The effect of sirolimus on angiomyolipoma is determined by decrease of fat-poor compartments and includes striking reduction of vascular structures.

Renal angiomyolipomas hemorrhage is associated with their size and vascular constitution. The effects of sirolimus on different components of angiomyolipomas was analyzed in patients with tuberous sclerosis complex, sporadic lymphangioleiomyomatosis and multiple sporadic angiomyolipomas. Thirty angiomyolipomas from 14 patients treated with sirolimus were retrospectively evaluated. A Hounsfield-unit threshold was used to classify angiomyolipomas in fat-rich, fat-poor and intermediate-fat tumors, and to categorize tumor compartments in fat rich, fat poor, intermediate fat and highly vascularized. Diameter variations were measured to assess the effects on aneurysmatic/ectatic vascular formations. Volume reduction following treatment with sirolimus was higher in fat-poor than fat-rich angiomyolipomas. Tumor reduction was mainly determined by decrease of the fat-poor and highly-vascularized compartments while the volume of the fat-rich compartment increased. Broad liposubstitution was observed in some tumors. A median reduction of 100% (75 to 100) in the diameter of aneurysmatic/ectatic vascular structures was observed. Our study showed that sirolimus reduces the size of angiomyolipomas by decreasing primarily their highly-vascularized and fat-poor compartments. This effect is associated with a remarkable reduction of tumoral aneurysms/ectatic vessels, revealing the likely mechanism responsible for the risk-decreasing effect of mTOR inhibitors on angiomyolipoma bleeding. These findings support the role of mTOR in the development of angiomyolipoma blood vessels.

Two cases of fungal cyst infection in ADPKD: is this really a rare complication?

BACKGROUND: Cyst infection is a prevalent complication in autosomal dominant polycystic kidney disease (ADPKD) patients, however therapeutic and diagnostic approaches towards this condition remain unclear. The confirmation of a likely episode of cyst infection by isolating the pathogenic microorganism in a clinical scenario is possible only in the minority of cases. The available antimicrobial treatment guidelines, therefore, might not be appropriate to some patients. CASE PRESENTATION: We describe two unique cases of kidney cyst infection by Candida albicans, a condition that has not been previously described in literature. Both cases presented clear risk factors for Candida spp. infection. However, since there was no initial indication of cyst aspiration and culture, antifungal therapy was not immediately started and empirical treatment was initiated as recommended by the current guidelines. Antifungal treatment was instituted in both cases along the clinical course, according to their specificities. CONCLUSION: Our report highlights the possibility of Candida spp. cyst infection. Failure of clinical improvement with antibiotics should raise the suspicion of a fungal infection. Identification of infected cysts should be pursued in such cases, particularly with PET-CT, and when technically possible followed by cyst aspiration and culture to guide treatment. Risk factors for this condition, such as Candida spp. colonization, previous antimicrobial therapy, hemodialysis, necrotizing pancreatitis, gastrointestinal/hepatobiliary surgical procedure, central venous catheter, total parenteral nutrition, diabetes mellitus and immunodeficiency (neutropenia < 500 neutrophils/mL, hematologic malignancy, chemotherapy, immunosuppressant drugs), should be also considered accepted criteria for empirical antifungal therapy.

A novel single amino acid deletion impairs fibronectin function and causes familial glomerulopathy with fibronectin deposits: case report of a family.

BACKGROUND: Glomerulopathy with fibronectin deposits is an autosomal dominant disease associated with proteinuria, hematuria, hypertension and renal function decline. Forty percent of the cases are caused by mutations in FN1, the gene that encodes fibronectin. CASE PRESENTATION: This report describes two cases of Glomerulopathy with fibronectin deposits, involving a 47-year-old father and a 14-year-old son. The renal biopsies showed glomeruli with endocapillary hypercellularity and large amounts of mesangial and subendothelial eosinophilic deposits. Immunohistochemistry for fibronectin was markedly positive. Whole exome sequencing identified a novel FN1 mutation that leads to an amino-acid deletion in both patients (Ile1988del), a variant that required primary amino-acid sequence analysis for assessment of pathogenicity. Our primary sequence analyses revealed that Ile1988 is very highly conserved among relative sequences and is positioned in a C-terminal FN3 domain containing heparin- and fibulin-1-binding sites. This mutation was predicted as deleterious and molecular mechanics simulations support that it can change the tertiary structure and affect the complex folding and its molecular functionality. CONCLUSION: The current report not only documents the occurrence of two GFND cases in an affected family and deeply characterizes its anatomopathological features but also identifies a novel pathogenic mutation in FN1, analyzes its structural and functional implications, and supports its pathogenicity.

Functional Budd-Chiari Syndrome Associated With Severe Polycystic Liver Disease.

A 50-year-old woman with end-stage renal disease secondary to autosomal dominant polycystic kidney disease was referred to a quaternary care center due to significantly increased abdominal girth. Her physical examination revealed tense ascites and abdominal collateral veins. A 10-L paracentesis improved abdominal discomfort and disclosed a transudate, suggestive of portal hypertension. A computed tomographic scan revealed massive hepatomegaly caused by multiple cysts of variable sizes, distributed throughout all hepatic segments. Contrast-enhanced imaging uncovered extrinsic compression of hepatic and portal veins, resulting in functional Budd-Chiari syndrome and portal hypertension. Although image-guided drainage followed by sclerosis of dominant cysts could potentially lead to alleviation of the extrinsic compression, the associated significant risk of cyst hemorrhage and infection precluded this procedure. In this scenario, the decision was to submit the patient to a liver-kidney transplantation. After 1 year of this procedure, the patient maintains normal liver and kidney function and refers significant improvement in quality of life.

Camundongos com deficiência em Pkd1 apresentam disfunção cardíaca, fenótipo atenuado por knockout de galectina-3 / Cardiac dysfunction in Pkd1-deficient mice and phenotype rescue by galectin-3 knockout

Anormalidades miocárdicas destacam-se entre as manifestações cardiovasculares da doença renal policística autossômica dominante (DRPAD). Para investigar a patogênese dessas manifestações, analisamos o fenótipo cardíaco em camundongos com diferentes perfis de deficiência de Pkd1. Avaliamos o modelo Pkd1cond/cond:Nestincre (CI), com cistos renais e hipertensão, na idade de 20-24 semanas, e heterozigotos para mutação nula em Pkd1 (Pkd1+/-; HT) entre 10-13 semanas, representando um modelo não cístico de haploinsuficiência gênica. Animais Pkd1cond/cond (não cístico; NC) e Pkd1+/+ (selvagem, SV) foram usados como controles. Análises ecocardiográficas de camundongos CI e HT revelaram diminuição da fração de ejeção do ventrículo esquerdo, indicando disfunção sistólica. A relação E/A e o tempo de desaceleração foram consistentes com disfunção diastólica em animais CI. Ecocardiografia por speckle-tracking mostrou redução na deformidade cardíaca (strain) nos modelos CI e HT. Os corações de ambos os grupos apresentaram índices de apoptose maiores e fibrose discreta. Neste cenário, investigamos galectina-3 (Gal-3) como modificador potencial do fenótipo cardíaco na DRPAD. Duplos-mutantes Pkd1cond/cond:Nestincre;Lgals3-/- (CIG-) e Pkd1+/- ;Lgals3-/- (HTG-) cursaram com melhora da função sistólica e de strain comparados a CIs e HTs, não diferindo de NCs e SVs. Animais HTG- apresentaram melhora parcial da função diastólica. Apoptose e fibrose cardíaca mostraram-se reduzidas em CIG-s e HTG-s, alcançando valores similares a NCs e SVs. Análises de western blot revelaram expressão de Gal-3 maior em corações CIs que NCs, porém o mesmo não ocorreu entre HTs e SVs. Os duplos-mutantes não apresentaram diferença na ureia sérica quando comparados a CIs e HTs, assim como nas frações de excreção de Na+, Cl- e K+. Por fim, empregamos um modelo renal cístico grave, homozigoto para um alelo que impede a clivagem da policistina-1 no sítio GPS (Pkd1V/V; VV), e mostramos que a ausência...

Myocardial abnormalities stand out among ADPKD cardiovascular manifestations. To elucidate their pathogenesis, we analyzed the cardiac phenotype in distinct models of Pkd1-deficiency. We evaluated Pkd1cond/cond:Nestincre (CY) cystic, hypertensive mice at 20-24 weeks of age, and Pkd1+/- (HT) noncystic mice at 10-13 weeks, a model of gene haploinsufficiency. Pkd1cond/cond (noncystic; NC) and Pkd1+/+ (wild type, WT) animals were used as controls. Echocardiographic analyses in CY and HT mice revealed decreased left ventricle ejection fraction (LVEF), indicating systolic dysfunction, as well as E/A ratios and deceleration times consistent with diastolic dysfunction in CY animals. Speckle-tracking echocardiography showed reduced cardiac deformability in both models. CY and HT hearts presented higher apoptotic rates and mild fibrosis. In this scenario, we investigated galectin-3 (Gal-3) as a potential modifier of the ADPKD cardiac phenotype. Double mutants Pkd1cond/cond:Nestincre;Lgals3-/- (CYG-) and Pkd1+/-;Lgals3-/- (HTG-) displayed improved systolic and deformability parameters compared to single mutants, while such values did not differ from NCs and WTs. HTG-s presented a partial improvement in diastolic function. CYG- and HTG- hearts showed decreased apoptosis and fibrosis, reaching NC and WT baselines. Western blot analyses revealed higher Gal-3 expression in CY than NC hearts but no difference between HT and WT mice. CYG- and HTG- animals showed no difference in BUN and in the fractional excretion of Na+, Cl- and K+ compared to CYs and HTs. We also employed a more severe renal cystic model, homozygous for an allele that hinders polycystin-1 cleavage at the GPS site (Pkd1V/V; VV), and showed that Pkd1V/V;Lgals3-/- mice present longer survival than VVs. Our findings demonstrate myocardial dysfunction and abnormal deformability in different Pkd1-deficient models, reproducing human ADPKD, and reveals that Gal-3 knockout significantly rescues this phenotype...

Perfil dos pacientes encaminhados à terapia renal substitutiva de umambulatório de nefrologia pertencente a um hospital terciário / Profile of patients with end-stage renal disease before starting renalreplacement therapy, derived from a tertiary nephrology center

ambulatório de nefrologia de um hospital terciário. Materiais e métodos: Foram analisados retrospectivamente dados epidemiológicos, clínicos elaboratoriais de 246 pacientes com DRC encaminhados para TRS entre janeiro de 2004 e janeiro de 2006. Resultados: 50,6% eram homens, com54,5±15,5 anos de idade e tempo médio de acompanhamento de 24,8+34,5 meses. As principais causas de DRC foram: diabetes (DM-32,9%), hipertensãoarterial (HAS-25,2%) e glomerulonefrite crônica (GNC-13%). Apenas 20,6% apresentavam fistula artério-venosa (FAV) funcionante. Apenas três pacientes(1,2%) foram encaminhados a programa de diálise peritoneal (DP). Os homens tiveram chance 2,3 vezes maior de ter FAV confeccionada em relação àsmulheres (p=0,012 IC 1,2-4,4). Nos pacientes com mais de 12 meses de acompanhamento, havia chance 4,6 vezes maior para a presença de FAV(p=<0,0001 e IC 2,1-10,0). A doença com maior prevalência de FAV confeccionada foi doença renal policística (31,8%) e a com menor, DM (13,4%). Ospacientes diabéticos apresentaram risco 2,3 vezes maior de ter tempo de seguimento ambulatorial inferior a 12 meses (p=0,0027 e IC 1,3-3,9) e risco de2,3 vezes maior de não ter FAV confeccionada (p=0,029 e IC 1,1-4,9). Conclusão: Os dados analisados assemelham-se à estatística norte-americana emrelação ao DM como causa principal de DRC. O baixo encaminhamento para DP sugere dificuldade do sistema para absorver pacientes nesta modalidadee/ou tendência preferencial de encaminhamento para hemodiálise. Dificuldades locais concernentes à confecção de FAV refletem-se na baixa prevalênciade acessos funcionantes por ocasião do encaminhamento (20,6%), principalmente quando o tempo de seguimento é inferior a 12 meses, o sexo é ofeminino e a doença de base é DM.

Objectives: to analyze the profile of chronic kidney disease (CKD) patients before starting renal replacement therapy (RRT), from a tertiary nephrologycenter. Materials and Methods: we analyzed retrospectively, epidemiologic, clinical and laboratory data from 246 CKD patients assigned to RRT, fromJanuary 2004 to January 2006. Results: In this study, 50.6% were male. The main etiologies of CKD were: diabetes (DM-32.9%), hypertension (HTN-25.2%), and chronic glomerulonephritis (CGN-13%). The median age and follow-up time were 54.5+15.5 years and 24.8+34.5 months, respectively. Only20.6% patients had a patent arteriovenous fistula (AVF). Only 3 patients were assigned to a peritoneal dialysis program (PDP). After analysis, men had 2.3times greater chance of AVF through vascular access, than women (p=0.012, CI 1.2-4.4). However, for those with more than 12 months of follow-up, ahigher probability (4.6 times) of AVF was detected (p<0.0001, CI 2.1-10.0). PKD patients had the best scores for AVF placements (31.8%) and patients withdiabetes revealed the worst scores (13.4%). CGN presented the longest ambulatory follow-up time before starting RRT, whereas obstructive nephropathypresented the smallest. There was no difference between gender distribution and creatinine clearance in patients with and without diabetes. However,diabetic patients were 2.3 times more prone to have a follow-up time less than 12 months (p=0.0027, CI 1.3-3.9) and 2.3 times less prone to have anaccessible AVF (p=0.029, CI 1.1-4.9). Conclusions: The analyzed data in this tertiary hospital are in tandem with the North-American statistics, which referto diabetes as the main cause of CKD. The low number of patients assigned to a PDP suggests that the structure and organization of peritoneal dialysisfacilities cannot meet the demand and also suggests a preference towards hemodialysis as the mode of choice for RRT...

Hypercalcemia and suppressed PTH levels in a renal transplant patient infected with Pneumocystis carinii.

Pneumocystis carinii pneumonia is a serious and relatively common complication of immunosuppressive therapy. In immunocompromised patients, P. carinii pneumonia can cause significant morbidity and mortality. Another common complication, typically seen in the subpopulation of renal transplant recipients, is hypercalcemia. The prevalence of hypercalcemia varies, reaching as high as 71%. We report the case of a renal transplant recipient who developed P. carinii pneumonia and hypercalcemia, the latter being resolved after the successful treatment of the former. We argue that there is a causal relationship between P. carinii pneumonia and hypercalcemia in renal transplant recipients. In immunocompromised patients, pulmonary infection accompanied by hypercalcemia should raise the suspicion of P. carinii pneumonia.