Chronic Nephrosis Research Articles

Fucoidan from Laminaria japonica protects renal tubular epithelial cells from uric acid induced NLRP3-mediated pyroptosis through inhibition of NF-κB pathway

Ethnopharmacological relevanceHyperuricemia is a common metabolic disease with prominent morbidity, it can lead to many adverse effects and complications, such as chronic nephrosis. Fucoidan has been used as natural drug for acute and chronic kidney disease for over 20 years in China, but the precise mechanisms underlying the renal protective function are still indefinable. PurposeThis study is conducted to explore alleviation of fucoidan (FPS) from Laminaria japonica on urate-induced NOD-like receptor family, pyrin domain-containing 3 (NLRP3)-mediated pyroptosis in renal tubular epithelial cells HK-2, as well as the mechanism of nuclear factor κB (NF-κB) signaling pathway involved. Materials and methodsHK-2 cells were treated with FPS, uric acid (UA), and inhibitor of NF-κB signaling pathway. Nitric oxide (NO) content and inducible nitric oxide synthase (iNOS) activity were determined with detection kits. Activation of intercellular NLRP3 inflammasome and NF-κB signaling pathway, gasdermin D (GSDMD) expression level were evaluated with Western blot and quantitative reverse transcription-PCR (qRT-PCR), and immunofluorescent analysis. ResultsData showed that UA induced cellular inflammatory response demonstrated by elevated NO content, iNOS activity and expression level of NLRP3 inflammasome-mediated pyroptosis associated molecules including NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), Caspase-1, interleukin 18 (IL-18) and GSDMD, moreover the NF-κB signaling pathway was activated by UA. However, FPS exposure inhibited efficiently the UA induced adverse effect. ConclusionIt can be concluded that FPS inhibited UA-induced NLRP3-mediated pyroptosis in HK-2 cells through repressing NF-κB signaling pathway.

Nocardiosis: A two-center analysis of clinical characteristics.

The objective of the present study was to describe and analyze the clinical characteristics of nocardiosis. We described and analyzed the clinical characteristics of nocardiosis cases from two centers over the past 5 years from the following aspects: age and sex, Nocardia species, sites of Nocardia infection, test specimens, detection methods, concurrent pathogens, symptoms, imaging features, co-conditions, drug susceptibility tests, antibiotic therapy/duration, outcomes, and follow-up. The median age of the 19 cases was 64 years, with an interquartile range (IQR) of 56-68 years. Eight cases (42.1%) were immunocompromised [those who had been on corticosteroid use (62.5%), those who had used immunosuppressants (50.0%), or those who had suffered from chronic nephrosis (37.5%) or diabetes mellitus (DM) (25.0%)]. The plethora of comorbidities of these cases included diabetes (10.5%), chronic kidney disease (CDK) (15.8%), chronic lung disease (36.8%), and rheumatic diseases (10.5%). Cough and expectoration (73.7%) was the most common symptom of nocardiosis. The respiratory tract (89.5%) was the most common site of the clinical disease. Nearly half (9 cases, 47.3%) of these patients had concurrent infections. The most common Nocardia isolation site was the respiratory tract (73.7%). All patients were given antibiotic therapies, out of whom as many as 63.6% of patients were treated with two concurrent antimicrobial agents, 15.8% of patients were treated under monotherapy and 21.1% of patients were treated with three or more concurrent antimicrobial agents. An uncommon life-threatening infection, nocardiosis, affects those patients with structural lung disease or immunosuppression. Although nocardiosis is capable of progressing into a serious and metastatic disease, early recognition and prompt treatment usually result in successful outcomes benefitting the patient.

Prevalence and correlates of depressive and anxiety symptoms among adults in Guangdong Province of China: A population-based study

AimsTo examine the prevalence and health correlates of depressive and anxiety symptoms among adults living in Guangdong province of China with a large population and rapid urbanization. MethodsThe Guangdong Sleep and Psychosomatic Health Survey was conducted from September to November in 2019, which was a population-based study with a representative sample of adults aged 18–85 years. Multistage stratified cluster sampling was used. A total of 13,768 inhabitants were included and face-to-face interviewed using standardized assessment tools. Depressive and anxiety symptoms were evaluated using the Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder Scale (GAD-7), respectively. ResultsThe weighted prevalence rates of depressive and anxiety symptoms were 8.6% (95% confidence interval [CI]: 8.0%–9.3%) and 6.0% (95%CI, 5.4%–6.5%) respectively. People who have never married, irregular diet rhythm, hardly exercise, poorer sleep, alcohol consumption, chronic diseases and being unemployment and retirement were more likely to suffer depressive and anxiety symptoms. Moreover, the prevalence of depressive symptoms was significantly higher in those suffering from cardiovascular disease (Odds ratio[OR]:3.89, 95%CI: 1.77–8.54), chronic nephrosis (OR:3.89, 95%CI: 1.52–9.94), hyperlipidemia (OR:2.68, 95%CI: 1.57–4.59), anemia (OR:1.96, 95%CI: 1.33–2.89) and arthritis (OR:1.93, 95%CI: 1.17–3.16). The prevalence of anxiety symptoms was evidently greater within patients with cardiovascular disease (OR:3.15, 95%CI: 1.39–7.14), chronic nephrosis (OR: 2.89, 95%CI: 1.22–6.83), hyperlipidemia (OR:2.27, 95%CI: 1.20–4.29) and diabetes (OR:1.99, 95%CI: 1.15–3.44). ConclusionsDepressive and anxiety symptoms are commonly found in patients with chronic diseases. Given these adverse outcomes on health, health professionals should pay more attention to depressive and anxiety problems in health care for high-risk population.

Clinical Characteristics and Controllable Risk Factors of Osteoporosis in Elderly Men with Diabetes Mellitus.

ObjectiveTo analyze the clinical characteristics and controllable risk factors of osteoporosis in elderly men with type‐2 diabetes mellitus (T2DM).MethodsA total of 250 elderly OP patients with T2DM were included in the present study. Patients with one or more common chronic diseases (including hypertension, coronary heart disease, heart failure, chronic bronchitis, chronic nephrosis, and cirrhosis), and a course of more than 3 years were defined as complicated with chronic diseases. Blood glucose, cholesterol, triglyceride, low‐density lipoprotein, high‐density lipoprotein, calcium, phosphorus, glycosylated hemoglobin, urea nitrogen, creatinine, fasting insulin, liver function, and 25‐hydroxy vitamin D3 levels were measured. Bone mineral density was also measured.ResultsA total of 16 patients (6.4%) had severe osteoporosis. Furthermore, 66 patients (26.4%) had blood glucose control that reached the standard, while 176 patients (70.4%) used more than two anti‐diabetic drugs. The serum testosterone level was lower than the median in 87 patients (34.8%) and in 56 smokers (22.4%). Furthermore, 138 patients (55.2%) were overweight and obese, six patients (2.4%) were underweight, 197 patients (78.8%) had chronic diseases, 88 patients (35.2%) were sticking to exercise, and 117 patients (46.8%) had less exercise. In addition, 92 patients (36.8%) were treated with osteotrophy‐protective agents, and 24 patients (9.6%) received anti‐osteoporosis therapy. Smoking, poor glycemic control, low testosterone levels, less exercise, and complications with chronic diseases were the most relevant controllable risk factors.ConclusionFor elderly male osteoporosis patients with type‐2 diabetes, smoking cessation, blood sugar control up to the standard, regular exercise, active prevention and treatment of complications, and appropriate testosterone supplementation are necessary for preventing and curing osteoporosis.

STAT1-p53-p21axis-dependent stress-induced progression of chronic nephrosis in adriamycin-induced mouse model.

BackgroundChronic nephrosis (CN) is an aging-related disease with high mortality. Signal transduction and transcriptional activator 1 (STAT1) protein promotes senescence in human glomerular mesangial cells (HMCs), but whether it affects the progression of adriamycin (ADR)-induced CN in vivo remains unclear.MethodsWe established an ADR-induced CN mouse model that was completed in wild-type (wt) mice by a single intravenous injection of 10 mg/kg ADR for 2 or 4 weeks. Clinical indexes in each group were determined. Hematoxylin and eosin staining (H&E) was employed to determine renal histopathological damage, SA-β-gal staining was used to evaluate cell senescence phenotype. TUNEL and immunohistochemistry (IHC) staining were used to detect renal apoptosis. Protein levels of Bcl-2, Bax, STAT1, p53 and p21 were measured by Western Blot.ResultsSTAT1 intervention ameliorated renal function. H&E staining indicated that STAT1-deficient (stat1−/−) improved the renal tubular injury, and stat1−/− obviously inhibited the apoptosis and Caspase-3+ number in kidney tissues. Besides, stat1−/− decreased proteinuria, and the levels of urea nitrogen and creatinine as well as that of reactive oxygen species induced by ADR. Also, stat1−/− resulted in the reduced expression of p53 and p21.ConclusionsOur current study strongly demonstrated the involvement of the STAT1-p53-p21 axis in the regulation of CN and is a potential target for the nephrosis treatment.

TGF-β1 expression and mesangial alterations in rat glomeruli of an experimental chronic nephrosis model

TGF-β1 expression and mesangial alterations in rat glomeruli of an experimental chronic nephrosis model

A clinical study on the difference among proteinuria components in preeclampsia and pregnancies complicated with chronic nephrosis

ObjectiveTo explore proteinuria components in preeclampsia (PE) and pregnancies complicated with chronic nephrosis (PCCN). MethodsA case-control study was conducted with 81 PE and 95 PCCN patients and 192 normal pregnancies from April 2016 to March 2018. The results of a 24 h proteinuria test and a proteinuria component analysis (PCA) of all enrolled patients were collected. Statistical analyses of variance and SNK-q were conducted to identify the difference between PE and PCCN in urinary protein components using SPSS 23.0 software. A Pearson test and linear regression were conducted to explore the association between 24 h proteinuria and PCA. ResultsAmong the PE, PCCN and control groups, the average values of mAlb(2868.5 ± 3119.3 vs 1586.2 ± 3627.0 vs 21.6 ± 23.6), TRF(252.0 ± 280.5 vs 112.9 ± 164.5 vs 3.1 ± 2.7), α1-MG(40.4 ± 40.7 vs 34.0 ± 38.6 vs 10.3 ± 8.0), β2-MG(1.9 ± 5.1 vs 6.8 ± 15.8 vs 0.9 ± 2.3), and RBP(0.9 ± 1.7 vs 3.1 ± 4.5 vs 0.4 ± 0.7) were significantly different (P＜0.001). According to the SNK-q test, the average value of mAlb and TRF in the PCCN group is lower than that in the PE group, but higher than the control group (P < 0.05). The average value of RBP and β2-MG in the PCCN group was higher than the PE and control groups (P < 0.05). The mAlb, TRF, and α1-MG values separately had a significant correlation with the 24 h proteinuria value in PE. The linear regression equation was 24 h proteinuria value = 0.891*mAlb + 5.969*TRF + 1742.378. The mAlb, TRF, α1-MG, β2-MG, and RBP values separately had a significant correlation with the 24 h proteinuria value in PCCN and a linear regression equation of PCCN was as follows: 24 h proteinuria value = 15.148*TRF + 0.571*mAlb. ConclusionsThe proteinuria components of PE and PCCN patients were different in the elevated β2-MG and RBP. The PCA could be a suitable test for qualitative analysis and an antidiastole for PE and PCCN.

The application effect of PDCA model on healthy education in patients with chronic nephropathy

Objective To explore the effect of PDCA method in improving education effect of chronic kidney disease. Methods A total of 80 patients with chronic nephropathy were selected, among which 40 were in the control group and 40 in the intervention group. In the control group, traditional healthy education mode was implemented, and the intervention group was implemented the PDCA healthy education mode.A database was set up.SPSS 18.0 statistical software was used for statistical analysis. Results In the intervention group, the positive and compliance of PDCA healthy education mode were higher than those of the control group, and the differences were statistically significant(P<0.05). Conclusions PDCA method can improve the treatment enthusiasm and compliance of patients with chronic kidney disease, and it is worthy of clinical promotion. Key words: PDCA model; Chronic nephrosis; Health education

CRISPR/Cas9 Deletion of a Portion of Exon 2 in the Trpc6 Gene Produces a Hypomorphic Variant that Confers Protection in the Chronic Puromycin Aminonucleoside Nephrosis Model in Sprague‐Dawley Rats

Mutations in TRPC6 channels give rise to rare familial forms of focal and segmental glomerulosclerosis (FSGS). Here we examined the role of TRPC6 channels in the chronic puromycin aminonucleoside (PAN) model of acquired FSGS in Sprague‐Dawley rats, using protocols approved by the University of Houston IACUC. In our disease model, animals received two i.p. injections of PAN at 30 day intervals, a protocol that has long been known to induce albuminuria and FSGS lesions in this species. To test our central hypothesis, we used CRISPR/Cas9 methods to delete a 239‐bp fragment in Exon 2 of Trpc6, which resulted in a frame shift that we expected to introduce numerous premature stop codons downstream of the deletion. However as a result of a recently described process known as exon skipping, short Trpc6 transcripts missing Exon 2 were detected by RT‐PCR in Trpc6del/del rats, albeit at considerably lower levels in renal cortex compared to the normal full‐length transcripts seen in Trpc6wt/wt controls. The Exon 2 deletion encodes a portion of an ankyrin‐repeat domain in the N‐terminal of the channel subunit. The function of that domain in the channel protein is not known. Using two different antibodies directed at different motifs downstream of the deletion, we detected very low levels of TRPC6 protein in immunoblots of the renal cortex of Trpc6del/del rats, whereas signal was robust in Trpc6wt/wt controls with both antibodies. In addition, we did not observe ATP‐activated cationic currents mediated by TRPC6 in whole‐cell recordings from glomerular cells resembling podocytes cultured from Trpc6del/del rats, but these currents were readily seen in Trpc6wt/wt controls. Kidney disease in chronic PAN nephrosis (measured 60 days after the first PAN injection) was markedly decreased in Trpc6del/del rats compared to Trpc6wt/wt littermates. This conclusion is based on reduced 24‐hr albumin excretion, reduced serum cholesterol and triglycerides, and improved blood urea nitrogen in Trpc6del/del rats. Trpc6del/del rats also had reduced glomerulosclerosis, less severe tubulointerstitial disease based on biochemical and histological measures, and reduced foot process effacement and glomerular basement thickening in transmission EM compared to Trpc6wt/wt rats. Protection in Trpc6del/del rats was robust but not complete. Thus, most of the quantifiable parameters of disease severity were reduced by about 50% in Trpc6del/del rats compared to wild‐type littermates. We did not discern any difference between renal function or glomerular structure in saline‐treated Trpc6del/del and Trpc6wt/wt rats. We also observed that glomerular TRPC3 abundance in renal cortex was increased in Trpc6del/del rats, although TRPC3 abundance did not increase further in chronic PAN nephrosis. None of the manipulations in this study affected the abundance of TRPC5 channels in renal cortex. These results support TRPC6 family channels as therapeutic targets for acquired forms of FSGS.Support or Funding InformationSupported by NIH grant RO1‐DK104708This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Risk factors of the bladder cancer occurrence after radical nephroureterectomy of the upper tract urothelial carcinoma

Objective To study the clinic features and risk factors of bladder cancer occurrence after radical nephroureterectomy of urothelial carcinoma of the upper tract. Methods 61 cases of urothelial carcinoma of the upper tract from March 2013 to December 2013 in Beijing Friendship Hospital are retrospectively studied. 31 patients are male, while the other 30 patients are female. Age of them ranges from 43 to 90 years old, and the average age is 69 years old. 17 patients are accompanied with diabetes. 32 patients are accompanied with hypertension. 12 patients have the history of chronic nephrosis. 7 patients have the history of renal transplation operation. 47 patients have the symptom of hematuresis. 16 patients have the symptom of lumbago. Body mass index <18.5 kg/m2 2 cases, 18.5~22.9 kg/m2 25 cases, 23.0~24.9 kg/m2 10 cases, 25.0~29.9 kg/m2 20 cases, ≥30.0 kg/m2 4 cases. 25 patients' serum creatinine is abnormal, while the other 36 patients' is normal. 36 patients have left tumors, while the other 25 patients have right tumors. 39 patients have hydronephrosis before operation. 25 patients go through ureteroscopy. 11 patients have the concurrence of bladder cancer preoperatively. 25 patients have renal pelvic carcinoma, while the other 36 patients have carcinoma of ureter. 14 patients have multiple tumors, while the other 47 patients just have single tumors. The size of tumor ranges from 0.5cm to 8.0cm, and the average size is 2.9cm. 27 patients have the cauliflower-like tumors, while the other 34 patients have other shaped tumors. 28 cases have the positive results of cytology, while the other 33 cases don't have. 6 patients go through cystoscopic operation of ureterovesical junction, while the other 55 patients go through open operation of ureterovesical junction. Kaplan Meier analysis is used to find univariate risk factors of the bladder cancer occurrence postoperatively, and Log-rank test is used after that. Cox regression analysis is used to identify the independent risk factor from all the univariate risk factors. Results Time of surgery ranges from 2.0 hours to 7.5 hours, and the average time is (4.9±1.2 ) hours.39 patients' tumors are equal or greater than T2 stage, while the other 22 patients' tumors are less than T2 stage. 2 patients have I grade tumors, 40 patients have Ⅱ grade tumors, and the other 19 patients have Ⅲ grade tumors. 12 patients go through systematic chemotherapy, while the other 49 patients don't. 23 patients go through intravesical instillation postoperatively, while the other 38 don't. Follow-up time of 61 cases ranges from 22 months to 31 months, and the average time is (27.3±2.7) months. 3 to 30 months after radical nephroureterectomy, 21 cases(34.4%) have bladder cancer occurrence. 4 of patients who have concurrence of bladder cancer preoperatively go through the occurrence of bladder cancer(57.1%, 4/7), and 17 of patients who don't have concurrence of bladder cancer preoperatively go through the occurrence of bladder cancer(31.5%, 17/54). 8 of patients with multiple tumors go through the occurrence of bladder cancer(57.1%, 4/7), while 13 of patients with a single tumor go through the occurrence of bladder cancer(27.7%, 13/47). 18 of patients who have tumors equal or greater than T2 stage have the occurrence of bladder cancer(46.2%, 18/39), while 3 of patients who have tumors less than T2 stage have the occurrence of bladder cancer(13.6%, 3/22). 3 of patients with postoperative intravesical instillation have the occurrence of bladder cancer(13.0%, 3/23), while 18 of patients without postoperative intravesical instillation have the occurrence of bladder cancer(47.4%, 18/38). Single factor analysis shows that preoperative concurrence of bladder cancer(P=0.003), multiple tumors(P=0.044), T stage(P=0.023) and postoperative intravesical instillation(P=0.002) have significant influence on the occurrence of bladder cancer. And Cox proportional hazards regression model analysis shows that the preoperative concurrence of bladder cancer (RR=2.860, P=0.024, regression coefficient=1.051) and postoperative intravesical instillation(RR=0.201, P=0.011, regression coefficient= -1.065) are significantly related to the occurrence of bladder cancer after radical nephroureterectomy. Conclusions The preoperative concurrence of bladder cancer and postoperative intravesical instillation are the independent risk factors of the bladder cancer occurrence after radical nephroureterectomy. And the preoperative concurrence of bladder cancer is a risk factor, while the postoperative intravesical instillation is a protective factor. Key words: Urothelial carcinoma of the upper tract; Bladder cancer; Risk factors

Experimentally induced puromycine aminonucleoside nephrosis (PAN) in rats: evaluation of angiogenic protein platelet-derived endothelial cell growth factor (PD-ECGF) expression in glomeruli.

BackgroundIn experimentally induced puromycine aminonucleoside nephrosis (PAN) animal models, nephrotic syndrome with minimal change disease and focal and segmental sclerosis-like nephritis similar to that in human is demonstrated; however, the real mechanism of PAN is not yet elucidated. Platelet derived endothelial cell growth factor (PD-ECGF), an endothelial mitogen protein, is believed to take part in microvessel formation and in stimulation of angiogenesis and its expression has not been totally demonstrated in PAN rats yet. In this study, we aimed to examine PD-ECGF expression in acute and chronic PAN induced in rats and find out the association between its expression and the stages of angiogenesis in kidney.MethodsFor the experiment, twenty-four Male Wistar Albino rats were used and divided into four groups; control group (n = 6), pre-proteinuria group (n = 6), acute group (n = 6) and chronic group (n = 6). We compared statistically all data by One-way ANOVA Test followed by Dunn Multiple Comparison Test.ResultsProteinurea levels in control and pre-proteinuria groups were not statistically different; however, it was remarkably higher in the acute nephrosis group and significantly greater in the chronic nephrosis group than control group (p < 0.0025). In pre-proteinuria group, the serum albumin and creatinine clearances also did not significantly differ from the control group. On the other hand, in the acute and chronic nephrosis groups, serum albumin and creatinine clearances progressively decreased (p < 0.05). In our immunohistochemical studies, we showed elevated PD-ECGF expression in glomeruli of acute and chronic PAN rats. Microscopic and ultrastructural appearances of the glomeruli of acute and chronic PAN showed various sequential steps of angiogenesis, macrophages and immature capillaries with primitive lumens and apoptotic endothelial cells in the increased mesangial matrix.ConclusionsIt is reported that acute and chronic PAN progressively increase PD-ECGF expression and following induction of angiogenesis in the affected glomeruli.

Mesenchymal Stem Cells Protective Effect in Adriamycin Model of Nephropathy

Mesenchymal stem cells (MSCs) may be of value in regeneration of renal tissue after damage; however, lack of biological knowledge and variability of results in animal models limit their utilization. We studied the effects of MSCs on podocytes in vitro and in vivo utilizing adriamycin (ADR) as a model of renal toxicity. The in vivo experimental approach was carried out in male Sprague-Dawley rats (overall 60 animals) treated with different ADR schemes to induce acute and chronic nephrosis. MSCs were given a) concomitantly to ADR in tail vein or b) in aorta and c) in tail vein 60 days after ADR. Homing was assessed with PKH26-MSCs. MSCs rescued podocytes from apoptosis induced by ADR in vitro. The maximal effect (80% rescue) was obtained with MSCs/podocytes coculture ratio of 1:1 for 72 h. All rats treated with ADR developed nephrosis. MSCs did not modify the clinical parameters (i.e., proteinuria, serum creatinine, lipids) but protected the kidney from severe glomerulosclerosis when given concomitantly to ADR. Rats given MSCs 60 days after ADR developed the same severe renal damage. Only a few MSCs were found in renal tubule-interstitial areas 1-24 h after injection and no MSCs were detected in glomeruli. MSCs reduced apoptosis of podocytes treated with ADR in vitro. Early and repeated MSCs infusion blunted glomerular damage in chronic ADR-induced nephropathy. MSCs did not modify proteinuria and progression to renal failure, which implies lack of regenerative potential in this model.

Relaxin Improves Renal Function and Histology in Aging Munich Wistar Rats

Administration of recombinant human relaxin (rhRLX) to conscious, chronically instrumented rats increases GFR and effective renal plasma flow (ERPF) and decreases effective renal vascular resistance (ERVR) with no significant change in mean arterial pressure. The Munich Wistar albino rat shows progressive chronic nephrosis with age and therefore was used to determine the functional and histologic consequences of rhRLX on matrix remodeling in the kidney of older rats. RLX-infused rats showed increased GFR and ERPF with decreased ERVR. Furthermore, in a double-blinded examination, the renal histology showed a significant decrease in glomerular and tubular collagen deposition in the rhRLX-infused aged rats. During short-term rhRLX administration (24 h), gelatinase activity was found to be essential for renal vasodilation and hyperfiltration. Surprisingly, after 20 d, improved renal function was insensitive to the inhibition of gelatinase activity, suggesting that collagen degradation in these rats had permanently altered the matrix of the renal vasculature. In conclusion, long-term administration of rhRLX improves renal function and ameliorates renal pathology in an aging rat model. The biphasic action of rhRLX on the kidney indicates that, acutely, the vessels dilate, causing increased filtration and renal blood flow with decreased vascular resistance as a result of upregulation of gelatinase activity. Subsequently, the renal vessels undergo alteration in supporting matrix, showing increased blood supply even in the face of acute matrix metalloproteinase inhibition, most likely as a result of the inhibitory properties of RLX on collagen production or increased collagen breakdown.

Fertility diminution in female rats with experimental chronic nephrosis.

Chronic aminonucleoside nephrosis in rats is an experimental analogue of human focal segmental glomerulosclerosis. This study was undertaken to define the effects of chronic nephrosis on the pituitary-ovarian axis and on fertility. Chronic nephrosis was induced by puromycin aminonucleoside and followed for 112 days. The estrous cycle was evaluated daily in all rats, whereas biochemical parameters, hormonal concentrations, and fertility were measured on Days 7, 14, 28, 56, 84, and 112 (n = 8). Animals were divided in four experimental groups: A, B, C, and D. Group A was used to determine LH, FSH, progesterone, and estradiol concentrations. Group B was used to evaluate fertility, and groups C and D were added to clarify the role of male rats in the fertility of nephrotic female rats. The results showed a persistent proteinuria in nephrotic rats; the estrous cycle of nephrotic animals was disrupted. The LH and estradiol concentrations were significantly low at all time points evaluated, whereas no significant changes were noted in FSH or progesterone values. In addition, fertility and litter size were diminished in nephrotic female rats. Interestingly, the presence of a male rat or its urine resulted in a positive influence on serum estradiol concentrations of nephrotic female rats. These data indicate that experimental chronic nephrosis results in a pituitary-ovarian dysfunction that is characterized by low LH concentration, hypoestrogenism, failure of the hormonal feedback control, and diminution of fertility. In addition, they show the positive effect of a male rat on the fertility of a nephrotic female, which strongly suggests the participation of pheromones.

Bilateral malfunction of peripheral vestibular organs. Observations of 20 cases of Dandy syndrome

Dandy's Syndrome initially provokes dizziness and vertigo. Later on patients suffer from motion unsteadiness especially in dark surroundings and from oscillopsies. Gentamicin is ototoxic mostly for the vestibular part of the inner ear, and it is nephrotoxic. It may cause transitory renal dysfunction. Chronic or acute renal insufficiencies inhibit gentamicin clearance. Among 20 cases we found 15 who had previously been treated with aminoglycosides (13 with gentamicin and two with streptomycin). Ten of our patients showed symptoms of preexistant chronic nephrosis or of transitory renal insufficiency caused by gentamicin therapy. In all 13 cases, peripheral vestibular function was destroyed or severely damaged by antibiotic. The same patients had no hearing loss. The different reactions of the cochlear and the vestibular end organs support the theoretical basis for transtympanic gentamicin treatment of Menière's disease.--Other reasons for Dandy's Syndrome were bilateral Menière's disease, skull fractures, and bilateral vestibular disorders.

Reproductive function in male rats with chronic nephrosis.

Endocrine dysfunction has been associated with renal diseases. The present study was conducted to explore reproductive function in male rats with chronic nephrosis. Experimental chronic nephrosis was induced by the administration of 7.5, 5.0 and 5.0 mg per 100 g body weight of puromycin aminonucleoside on days 0, 21 and 35, respectively. Reproductive function was evaluated on the basis of hormonal concentrations, mass of accessory sex organs and fertility during an 84 day period. Circulating LH, FSH, testosterone and oestradiol concentrations were measured by specific radioimmunoassays, while fertility was estimated by the rate of pregnancy induction. Samples were collected on days 7, 14, 28, 56 and 84. The results showed an important endocrine dysfunction characterized by low concentrations of LH and FSH during the first month, after which concentrations were similar to control values or even increased on days 56 and 84. Testosterone and oestradiol decreased significantly at all time points evaluated. The mass of the testes did not alter. However, the mass of the prostate and seminal vesicle decreased only during the first 2 weeks, and became essentially normal thereafter. The reproductive capacity of nephrotic males was eliminated on day 7, whereas on day 14, 16% of the group was able to mate successfully and subsequently most animals recovered their normal reproductive function. This study demonstrates for the first time that rats with experimental chronic nephrosis develop an important endocrine dysfunction, characterized mainly by persistent reduction in testosterone concentrations, which impairs reproductive capacity only transiently.

Overcoming the nephrotoxicity of radiometal-labeled immunoconjugates: improved cancer therapy administered to a nude mouse model in relation to the internal radiation dosimetry.

Elevated renal uptake and extended retention of radiolabeled antibody fragments and peptides is a problem in the therapeutic application of such agents. However, cationic amino acids have been shown to reduce renal accretion. The aims of the current study were to evaluate whether this methodology would benefit therapy with yttrium 90 (90Y)-labeled antibody fragments (Fab, F(ab)2), to establish the relationship between radiation dosimetry and observed biologic effects, and to compare the antitumor efficacy of antibody fragments with that of whole immunoglobulin (Ig)G. The maximum tolerated dose (MTD) and the dose-limiting organ toxicity of 90Y-labeled anti-carcinoembryonic antigen (CEA) MN-14 monoclonal antibodies (Fab, F(ab)2, and IgG) were determined in nude mice bearing GW-39 human colon carcinoma xenografts. The mice were treated with or without kidney protection by administration of D-lysine, with or without bone marrow transplantation (BMT), or with combinations of each. Toxicity and tumor growth were monitored at weekly intervals after radioimmunotherapy. Dosimetry was calculated from biodistribution studies using 88Y-labeled antibody. Three different dosimetric models were examined: 1) taking solely self-to-self doses into account, using S factors for 90Y in spheroids from 0.1 to 1 g; 2) correcting for cross-organ radiation; and 3) using actual mouse anatomy as represented by nuclear magnetic resonance imaging with a three-dimensional internal dosimetry package (3D-ID). The kidney was the first dose-limiting organ with the use of Fab fragments. Acute radiation nephritis occurred at injected activities > or = 325 microCi, and chronic nephrosis at doses > or = 250 microCi. Activities of 200 microCi were tolerated by 100% of the animals (i.e., the MTD). Application of lysine decreased the renal dose by approximately fivefold, facilitating a 25% increase in the MTD (to 250 microCi), because myelotoxicity became dose-limiting despite red marrow doses of less than 5 gray (Gy). By using BMT and lysine, the MTD could be doubled from 200 to 400 microCi, where no biochemical or histologic evidence of renal damage was observed (kidney dose, < or = 40 Gy). With injected activities of > or = 325 microCi without kidney protection, and with a hepatic self-to-self dose of only 4 Gy, rising liver enzymes were observed, which could be explained only by cross-organ radiation from radioactivity in the kidneys (in the immediate neighborhood of the right kidney up to > or = 150 Gy). The MTD of F(ab)2 fragments could be elevated only by a combination of BMT and lysine. With IgG, the bone marrow alone was dose-limiting. Tumor dosimetry correlated well with antitumor effects; Fab was more effective than F(ab)2, which was consistent with its more favorable dosimetry, and it may also be more effective than IgG due to its higher dose rate and more homogenous distribution. Dosimetry Model 1 was insufficient for predicting biologic effects. Model 2 seemed to be more accurate, accounting for interorgan crossfire. However, Model 3 showed an additional substantial contribution to the red bone marrow dose due to crossfire from the abdominal organs. These data show that radiation nephrotoxicity is an important effect of cancer therapy with radiometal-conjugated antibody fragments or peptides. However, this effect can be overcome successfully with the application of cationic amino acids, which substantially increase the anti-tumor efficacy of radiometal-labeled immunoconjugates. For understanding the biologic effects (e.g., liver toxicity) of 90Y in a mouse model, accounting for cross-organ radiation is essential. Further studies with radiometal-conjugated monoclonal antibody fragments and peptides are necessary to determine the MTD, dose-limiting organs, antitumor effectiveness, and nephroprotective effects of cationic amino acids in humans.

Pregnancy induced hypertension in rats with chronic nephrosis is due to decreased synthesis of nitric oxide

Pregnancy induced hypertension in rats with chronic nephrosis is due to decreased synthesis of nitric oxide

Behavioral assessment of aging in male Fischer 344 and Brown Norway rat strains and their F 1 hybrid

Male Fischer-344 (F344) and Brown Norway (BN) rats 7-, 13-, and 24-month-old their F344 × BN hybrid (F 1) 7-, 13-, 24- and 31-month-old weretested in a behavioral battery (15-min and 24-h locomotor activity, inclined screen, rod suspension, rotorod, shock-motivated learning in a straight runway and 14-unit T maze). Necropsy was performed 3 days later and the results rated for pathology (i.e., severity of lesions observed). Age-related performance declines were observed in all behavioral tests except 15-min locomotor activity. Strain effects were observed in 15-min (BN more active than F344 and F 1 and 24-h locomotor activity test (F344 more active than BN and F 1 strains); rotorod performance (F344 fell more than BN and F 1); and in all measures [errors (E), runtime (RT)], shock frequency (SF), and duration (SD)] in the 14-unit T maze (F344 worse than BN, BN worse than F 1). T maze performance of 31-month-old F 1 rats was deficient in RT, SD, and SF but E performance was equivalent to that of 7-month-old F 1 rats. In a second experiment, only 7- and 31-month-old F 1 rats were tested in the 14-unit T maze and the results obtained in Experiment 1 were replicated. Gross necropsy revealed age and strain effects in the number of lesions observed and the mean ratings of pathology. The 24-month-old F344 rats exhibited the greatest number of lesions and had the highest ratings (generally observed as chronic nephrosis and enlarged spleens characteristic of mononuclear cell leukemia). BN rats exhibited a high incidence of hydronephrosis at all age levels. While experiencing less obvious pathology, F 1 rats experienced a significant number of lesions in the 31-month-old group. Pathology ratings correlated with behavioral performance but only for a few tests (e.g., SD and RT in 14 unit T maze in 24-month-old F344). Thus, behavioral performance declined with age and the battery of tests differentiated between the strains tested (in general, F344 worse than BN; BN worse than F 1). The correlation of pathology ratings at gross necropsy with behavior did not appear to be systematic, suggesting that morbidity was not responsible for the age-related performance declines. However, more extensive evaluation of the relationship of age-related changes in health status to behavior with larger samples of rats is suggested.

Plasma lipoproteins and renal apolipoproteins in rats with chronic adriamycin nephrosis

The relation between plasma lipoprotein composition and renal apolipoprotein deposition was studied in nephrotic rats in which stable renal function had been monitored for 7 months after a single low dose of adriamycin (ADR, 3 mg/kg). Proteinuria was observed 3 weeks after ADR and increased progressively up to about 0.5 g/day (versus 0.07 g/day in controls; P < 0.001), while the creatinine clearance remained stable at about 80% of control values. Hypercholesterolaemia was observed 6 weeks after ADR, and increased progressively up to 7.0 +/- 1.0 mmol/l (versus 2.3 +/- 0.1 mmol/l in controls; P < 0.001). Cholesterol was primarily located in LDL2 and HDL2 lipoproteins. Plasma apolipoprotein (apo) A-I increased by more than 400% in the nephrotic rats (P < 0.001). Apo B and apo E increased by about 60% (P < 0.01), whereas apo A-IV remained unchanged. Focal sclerotic lesions in glomeruli had an incidence of 50 +/- 10% in ADR rats versus 2 +/- 1% in controls (P < 0.001). Immunohistochemistry revealed apo A-I and apo A-IV in the visceral epithelium. Apo E immunoreactivity and lipid deposits were observed in focal glomerular sclerotic lesions of ADR rats. Neither apolipoproteins nor lipids were detected in glomeruli of controls. Proximal tubular localization of apolipoproteins was extensive for apo A-I, apo A-IV and apo E, but no differences were observed in tubular deposition of apolipoproteins between ADR and control rats.(ABSTRACT TRUNCATED AT 250 WORDS)