The Importance of Genetic Testing in the Differential Diagnosis of Atypical TSC2-PKD1 Contiguous Gene Syndrome-Case Series.

BACKGROUND: In clinical practice, the possible diagnosis of tuberous sclerosis or polycystic kidney disease is primarily based on clinical criteria, which can later be verified by genetic testing. But in the case of TSC2/PKD1 contiguous gene syndrome (TSC2/PKD1-CGS), the renal appearance of the disease is more serious. Therefore, early genetic analysis is recommended. METHODS: Herein we present the report of four children with TSC2/PKD1-CGS, one involving the NTHL1 gene. We aim to emphasize the importance of genetic testing in this rare syndrome. RESULTS: During the follow-up of tuberous sclerosis and polycystic kidney disease patients, it is essential to reappraise the diagnosis if the clinical symptoms' appearance or onset time is unusual. Targeted genetic testing is recommended. However, early tumor formation necessitates the extension of genetic analysis. CONCLUSIONS: An appropriate evaluation of the phenotype is the cornerstone of diagnosing the rare TSC2/PKD1-CGS with the help of genetic results. In addition, malignant tumors could draw attention to an infrequent large deletion.

Body composition, physical activity, and quality of life in pediatric patients with inflammatory bowel disease on anti-TNF therapy-an observational follow-up study.

BACKGROUND: Poor outcome of inflammatory bowel disease (IBD) is associated with malnutrition. Our aim was to compare body composition (BC) and physical activity (PA) between patients with IBD and healthy controls, and to assess the changes in BC, PA and health related quality of life (HRQoL) in children with IBD during anti-TNF therapy. METHODS: 32 children with IBD (21 with Crohn's disease (CD), (age: 15.2 ± 2.6 years, 9 male) and 11 with ulcerative colitis (UC), (age: 16.4 ± 2.2 years, 5 male) participated in this prospective, observational follow up study conducted at Semmelweis University, Hungary. As control population, 307 children (age: 14.3 ± 2.1) (mean ± SD) were included. We assessed BC via bioelectric impedance, PA and HRQoL by questionnaires at initiation of anti-TNF therapy, and at two and six months later. The general linear model and Friedman test were applied to track changes in each variable. RESULTS: During follow-up, the fat-free mass Z score of children with CD increased significantly (-0.3 vs 0.1, p = 0.04), while the BC of patients with UC did not change. PA of CD patients was lower at baseline compared to healthy controls (1.1 vs. 2.4), but by the end of the follow up the difference disappeared. CONCLUSIONS: The fat-free mass as well as PA of CD patients increased during the first six months of anti-TNF treatment. As malnutrition and inactivity affects children with IBD during an important physical and mental developmental period, encouraging them to engage in more physical activity, and monitoring nutritional status should be an important goal in patient care.

Ocular treatment of cystinosis with eye drop containing cysteamine / Ciszteamintartalmú szemcsepp alkalmazása cystinosisban

Cystinosis is a rare lysosomal storage disease affecting amino acid metabolism, characterized by the accumulation and crystallization of cystine in various tissues, primarily in the eye and kidney. The major ophthalmic symptom is photophobia, which is related to the corneal deposition of cystine crystals. The light sensitivity significantly impairs the quality of life of the affected patients, thus, effective ophthalmic treatment to reduce the crystal density is very importance. In the current case report, we present the characteristic ocular clinical appearance and treatment options of cystinosis by reviewing the literature. A simple aqueous solution of cysteamine, which aids in the dissolution of crystals, has been widely used in topical treatment in the past, however, its therapeutic efficacy is debatable. Recently, a new viscous formulation of cysteamine has been proposed for ophthalmic treatment. For the treatment of corneal cystine crystals in our patient, the new viscous format of cysteamine has been applied, and therapeutic effects were recorded for a year. Applying the viscous cysteamine formulation, a marked and gradual decrease in photophobia was observed in our patient in the first year of the treatment. Anterior-segment optical coherence tomography and in vivo confocal microscopy represented a continuous decrease in the density of corneal crystals even from the first month of the treatment period. The aim of our case report is to present the ophthalmic symptoms of cystinosis and the results of the first clinical application of viscous formulation of cysteamin eye drops in Hungary in a cystinosis patient.

De novo inflammatory bowel disease in children after solid organ transplantation / Szolidszerv-transzplantáció után kialakuló de novo gyulladásos bélbetegség gyermekkorban.

Összefoglaló. A gyulladásos bélbetegség (inflammatory bowel disease, IBD) incidenciája folyamatosan no, etiológiája egyelore ismeretlen. Kezelésében gyakran alkalmazunk immunszuppresszív, illetve immunmoduláns szereket. Egyes esetekben azonban szolidszerv-transzplantációt követoen, folyamatos immunszuppresszív kezelés mellett is megfigyelheto de novo IBD kialakulása. Célunk az volt, hogy Klinikánk beteganyagából összesítsük azon eseteket, amelyekben szolid szerv (máj, vese, tüdo) transzplantációját követoen de novo IBD alakult ki. A transzplantációt megelozoen szklerotizáló cholangitis miatt gondozott betegeket kizártuk. A Klinikánkon gondozott, szolid szerv transzplantációján (179 máj, 197 vese, 29 tüdo) átesett betegek közül 4 (2 máj- és 2 vesetranszplantált) gyermeknél alakult ki de novo IBD. A transzplantációhoz vezeto alapbetegségek biliaris atresia, polycystás vese és Denys-Drash-szindróma voltak. A transzplantációt követo immunszuppresszív terápia mind a 4 esetben tartalmazott szisztémásszteroid- és takrolimuszkezelést, emellett 3 esetben mikofenolát-mofetil (MMF)-terápiát is. A kivizsgálást indikáló fobb tünetek a haematochesia, hasmenés, fáradékonyság és fogyás voltak. A családi anamnézis 1 esetben volt pozitív. A de novo IBD diagnózisának felállítását követoen mind a 4 betegnél az addigi immunszuppressziós terápia módosításra került. Összességében elmondható, hogy a szolidszerv-transzplantációt követo de novo IBD kialakulása ritka, etiológiája tisztázatlan. Az irodalom felveti az alkalmazott immunszuppresszív szerek (takrolimusz és MMF), illetve infekciók etiológiai szerepét, de az is felmerül, hogy a de novo IBD olyan önálló entitás, mely elkülönül a klasszikus IBD kategóriáitól. Klinikai szempontból fontos a tünetek hátterében álló betegség tisztázása, hiszen a prezentációs tüneteknek megfelelo, a differenciáldiagnosztika során felmerülo egyéb betegségek terápiája meroben eltér. A megfelelo terápia hozzájárulhat a transzplantált betegek morbiditásának és mortalitásának csökkentéséhez. Orv Hetil. 2021; 162(18): 720-726. Summary. The incidence of inflammatory bowel disease (IBD) is increasing, however, the aetiology is still unknown. The therapy consists of immunosuppressants and immunomodulators. In some cases, despite the continuous immunosuppressant therapy, de novo IBD develops. Our aim was to evaluate patients diagnosed with de novo IBD after solid organ (liver, kidney, or lung) transplantation. Patients treated with sclerosing cholangitis prior to liver transplantation were excluded. 4 patients (two kidney and two liver transplants) were diagnosed with de novo IBD. The underlying diseases leading to transplantation were biliary atresia, polycystic kidney, and Denys-Drash syndrome. All patients received systemic steroid and tacrolimus treatment, and 3 patients (2 kidney and 1 liver transplant) also received mycophenolate mofetil (MMF). The main symptoms indicative of de novo IBD were haematochezia, diarrhoea, fatigue, and weight loss. Family history for IBD was positive in 1 case. Following the diagnosis of IBD, immunosuppressive therapy was modified. Overall, the development of de novo IBD following solid organ transplantation is quite rare, and its aetiology is unknown. According to the literature, immunosuppressants (tacrolimus and MMF) and infections play a role in the pathomechanism, but it seems that de novo IBD is a separate entity from the classical IBD categories. From a clinical point of view, it is important to elucidate the underlying disease of the symptoms, as the treatment of other diseases that arise during differential diagnosis according to the presentation symptoms is very different. Appropriate therapy can help reduce morbidity and mortality in transplant patients. Orv Hetil. 2021; 162(18): 720-726.

Association of affective temperaments with blood pressure and arterial stiffness in hypertensive patients: a cross-sectional study.

BACKGROUND: Affective temperaments (anxious, depressive, cyclothymic, irritable and hyperthymic) measure subclinical manifestations of major mood disorders. Furthermore, cumulating evidence suggests their involvement in somatic disorders as well. We aimed to assess associations between affective temperament scores and blood pressure and arterial stiffness parameters in hypertensive patients. METHODS: In this cross-sectional study, 173 patients with well-controlled or grade 1 chronic hypertension, with no history of depression, completed the TEMPS-A, Beck Depression Inventory (BDI) and Hamilton Anxiety Scale (HAM-A) questionnaires in three GP practices. Arterial stiffness was measured with tonometry (PulsePen). RESULTS: According to multiple linear regression analysis, cyclothymic temperament score was positively associated with brachial systolic blood pressure independently of age, sex, total cholesterol, brachial diastolic blood pressure, BDI, HAM-A and the use of alprazolam (ß = 0.529, p = 0.042), while hyperthymic temperament score was negatively related to augmentation index independent of age, sex, smoking, heart rate, BDI, HAM-A and the use of alprazolam (ß = -0.612, p = 0.013). A significant interaction was found between cyclothymic temperament score and sex in predicting brachial systolic blood pressure (p = 0.025), between irritable and anxious temperament scores and sex in predicting pulse wave velocity (p = 0.021, p = 0.023, respectively) and an interaction with borderline significance between hyperthymic temperament score and sex in predicting augmentation index (p = 0.052). CONCLUSIONS: The present findings highlight elevated blood pressure among subjects with high cyclothymic temperament as well as an increased level of arterial stiffening in subjects with low hyperthymic scores suggesting that affective temperaments may play a role in the development of hypertension and arterial stiffening and may thus represent markers of cardiovascular risk. Sex differences were also present in these associations.

[Post-transplantation lymphoproliferative disorder in childhood]. / Poszttranszplantációs lymphoproliferativ betegség gyermekkorban.

INTRODUCTION: Among possible complications of transplantation the post-transplant lymphoproliferative disease due to immunosuppressive therapy is of paramount importance. In most cases the direct modulating effect of Epstein-Barr virus on immune cells can be documented. AIM: The aim of the authors was to evaluate the incidence os post-transplant lymphoproliferative diseases in pediatric transplant patients in Hungary. METHOD: The study group included kidney, liver and lung transplant children followed up at the 1st Department of Pediatrics, Semmelweis University, Budapest and stem cell transplant children at Szent László Hospital, Budapest. Data were collected from 78 kidney, 109 liver and 17 lung transplant children as well as from 243 children who underwent allogenic stem cell transplantation. RESULTS: Between 1998 and 2012, 13 children developed post-transplant lymphoproliferative disorder (8 solid organ transplanted and 5 stem cell transplanted children). The diagnosis was based on histological findings in all cases. Mortality was 3 out of the 8 solid organ transplant children and 4 out of the 5 stem cell transplant children. The highest incidence was observed among lung transplant children (17.6%). CONCLUSIONS: These data indicate that post-transplant lymphoproliferative disease is a rare but devastating complication of transplantation in children. The most important therapeutic approaches are reduction of immunosuppressive therapy, chemotherapy and rituximab. Early diagnosis may improve clinical outcome and, therefore, routine polymerase chain reaction screening for Epstein-Barr virus of high risk patients is recommended.

Aldosterone antagonists in monotherapy are protective against streptozotocin-induced diabetic nephropathy in rats.

Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are the standard clinical therapy of diabetic nephropathy (DN), while aldosterone antagonists are only used as adjuncts. Previously in experimental DN we showed that Na/K ATPase (NKA) is mislocated and angiotensin II leads to superimposed renal progression. Here we investigated the monotherapeutic effect of aldosterone blockers on the progression of DN and renal NKA alteration in comparison to ACEi and ARBs. Streptozotocin-diabetic rats developing DN were treated with aldosterone antagonists; ACEi and ARB. Renal function, morphology, protein level and tubular localization of NKA were analyzed. To evaluate the effect of high glucose per se; HK-2 proximal tubular cells were cultured in normal or high concentration of glucose and treated with the same agents. Aldosterone antagonists were the most effective in ameliorating functional and structural kidney damage and they normalized diabetes induced bradycardia and weight loss. Aldosterone blockers also prevented hyperglycemia and diabetes induced increase in NKA protein level and enzyme mislocation. A monotherapy with aldosterone antagonists might be as, or more effective than ACEi or ARBs in the prevention of STZ-induced DN. Furthermore the alteration of the NKA could represent a novel pathophysiological feature of DN and might serve as an additional target of aldosterone blockers.

Prevalence and predictors of the sub-target Hb level in children on dialysis.

BACKGROUND: Anaemia is a common and potentially treatable co-morbidity of end-stage renal disease. We aimed to determine the prevalence of the sub-target haemoglobin (Hb) level among European children on dialysis and to identify factors associated with a low Hb level. METHODS: From the European Society for Paediatric Nephrology (ESPN)/European Renal Association-European Dialysis Transplant Association (ERA-EDTA) registry, data were available on 2351 children between 1 month and 18 years of age, totalling 5546 measurements from 19 countries. RESULTS: The mean Hb level was 10.8 g/dL (5th-95th percentiles, 7.4-13.9). Among those above 2 years of age, the mean Hb level was 10.9 g/dL (11.4% below 8.5 g/dL), while it was 10.3 g/dL among those below 2 years (11.2% below 8.0 g/dL). A total of 91.2% of the patients were on an erythropoiesis-stimulating agent (ESA). Hb levels increased with age and were higher in peritoneal dialysis compared with haemodialysis patients. Patients with congenital anomalies of the kidney and urinary tract showed the highest Hb levels, and those with cystic kidney diseases or metabolic disorders the lowest ones. Ferritin levels between 25 and 50 ng/mL were associated with the highest Hb levels. We found a weak inverse association between parathyroid hormone (PTH) and Hb. Whereas standardized blood pressure (BP) was not elevated in patients with above-target Hb, elevated systolic BP z-score was noted in those with sub-target Hb levels. CONCLUSIONS: Sub-target Hb levels remain common in children on dialysis, in spite of virtually all children being treated with ESA; although we cannot exclude under-dosing. Optimal ferritin levels seemed to be slightly lower in children (25-50 ng/mL) than those in adults. Other risk factors for sub-target Hb are dialysis modality and a high PTH level.

Renoprotective effect of erythropoietin in rats subjected to ischemia/reperfusion injury: gender differences.

BACKGROUND: Renal ischemia reperfusion injury induces gender-dependent heat-shock protein 72 expression, which maintains membrane localization of renal Na(+)/K(+)ATPase-α1. The erythropoietin has a protecting effect against ischemia reperfusion injury in various organs. In this study, we investigated whether erythropoietin exerts a beneficial effect against post-ischemic renal injury. Furthermore, we studied the erythropoietin signaling on heat-shock protein 72 and Na(+)/K(+)ATPase-α1 expression and localization. METHODS: In male and female Wistar rats, rHuEPO (1000 IU/bwkg intraperitoneal) or vehicle was administered 24 hours prior to unilateral left renal ischemia reperfusion (50 minutes). Kidneys were subsequently removed at hours 2 or 24 of the reperfusion; sham-operated rats served as controls (C) (n = 8/group). We measured serum erythropoietin, renal function, evaluated histological injury, and observed heat-shock protein 72 as well as Na(+)/K(+)ATPase-α1 protein level and localization. Additional groups were followed for 7-day survival. RESULTS: Erythropoietin treatment was associated with better post-ischemic survival and less impaired renal function in males while diminishing the renal structural damage in both sexes. Endogenous erythropoietin was higher in males and increased in both genders after erythropoietin treatment. The erythropoietin treatment elevated protein levels of heat-shock protein 72 and Na(+)/K(+)ATPase-α1 in 24 hours in males, whereas in females, the already higher expression of heat-shock protein 72 and Na(+)/K(+)ATPase-α1 was not increased. Moreover, erythropoietin prevented ischemia reperfusion induced Na(+)/K(+)ATPase-α1 translocation from the basolaterale membrane in males. CONCLUSION: Erythropoietin diminishes gender difference in the susceptibility to renal post-ischemic injury and reduces post-ischemic structural damage while preserving kidney function, particularly in males. This additional protection may be associated with a heat-shock protein 72-mediated effect on Na(+)/K(+)ATPase-α1 expression and translocation.

Increased heat shock protein 72 expression in celiac disease.

BACKGROUND AND OBJECTIVES: Heat shock protein (HSP) 72, a known chaperone, has potential epithelial barrier protecting, antiapoptotic, and immune system regulatory effects; therefore, our aim was to study its involvement in the pathology of celiac disease (CD). PATIENTS AND METHODS: Duodenal biopsy specimens were collected from children with untreated and treated CD and from controls. mRNA expression, protein level, and localization of HSP72 were determined. RESULTS: Elevated HSP72 mRNA expression and higher protein levels were found in the duodenal mucosa of children with untreated CD as well as in children with treated CD compared with those in controls. In the duodenal mucosa of children with treated CD, HSP72 mRNA expression was decreased and HSP72 protein levels were lower than those in children with untreated CD. We detected intensive HSP72 staining in the villous enterocytes and immune cells of the lamina propria in the duodenal villi of children with untreated CD compared with that in controls. CONCLUSIONS: The increased expression and altered localization of HSP72 in CD indicate that HSP72 should have a role in protection against gliadin-induced cytotoxicity. HSP72 may exert antiapoptotic effect and contribute to preservation of intestinal epithelial barrier integrity. Moreover, HSP72 as a ligand of TLR2 and TLR4 may promote innate immune responses and warn the cells of the potential injury.

Voiding urosonography with second-generation contrast agent versus voiding cystourethrography.

Contrast-enhanced voiding urosonography (VUS) is becoming more widely used for the diagnosis of vesicoureteric reflux (VUR). The purpose of this study was to evaluate the sensitivity of VUS using a second-generation ultrasound (US) contrast agent and compare it with standard fluoroscopic voiding cystourethrography (VCUG). A total of 183 children with 366 kidney-ureter units (KUUs) underwent VUS and VCUG in the same session with the same catheterization. VUS was performed after intravesical administration of 1 ml of a second-generation ultrasound contrast agent (UCA; SonoVue, Bracco, Italy). VUR was detected in 140 out of 366 cases (38%); in 89 (24.3%) by both methods, in 37 (10.1%) by VUS only, and in 14 (3.8%) by VCUG only. Although there was considerable agreement in the diagnosis of VUR by VUS and VCUG (κ=0.68, standard error [κ]=0.04), the difference in the detection rate of reflux between VUS and VCUG was significant (p<0.00001). The grade of VUR detected with VUS showed moderate agreement with grading by VCUG. Our findings suggest that contrast-enhanced harmonic VUS using a second-generation contrast agent is superior to VCUG in the detection and grading of VUR, and it should be the method of choice for this clinical indication.

Captopril-enhanced renal scintigraphy in the diagnosis of pediatric hypertension.

Hypertension in childhood is no longer a rare condition mainly secondary to renal, or renovascular diseases, as a growing proportion of children are obese and hypertensive, with the phenotype of metabolic syndrome. Thus, we need to reconsider our practice in the examination of the hypertensive child and redefine the place of non-invasive methods for screening of renovascular hypertension, and specifically, to evaluate the value of captopril-enhanced renal scintigraphy at the two ends of the palette: the obese child with hypertension and the severely hypertensive prepubertal child. Renal artery stenosis in children is mainly due to fibromuscular dysplasia and stenoses associated with syndromes involving single or multiple smaller branch vessels. This explains the low specificity and sensitivity of the color-Doppler ultrasound method and captopril renal scintigraphy. Even the more sophisticated computed tomography (CT) and magnetic resonance imaging (MRI) angiographic techniques are, at present, not sensitive enough to exclude stenoses of the small branches definitely. Thus, children in whom there is a strong suggestion of renovascular hypertension should undergo angiography with a view to endovascular treatment, as non-invasive imaging has no significant benefit and might lead to a delay in treatment. In the cases when the probability of renovascular disease is moderate a basic assessment of renal function and structure is sufficient. In the neonate, catheter-associated thromboembolic disease is among the most common causes hypertension. It should be controlled medically until the patient is old enough to undergo angiography and angioplasty successfully. Thus, in this age group, there is a place for functional imaging with renal sonography and angiotensin-converting enzyme inhibitor (ACEI) renography to detect hemodynamically significant renovascular disease, with the limitations mentioned above. However, the rapid technical evolution of non-invasive methods requires periodic re-consideration of the actual standpoints.

Effects of bone and mineral metabolism on arterial elasticity in chronic renal failure.

Arterial stiffness (Ast) individually predicts cardiovascular (CV) mortality. Ast increases via vascular calcification and can be characterized by pulse wave velocity (PWV). We assessed the influence of mineral and bone metabolism on Ast in dialyzed (D) and renal transplanted (Tx) children by measuring fetuin-A and bone markers [bone-specific alkaline phosphatase (BALP); beta-CrossLaps (beta)]. Normalized PWV/height (PWV/h) of 11 D and 17 Tx patients was measured by applanation tonometry. Levels of calcium (Ca), phosphate (P), fetuin-A, and bone markers were analyzed. Ca x P/fetuin-A ratio was calculated to characterize the balance of calcification and inhibition. Cumulative dose of calcitriol was also assessed. Fetuin-A was lower in D and Tx compared with healthy controls. Bone markers and Ca x P/ fetuin-A of D were significantly higher than those of Tx and controls. In D PWV/h correlated with Ca x P/fetuin-A and BALP (r=0.8; p=0.005, r=0.6, p=0.05, respectively); BALP correlated with Ca x P/fetuin-A (r=0.7, p=0.01). In Tx, there was a correlation between calcitriol administered before transplantation and PWV/h (r=0.5, p=0.04). Increased bone turnover was coupled with an increased potential of calcium-phosphate precipitation, as shown by the increased Ca x P/fetuin-A. It might explain the connection between disturbed mineral and bone metabolism and Ast. Tx might be beneficial on Ast, though follow-up studies are needed.

Effects of histamine and the h2 receptor antagonist ranitidine on ischemia-induced acute renal failure: involvement of IL-6 and vascular endothelial growth factor.

BACKGROUND: Vascular endothelial growth factor (VEGF) exerts cytoprotective, antiapoptotic and proangiogenic effects; its synthesis is induced by hypoxia, several cytokines and histamine. The effects of histamine and the H2 receptor antagonist ranitidine on renal VEGF and IL-6 synthesis were investigated in a well-established rat model of renal ischemia/reperfusion injury. METHODS: Following 7 days of pretreatment with histamine (H group; n = 12), ranitidine (R group; n = 10) or vehicle (controls; n = 13), the left vascular pedicle was clamped for 50 min in uninephrectomized male rats and survival assessed in the different treatment groups. Additionally, renal IL-6 mRNA expression, as well as VEGF mRNA and protein abundance were measured in the three treatment groups following pretreatment only, 2 and 16 h after 50 min of renal ischemia (n = 6/group/timepoint). RESULTS: Ranitidine significantly increased, while histamine significantly decreased survival following renal ischemia. Renal IL-6 mRNA expression increased 2 h after reperfusion in all groups and decreased thereafter, with the lowest level observed in the R group. While VEGF mRNA did not change in controls, histamine increased, whereas ranitidine decreased its expression during the follow-up. Two hours after ischemia a twofold increase in renal VEGF protein abundance was observed in controls and the H group and significantly higher values were noted in the R group at this time point. A further increase in VEGF protein was only present in the H group 16 h after reperfusion. CONCLUSION: These results indicate an important role of histamine in kidney damage following renal ischemia. The beneficial effects of ranitidine were partly mediated by decreased IL-6 and VEGF mRNA expression and significant early increase in renal VEGF abundance.

Sex differences in the alterations of Na(+), K(+)-ATPase following ischaemia-reperfusion injury in the rat kidney.

Postischaemic acute renal failure (ARF) is influenced by sex. Na(+), K(+)-ATPase (NKA) plays a crucial role in the pathogenesis of postischaemic ARF. We tested the impact of sex on mRNA, protein expression, cellular distribution and enzyme activity of NKA following renal ischaemia-reperfusion (I-R) injury. The left renal pedicle of uninephrectomized female (F) and male (M) Wistar rats was clamped for 55 min followed by 2 h (T2) and 16 h (T16) of reperfusion. Uninephrectomized, sham-operated F and M rats served as controls (n= 6 per group). Blood urea nitrogen, serum creatinine and renal histology were evaluated to detect the severity of postischaemic ARF. mRNA expression of NKA alpha1 and beta1 subunits were detected by RT-PCR. The effect of I-R on cellular distribution was compared by Triton X-100 extraction. Cellular proteins were divided into Triton-insoluble and Triton-soluble fractions and assessed by Western blot. NKA enzyme activity was also determined. After the ischaemic insult blood urea nitrogen and serum creatinine were higher and renal histology showed more rapid progression in M versus F (P < 0.05). mRNA expression of the NKA alpha1 subunit decreased in I-R groups versus controls, but was higher in F versus M both in control and I-R groups (P < 0.05). However, protein levels of the NKA alpha1 subunit in total tissue homogenate did not differ in controls, but were higher in F versus M in I-R groups (P < 0.05). Triton X-100 extractability was lower in F versus M at T16 (P < 0.05). NKA enzyme activity was the same in controls, but was higher in F versus M in I-R groups (T2: 14.9 +/- 2.3 versus 9.15 +/- 2.21 U) (T16: 11.7 +/- 4.1 versus 5.65 +/- 2.3 U; P < 0.05). mRNA and protein expression of the NKA beta1 subunit did not differ between F and M in any of the protocol. We concluded that NKA is more protected from the detrimental effects of postischaemic injury in females. Higher mRNA and protein expression of the NKA alpha1 subunit and higher enzyme activity might be additional contributing factors to the improved postischaemic renal function of female rats.

Sexual dimorphism in renal ischemia-reperfusion injury in rats: possible role of endothelin.

BACKGROUND: Postischemic organ dysfunction is influenced by gender and sexual steroids. METHODS: To compare the susceptibility of the kidney to postischemic failure between sexes, the left vascular pedicle was clamped for 50 minutes in anesthetized male and female Wistar rats. Survival rate, renal and systemic hemodynamics and renal prepro-endothelin (pp-ET) mRNA expression were measured. RESULTS: Eight percent of males as compared to 75% of females survived for more than 7 days. Previous orchidectomy of mature rats or sexual immaturity improved the rate of 7 day survival to 67% and 58%, respectively, as compared to intact males (P < 0.05). Estradiol treatment of mature male animals also resulted in a significantly better survival. Ovariectomy, sexual immaturity or testosterone treatment had no impact on the course of renal failure in females. The early postischemic recovery of renal blood flow was delayed due to a dramatic increase in renal vascular resistance in male versus female rats. The expression of pp-ET gene in the kidneys was increased at 5 minutes following reperfusion and was significantly higher 2 hours after ischemia in males, but not in females. Pretreatment with the endothelin A receptor antagonist LU 135252 provided indistinguishable survival rates in intact male and female rats after warm renal ischemia. CONCLUSION: Female rats enjoy relative protection against postischemic renal failure. Furthermore, in intact males the effects of androgens upon ischemic kidney damage seem to be mediated by endothelin-induced vascular changes.