Various Forms Of Renal Disease Research Articles

Treatment with rapamycin reduces progressive proteinuria while inducing hyperglycemia in obese Dahl salt‐sensitive leptin‐receptor mutant rats prior to puberty

Prepubertal obesity (PPO) is now considered a risk factor for the development of proteinuria and renal injury in children. Recently, we observed the early development of renal injury in the obese SSLepRmutant strain is associated with elevations in GFR and glomerular injury prior to puberty. However, the mechanisms involved remain unclear. The mammalian target of rapamycin (mTOR) signaling pathway has been shown to contribute to various forms of renal disease. In the current study, we examined whether treatment with the mTOR inhibitor, rapamycin, reduces the early progression of renal injury in SSLepRmutant rats during PPO. Four week‐old SS and SSLepRmutant rats were treated with either vehicle (saline) or rapamycin (1.5 mg/kg/day, ip) until rats reached 8 weeks of age. At baseline, body weight was significantly higher in vehicle‐treated SSLepRmutant rats compared to SS rats and remained elevated over the course of the study (309±13 vs. 219±27 g, respectively). Treatment with rapamycin significantly reduced body weight in SSLepRmutant rats compared to vehicle SSLepRmutant rats (206±9 g). At baseline, non‐fasting blood glucose levels were similar in both SS and SSLepRmutant rats and were within normal physiological range (≤120 mg/dl). Interestingly, chronic treatment with rapamycin markedly increased blood glucose levels in SSLepRmutant rats vs. vehicle SSLepRmutant rats (438±8 vs. 123±5 mg/dl, respectively) but had no effects in SS rats. At the end of the study, plasma insulin levels were significantly elevated in vehicle‐treated SSLepRmutant rats compared to the values measured in SS rats (6±1 vs. 1±0.6 ng/dl, respectively), and rapamycin treatment only reduced plasma insulin in SSLepRmutant (2±0.7 ng/dl, respectively). At baseline, proteinuria was significantly higher in SSLepRmutant rats compared to SS rats (159±34 and 17±7 mg/day, respectively) and remained elevated throughout the study (558±79 and 73±34 mg/day, respectively). By the end of the study, rapamycin significantly reduced proteinuria in SSLepRmutant rats (225±67 mg/day). We observed a significant increase in creatinine clearance (CCr) in SSLepRmutant rats vs SS rats indicating increased GFR (4.0±0.6 vs. 0.9±0.1 ml/min, respectively). Chronic treatment with rapamycin significantly decreased CCr in SSLepRmutant rats (2.2±0.9 ml/min) while not affecting SS rats. Overall, these data suggest that treatment with rapamycin is effective in reducing progressive proteinuria via reducing GFR while reducing plasma insulin levels and contributing to hyperglycemia in obese SSLepRmutant rats.

Renal Counterbalance and the Reversibility of Renal Atrophy with Reduced Renal Mass

The mechanisms that regulate renal survival and atrophy under pathological stress remain incompletely understood. This knowledge is essential for developing new strategies to preserve renal function in patients with various forms of renal disease. We have utilized the 5/6 nephrectomy (5/6Nx) model to study the effects of renal insufficiency in 10 week old male Sprague Dawley rats. In this model excision of 2/3 of the left kidney and the entire right kidney induced substantial hypertrophy of the remnant kidney within 7 weeks of surgery. Conversely, excision of 2/3 of the left kidney, while leaving the right kidney intact (1/3 nephrectomy; 1/3Nx), resulted in atrophy of the remnant kidney within the same period. This lead us to hypothesize that removal of the right kidney 7 weeks after 1/3 surgery could induce hypertrophic remodeling of the left remnant kidney even after atrophic remodeling has occurred. To test this, we performed sham surgeries consisting of laparotomy and renal vessel isolation, right uninephrectomy (1Nx), 1/3Nx, or 5/6Nx surgery, as described above (n= 4–11/group). After 7 weeks we performed ultrasound analysis to evaluate the transverse renal cross‐sectional area (CSA) of the left kidney in each model. Sham surgery was then performed on all animals except for a subset of the 1/3Nx group which had their right kidneys excised. The animals were allowed to recover for another 3 weeks before the left kidney remodeling was again evaluated by ultrasound, acute anesthetized blood pressure was measured, and blood and tissues were collected for analysis. Statistical analysis of ultrasound data was completed using two‐way RM ANOVA, and all other by one‐way ANOVA. Ultrasound analysis of left kidney CSA revealed significant hypertrophy in the 1Nx and 5/6Nx models by week 7, when compared to sham‐operated controls, with no further increase in size evident by week 10. We observed the anticipated reduction in CSA in the 1/3Nx group by week 7 (1.06 ± 0.02, sham vs. 0.58 ± 0.01 cm2, 1/3Nx; p <0.05). The 1/3Nx rats subjected to removal of the right kidney experienced a significant hypertrophy of the remnant kidney (1.31 ± 0.04 cm2) between weeks 7 and 10, however this hypertrophy failed to reach the level observed in the 5/6Nx model (2.06 ± 0.05 cm2). Those 1/3Nx rats that retained their right kidney had no apparent change in remnant kidney size by week 10 (0.56 ± 0.03 cm2). These changes in renal dimensions were consistent with wet weights of the remnant kidney weights. Systolic and diastolic blood pressures measured at the end of the study were not statistically different from that of sham operated controls in any surgical group, however pressures tended to be higher in the 1/3Nx rats that had their right kidneys removed at week 7. We determined that removal of the right kidney could stimulate an atrophied left kidney to hypertrophy. In conclusion, the changes observed in this study suggest that these surgical models will allow us to study the mechanisms that regulate hypertrophy and atrophy.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Spectrum of renal disease in HIV-infected children: report of five cases

There is a paucity of literature on renal diseases associated with HIV infection in Asian countries. Renal disease in HIV-infected children can involve the glomerulus, interstitium, tubules or blood vessels of the kidney. In this case series, five HIV-infected children with various forms of renal disease are reported. The renal pathology included HIV-associated nephropathy, collapsing focal segmental glomerulosclerosis without tubular changes, tubule-interstitial nephritis and minimal change disease (MCD). Case five fulfilled the classification criteria for childhood polyarteritis nodosa (PAN). It is important to screen all HIV-infected children for renal disease to enable detection at an early stage.

An insight into renal disease associated with infective endocarditis

This review on renal involvement associated with infective endocarditis offers clinicians insight into the pathophysiology behind each major mechanism of the renal disease. It briefly discusses the treatment of the various forms of renal disease, and describes pitfalls in the management of endocarditis that may significantly worsen the renal outcome. A practical approach is provided, based on the timing of onset of the renal disease, the patient’s history, and the correct interpretation of various clinical and biochemical parameters.

Systemic Arterial Hemodynamics and the “Renal Resistive Index:” What is in a Name?

Systemic Arterial Hemodynamics and the “Renal Resistive Index:” What is in a Name?

Podocyte culture: Tricks of the trade

Podocytes (glomerular epithelial cells) lie on the urinary aspect of the glomerular capillary and play a key role in the selective filter that underlies kidney function. They are injured in various forms of renal disease: the extents of this injury and its reversibility have major implications for treatment and prognosis. Until recently, podocytes were difficult to study in vitro because of a previous lack of techniques for obtaining differentiated cells in quantities adequate for research. In recent years, this problem has been solved for rodent and human podocytes and there has been an explosion of research using cultured cells. These authors have led the development and characterization of human podocyte cell lines and in this article describe the methods that have allowed them to do this.

Angiogenesis in the kidney: a new therapeutic target?

The prevalence of chronic kidney disease has been growing consistently for the past decades. Renal failure is often associated with defective angiogenesis, and recognition of the contribution of the renal microcirculation to the progression of chronic renal disease may aid in the development of therapeutic interventions. Intra-renal proliferation, remodeling, and/or rarefaction of microvessels in response to injury can all aggravate nephron damage, and experimental evidence suggests that they may constitute the early steps in the complex pathways involved in progressive renal injury. Recent studies showed the benefits of targeted interventions deemed to promote neovascularization (e.g. progenitor cells, growth factors) on the ischemic myocardium and brain and in a few models of renal disease. Evidence of aberrant renal microvascular architecture in various forms of renal disease provides the impetus to attempt modulating the renal microcirculation to interfere with the disease process. Targeted interventions to preserve the renal microcirculation may not only decrease the evolving injury in renal vascular disease but also potentially constitute a coadjuvant intervention to become part of a comprehensive management plan to improve the success of parallel strategies to preserve renal function, such as revascularization.

Urinary excretions of lipocalin-type prostaglandin D synthase predict renal injury in type-2 diabetes: a cross-sectional and prospective multicentre study

Urinary excretions of lipocalin-type prostaglandin D synthase/beta-trace (L-PGDS) probably reflect the increased permeability of injured glomerular capillary walls of the kidney. We tested the hypothesis in cross-sectional and prospective studies that urinary L-PGDS excretions predict renal injury in type-2 diabetes. (1) In the cross-sectional studies, we evaluated whether urinary L-PGDS excretions were able to predict renal diseases in a pooled population including 793 healthy subjects and 200 patients with various forms of renal diseases. (2) We determined the cut-off point of urinary L-PGDS excretions to predict >or=30 mg/gCr albuminuria in 666 patients with type-2 diabetes. (3) In the prospective study, 121 type-2 diabetic patients with <30 mg/gCr albuminuria were followed for almost 2 years to examine whether urinary L-PGDS excretions predict the future status of renal injury in type-2 diabetes. (1) In the cross-sectional studies, receiver operating characteristic analysis revealed that urinary L-PGDS excretions better predicted the patients with kidney diseases than the other markers of renal injury. (2) It was also demonstrated that >or=4.2 mg/gCr urinary L-PGDS excretions better predicted >or=30 mg/gCr albuminuria in type-2 diabetic patients than other markers. (3) The prospective study revealed that in type-2 diabetic patients with <30 mg/ gCr albuminuria, the patients with >or=4.2 mg/gCr urinary L-PGDS excretions more likely exhibited the renal injury during the follow-up periods than those with <4.2 mg/gCr urinary L-PGDS excretions. Urinary L-PGDS excretions reflect the current increased permeability of injured glomerular capillary walls and better predict the future status of renal injury in type-2 diabetes with <30 mg/gCr albuminuria.

Lipoprotein(a) induces glomerular superoxide anion production.

Lipoprotein(a) (Lp(a)) is considered to accelerate glomerular injury in various forms of renal disease. Several tissue culture studies suggested that biological effects of Lp(a) are inhibitable by oxygen radical scavengers. Since reactive oxygen metabolites (ROM) are important mediators of renal disease, we studied the effects of native and oxidized Lp(a) on generation of the ROM superoxide anion in isolated glomeruli and compared them with the effects of native (nLDL) and oxidized LDL cholesterol (oxLDL). The effect of native and oxidized Lp(a) and LDL on ROM production in isolated rat glomeruli was investigated with a lucigenin chemiluminescence assay. Native Lp(a) caused a moderate, dose dependent stimulation of glomerular ROM production: Maximum ROM production to 159 +/- 9% of control glomeruli was induced by nLp(a) 20 micrograms/ml. Lp(a)-induced chemiluminescence was completely inhibited by the cell permeable oxygen radical scavenger Tiron (10 Mm). Oxidized Lp(a) (20 micrograms/ml) caused a more pronounced stimulation of ROM production to 204 +/- 12% of control values. Interestingly, only oxLDL, but not nLDL had a significant effect on glomerular ROM production (ox LDL 50 micrograms/ml: 192 +/- 19% of control). Lp(a) stimulated ROM production was completely inhibited by the protein kinase C inhibitor bis- indolyl malemide (BIM): BIM 10(-6) M inhibited 52 +/- 3%, BIM 10(-5) M inhibited 94 +/- 5% of Lp(a)-induced ROM production. ROM production was also inhibited, when intracellular CAMP levels were elevated by forskolin. Lp(a) and oxLp(a) induce the activation of ROM in glomeruli by a pathway that is sensitive to inhibition of protein kinase C and elevation of intracellular CAMP levels.

Effects of lipoprotein(a) on mesangial cell proliferation and viability

Lipoprotein abnormalities are considered to accelerate glomerular injury in various forms of renal disease, probably affecting mesangial proliferation. Serum levels of the atherogenic Lipoprotein(a) (Lp(a)) are elevated in patients with nephrotic syndrome and Lp(a) deposits have been identified in diseased glomeruli. So far, the influence of Lp(a) on mesangial cell function has not been defined. The influence of Lp(a) on mesangial cell proliferation was assessed in a rat mesangial cell culture model by direct measurement of cell growth as well as analysis of DNA-synthesis and mRNA levels of c-fos and c-myc, two growth-associated 'immediate early response genes'. Results. Lp(a) triggered a biphasic response on DNA synthesis: 3H-thymidine uptake was increased when cells were incubated with Lp(a) (2.5-10 microg/ml) for 24 h. The response was dose dependent, a maximal effect was seen for Lp(a) 5 microg/ml. The stimulatory properties of Lp(a) were comparable to 10% fetal calf serum (FCS). No additive effect of 10% FCS and Lp(a) on DNA synthesis was observed. Cell proliferation was moderately stimulated (120+/-9% of control) by low levels of Lp(a) in the presence of small amounts of FCS. Messenger RNA levels for c-fos and c-myc were upregulated as early as 15 min after incubation with Lp(a) 5 microg/ml, a maximum response was observed after 20 and 240 min respectively. Stimulation of DNA synthesis was partly blunted when cells were incubated with Lp(a) in the presence of catalase 100 U/ml and superoxide dismutase 10(-7)M (SOD) but not in the presence of SOD alone. Lp(a) in concentrations above 10 microg/ml depressed DNA-synthesis and elicited signs of cytotoxicity. The cytotoxic effects of Lp(a) were not blunted by oxygen radical scavengers. The stimulatory and cytotoxic effects of Lp(a) were not restricted to specific isoform. Low concentrations of Lp(a) stimulated growth of mesangial cells, whereas higher concentrations had antiproliferative or toxic effects. The stimulation on mesangial cell proliferation as well as the cytotoxic effects caused by Lp(a) are both likely to have a negative impact on the course of renal disease.

アンチセンスオリゴヌクレオチドによるメサンギウム細胞増殖抑制

Mesangial cell (MC) proliferation is the hallmark of various forms of renal disease. Many protooncogenes are involved in the signal transduction pathways leading to cell proliferation induced by a wide variety of growth factors. We evaluated the inhibitory effects of antisense oligonucleotides (AS-ODNs) targeting protooncogenes on MC proliferation. The antisense and sense phosphorothioate ODNs of c-myc, c-fos and c-myb were synthesized. Quiescent MCs were stimulated with 20% FCS in the presence of AS-ODN or control sense ODN, which were mixed with liposome. Cell proliferation was determined by counting the number of trypan blue-viable cells. Inhibition of protooncogene mRNA was monitored by reverse transcriptase polymerase chain reaction (RT-PCR) . AS-ODN inhibited MC proliferation in a dose-dependent manner. Inhibitory effects of 10μM of each AS-ODN for MC proliferation were : c-myc 56%, c-myb 45% and c-fos 12%. Sense-ODN had little effect. Any significant morphological change in MC was not noticed with ASODN treatment.These results indicate that these protooncogenes are involved in the signal transduction pathways mediating MC proliferation. Furthermore, the results suggest a potential role of antisense strategies designed to inhibit protooncogene expression to prevent MC proliferation.

Urinary tissue plasminogen activator in renal disease.

Whereas plasminogen activator of the tissue-type (t-PA) is present in extracts of kidney parenchyma, only small amounts of the enzyme can be detected in normal urine where the major plasminogen activator is of the urokinase-type (u-PA). These observations suggest the existence of physiological or anatomical barriers that effectively confine t-PA to renal tissue and exclude it from the urine. We examined the notion that disease might breach these barriers and so lead to the appearance of abnormal amounts of t-PA in the urine. Under the conditions of the simple fibrinolytic assay that we have developed, urine samples from 30 normal subjects did not contain detectable amounts of t-PA whereas we were able to demonstrate t-PA in samples from 43 of 65 patients with various forms of renal disease. When positive, therefore, tests for the presence of t-PA in human urine provide evidence for renal disease that may not otherwise be apparent.

Study of T cell subsets in various forms of renal disease in childhood

Study of T cell subsets in various forms of renal disease in childhood

Hypertriglyceridemia and atherosclerosis analysis of an abnormal lipoprotein system and potential beneficial effects of triglyceride lowering therapy.

Hypertriglyceridemia is the most common form of lipid transport disorders. In spite of insufficient markers for accurate diagnosis, hypertriglyceridemic states can be divided by several criteria. For example, high plasma triglyceride levels are often found in humans with a variety of diseases, and in such subjects the hypertriglyceridemic state reflects the status of the underlying disease. Diabetes mellitus, nephrotic syndrome, various forms of renal diseases (including hemodialysis and renal transplantation), and hypothyroidism are a few examples. Primary hypertriglyceridemic state consists of several forms of familial diseases. The commonest types are familial hypertriglyceridemia (FHTG) and familial combined hyperlipoproteinemia (FCHL)1-3 Rarer forms of hypertriglyceridemia are lipoprotein lipase (or apo C-II deficiency) syndromes4,5 and familial dysbetalipoproteinemia (“type III hyperlipoproteinemia”), a distinct disease entitv that reflects combination of genetic absence of apo E-3 and E-46-8 together with a second metabolic disease.9 Sporadic, polygenic and ill-defined syndromes also contribute a large number of subjects to total hypertriglyceridemic population.KeywordsCholesteryl EsterLipoprotein LipasePlasma Triglyceride LevelVLDL ParticleCholesteryl Ester ContentThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Immunoglobulin Cμ gene restriction fragment length polymorphisms associated with chronic renal failure

The DNA's of 41 patients with various forms of renal disease and of 52 controls were investigated for restriction fragment length polymorphisms (RFLP), using a probe recognising the immunoglobulin Cμ heavy chain gene. With the restriction endonuclease Sst 1, 50 of the controls and 12 of the patients had the expected single 4.3 kilobase (kb) fragment. The remaining 29 patients and 2 controls displayed two patterns of banding, 8 patients and 1 control had a 6.8 kb band in addition to the 4.3 kb, and 21 patients and 1 control had a single band of 5.1 kb. In addition, a significant association between high creatinine levels (> 150 μmol/l) and abnormal bands was found ( 21 25 patients with high levels had abnormal bands compared with only 5 16 patients with normal levels). These results are evidence for an association between the human immunoglobulin heavy chain region and renal disease and they apparently confirm an association already reported at the protein level. However, the new RFLP bands, although reproducible and restricted to renal patients, occur in an area where few polymorphisms would be expected. Further, the association with high creatinine suggests some subtle interaction between the creatinine pathway and this area of the human chromosome.

PLASMA INHIBITORS OF CLONERULAR FIBRINOLYSIS (GF) IN HUMAN RENAL DISEASE

To detect a circulating inhibitor of GF, serial dilutions of human plasma were incubated with 2 frozen sections from a single normal human kidney. The slides were washed and studied by the fibrin slide technique. The Lysis Inhibitory Titer (LIT) was defined as the highest dilution completely inhibiting GF. Of 146 controls with normal urinalyses and renal function, none had a LIT greater than 1:2. Defining an elevated LIT as 1:8 or greater, we found an elevated LIT in plasma from 42 of 119 patients with various forms of renal disease including 14 of 14 patients with the Hemolytic-uremic Syndrome (HUS) and 15 of 57 with qlomerulonephritis. In patients with renal disease, no difference was found in the frequency of anemia, leukopenia, or prolonged PT when comparing patients with normal against those with elevated LIT. Diminished renal function (64% vs. 36%), thrombocytopenia (42% vs. 5%), and prolonged PTT (30% vs. 0%) were more common in patients with elevated LIT. No correlation was detected between the LIT and plasma concentrations of the antiplasmins α1 -antitrypsin, α2 -macroglobulin, and C1 -esterase inhibitor. Daily analysis of plasma from 3 patients with HUS showed a close correlation between the LIT and clinical course. In each case, removal of the inhibitor from the plasma by peritoneal dialysis was associated with recovery of renal function. Results suggest that the inhibitor may play an important role in the pathogenesis of glomerular fibrin deposition.

Cellular immunity in renal diseases.

Cellular immune reactivity was studied in 78 patients with various forms of renal disease by skin testing with four recall antigens and a lymphocyte transformation test with tuberculin PPD and leucoagglutinin. Patients with S-creatine greater than or equal to 230 micromol/l as well as those with chronic pyelonephritis who had S-creatinine values below 230 micromol/l had significantly lower skin reactions than the controls to streptokinase-streptodornase, parotitis and PPD. Glomerulonephritic patients with S-creatinine values below 230 micromol/l had normal skin reactivity. Lymphocyte transformation tests showed decreased reactivity only in patients with S-creatinine level greater than or equal to 230 micromol/l. The results suggest an association of chronic pyelonephritis with a defective efferent, nonspecific arm of cellular immunity.

Glomerular C3 receptors in human renal disease

The relationship between glomerular C3 receptor activity and intraglomerular C3 deposition was studied in 73 cases of various forms of renal disease. C3 receptor activity was measured by enumeration of complement-coated sheep red blood cells (IgM EAC) that adhered to glomeruli in frozen sections and expressed as a percentage of the mean number present in control kidneys. Adjacent sections were studied for the presence and distribution of C3 deposits. The precise location of corresponding dense deposits was determined through 1-mu sections or electron micrographs. Marked depression of C3 receptor activity was found in most cases in which there was accumulation of C3 along the glomerular basement membrane, irrespective of whether the deposits were in a subepithelial, intramembranous, or subendothelial location. In contrast, when C3 was not detectable or was found exclusively in the mesangium, C3 receptor activity was affected only moderately, if at all. These data are consistent with the hypothesis that the interaction of C3 with podocytes is a major determinant in the loss of C3 receptor activity in glomerular disease, but do not exclude the possibility that interaction with mesangial or endothelial cells may also influence C3 receptor activity.

Renal disease in pregnancy

Renal biopsy was obtained in 11 primiparous and 9 multiparous patients with severe pre-eclampsia. The large number of patients with renal disease allowed for single-case evaluation. Eclamptic convulsions and fetal deaths were observed in association with renal disease without foci of additional primary glomerular endotheliosis. The data indicate that pregnancy can exacerbate renal disease and allow for early diagnosis. Fluorescence angiography revealed changes in patients in whom the optic fundi were normal. Tissues of glomerulonephritis stained by immune fluorescence against immunoglobulins and on occasion against human fibrinogen. Primary endotheliosis and nephrosclerosis stained against fibrinogen only. There was no pattern of laboratory data to make the differential diagnosis between primary endotheliosis and various forms of renal disease. Fibrinogen breakdown products were inconsistently increased in contrast to fibrin monomer formation, which was increased regardless of the underlying morphology. It is our feeling that renal biopsy with subsequent pathologic classification is the only technique we have at present which provides relevant information on the effect of renal disease on pregnancy and vice versa.

Fibrin-fibrinogen degradation products in children with renal disease.

Fibrin/fibrinogen degradation products (FDP) were measured in the serum and urine of children with various forms of renal disease. Serum FDP was raised both with nephrosis and with active proliferative nephritis. Urine FDP was rarely present in nephrosis but was significantly increased during the active phase of proliferative nephritis and also in urinary tract infection with frank haematuria. Urinary FDP correlated with total urinary protein in proliferative nephritis but not in nephrosis, nor did it correlate with serum FDP in either condition. The major application of urinary FDP determination in clinical practice is as an indicator of activity and possible response to treatment in the management of active proliferative nephritis.