (T2DM) patients. METHODS: We post-hoc evaluated renal outcome-data of 54 overweight T2DM patients (mean  ±â€¯SD age 60 ±â€¯8 years, HbA1c 7.5 ±â€¯0.9%, eGFR 86 ±â€¯16 mL/min/1.73 m2, median [IQR] urinary albumin-to-creatinine-ratio (UACR) 0.75 [0.44-1.29] mg/mmol) randomised to exenatide 10 µg twice-daily or titrated iGlar on-top-of metformin for 52-weeks. Renal efficacy endpoints were change in creatinine clearance (CrCl) and albuminuria (urinary albumin-excretion [UAE] and UACR) based on 24-h urines, collected at baseline and Week-52. eGFR and exploratory endpoints were collected throughout the intervention-period, and after a 4-week wash-out. RESULTS: HbA1c-reductions were similar with exenatide (mean ±â€¯SEM -0.80 ±â€¯0.10%) and iGlar (-0.79 ±â€¯0.14%; treatment-difference 0.02%; 95% CI -0.31 to 0.42%). Change from baseline to Week-52 in CrCl, UAE or UACR did not statistically differ; only iGlar reduced albuminuria (P < 0.05; within-group). eGFR decreased from baseline to Week-4 with exenatide (-3.9 ±â€¯2.1 mL/min/1.73 m2; P = 0.069) and iGlar (-2.7 ±â€¯1.2 mL/min/1.73 m2; P = 0.034), without treatment-differences in ensuing trajectory. Exenatide versus iGlar reduced bodyweight (-5.4 kg; 2.9-7.9; P < 0.001), but did not affect blood pressure, lipids or plasma uric acid. CONCLUSIONS: Among T2DM patients without overt nephropathy, one-year treatment with exenatide twice-daily does not affect renal function-decline or onset/progression of albuminuria compared to titrated iGlar. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT00097500.

H3K27 acetylation and gene expression analysis reveals differences in placental chromatin activity in fetal growth restriction.

Background: Posttranslational modification of histone tails such as histone 3 lysine 27 acetylation (H3K27ac) is tightly coupled to epigenetic regulation of gene expression. To explore whether this is involved in placenta pathology, we probed genome-wide H3K27ac occupancy by chromatin immunoprecipitation sequencing (ChIP-seq) in healthy placentas and placentas from pathological pregnancies with fetal growth restriction (FGR). Furthermore, we related specific acetylation profiles of FGR placentas to gene expression changes. Results: Analysis of H3K27ac occupancy in FGR compared to healthy placentas showed 970 differentially acetylated regions distributed throughout the genome. Principal component analysis and hierarchical clustering revealed complete segregation of the FGR and control group. Next, we identified 569 upregulated genes and 521 downregulated genes in FGR placentas by RNA sequencing. Differential gene transcription largely corresponded to expected direction based on H3K27ac status. Pathway analysis on upregulated transcripts originating from hyperacetylated sites revealed genes related to the HIF-1-alpha transcription factor network and several other genes with known involvement in placental pathology (LEP, FLT1, HK2, ENG, FOS). Downregulated transcripts in the vicinity of hypoacetylated sites were related to the immune system and growth hormone receptor signaling. Additionally, we found enrichment of 141 transcription factor binding motifs within differentially acetylated regions. Of the corresponding transcription factors, four were upregulated, SP1, ARNT2, HEY2, and VDR, and two downregulated, FOSL and NR4A1. Conclusion: We demonstrate a key role for genome-wide alterations in H3K27ac in FGR placentas corresponding with changes in transcription profiles of regions relevant to placental function. Future studies on the role of H3K27ac in FGR and placental-fetal development may help to identify novel targets for therapy of this currently incurable disease.

Targeting multiple pathways reduces renal and cardiac fibrosis in rats with subtotal nephrectomy followed by coronary ligation.

AIM: Multiple interacting pathways contribute to progression of renal and cardiac damage in chronic kidney disease followed by chronic heart failure (renocardiac syndrome). We hypothesized that simultaneous pharmacological modulation of critical pathways implicated in renocardiac syndrome would effectively reduce fibrosis in and preserve function of heart and kidney. METHODS: Rats were subjected to subtotal nephrectomy followed 9 weeks later by coronary artery ligation. From week 11 until week 16, rats received vehicle or losartan, or a combination of the NF-kB inhibitor PDTC, the NO donor molsidomine and superoxide dismutase mimetic tempol, or a combination of all four of these plus metoprolol together. At week 16, renal and cardiac structure, function and gene expression were assessed. RESULTS: Individual and combined treatments were similarly effective in limiting cardiac fibrosis and further decline in systolic function. Combined treatment with all five drugs reduced renal fibrosis and CTGF gene expression more effectively than other strategies. Combining all five drugs reduced heart rate, inotropy and mean arterial pressure (MAP). CONCLUSION: Thus, in our model of chronic renocardiac syndrome, combined treatments similarly decreased cardiac fibrosis and stabilized systolic function as losartan alone, perhaps suggesting a dominant role for a single factor such as angiotensin II type 1 (AT1) receptor activation or inflammation in the network of aberrant systems in the heart. However, tubulointerstitial fibrosis was most effectively reduced by a five-drug regimen, pointing to additive effects of multiple pathophysiological pathways in the kidney.

Pregnancy as a critical window for blood pressure regulation in mother and child: programming and reprogramming.

Pregnancy is a critical time for long-term blood pressure regulation in both mother and child. Pregnancies complicated by placental insufficiency, resulting in pre-eclampsia and intrauterine growth restriction, are associated with a threefold increased risk of the mother to develop hypertension later in life. In addition, these complications create an adverse intrauterine environment, which programmes the foetus and the second generation to develop hypertension in adult life. Female offspring born to a pregnancy complicated by placental insufficiency are at risk for pregnancy complications during their own pregnancies as well, resulting in a vicious circle with programmed risk for hypertension passing from generation to generation. Here, we review the epidemiology and mechanisms leading to the altered programming of blood pressure trajectories after pregnancies complicated by placental insufficiency. Although the underlying mechanisms leading to hypertension remain the subject of investigation, several abnormalities in angiotensin sensitivity, sodium handling, sympathetic activity, endothelial function and metabolic pathways are found in the mother after exposure to placental insufficiency. In the child, epigenetic modifications and disrupted organ development play a crucial role in programming of hypertension. We emphasize that pregnancy can be viewed as a window of opportunity to improve long-term cardiovascular health of both mother and child, and outline potential gains expected of improved preconceptional, perinatal and post-natal care to reduce the development of hypertension and the burden of cardiovascular disease later in life. Perinatal therapies aimed at reprogramming hypertension are a promising strategy to break the vicious circle of intergenerational programming of hypertension.

Rapid hepatic clearance of full length CCN-2/CTGF: a putative role for LRP1-mediated endocytosis.

CCN-2 (connective tissue growth factor; CTGF) is a key factor in fibrosis. Plasma CCN-2 has biomarker potential in numerous fibrotic disorders, but it is unknown which pathophysiological factors determine plasma CCN-2 levels. The proteolytic amino-terminal fragment of CCN-2 is primarily eliminated by the kidney. Here, we investigated elimination and distribution profiles of full length CCN-2 by intravenous administration of recombinant CCN-2 to rodents. After bolus injection in mice, we observed a large initial distribution volume (454 mL/kg) and a fast initial clearance (120 mL/kg/min). Immunosorbent assay and immunostaining showed that CCN-2 distributed mainly to the liver and was taken up by hepatocytes. Steady state clearance in rats, determined by continuous infusion of CCN-2, was fast (45 mL/kg/min). Renal CCN-2 clearance, determined by arterial and renal vein sampling, accounted for only 12 % of total clearance. Co-infusion of CCN-2 with receptor-associated protein (RAP), an antagonist of LDL-receptor family proteins, showed that RAP prolonged CCN-2 half-life and completely prevented CCN-2 internalization by hepatocytes. This suggests that hepatic uptake of CCN-2 is mediated by a RAP-sensitive mechanism most likely involving LRP1, a member of the LDL-receptor family involved in hepatic clearance of various plasma proteins. Surface plasmon resonance binding studies confirmed that CCN-2 is an LRP1 ligand. Co-infusion of CCN-2 with an excess of the heparan sulphate-binding protamine lowered the large initial distribution volume of CCN-2 by 88 % and reduced interstitial staining of CCN-2, suggesting binding of CCN-2 to heparan sulphate proteoglycans (HSPGs). Protamine did not affect clearance rate, indicating that RAP-sensitive clearance of CCN-2 is HSPG independent. In conclusion, unlike its amino-terminal fragment which is cleared by the kidney, full length CCN-2 is primarily eliminated by the liver via a fast RAP-sensitive, probably LRP1-dependent pathway.

Acute renal haemodynamic effects of glucagon-like peptide-1 receptor agonist exenatide in healthy overweight men.

AIMS: To determine the acute effect of glucagon-like peptide-1 (GLP-1) receptor agonist exenatide and the involvement of nitric oxide (NO) on renal haemodynamics and tubular function, in healthy overweight men. METHODS: Renal haemodynamics and tubular electrolyte handling were measured in 10 healthy overweight men (aged 20-27 years; BMI 26-31 kg/m(2)) during intravenous administration of placebo (saline 0.9%), exenatide, and exenatide combined with the NO-synthase inhibitor L-N(G)-monomethyl arginine (L-NMMA). Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance techniques, respectively, based on timed urine sampling. Glomerular hydrostatic pressure and vascular resistance of afferent and efferent renal arterioles were calculated using the Gomez formulae. Urinary electrolytes, osmolality and pH were also measured. RESULTS: GFR increased by a mean of 18 ± 20 (+20%; p = 0.021) and ERPF increased by a median (interquartile range) of 68 (26; 197) ml/min/1.73 m(2) (+14%; p = 0.015) during exenatide infusion versus placebo. During L-NMMA infusion, exenatide increased GFR by mean 8 ± 12 ml/min/1.73 m(2) (+9%; p = 0.049). Exenatide increased estimated glomerular pressure by +6% (p = 0.015) and reduced afferent renal vascular resistance by -33% (p = 0.038), whereas these effects were blunted during L-NMMA infusion. Exenatide increased absolute and fractional sodium excretion, urinary osmolality and urinary pH. The tubular effects of exenatide were not altered by concomitant L-NMMA infusion. CONCLUSIONS: Exenatide infusion in healthy overweight men acutely increases GFR, ERPF and glomerular pressure, probably by reducing afferent renal vascular resistance, and at least partially in an NO-dependent manner. As baseline renal haemodynamics in patients with type 2 diabetes differ from those in healthy individuals, clinical studies on the renal effects of GLP-1 receptor agonists are warranted.

Left ventricular assist devices: a kidney's perspective.

The left ventricular assist device (LVAD) has become an established treatment option for patients with refractory heart failure. Many of these patients experience chronic kidney disease (CKD) due to chronic cardiorenal syndrome type II, which is often alleviated quickly following LVAD implantation. Nevertheless, reversibility of CKD remains difficult to predict. Interestingly, initial recovery of GFR appears to be transient, being followed by gradual but significant late decline. Nevertheless, GFR often remains elevated compared to preimplant status. Larger GFR increases are followed by a proportionally larger late decline. Several explanations for this gradual decline in renal function after LVAD therapy have been proposed, yet a definitive answer remains elusive. Mortality predictors of LVAD implantation are the occurrence of either postimplantation acute kidney injury (AKI) or preimplant CKD. However, patient outcomes continue to improve as LVAD therapy becomes more widespread, and adverse events including AKI appear to decline. In light of a growing destination therapy population, it is important to understand the cumulative effects of long-term LVAD support on kidney function. Additional research and passage of time are required to further unravel the intricate relationships between the LVAD and the kidney.

Increased susceptibility to hypertensive renal disease in streptozotocin-treated diabetic rats is not modulated by salt intake.

AIMS/HYPOTHESIS: In early type 1 diabetes mellitus, renal salt handling is dysregulated, so that the glomerular filtration rate becomes inversely proportional to salt intake. The salt paradox occurs in both humans and rats and, with low salt intake, results in diabetic hyperfiltration. We tested whether increased salt intake could reduce the susceptibility to injury of non-clipped kidneys in diabetic rats with pre-existing Goldblatt hypertension. METHODS: Male Long-Evans rats were made hypertensive and half were then made diabetic. Blood glucose was maintained at ~20-25 mmol/l by insulin implants. One half of each received only the salt in normal chow (1% by weight) and the other half received added salt in drinking water to equal 2.7% by weight of food intake. Weekly 24 h blood pressure records were acquired by telemetry during the 4-month experiment. RESULTS: Systolic blood pressure was not affected by diabetes or increased salt intake, alone or together. Autoregulation was highly efficient in the non-clipped kidney of both intact and diabetic rats. Histological examination showed minor injury in the clipped kidney, which did not differ among groups. The non-clipped kidney showed extensive pressure-dependent glomerular and vascular injury in both intact and diabetic rats. CONCLUSIONS/INTERPRETATION: The relationship between pressure and injury was shifted toward lower blood pressure in diabetic rats, indicating that diabetes increased the susceptibility of the kidney to injury despite preservation of autoregulation. The increased susceptibility was not affected by high salt intake in the diabetic rats, thus disproving the hypothesis.

Proteinuria in aging rats due to low-protein diet during mid-gestation.

Nephrogenesis in the rat starts mid-gestation and continues into lactation. Maternal low protein (LP) intake leads to renal injury in rats and associates with mild renal injury in humans. We hypothesized that LP during early nephrogenesis or throughout gestation would induce more renal injury in rat offspring than when LP was only present before nephrogenesis. Pregnant rats were fed LP diet (9% casein) at early gestation (LPE, day 0-7), mid (LPM, day 8-14), late (LPL, day 15-22) or throughout gestation (LPA, day 0-22) and compared to controls on 18% casein diet. Offspring were studied at 18 months. Renal injury was assessed by 24 h proteinuria, plasma urea, antioxidant enzyme activities, and apoptosis (Bax/Bcl2). Proteinuria was higher in LPM males and LPE and LPM females. In LPM males glutathione peroxidase activity was lower, while in LPE males catalase activity was higher. Antioxidants were not much affected in females. Bax expression was higher in LPM males and females, while Bcl2 expression was higher in LPA females. Thus even before nephrogenesis (day 0-7), LP impacted on renal integrity in adult life, while LP during a later phase (day 15-22) or throughout gestation had less effect. In summary, for aging rat kidney LP poses the greatest threat when restricted to early nephrogenesis.

Transient nitric oxide reduction induces permanent cardiac systolic dysfunction and worsens kidney damage in rats with chronic kidney disease.

Left ventricular systolic dysfunction (LVSD) in patients with chronic kidney disease (CKD) is associated with poorer prognosis. Because patients with CKD often exhibit progressively decreased nitric oxide (NO) availability and inhibition of NO production can reduce cardiac output, we hypothesized that loss of NO availability in CKD contributes to pathogenesis of LVSD. Subtotally nephrectomized (SNX) rats were treated with a low dose of the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA; 20 mg/l water; SNX+L-NNA) and compared with relevant control groups. To study permanent changes separate from hemodynamic effects, L-NNA was stopped after week 8 and rats were followed up to week 15, until blood pressure was similar in SNX+L-NNA and SNX groups. To study effects of NO depletion alone, a control group with high-dose L-NNA (L-NNA-High: 100 mg/l) was included. Mild systolic dysfunction developed at week 13 after SNX. In SNX+L-NNA, systolic function decreased by almost 50% already from week 4 onward, together with markedly reduced whole body NO production and high mortality. In L-NNA-High, LVSD was not as severe as in SNX+L-NNA, and renal function was not affected. Both LVSD and NO depletion were reversible in L-NNA-High after L-NNA was stopped, but both were persistently low in SNX+L-NNA. Proteinuria increased compared with rats with SNX, and glomerulosclerosis and cardiac fibrosis were worsened. We conclude that SNX+L-NNA induced accelerated and permanent LVSD that was functionally and structurally different from CKD or NO depletion alone. Availability of NO appears to play a pivotal role in maintaining cardiac function in CKD.

A fat chance of renal injury.

Williams et al. demonstrate in sheep that juvenile obesity per se leads to renal pathology but that prenatal undernutrition effectively abolishes any renal pathology associated with juvenile obesity. These peculiar findings are quite opposite to what has been documented in many epidemiological and animal studies. They provoke questions about how adverse developmental conditions can either support or compromise adaptation to excess nutrient intake and low motor activity later in life.

Nitric oxide, superoxide and renal blood flow autoregulation in SHR after perinatal L-arginine and antioxidants.

AIM: Nitric oxide (NO) and superoxide are considered to be regulatory in renal blood flow (RBF) autoregulation, and hence may contribute to development of hypertension. To extend our previous observations that dynamic NO release is impaired in the spontaneously hypertensive rat (SHR) we investigated, firstly, if superoxide dependency of RBF autoregulation is increased in SHR and, secondly, if the beneficial effect of perinatal supplementation in SHR is partly as a result of early correction of RBF autoregulation. We hypothesized that perinatal supplementation by restoring dynamic NO release and/or decreasing superoxide dependency and would improve life-long blood pressure regulation. METHODS: Autoregulation was studied using stepwise reductions in renal perfusion pressure in anaesthetized male SHR, SHR perinatally supplemented with arginine and antioxidants (SHRsuppl) and Wistar-Kyoto (WKY), prior to and during i.v. Nomega-nitro-l-arginine (NO synthase inhibitor) or tempol (superoxide dismutase mimetic). RESULTS: Spontaneously hypertensive rat displayed a wider operating range of RBF autoregulation as compared with WKY (59 +/- 4 vs. 33 +/- 2 mmHg, respectively; P < 0.01). Perinatal supplementation in SHR decreased mean arterial pressure, renal vascular resistance and the operating range of RBF autoregulation (43 +/- 3 mmHg; P < 0.01). In addition autoregulation efficiency decreased. RBF autoregulation characteristics shifted towards those of normotensive WKY. However, dynamic NO release was still impaired and no clear differences in superoxide dependency in RBF autoregulation between groups was observed. CONCLUSION: Perinatal supplements shifted RBF autoregulation characteristics of SHR towards WKY, although capacity of the SHRsuppl kidney to modulate NO production to shear stress still seems impaired. The less strictly controlled RBF as observed in perinatally supplemented SHR could result in an improved long-term blood pressure control. This might partly underlie the beneficial effects of perinatal supplementation.

Albumin-bound fatty acids induce mitochondrial oxidant stress and impair antioxidant responses in proximal tubular cells.

Albumin induces oxidative stress and cytokine production in proximal tubular cells (PTECs). Albumin-bound fatty acids (FAs) enhance tubulopathic effects of albumin in vivo. We proposed that FA aggravation of albumin-induced oxidative stress in PTECs might be involved. We hypothesized that mitochondria could be a source of such stress. Using a fluorescent probe, we compared reactive oxygen species (ROS) production after exposure of PTECs to bovine serum albumin (BSA) alone or loaded with oleic acid (OA-BSA) (3-30 g/l for 2 h). There was no difference in cellular albumin uptake, but OA-BSA dose-dependently induced more ROS than BSA alone (P<0.001). OA-BSA-induced ROS was significantly alleviated by mitochondrial inhibition, but not by inhibitors of nicotinamide adenine dinucleotide phosphate hydrogenase (NADPH) oxidase, xanthine oxidase, or nitric oxide synthase. Gene expression analysis showed that neither the NADPH oxidase component p22phox nor xanthine oxidase was induced by BSA or OA-BSA. OA-BSA, in contrast to BSA, failed to induce mitochondrial manganese superoxide dismutase 2 (SOD2) expression. OA-BSA showed a greater capacity than BSA to downregulate heme oxygenase-1 mRNA expression and accentuate inflammatory cytokine mRNA and protein. Supplementation of SOD activity with EUK-8 reduced ROS, and interleukin-6 protein expression was suppressed by both mitochondrial inhibition and SOD augmentation. Thus, in PTECs, FAs accentuate albumin-induced oxidative stress and inflammatory cytokine expression via increased mitochondrial ROS, while frustrating protective antioxidant responses.

ACE inhibition and glomerular repair: restructuring or regeneration?

In this issue of Kidney International, Andrea Remuzzi et al. convincingly demonstrate glomerular repair in spontaneous renal disease by ACE inhibition. These findings provoke questions about how ACE inhibition (or AT1R blockade) can on the one hand actually repair some diseased kidneys while on the other interfering with normal renal development or the recovery of other diseased kidneys.

Albumin restores lysophosphatidylcholine-induced inhibition of vasodilation in rat aorta.

BACKGROUND: Impairment of vasodilation by oxidized low-density lipoprotein has been attributed to lysophosphatidylcholine (LPC). Albumin avidly binds LPC. Therefore, hypoalbuminemia may directly impair vasodilation and thus contribute to increased risk of atherosclerosis in nephrotic syndrome. The addition of albumin reduces LPC in erythrocytes and endothelial cells. We hypothesized that the addition of albumin will salvage vasodilation in aortic rings previously exposed to LPC. LPC increases superoxide production and disturbs L-arginine availability. Therefore, we also decreased superoxide with a superoxide dismutase mimic, MnCl(2), and supplemented L-arginine in an attempt to restore vasodilation. METHODS: Rat aorta rings, which had been incubated with various concentrations of LPC and human serum albumin (HSA), were mounted in organ chambers. Relaxation was studied with acetylcholine (0.01 to 100 micromol/L) after precontraction with phenylephrine (CON, 0.3 micromol/L; LPC, 0.03 micromol/L). In some studies MnCl(2) or L-arginine was added to the organ chamber. RESULTS: LPC had time- and dose-dependent inhibitory effects on acetylcholine-mediated vasodilation, but no effect on nitroprusside-mediated vasodilation. Preincubation with albumin (50 or 6 g/L) could protect vasodilation against very high levels of LPC. After preincubation with LPC, the addition of albumin to the incubation salvaged vasodilation. Albumin was more effective after short LPC incubation. MnCl(2) had no specific effect on the LPC-mediated disturbance in vasodilation. L-arginine completely salvaged vasodilation at low concentrations of LPC. However, even high concentrations of L-arginine (1 mmol/L) could not improve vasodilation at LPC levels at which vasodilation was restored by albumin. CONCLUSIONS: LPC affects several pathways that inhibit vasodilation, all of which are salvaged by addition of albumin.

Chronic blockade of angiotensin II action prevents glomerulosclerosis, but induces graft vasculopathy in experimental kidney transplantation.

Long-term renin-angiotensin system blockade is beneficial in a variety of renal diseases. This study examines the long-term (34 weeks) effects of the angiotensin-converting enzyme inhibitor lisinopril and the angiotensin II receptor type I blocker L158,809 in the Fisher to Lewis rat model of chronic renal transplant failure. Treatment in allografted rats with lisinopril or L158,809 was initiated 10 days after transplantation, or at the time when proteinuria exceeded 50 mg/24 h. Untreated allografts and syngrafts served as controls. In contrast to syngrafts, untreated allografts developed proteinuria, hypercholesterolaemia, interstitial damage, and glomerulosclerosis. Lisinopril or L158,809 treatment in allografts starting at day 10 after transplantation completely prevented this, with the exception of interstitial damage, but this treatment also caused a reduction in blood pressure and renal function. Moreover, the intimal surface area of the renal arteries was dramatically increased in allografts treated with either lisinopril or L158,809 compared with untreated allografted rats. Treatment once proteinuria had developed was less effective in preventing glomerulosclerosis, but also caused less intimal expansion. Thus, chronic renin-angiotensin system blockade preserves glomerular morphology in the absence of proteinuria, but enhances intimal hyperplasia and reduces renal function in experimental transplantation. In view of these results, it should be questioned whether such treatment benefits renal transplant patients in the long term.

Losartan versus enalapril on cerebral edema and proteinuria in stroke-prone hypertensive rats.

Stroke-prone spontaneously hypertensive rats (SHRSP), subjected to high NaCl, show severe hypertension, organ damage, and early death. Preventive treatment with angiotensin II type 1 (AT1) receptor antagonists is known to be effective. Previously, we found that angiotensin converting enzyme (ACE) inhibition could reduce cerebral edema when treatment was started after manifestation of either proteinuria or cerebral edema. In this study AT1 receptor blockade was started at the same time points to evaluate whether this had an effect superior to ACE inhibition. SHRSP drank 1% NaCl. Group 1 served as controls. Group 2 and 3 rats were started on losartan and enalapril after proteinuria exceeded 40 mg/day. Group 4 and 5 rats were started on losartan and enalapril after the first observation of cerebral edema with T2-weighted magnetic resonance imaging scans. In controls, median survival was 54 days (range, 35 to 80 days) after the start of salt loading. With early-onset losartan and enalapril, survival increased to 305 days (range, 184 to 422 days) and 320 days (range, 134 to 368 days) (both P < .01 v group 1). Cerebral edema formation was prevented in all but two rats, one from each treatment modality. Development of proteinuria was markedly reduced. With late-onset treatment with losartan and enalapril, survival was 290 days (range, 120 to 367 days) and 264 days (range, 154 to 319 days) (both P < .01). Both losartan and enalapril decreased cerebral edema to baseline levels. Ultimately cerebral edema reoccurred, despite continued treatment, in 75% of the rats. Systolic blood pressure did not decrease after losartan treatment, but, similarly to early-onset treatment, decreased transiently after enalapril treatment. Cerebral edema and proteinuria were prevented and reduced in SHRSP treated with either an AT1 receptor antagonist or an ACE inhibitor. Survival was markedly and similarly prolonged by both treatments, whether initiated directly before or after development of cerebral edema. In rats where treatment was initiated after manifestation of cerebral edema, both cerebral edema and proteinuria reappeared despite continued treatment. Apparently, when hypertension is sustained, reappearance of target organ damage may not be entirely dependent on angiotensin.