Decrease In Protein Excretion Research Articles

Caloric restriction reduces proteinuria in male rats with established nephropathy.

Reducing proteinuria is a crucial approach in preventing kidney function loss. Previous preclinical studies indicated that caloric restriction (CR) imposed at a young age protects against age-related proteinuria. However, these studies have not explored CR in established renal disease. Therefore, this study aimed to investigate the impact of CR on established proteinuria. Rats, aged 12 ± 2 weeks, were administered 2.1 mg/kg of Adriamycin. Six weeks after injection, protein excretion was measured, and a [13 N]ammonia positron emission tomography (PET) scan was conducted to assess kidney perfusion. After 7 weeks rats were divided into four groups: adlibitum (AL) and CR groups fed either a 12% or a 20% protein diet. All groups were treated for 12 weeks. Blood pressure was measured and a second PET scan was acquired at the end of the study. The animals subjected to CR exhibited a 20.3% decrease in protein excretion (p = 0.003) compared to those in the AL groups. Additionally, blood pressure in the CR group was 21.2% lower (p < 0.001) than in the AL groups. While kidney function declined over time in all groups, the 20% CR group demonstrated the smallest decline. Thus CR effectively reduces urinary protein excretion and lowers blood pressure in rats with established proteinuria.

37-Year-Old Woman With Bilateral Lower Extremity Edema, Proteinuria, and Microscopic Hematuria

37-Year-Old Woman With Bilateral Lower Extremity Edema, Proteinuria, and Microscopic Hematuria

The Influence of Peptides on the Morphofunctional State of Kidneys in Old Rats

More than a quarter of the elderly and senile age population suffers from kidney pathology. For this reason, a prophylaxis of kidney diseases with safe and effective nephroprotectors is a priority of gerontology. This work studies the influence of the polypeptide kidney complex (PKC) and peptides AED, EDL, and AEDG, on the functional state of kidneys in old rats. The administration of the PKC and peptides AED and EDL increased diuresis by 1.2–1.4 times. The PKC and peptide AED reduced the urine protein level and protein excretion by 1.5–2.8 times. The PKC and peptides AED and EDL increased distal sodium transport by 1.2–1.3 times. The peptides AED and EDL increased sodium excretion by 1.3 and 1.6 times respectively. The renal effects of the peptide AEDG resulted in a 21% reduction of glomerular filtration rate, a 3.1-fold decrease in the urine protein level, and a 2.5-fold decrease in protein excretion. The peptide AEDG reduced absolute sodium reabsorption by 1.3 times and increased distal sodium transport by 1.4 times. The realization of glomerular–tubular and tubular–tubular balances is verified by the correlation between the glomerular filtration rate (GFR) and absolute, proximal, and distal sodium reabsorption. In kidney tissue, stimulation of the antioxidant enzyme activity on the background of inhibition of the intensity peroxidation processes was observed, which, together with morphological data, reflects the absence of nephrotoxic effects. PKC and peptides AED, EDL, and AEDG may be considered nephroprotective agents in kidney aging.

Infant Birthweight and Postpartum Hypertension in African Green Monkeys

Postpartum hypertension (PPHT) is characterized by significantly elevated arterial pressure developing within 48 hours following delivery. PPHT affects 2% of all pregnancies and the etiology remains unclear. We have previously reported that the African Green Monkey (AGM; Chlorocebus aethiops sabaeus) develops gestational hypertension with pathophysiological features of preeclampsia. In this study, we report characteristics of PPHT in the AGM that occurs in the absence of hypertension before or after the onset of pregnancy. Systolic blood pressures (SBP) were collected using forearm plethysmography under ketamine sedation (15 mg/kg i.m.). Animals were characterized normotensive (NT; SBP &lt; 120 mmHg) and postpartum hypertensive (PPHT; SBP ≥ 140 mmHg developing within 48 hours following delivery). All PPHT were NT pre‐ and during pregnancy. Twenty‐four hour urine was collected in the third trimester and two weeks postpartum for three consecutive days. SBP for nonpregnant, NT was 98.7 ± 3.7 mmHg (n=18), third trimester SBP for NT was 107.0 ± 4.4 mmHg (n=5), and postpartum day 14 (PP14) SBP for NT was 94.0 ± 12.3 mmHg (n=4; p&gt;0.05). Nonpregnant SBP for PPHT was 115.8 ± 17.6 mmHg (n=8), third trimester SBP was 112.1 ± 13.3 mmHg (n=6), and PPHT, PP14 SBP was 137.2 ± 14.3 mmHg (n=6; p &lt;0.05 PP14 vs. third trimester). Nonpregnant plasma osmolality for NT was 306.3 ± 3.6 mOsm/kg (n=13) and third trimester NT plasma osmolality was 298.7 ± 4.6 mOsm/kg (n=7; p&gt;0.05). Third trimester plasma osmolality for PPHT was 288.8 ± 4.6 mOsm/kg (n=6) and 312.5 ± 5.7 mOsm/kg at PP14 (n=6; p&lt;0.05 vs. third trimester). Nonpregnant protein excretion for NT was 472.5 ± 58.0 mg/day (n=13) and 501.8 ± 104.6 mg/day in third trimester (n=5; p&gt;0.05). In PPHT animals, nonpregnant protein excretion was 684.5 ± 152.1 mg/day (n=1), 472.7 ± 62.1 mg/day in third trimester (n=6), and 171.7 ± 68.0 mg/day at PP14 (n=5; p&lt;0.05 PP14 vs. third trimester). Nonpregnant sodium excretion for NT was 2.4 ± 0.4 mmol/day (n=13) and third trimester for NT was 1.8 ± 0.6 mmol/day (n=5; p&gt;0.05). Nonpregnant sodium excretion for PPHT was 0.3 ± 1.4 mmol/day (n=1), third trimester for PPHT was 2.2 ± 0.5 mmol/day (n=6), and PP14 sodium excretion for PPHT was 3.4 ± 0.6 mmol/day (n=5; p &gt;0.05). Babies born to mothers who ultimately developed PPHT were of a higher birthweight than those born to NT mothers (NT 338.2 ± 25.5 g, n=7; PPHT 404.5 ± 14.1 g, n=6; p&lt;0.05). This data demonstrates that postpartum hypertension in the AGM is associated with decreased protein excretion, and increased SBP after delivery when compared to the third trimester of pregnancy. The mechanisms of this PPHT are largely unknown. Ongoing studies will evaluate changes in kidney function, plasma vasopressin concentrations, and plasma renin activity. The AGM has many physiological and behavioral similarities to humans, making the species an optimal model for the study of pregnancy disorders such as PPHT.Support or Funding InformationBiomedical Science Research Group, American Heart Association Predoctoral Fellowship 17PRE33670127This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The effect of vasodilator β-blockers on renal function in hypertensive patients.

Not only is there a limited number of studies on the effects of vasodilator β-blocker (VBB) therapy on kidney function - specifically, glomerular filtration rate (GFR), serum creatinine (sCr) and proteinuria - but of those that have been reported, the results are mixed. This meta-analysis seeks to assess the efficacy of VBBs on selected renal parameters in hypertensive patients. We conducted a meta-analysis of any prospective trial that provided both baseline and follow-up of at least 4 weeks of VBB therapy - carvedilol, labetalol, dilevalol, nebivolol and celiprolol in patients with hypertension. We used Ovid MEDLINE, EMBASE and PubMed, all without date restrictions. We included 39 studies totaling 3987 patients. Although VBBs did not significantly change GFR or sCr levels after at least 4 weeks of therapy, they did significantly decrease protein excretion by -0.12 SD units [95% confidence interval (CI) -0.19 to -0.04; P < 0.01]. VBBs did not alter renal blood or plasma flow, but renal vascular resistance (RVR) decreased by -20.03 mmHg min/l (95% CI -28.92 to -11.15; P < 0.01). In the analysis which compared VBBs with non-VBBs, the only significant difference was the greater decrease in RVR in the VBB group by -38.44 mmHg min/l (95% CI -60.57 to -16.31; P < 0.01). VBBs do not affect GFR or sCr levels, but decrease protein excretion. This class of β-blockers, however, is not superior to non-VBBs in reducing proteinuria. VBBs decrease RVR significantly more than non-VBBs.

Peptides Restore Functional State of the Kidneys During Cisplatin-Induced Acute Renal Failure.

The effects of polypeptide complex from the kidney and short peptides AED, EDL, and AEDG on renal functions were studied in rats with cisplatin-induced acute renal failure. AED peptide decreased protein excretion and electrolyte concentration in the urine. Polypeptide complex from the kidney and peptides EDL and AEDG normalized diuresis, creatinine concentration in the urine and its excretion, glomerular filtration rate, and absolute resorption of sodium ions and reduced protein concentration in the urine and its excretion, the concentrations of sodium and potassium ions in the urine, and other parameters. EDL peptide produced was potent nephroprotective effect. It is known that the polypeptide complex of the kidney and short peptides restore the expression of signal molecules (marker of functional state of the kidneys), so these peptide substances can have nephroprotective effect during various renal pathologies.

Abstract 50: Characterization of the Gwas-nominated Agtrap-plod1 Locus Using Zfn-mutated Rats

Background: Genome-wide association studies (GWAS) are frequently used to nominate candidate genes for complex diseases, but are largely unable to identify the causative variant(s). One example: the AGTRAP-PLOD1 locus contains 6 genes in close proximity that are all associated with blood pressure (BP), making it difficult to delineate specific allele(s) that underlie human hypertension at this locus. Here we present a novel rat model that was developed to rapidly dissect GWAS loci using high-throughput gene mutation on a single hypertensive background. METHODS: Agtrap, Mthfr, Clcn6, Nppa, Nppb, and Plod1 were individually mutated in the Dahl SS rat by zinc finger nuclease (ZFN) injections. ZFN-mutated and wild type (WT) control SS rats (n=8-25 per group) were assessed for BP and renal damage after 10 days on a 4% NaCl diet. Temporal gene expression during development of hypertension was assessed by qRT-PCR and confirmed by RNA-seq. Results: Expression of all AGTRAP-PLOD1 transcripts changed significantly in response to elevated BP, indicating possible roles of the entire AGTRAP-PLOD1 locus in salt-sensitive hypertension. However, compared with WT, only NPPA mutation further increased mean BP (Δ+27mmHg, P&lt;0.001) and heart weight (1.62±0.03 vs. 1.13±0.03g, P&lt;0.001) in response to 4% NaCl diet. In contrast, CLCN6 mutation significantly decreased diastolic BP (Δ-22mmHg, P&lt;0.001) but had no effect on systolic BP compared to WT. Following salt challenge, proteinuria was elevated by mutation of PLOD1 (147±12 mg/day, P&lt;0.001) and MTHFR (132±23 mg/day, P&lt;0.05) compared with WT littermates (91±5 mg/day), whereas AGTRAP mutation decreased protein excretion (54±9 mg/day, P&lt;0.05). Analysis of haplotype blocks that are associated with gene expression and human hypertension confirmed that NPPA, CLCN6, and MTHFR are the primary mediators of BP changes linked to the AGTRAP-PLOD1 locus. Conclusions: Combined with human GWAS, our data show for the first time that NPPA and CLCN6 are divergent mediators of BP at the AGTRAP-PLOD1 locus, while MTHFR mutation directly increases susceptibility to end-stage renal disease. These novel mechanistic data provide rationale for developing haplotype-specific therapies for treating hypertension.

Obesity-related focal and segmental glomerulosclerosis: normalization of proteinuria in an adolescent after bariatric surgery

Obesity-related glomerulopathy (ORG) is a secondary form of focal and segmental glomerulosclerosis (FSGS) occurring in severely obese patients. A significant percentage of individuals with ORG will develop renal insufficiency or end stage renal disease. We report here a 17-year-old girl with morbid obesity (body mass index 56.8 kg/m(2)) and ORG presenting with nephrotic range proteinuria, who failed to improve following treatment with diet, exercise and angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) therapy. Laparoscopic gastric bypass surgery was performed, and within 2 weeks following the surgery, the patient had lost 5.7 kg body weight and showed a remarkable decrease in protein excretion to one tenth of pre-surgery levels. More than 1 year after surgery, the patient's urine protein and kidney function have remained normal while off renin-angiotensin system inhibition therapy. This is the first report of successful use of gastric bypass surgery for obesity-related glomerulopathy in an adolescent. We propose that gastric bypass surgery be considered for patients with ORG.

Influence of microalbuminuria in achieving blood pressure goals

In all individuals with hypertension regardless of diabetes status, microalbuminuria is an independent risk marker for cardiovascular events including myocardial infarction, stroke and other conditions. While blood pressure reduction is important in reducing this marker in individuals with hypertension other factors such as salt intake play an important role in reducing oxidant stress and other factors related to the genesis of microalbuminuria. Clinical trials demonstrate that drugs interfering with the renin-angiotensin system--angiotensin-converting enzyme inhibitors and angiotensin receptor blockers--should be used as first-line antihypertensive therapy in patients with microalbuminuria because they seem to have a blood pressure-independent antiproteinuric effect. A combination of an angiotensin-converting enzyme inhibitor with an angiotensin receptor blocker or other classes of medications shown to decrease protein excretion, such as nondihydropyridine calcium antagonists or aldosterone receptor blockers, should be considered to decrease albuminuria further; beta-blockers with alpha-blocking properties such as carvedilol have also been shown to reduce microalbuminuria probably secondary to its antioxidant properties. This review provides a summary of current evidence regarding the associations of blood pressure with microalbuminuria, the rationale for currently recommended blood pressure goals, and the use of various classes of antihypertensive agents in proteinuric patients.

The histone deacetylase inhibitor trichostatin A upregulates regulatory T cells and modulates autoimmunity in NZB/W F1 mice

We sought to determine if the histone deacetylase inhibitor (HDI), trichostatin A (TSA), would alter systemic lupus erythematosus (SLE) in NZB/W mice. Fourteen to sixteen-week-old female NZB/W F1 mice were given TSA (1.0mg/kg body weight (BW)) intraperitonealy (i.p.) daily, TSA (1.0mg/kg BW) i.p.+anti-CD25 (250mg/mouse) i.p. every third day, only anti-CD25 (250mg/mouse) i.p., DMSO or isotype IgG. Disease progression was assessed as they aged. Mice were sacrificed at 26 or 38 weeks of age, tissues collected and evaluated. At 36 weeks, TSA-treated animals had decreased anti-double stranded DNA (dsDNA) autoantibodies and decreased protein excretion compared to controls. Spleen size and the percentage of CD4+CD69+ cells were decreased, with an increase in CD4+CD25+ T cells in the TSA-treated mice. Real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis of T cells showed a decrease in IL-6 production but an increase in TGF-beta1 and Foxp3 in the TSA-treated animals. Kidney analysis showed a decrease in IgG and C3 deposition, decrease in pathologic glomerular disease and renal MCP-1, MMP-9, and IL-6 mRNA expression. Anti-CD25-treated mice euthanized at 26 weeks of age showed decreased Foxp3+CD4+CD25+ T cells compared to TSA-treated mice. These data suggest TSA administration modulates lupus-like disease, in part, by increasing T regulatory cells.

The Effect of Pentoxifylline on Proteinuria in Diabetic Kidney Disease: A Meta-analysis

Pentoxifylline is a potential therapeutic agent for diabetic kidney disease because it has anti-inflammatory, antifibrotic, and hemorheological properties. Systematic review and meta-analysis of randomized controlled trials. Adult patients with diabetic kidney disease who received oral pentoxifylline. We searched bibliographic databases for trials involving pentoxifylline that reported proteinuria, glomerular filtration rate, or blood pressure. The primary outcome measure was the effect of pentoxifylline on proteinuria stratified by whether pentoxifylline was compared with renin-angiotensin system blockade. 10 studies including a total of 476 participants with a median duration of 6 months were identified. Pentoxifylline significantly decreased proteinuria (weighted mean difference, -278 mg/d of protein; 95% confidence interval [CI], -398 to -159; P < 0.001) compared with placebo or usual care. Compared with captopril, the decrease in proteinuria with pentoxifylline was similar (weighted mean difference, 0 mg/d of protein; 95% CI, -17 to 18; P = 0.9). Secondary analysis showed that patients with microalbuminuria had a nonsignificant decrease in protein excretion (weighted mean difference, -87 mg/d; 95% CI, -201 to 27; P = 0.1), whereas those with overt proteinuria (protein > 300 mg/d) had a significant decrease (weighted mean difference, -502 mg/d; 95% CI, -805 to -198; P = 0.001). No significant changes in systolic or diastolic blood pressure or glomerular filtration rate were found. Quality scores of studies were low, and there was significant heterogeneity. Available evidence suggests that pentoxifylline may decrease proteinuria in patients with diabetic nephropathy. To confirm these findings, large high-quality studies are required.

Maximizing inhibition of the renin-angiotensin system with high doses of converting enzyme inhibitors or angiotensin receptor blockers

Over the last 20 years, inhibitors of the renin–angiotensin– aldosterone system (RAAS) have become the cornerstone inthetreatmentofhypertension.Likewise,thesedrugshave found an increasing use in patients with underlying renal disease, as numerous lines of evidence have pointed to theirhavingabloodpressureloweringindependent antiproteinuric effect [1]. This effect of renin–angiotensin system (RAS)inhibitorsgainsinsignificanceasseverallargeinterventional studies have uniformly found that proteinuria is a major risk factor for progression of renal disease [2–5]. In fact, in some of these studies [3,4] the reduction of proteinuria in patients with diabetic nephropathy was associated with a decreased risk of reaching a renal endpoint which included doubling of serum creatinine and end-stage renal disease (ESRD). A similar observation has been made in non-diabetic kidney disease with lower levels of baseline proteinuria [5], demonstrating the importance of lowering protein excretion in a variety of renal disorders and across a broad spectrum of protein excretions. In view of the above-described observations, it is not surprising that there have been attempts to determine whether inhibition of the renin–angiotensin system at various levels could produce additive renoprotective effects. With the advent of a direct renin inhibitor (DRI), in addition to converting enzyme inhibitors (ACEs) and angiotensin receptor blockers (ARBs), there are no less than four potential drug combinations. Furthermore, since antagonists of aldosterone have been shown to decrease protein excretion in patients with renal diseases [6,7], the option of also employing aldosterone inhibitors doubles the potential combination of drugs to eight (Table 1). As would be expected, the most frequently used combination is that of an ACE with an ARB. Many of the studies that have been undertaken with this approach suffer from the confounding effect of further blood pressure lowering with the dual treatment, particularly when the doses used in the combination were the same as those employed in the comparator monotherapies [8]. However, when taken together, in a thoroughly and

The histone deacetylase inhibitor trichostatin A (TSA) upregulates regulatory T cells and modulates renal disease in NZB/NZW F1 mice

In our present studies we sought to determine if the histone deacetylase inhibitor (HDI), trichostatin A (TSA), would alter systemic lupus erythematosus (SLE) in NZB/W mice by regulating CD4+CD25+ T‐regulatory cells. Fourteen to sixteen‐week‐old female NZB/W mice were injected with TSA (1.0 mg/kg BW) intraperitoneally (i.p.) daily, anti‐CD25 (250 mg/mouse) i.p. weekly, both TSA (1.0 mg/kg BW) and anti‐CD25 (250 mg/mouse) i.p. bi‐weekly, or untreated. The mice were monitored for various disease parameters as they aged. Mice were sacrificed at either 26 or 36 weeks of age, tissues collected and assessed for various parameters of disease. Flow cytometric analysis of splenic tissue showed TSA treated mice exhibited increased FOXP3 expression and increased CD4+CD25+ T‐regulatory cells. At 36 weeks, TSA treated animals had decreased anti‐double stranded DNA autoantibodies and decreased protein excretion. Renal pathology showed a decrease in IgG and C3 deposition in renal tissue and a decrease in pathologic glomerular disease in the TSA treated mice. These data indicate TSA decreases lupus nephritis by upregulating FOXP3 expression and CD4+CD25+T cells in NZB/W mice. Taken together, these data show TSA administration modulates lupus in part by increasing T‐regulatory cell function, and warrants further investigation as to its potential in treating SLE.

Amelioration of Genetic Hypertension by Suppression of Renal G Protein–Coupled Receptor Kinase Type 4 Expression

Abnormalities in D1 dopamine receptor function in the kidney are present in some types of human essential and rodent genetic hypertension. We hypothesize that increased activity of G protein-coupled receptor kinase type 4 (GRK4) causes the impaired renal D1 receptor function in hypertension. We measured renal GRK4 and D1 and serine-phosphorylated D1 receptors and determined the effect of decreasing renal GRK4 protein by the chronic renal cortical interstitial infusion (4 weeks) of GRK4 antisense oligodeoxynucleotides (As-Odns) in conscious- uninephrectomized spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar-Kyoto (WKY) rats. Basal GRK4 expression and serine-phosphorylated D1 receptors were &90% higher in SHRs than in WKY rats and were decreased to a greater extent in SHRs than in WKY rats with GRK4 As-Odns treatment. Basal renal D1 receptor protein was similar in both rat strains. GRK4 As-Odns, but not scrambled oligodeoxynucleotides, increased sodium excretion and urine volume, attenuated the increase in arterial blood pressure with age, and decreased protein excretion in SHRs, effects that were not observed in WKY rats. These studies provide direct evidence of a crucial role of renal GRK4 in the D1 receptor control of sodium excretion and blood pressure in genetic hypertension.

Decrease in laminin content and protein excretion rate after five sixths nephrectomy and low-dose irradiation in the rat

The effect of low-dose irradiation on laminin distribution and urine protein excretion in the remnant rat kidney has been studied. The rat remnant kidney formed after 5/6 nephrectomy is an experimental model of chronic renal failure. In the remnant kidney, focal segmental glomerulosclerosis is developed characterized by focal or segmental sclerosis in glomeruli, alterations in the tubules and thickening of the glomerular basement membrane. Low dose irradiation has been presumed to suppress sclerotic processes. In this study 24 male Wistar rats were subdivided into the nephrectomized group, nephrectomized and irradiated groups (1 or 3 Grey), and healthy control group. Animals were sacrificed at 2, 4 and 8 weeks after beginning the experiment. Laminin immunohistochemical staining was found along the tubular and glomerular basement membranes in all experimental groups, but with varying intensity. Laminin content in the basement membranes was decreased in early stages (week 2), especially after irradiation followed by increase during the later stages with relatively high levels at the end of the experiment (week 8). Irradiation at a dose of 3 Grey decreased protein excretion compared to the nephrectomized rats at all stages, while 1 Grey dose was ineffective. Based on decreased proteinuria we conclude that moderate low-dose irradiation has beneficial effects on the rat remnant kidney and that laminin in basement membranes is probably not the most crucial component in regulating membrane permeability.

Modulation of renal disease in MRL/lpr mice by pharmacologic inhibition of inducible nitric oxide synthase

MRL-MPJFaslpr (MRL/lpr) mice spontaneously develop lupus-like disease characterized by immune complex glomerulonephritis and overproduction of nitric oxide (NO). Blocking NO production pharmacologically by a non-specific nitric oxide synthase (NOS) inhibitor ameliorated renal disease in MRL/lpr mice while genetically deficient inducible NOS (iNOS) mice developed proliferative glomerulonephritis similar to wild-type controls. To clarify the role of iNOS in the pathogenesis of nephritis in MRL/lpr mice, we treated mice with two different NOS inhibitors. Either NG-monomethyl-l-arginine (L-NMMA), a nonspecific NOS inhibitor, or l-N6-(1-iminoethyl)lysine (L-NIL), an iNOS specific inhibitor, was administered in the drinking water from 10 through 22 weeks of age with disease progression monitored over time. Control mice received water alone. Both L-NMMA and L-NIL blocked NO production effectively in MRL/lpr mice. As expected, neither L-NNMA nor L-NIL had an effect on antibody production, immune complex deposition or complement activation. Although both NOS inhibitors decreased protein excretion, L-NMMA was more effective than L-NIL. Pathologic renal disease was significantly decreased at 19 weeks in both treatment groups. At 22 weeks the L-NIL treated mice, but not the L-NMMA mice, had significantly reduced renal disease scores compared to controls. These results indicate that specific inhibition of iNOS blocks the development of pathologic renal disease in MRL/lpr mice.

CAPTOPRIL REDUCES THE POTENTIAL PROTEINURIC EFFECT OF EXOGENOUS GROWTH HORMONE IN ADRIAMYCIN NEPHROSIS (AN). † 2176

Growth Hormone (GH) is being increasingly used for growth failure associated with renal disease. Over time, however, GH, by increasing glomerular perfusion, might compromise residual renal function. Since Captopril (C) decreases glomerular perfusion and has been shown to decrease protein excretion in the presence of renal disease, we tested its potential protective effect in GH treated rats with AN, a model of heavy proteinuria and glomerular injury. We induced AN in Sprague-Dawley rats ≈125 g body weight with Adriamycin given as an initial dose of 5 mg/kg and as a subsequent dose 3 weeks later of 2 mg/kg. Rats with AN received either saline (S), GH (0.2 mg/day SC 5 days/week) alone, or GH + C (100 mg/kg/day PO). At 40 and 76 days after induction of AN, proteinuria was reduced in AN rats receiving growth hormone + captopril compared to those receiving either saline or GH alone(p<0.05). Serum cholesterol (mg/dl) was lower (p < 0.05) in AN + GH + C(211 ± 47) than in AN + S (521 ± 27) and AN + GH (412 ± 37) treated rats. We conclude that large doses of growth hormone increase proteinuria in rats with Adriamycin Nephrosis and this effect is partially ameliorated by captopril. (Funded by Genentech, Inc).Table

Role of cyclosporine in glomerular diseases.

Clinical researchers are beginning to use the immunosuppressive agent cyclosporine to treat a variety of immunologically mediated diseases. To review the clinical experience with cyclosporine in the nephrotic syndrome and in lupus nephritis. Most studies to date have been small or uncontrolled, or both. Nevertheless, cyclosporine appears to produce remissions in adults and children with the nephrotic syndrome with minimal histologic changes ("minimal-change disease"). It also appears to produce remissions in children with focal and segmental glomerulosclerosis; it is less effective in adults and in individuals with focal and segmental glomerulosclerosis that is resistant to steroids. It appears to reduce proteinuria and to slow the progression of renal insufficiency in membranous glomerulonephritis but has little beneficial effect in IgA nephropathy. Anecdotal experience in patients with lupus nephritis suggests cyclosporine produces an improvement in symptoms, a decrease in protein excretion, and improvement in renal function when other treatments have failed. Cyclosporine's pharmacokinetic properties vary widely with the age of the patient and the presence of concomitant diseases and drugs. Relapses are common after the drug is stopped, and nephrotoxicity is a real risk with prolonged treatment. Cyclosporine shows promise in treating immunologically mediated glomerular diseases, but larger randomized studies will be needed to define its role in this setting. Physicians should become more familiar with this drug as its indications increase.

12 Renal pathology in pre-eclampsia

Pre-eclampsia affects the kidney both functionally and morphologically. Renal haemodynamics decrease and urinary protein excretion increases, in part due to lesions affecting the glomerulus, where a combination of changes produces a characteristic appearance and permits differentiation of pre-eclamptic nephropathy from other glomerular alterations associated with hypertension in pregnancy. In pre-eclampsia the glomerulus is diffusely enlarged and bloodless, due not to proliferation, but to hypertrophy of the intracapillary cells. These alterations, best described ultrastructurally, include hypertrophy of the cytoplasmic organelles in endothelial and occasionally mesangial cells, particularly the lysosomes, which undergo marked enlargement and vacuolization (due to accumulation of free neutral lipids). These reactive changes have been termed 'glomerular capillary endotheliosis'. Other lesions, observed occasionally, include subendothelial and mesangial electron-dense deposits, as well as interposition of mesangial cell cytoplasm or mesangial matrix along an otherwise normal basement membrane. Some investigators have described immunohistological findings (presence of IgM, IgG and fibrin) which they believe specific for pre-eclampsia, and others have claimed the disease may cause focal segmental glomerulosclerosis (FSGS). We believe the immunohistological findings are non-specific and insudative, and that FSGS when present predates the pre-eclamptic complication. Finally, the renal lesions appear fully reversible and the disease has no remote cardiorenal effects on its patients.

Improvement of Lipid Abnormalities Associated with Proteinuria Using Fosinopril, an Angiotensin-Converting Enzyme Inhibitor

To examine whether reducing protein excretion in patients with proteinuric renal disease using an angiotensin-converting enzyme inhibitor, fosinopril sodium, would be accompanied by an amelioration of the associated hyperlipidemia. A randomized, placebo-controlled, double-blind study of 12 weeks, followed by 23 weeks of an open-label trial using fosinopril. Outpatient renal clinics. Twenty-six patients (age range, 28 to 70 years) with mild to moderate renal impairment and proteinuria associated with type II diabetes (15 patients) and other causes of nondiabetic renal disease (11 patients) completed the double-blind phase of the study. All patients except one were men. Fosinopril, 10 mg initial oral daily dose (randomized trial), and 20 mg orally once a day (open-label phase). Proteinuria and serum lipids (total cholesterol, high-density lipoprotein, and low-density lipoprotein [LDL] cholesterol, and lipoprotein(a) protein). In a group of 17 patients treated with fosinopril, protein excretion decreased from 5.56 to 4.28 g/d, a reduction of 1.28 (95% CI, -2.49 to -0.08). The reduction was associated with a decrease in serum total cholesterol from 6.39 to 5.82 mmol/L, a decrease of 0.58 mmol/L (CI, -1.01 to -0.15 mmol/L). In a group of nine patients treated with placebo, neither protein excretion (from 5.11 to 4.81 g/d, a change of -0.29 g/d [CI, -1.78 to +1.13 g/d]) nor serum total cholesterol (from 6.08 to 5.77 mmol/L, a change of -0.31 mmol/L [CI, -0.78 to +0.13 mmol/L]) change significantly. At the end of the double-blind phase, plasma lipoprotein(a) protein decreased in the fosinopril-treated group (from 3.94 to 3.33 mg/dL, a reduction of 0.60 mg/dL [CI, -1.02 to -0.18 mg/dL]) but not in the placebo group (from 2.85 to 3.19 mg/dL, a change of +0.34 mg/dL [CI, -0.53 to +1.2 mg/dL]). Dietary protein and fat intake were similar in the two groups throughout the study. In 16 patients who completed an extended open-label phase, fosinopril was associted with a decrease in protein excretion from 4.53 to 3.22 g/d, a reduction of 1.29 g/d (CI, -2.54 to -0.05 g/d), which was associated with a reduction in serum total cholesterol (from 6.37 to 5.54 mmol/L, a decrease of 0.84 mmol/L [CI, -1.59 to -0.08 mmol/L]), LDL cholesterol (from 4.38 to 3.72 mmol/L [a decrease of 0.68 mmol/L [CI, -1.33 to -0.03 mmol/L]), and plasma lipoprotein(a) protein (from 3.58 to 2.81 mg/dL, a reduction of 0.82 mg/dL [CI, -1.58 to -0.05 mg/dL]). The angiotensin-converting enzyme inhibitor, fosinopril, can result in a sustained reduction in serum total cholesterol, LDL cholesterol, and plasma lipoprotein(a) protein levels in conjunction with a partial reduction in proteinuria.