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.

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.

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.

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.

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.

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.

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.

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.

Early-onset but not late-onset endothelin-A-receptor blockade can modulate hypertension, cerebral edema, and proteinuria in stroke-prone hypertensive rats.

-The ability of endothelin receptor blockade to prevent and to treat established cerebral and renal injury was explored in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP) with the endothelin receptor subtype-A antagonist A127722. SHRSP were subjected to 1% NaCl intake. The start of treatment with A127722 (35 and 70 mg. kg-1. d-1, respectively) was either synchronized with salt loading or initiated after the first observation of cerebral edema with T2-weighted magnetic resonance imaging. In untreated control animals median survival was 54 days (range, 32 to 80 days) after the start of salt loading. Early-onset A127722 treatment increased median survival to 233 days (range, 92 to 407 days; P<0.05 versus controls) with 35 mg/kg and to 124 days (range, 97 to 169 days; P<0.05 versus control) with 70 mg/kg. The development of cerebral edema was prevented, and systolic blood pressure and proteinuria were dose-dependently reduced. However, all rats in the 70-mg/kg treatment group developed hemorrhages in the basal ganglia shortly before death. Late-onset A127722 treatment failed to affect survival, systolic blood pressure, or proteinuria. Nevertheless, cerebral edema was reduced but not as well as in early-onset treatment. Development of hypertension, cerebral edema, and proteinuria was prevented in SHRSP when A127722 treatment was initiated at the start of salt-loading. However, A127722 treatment did not prolong survival in SHRSP with cerebral edema. This suggests that in SHRSP the endothelin A receptor participates actively in the development of increased blood pressure and initiation of organ damage but participates minimally in established malignant hypertension and progression of target-organ damage.

Ovariectomy decreases plasma triglyceride levels in analbuminaemic rats by lowering hepatic triglyceride secretion.

In mutant analbuminaemic rats (NAR), females demonstrate a more marked hypertriglyceridaemia than males. Ovariectomy decreases triglyceride levels in female NAR. We measured triglyceride secretion rates in vivo as well as the activity of acetyl CoA carboxylase (ACC) and fatty acid synthase (FAS) in hepatic cytosol obtained from female control Sprague-Dawley (SD) rats and NAR with or without ovariectomy. NAR were severely hyperlipidaemic, and triglyceride, cholesterol, apolipoprotein A-I and plasma protein concentrations levels were decreased (all P < 0.01) by ovariectomy. Only triglyceride levels were decreased by ovariectomy in the SD rats (P < 0.05). Oestradiol treatment in ovariectomized NAR restored plasma protein and triglyceride concentrations to levels similar to those observed in intact female NAR and caused a marked increase in plasma cholesterol. Ovariectomy in NAR reduced lipoprotein triglycerides and cholesterol in VLDL, IDL and LDL1, but had little effect on the triglyceride-cholesterol ratio of these particles. Both ACC and FAS activities were markedly increased in NAR vs. SD rats (P < 0.01). This increase was partially corrected by ovariectomy. There was no significant effect of ovariectomy on ACC or FAS activity in the SD rats. Triglyceride secretion rates were significantly increased in NAR vs. SD rats (135 +/- 10 vs. 103 +/- 12 nmol/min per 100 g body weight; P < 0.05). Ovariectomy markedly decreased triglyceride secretion rate in NAR to 69 +/- 6 (P < 0.01), but not in SD rats (92 +/- 8 nmol/min per 100 g body weight, NS). Oestradiol treatment in ovariectomized SD rats restored triglyceride levels but had no significant effect on triglyceride secretion rate (106 +/- 23 nmol/min per 100 g).(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperlipoproteinemia in one-year-old analbuminemic rats.

Plasma lipoprotein distribution and apolipoprotein concentrations, as well as kidney function and histopathology of heart, aorta, liver and kidney were investigated in 1-year-old Nagase analbuminemic rats (NAR) and control Sprague-Dawley rats (SDR). The NAR, particularly the females, were found to be severely hyperlipidemic. Plasma total cholesterol in non-fasted animals was 6.1 +/- 0.3 mM in the female NAR vs. 2.5 +/- 0.2 mM in the female SDR (P less than 0.01). Most of the cholesterol was located in the LDL (1.019-1.063 g/ml) and HDL2 (1.063-1.125 g/ml) density range. Plasma triglycerides were 6.1 +/- 0.6 mM in the female NAR vs. 1.3 +/- 0.3 mM (P less than 0.01) in the female SDR. Plasma phospholipids were raised up to 5.4 +/- 0.3 mM vs. 2.4 +/- 0.1 mM (P less than 0.01). NAR have increased concentrations of plasma apolipoproteins A-I (about 3-4-fold) and B (about 2-fold), but the levels of apolipoproteins A-IV and E are not increased. There was less proteinuria in the male NAR than in the male SDR (P less than 0.01). Relevant histopathological findings in the NAR included hepatocytic lipofuscinosis and hemosiderosis in Kupffer cells. Tubular lesions were more common in kidneys from NAR than from SDR, and included protein casts, cortical lipofuscinosis, proximal tubular hyperplasia and proliferative interstitial nephritis. Glomerular changes were similar in both strains. Calcinosis of the aortic media and the corticomedullary region of the kidney was characteristically present in the female SDR but absent in the female NAR. Atherosclerotic lesions were not observed. In summary, 1-year-old NAR maintained on standard rat chow, are hyperlipoproteinemic. The increased levels of plasma LDL and HDL cholesterol are not associated with an increase in the incidence or severity of atherosclerotic or glomerular lesions.

Conversion to mycophenolate mofetil in conjunction with stepwise withdrawal of cyclosporine in stable renal transplant recipients.

BACKGROUND: Mycophenolate mofetil (MMF) is now part of standard immunosuppression in the first phase after renal transplantation. A relevant question is if it can replace drugs such as cyclosporine (CsA) in the maintenance treatment, improving cardiovascular risk profile. METHODS: In 17 patients with a stable renal function (at least 6 months) posttransplantation, we studied the effect of CsA replacement by MMF. After starting MMF (1 g b.i.d.), CsA dosage was reduced from regular to low (median trough level 130 microg/L, respectively, 45 microg/L), followed by complete withdrawal, while prednisone (7.5 mg daily) was continued. We measured ambulatory blood pressure, glomerular filtration rate, renal plasma flow, renal vascular resistance, and metabolic factors at start and after 8 weeks on regular, low-dose CsA, respectively, no CsA with MMF and prednisone. RESULTS: Two patients dropped out after the switch to low-dose CsA/MMF, due to diarrhea in one and a steroid responsive rejection in the other. The complete switch from CsA to MMF was successful in all 15 patients and accompanied by a decrease in 24 hr systolic blood pressure (from 152+/-13 to 145+/-13 mmHg; P<0.01), diastolic blood pressure (93+/-9 to 89+/-12 mmHg; P<0.05), RVR (0.29+/-0.06 to 0.25+/-0.09 mmHg.ml/min; P<0.05), and an increase in glomerular filtration rate (46.6+/-8.8 to 58.0+/-10.5 ml/min; P<0.01) and renal plasma flow. Intermediate low density lipoprotein-cholesterol decreased (0.79+/-0.37 to 0.41+/-0.16 mmol/L; P<0.01). High density lipoprotein-cholesterol decreased, but remained in the safe range. After 1 year two patients stopped the MMF; one because of Kaposi's sarcoma and one because of recurrent infections CONCLUSIONS: The stepwise switch from CsA to MMF was safe and mostly successful, and had beneficial effects on blood pressure, glomerular hemodynamics, and lipid profile. Beneficial trends were already present after partial withdrawal of CsA.

Efficacy and muscle safety of fluvastatin in cyclosporine-treated cardiac and renal transplant recipients: an exercise provocation test.

BACKGROUND: Dyslipidemia is found in the majority of renal and cardiac transplant recipients. Although 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors significantly lower low-density lipoprotein cholesterol (LDL-C) levels, such treatment has been associated with muscle toxicity, especially when used in combination with cyclosporine (CsA). We investigated the efficacy and muscle safety of fluvastatin, a new 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, in CsA-treated transplant recipients. METHODS: The efficacy was determined by measuring the lipid profile before and after 8 weeks of fluvastatin therapy. As parameter for possible muscle damage, the rise in serum levels of the muscle proteins creatine kinase and myoglobin was measured after an exercise provocation test (30 min on a bicycle ergometer at 60% of their maximal work load) before and during fluvastatin therapy. Nineteen CsA-treated renal and cardiac transplant recipients with hypercholesterolemia were selected. RESULTS: After 8 weeks of treatment with a dose of fluvastatin necessary to reduce LDL-C below 3.5 mmol/L (20 mg for 3 and 40 mg for 16 patients), total cholesterol was lowered by 20% and LDL-C by 30%, and HDL2-C was increased by 35% (all P<0.01). The rise in creatine kinase after exercise before and during fluvastatin therapy was, respectively, 40% and 51%, and the rise in myoglobin was 64% and 50%. These rises were not significantly different. Hence, there was no indication for subclinical muscle pathology by fluvastatin use. Fluvastatin was well tolerated, and no adverse effects on liver or kidney function were found. CONCLUSIONS: Fluvastatin can effectively lower LDL-C in CsA-treated renal and cardiac transplant recipients, without demonstrable adverse effects.

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.

Endothelial function in proteinuric renal disease.

Nephrotic-range proteinuria is associated with a several-fold increase risk of cardiovascular infarction. This increased risk is accompanied by endothelial dysfunction, which is not related to increased blood pressure and is not correctable by acute administration of L-arginine. The latter is in direct contrast to what has been found in patients with primary hypercholesterolemia, suggesting that either hypoalbuminemia itself or other aspects of the dyslipidemia characteristic of the nephrotic syndrome impair endothelial function. Lysophosphatidylcholine (lyso-PC) is formed during oxidative modification of cholesterol, and lyso-PC in oxidized low-density lipoprotein (LDL) is responsible for reduced endothelial function in vitro. However, in the circulation, lyso-PC is tightly bound to albumin. Indeed, the addition of albumin can restore endothelial function, which was previously disturbed by lyso-PC. Hypoalbuminemia induces a shift in lyso-PC to lipoproteins, notably LDL, and to erythrocytes. The latter directly induces a reduction in deformability that can also be corrected by the addition of albumin. Hypoalbuminemia may disturb endothelial function, either by directly affecting Gi-protein-dependent signal transduction or indirectly by changing the configuration of the cell membrane. Such a change in cell membrane configuration will disturb binding of ligands to receptors and of endothelial nitric oxide (NO) synthase to caveolin. However, other pathways have been suggested, such as stimulation by lyso-PC of vasoconstriction mediated by protein kinase C. It remains to be shown whether lipid-lowering and antiproteinuric strategies have independent positive effects on endothelial function in nephrotic subjects.

Predisposition of spontaneously hypertensive rats to develop renal injury during nitric oxide synthase inhibition.

Chronic nitric oxide (NO) synthase (NOS) inhibition results in renal injury. Hypertension is an important risk factor for renal injury. We studied the influence of preexistent hypertension on the sensitivity for renal injury induced by chronic NOS inhibition in rats. Spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats were treated with 3, 10, 30 and 100 mg/l Nomega-nitro-L-arginine (L-NNA) until death. Systolic blood pressure and proteinuria were measured regularly and compared with time-control measurements in untreated SHR and WKY. In WKY, 3 and 10 mg/l L-NNA did not affect systolic blood pressure, while 30 and 100 mg/l L-NNA resulted in an increase in systolic blood pressure after 12 and 4 weeks, respectively. In contrast in SHR, every dose of L-NNA resulted in an increase in systolic blood pressure after 2 weeks. In WKY, 3 and 10 mg/l L-NNA did not affect proteinuria or survival, while 30 and 100 mg/l L-NNA resulted in an increase in proteinuria after 30 and 9 weeks, and a median survival of 36 and 12 weeks, respectively. In SHR, 3, 10, 30 and 100 mg/l L-NNA resulted in an increase in proteinuria after 30, 12, 3 and 3 weeks, and a median survival of 41, 20, 5 and 3 weeks, respectively. Thus, at every dose of the inhibitor, chronic NOS inhibition resulted in far earlier increases in systolic blood pressure and proteinuria and a marked increase in mortality in SHR as compared to WKY. Indeed, a very low dosage of L-NNA that caused no harm in WKY was followed by marked increases in proteinuria and blood pressure and decreased survival in SHR. Hypertension strongly increases the vulnerability to cardiovascular risk factors that compromise the NO-system.