Not only disease activity but also chronic hypertension and overweight are determinants of pregnancy outcomes in patients with systemic lupus erythematosus.

INTRODUCTION: Pregnancies in women with lupus nephritis are at high-risk of complications, while scarcity of scientific knowledge on prognostic factors impedes a fair medical counseling. We aimed to identify determinants associated with maternal and fetal complications. MATERIALS: We retrospectively reviewed medical charts of pregnancies that lasted more than 22 weeks in 66 patients with pre-existing lupus nephritis between 2004 and 2013 in France. Univariate and multivariate analyses were conducted to identify determinants for maternal complications, lupus renal flare and fetal prematurity or death. RESULTS: Eighty-four pregnancies were identified. A maternal complication occurred in 31 pregnancies (36.9%): mostly preeclampsia (17 pregnancies, 20.2%) and renal flares (12 pregnancies, 14.3%). Overall fetal survival was 94.0% (79/84). Maternal pregnancy complications were independently associated with prepregnancy body mass index >25 kg/m2 (OR 3.81, 95% CI 1.03-14.09) and immunological activity (positive anti-dsDNA antibodies or Farr assay lupus) (OR 4.95, 95% CI 1.33-18.43). Renal lupus flares were independently associated with maternal age (OR 1.50, 95% CI 1.12-2.01) and prepregnancy immunological activity (OR 15.99, 95% CI 1.57-162.68) while a remission time >12 months had a protective effect (OR 0.17, 95% CI 0.04-0.68). Three parameters were associated with a higher risk of fetal prematurity or death: a prepregnancy body mass index >25 kg/m2 (HR 3.58, 95% CI 1.45-8.83), hypertension (HR 8.97, 95% CI 3.32-24.25), and immunological activity (HR 3.34, 95% CI 1.30-8.63). CONCLUSION: Maternal age, prepregnancy hypertension, body mass index >25 kg/m2 and lupus immunological activity may be considered as the main determinants for fetal and maternal complications. A remission time above 12 months for patients with lupus nephritis could be associated with a reduced risk of renal flare during pregnancy.

Increased ischemic stroke, acute coronary artery disease and mortality in patients with granulomatosis with polyangiitis and microscopic polyangiitis.

OBJECTIVE: The aim of our study was to assess major cardiovascular event incidence, predictors, and mortality in ANCA-associated vasculitis (AAV). METHODS: We conducted a retrospective cohort study of all GPA or MPA, according to Chapel Hill Consensus Conference classification criteria, diagnosed between 1981 and 2015. Major cardiovascular event was defined as acute coronary artery disease, or ischemic stroke, or peripheral vascular disease requiring a revascularization procedure. We calculated the comparative morbidity/mortality figure (CMF) and we used Cox proportional hazards regression models to assess the risk of coronary artery disease, ischemic stroke associated with AAV, after adjusting for covariates. RESULTS: 125 patients, 99 GPA (79,2%) and 26 MPA (20,8%), were followed 88.4 ±â€¯78.3 months. Ischemic stroke incidence was four times higher than in the general population (CMF 4,65; 95% CI 4,06-5,31). Coronary artery disease incidence was four times higher than in the general population (CMF 4,22; 95% CI 1,52-11,68). Smoking habits and history of coronary artery disease were strongly associated with coronary artery disease occurrence (adjusted HR 8.8; 95% CI 2.12-36.56, and adjusted HR 10.3; 95% CI 1.02-104.5, respectively). ENT flare-up was an independent protective factor for coronary artery disease occurrence. We did not identify factors significantly associated with stroke occurrence. The age-adjusted mortality rate was 22.5 per 1000 person-years. Mortality in AAV was 1.5 times higher than in the general population (CMF 1.56; 95% CI 1.34-1.83). CONCLUSION: AAV have a significantly increased risk of mortality, ischemic stroke, and coronary artery disease.

[Renal unilateral oncocytis: case report]. / Oncocytose rénale unilatérale: à propos d'un cas.

The renal oncocytoma tumors are rare (5% of renal tumors). These benign tumors are incidentally diagnosed most often in an asymptomatic form. Sometimes it is multiple bilateral tumors affecting the renal parenchyma and forming a renal oncocytosis. We report the case of a unilateral right renal oncocytosis, very rare situation, characterized by a right renal parenchymal nodules with oncocytoma and a normal left kidney.

[Renal failure and cystic kidney diseases]. / Insuffisance rénale et maladies kystiques du rein.

Cystic kidney diseases often are discovered at the time of initial work-up of renal failure through ultrasound or family history, or incidentally at the time of an imaging test. Hereditary diseases include autosomal dominant or recessive polycystic kidney disease (PKD), tuberous sclerosis (TS) and medullary cystic kidney disease (MCKD). Autosomal dominant PKD is characterized by large renal cysts developing in young adults. Renal failure is progressive and becomes severe around 50-60 years of age. Atypical cysts (hemorrhagic or hyperdense) are frequent on CT and MRI examinations. Imaging plays a valuable role in the management of acute complications such as cyst hemorrhage or infection. Autosomal recessive PKD is often detected in neonates, infants or young adults. It is characterized by renal enlargement due to the presence of small cysts and liver disease (fibrosis and biliary ductal dilatation). Late manifestation or slow progression of autosomal recessive PKD may be more difficult to distinguish from autosomal dominant PKD. These cystic kidney diseases should not be confused with non-hereditary incidental multiple renal cysts. In tuberous sclerosis, renal cysts are associated with angiomyolipomas and sometimes pulmonary lymphangioleiomyomatosis. Renal failure is inconstant. Other hereditary cystic kidney diseases, including MCKD and nephronophtisis, are usually associated with renal failure. Non-hereditary cystic kidney diseases include multicystic renal dysplasia (due to complete pelvi-ureteric atresia or hydronephrosis), acquired multicystic kidney disease (chronic renal failure, chronic hemodialysis) and varied cystic kidney diseases (multicystic renal disease, glomerulocystic kidney disease, microcystic kidney disease).

Renal insufficiency, a frequent complication with age in oral-facial-digital syndrome type I.

The oral-facial-digital syndrome type I (OFD I) is characterized by multiple congenital malformations of the face, oral cavity and digits. A polycystic kidney disease (PKD) is found in about one-third of patients but long-term outcome and complications are not well described in the international literature. Renal findings have been retrospectively collected in a cohort of 34 females all carrying a pathogenic mutation in the OFD1 gene with ages ranging from 1 to 65 years. Twelve patients presented with PKD - 11/16 (69%) if only adults were considered -with a median age at diagnosis of 29 years [IQR (interquartile range) = (23.5-38)]. Among them, 10 also presented with renal impairment and 6 were grafted (median age = 38 years [IQR = (25-48)]. One grafted patient under immunosuppressive treatment died from a tumor originated from a native kidney. The probability to develop renal failure was estimated to be more than 50% after the age of 36 years. Besides, neither genotype-phenotype correlation nor clinical predictive association with renal failure could be evidenced. These data reveal an unsuspected high incidence rate of the renal impairment outcome in OFD I syndrome. A systematic ultrasound (US) and renal function follow-up is therefore highly recommended for all OFD I patients.

[Mitral regurgitation associated with Wegener's granulomatosis]. / Insuffisance mitrale et maladie de Wegener.

BACKGROUND: Wegener's granulomatosis (WG) is a granulomatous disease that can affect many organ systems. The most frequently involved organs include the upper and lower respiratory tract as well as the kidney. Cardiac involvement is rare. METHODS: We report the case of a patient with grade 4 mitral insufficiency associated with severe WG. RESULTS: Surgical analysis of the mitral valve revealed perforation of the anterior leaflet without evidence of endocarditis. Pathological examination of the anterior mitral leaflet revealed myxoid degeneration nodules and bacteriological examination was negative. As the perforated lesion was very close to the free margin of the anterior leaflet, valve replacement appeared a reasonable surgical option in a poor surgical candidate. Six months after the operation, the patient is doing well. CONCLUSION: Wegener's granulomatosis is an autoimmune necrotizing vasculitis that can affect many organ systems. Cardiac involvement is rare. Heart in his globality can be affected by WG in many different ways. Cardiac valvular involvement in WG is rare. The aortic valve seems to be more frequently affected. Cardiologic investigations should have an important place at diagnosis and supervision.

[Nephrogenic fibrosing dermopathy treated with extracorporeal photopheresis: role of gadolinium?]. / Dermopathie néphrogénique fibrosante traitée par photochimiothérapie extracorporelle: rôle du gadolinium?

BACKGROUND: Nephrogenic fibrosing dermopathy is a cutaneous and systemic sclerosis affecting patients with renal failure. CASE-REPORT: A 68-year-old man with renal insufficiency and on dialysis developed hardening of the skin and severe joint contractions. He had previously undergone angiography with gadolinium-containing contrast agents. A skin biopsy confirmed nephrogenic fibrosing dermopathy. The patient was treated by oral steroids followed by extracorporeal photopheresis. An improvement was seen after 12 cycles. DISCUSSION: Treatment of nephrogenic systemic fibrosis is not codified and is normally based on the methods used for other forms of systemic sclerosis. Six cases of patients showing improvement under extracorporeal photopheresis have been published. The physiopathology of the disease is unknown. Gadolinium could act as a triggering agent by attracting circulating fibrocytes in the dermis of patients. Medical authorities recommend avoidance of gadolinium in patients with advanced kidney failure unless strictly necessary.

[Membranous glomerulonephritis during primary Gougerot-Sjögren syndrome]. / Glomérulonéphrite extra-membraneuse au cours d'un syndrome de Gougerot-Sjögren primitif.

INTRODUCTION: Glomerulonephritis, mainly membranoproliferative or membranous (MG), is observed much less often than interstitial involvement in Sjögren's syndrome (SS). CASE: We report a case of MG revealed by thrombosis of the inferior vena cava and of a renal vein in a 40-year-old woman with primary SS, which began with polyarthritis, immune-type lymphadenopathy, and Hashimoto thyroiditis and did not include obvious sicca syndrome. After failure of moderate-dose steroids and then azathioprine, each over separate 9-month periods, the MG responded well within a few weeks to monthly alternation of methylprednisolone and oral cyclophosphamide for 6 months. DISCUSSION: SS may be an underestimated cause of glomerulonephritis, especially membranoproliferative and membranous glomerulonephritis. They should be considered even in the absence of obvious sicca syndrome. Although the prognosis is usually good, renal insufficiency can occur. In cases of MG, if moderate-dose steroids fail, monthly alternation of methylprednisolone and cyclophosphamide for 6 months appears effective and well tolerated, with a low risk of carcinogenicity.

Influence of plasma amino acid level on vasopressin secretion.

OBJECTIVES: Vasopressin (VP) is known to be elevated in patients with diabetes mellitus (DM). While the influence of acute hyperglycemia has been ruled out, the mechanism or the osmotically active compound responsible for the increase in VP secretion is still not elucidated. Because the plasma level of several amino acids (AAs) is increased in DM, we evaluated whether AAs could represent an effective osmotic stimulus for VP secretion. RESEARCH DESIGN AND METHODS: In a cross-over study, eight healthy volunteers randomly received an infusion of isotonic saline (control) or mixed AA solution, i.v., at a low or a high rate (2 or 4.5 mg/min/kg BW, respectively). Plasma VP (P(VP)) was measured for two hours before and three hours during AA or control infusion. RESULTS: AA infusion induced a dose-dependent elevation in plasma AA concentration but did not alter P(VP). However, effective plasma osmolality (P(osm)) (osmolality minus urea concentration) remained unchanged because a concommittant fall in plasma sodium concentration (P(Na)), likely due to sodium-linked uptake of AA in peripheral cells, compensated for the rise in plasma AA. CONCLUSION: The stability of effective P(osm) may explain the lack of change observed in P(VP). Because sodium is a very efficient stimulus for VP secretion, it may be assumed that the fall in P(Na) occurring during AA infusion should have reduced VP secretion and thus P(VP). In this setting, the stability of P(VP) suggests that AAs induced an increase in VP secretion which counterbalanced the fall attributable to the decrease in P(Na). In conclusion, in acute experiments, AAs seem to represent an effective stimulus for VP secretion, almost equally potent as sodium. Further studies are needed to evaluate their contribution to the high P(VP) seen in the chronic setting of DM.

Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss.

Autosomal recessive distal renal tubular acidosis (rdRTA) is characterised by severe hyperchloraemic metabolic acidosis in childhood, hypokalaemia, decreased urinary calcium solubility, and impaired bone physiology and growth. Two types of rdRTA have been differentiated by the presence or absence of sensorineural hearing loss, but appear otherwise clinically similar. Recently, we identified mutations in genes encoding two different subunits of the renal alpha-intercalated cell's apical H(+)-ATPase that cause rdRTA. Defects in the B1 subunit gene ATP6V1B1, and the a4 subunit gene ATP6V0A4, cause rdRTA with deafness and with preserved hearing, respectively. We have investigated 26 new rdRTA kindreds, of which 23 are consanguineous. Linkage analysis of seven novel SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and ATP6V0A4 suggested that four families do not link to either locus, providing strong evidence for additional genetic heterogeneity. In ATP6V1B1, one novel and five previously reported mutations were found in 10 kindreds. In 12 ATP6V0A4 kindreds, seven of 10 mutations were novel. A further nine novel ATP6V0A4 mutations were found in "sporadic" cases. The previously reported association between ATP6V1B1 defects and severe hearing loss in childhood was maintained. However, several patients with ATP6V0A4 mutations have developed hearing loss, usually in young adulthood. We show here that ATP6V0A4 is expressed within the human inner ear. These findings provide further evidence for genetic heterogeneity in rdRTA, extend the spectrum of disease causing mutations in ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the first time.

Modifier effect of ENOS in autosomal dominant polycystic kidney disease.

A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with altered endothelial-dependent vasodilation and decreased vascular production of nitric oxide (NO). Thus, ENOS, the gene coding for the endothelial nitric oxide synthase (eNOS), could have a modifier effect in ADPKD. In order to test this hypothesis, we genotyped 173 unrelated ADPKD patients from Belgium and the north of France for the Glu298Asp, intron 4 VNTR and T-786C polymorphisms of ENOS and looked for their influence on the age at end-stage renal disease (ESRD). In males (n = 93), the Glu298Asp polymorphism was associated with a lower age at ESRD (Glu/Asp + Asp/Asp: 49.0 +/- 1.2 years, n = 53; Glu/Glu: 53.5 +/- 1.5 years, n = 40; simple regression, P = 0.02; multiple regression, P = 0.006). This effect was confirmed in a subset of males linked to PKD1 and reaching ESRD before age 45, and by a cumulative renal survival analysis in PKD1-linked families. Further studies demonstrated that NO synthase (NOS) activity was decreased in renal artery samples from ADPKD males harbouring the Asp298 allele, in association with post-translational modifications and partial cleavage of eNOS. No significant effect of the other polymorphisms was found in males, and no polymorphism influenced the age at ESRD in females. In conclusion, the frequent Glu298Asp polymorphism of ENOS is associated with a 5 year lower mean age at ESRD in this subset of ADPKD males. This effect could be due to a decreased NOS activity and a partial cleavage of eNOS, leading to a further decrease in the vascular production of NO.

Autosomal recessive polycystic kidney disease in adulthood.

BACKGROUND: Renal cysts arising from collecting ducts, congenital hepatic fibrosis, and recessive inheritance characterize autosomal recessive polycystic kidney disease (ARPKD). The disorder usually manifests in infancy, with a high mortality rate in the first year of life. For the patients who survive the neonatal period, the probability of being alive at 15 years of age ranges from 50 to 80%, with 56--67% of them not requiring renal replacement therapy at that stage. Some develop portal hypertension. Long-term outcome of adults escaping renal insufficiency above age 18 is largely unknown. METHOD: In consecutive patients with ARPKD and autonomous renal function at age 18, clinical course of kidney and liver disease in adulthood and status at last follow-up were evaluated. Progression of renal insufficiency was assessed by the rate of decline of creatinine clearance, according to Schwartz's formula before age 18 and Cockcroft and Gault formula thereafter. Severity of liver involvement was estimated by imaging techniques, liver function tests, and endoscopy. RESULTS: Sixteen patients from 15 families were included. ARPKD was diagnosed between 1 day and 13 years of age. From diagnosis, mean follow-up period lasted 24+/-9 years. Before age 18, nine patients (56%) were hypertensive, nine (56%) had renal failure, and four (25%) had portal hypertension. Beyond age 18, no additional patient became hypertensive, and another five developed progressive renal insufficiency; altogether, the mean yearly decline of creatinine clearance was 2.9+/-1.6 ml/min. Portal hypertension was recognized in two additional patients. Four patients experienced gastro-oesophageal bleeding, while recurrent cholangitis or cholangiocarcinoma developed in one case each. At the end of follow-up, 15/16 patients (94%) were alive at a mean age of 27 (18--55) years. Two patients had a normal renal function, 11 had chronic renal insufficiency, one was on regular dialysis, and two had functioning kidney grafts. Four patients had required a porto-systemic shunt. CONCLUSIONS: A subset of ARPKD patients with autonomous renal function at age 18 experiences slowly progressive renal insufficiency. With prolonged renal survival, complications related to portal hypertension are not rare, requiring careful surveillance and appropriate management.

Hypokalaemic periodic paralysis type 2 caused by mutations at codon 672 in the muscle sodium channel gene SCN4A.

Hypokalaemic periodic paralysis (hypoPP) is an autosomal dominant muscle disorder characterized by episodic attacks of muscle weakness associated with a decrease in blood potassium levels. Mutations in the gene encoding the skeletal muscle voltage-gated calcium channel alpha-1 subunit (CACNL1A3) account for the majority of cases. Recently, mutations in the gene coding for the skeletal muscle voltage-gated sodium channel alpha subunit (SCN4A) have been reported in a small number of hypoPP families. In order to determine the relative frequency of the CANCL1A3 and SCN4A mutations in a large population of hypoPP patients, and to specify the clinical and pathological features associated with each of them, we searched for mutations in 58 independent hypoPP index cases. We detected the causative mutation in 45 cases: 40 were linked to the CACNL1A3 gene and five to the SCN4A gene. One mutation has not been described before. Some remarkable clinical features were observed in a large hypoPP family carrying an SCN4A mutation: a complete penetrance in men and women, an early age at onset, postcritic myalgias and an increased number and severity of attacks induced by acetazolamide. A muscle biopsy, performed in two members of this family, revealed a peculiar myopathy characterized by tubular aggregates. In contrast, vacuoles were predominant in muscles from hypoPP patients carrying CACNL1A3 mutations. Our findings point to the usefulness of a molecular characterization of hypoPP patients in clinical practice. They also provide new clues for understanding the mechanisms behind functional and structural alterations of the skeletal muscle in hypoPP.

[Prevention of renal carcinoma: the nutri-genetic approach]. / Prévention du carcinoma rénal: l'approche nutrigénétique.

The development of renal cell carcinoma (RCC) has been associated with both genetic and environmental factors, with somatic and germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and with tobacco smoking, obesity, long term exposure to some nutrients, pollutants, and industrial solvents such as trichloroethylene. Intra and interfamilial variability of expression of germline mutations in the VHL gene and variable susceptibility to carcinogens in the sporadic forms strongly suggest the involvement of conditional modifier genes. In order to identify sub groups of individuals at increased risk because of susceptibility genotypes, we have collected a series of 460 patients who developed an RCC and 79 families with the von Hippel Lindau disease. To collect clinical and mutational data for correlation analysis we have developed a unique tool the Universal Mutation Database. Comparison of the spectrum of germline and somatic mutations in the VHL gene showed that: 1) in sporadic RCC mutations lead more often to truncated proteins (83%), while the remaining mutations (17%), include 3/4 of transversions and 1/4 of transitions. This high proportion of transversions supports the involvement of carcinogens the impact of which is conditioned by the genetic variability of xenobiotic metabolizing enzymes; 2) whereas in familial cases missense mutations are more common; this difference allowed us to define a prognostic factor for the occurrence of RCC in a VHL context. In order to look for genotypes conferring a higher risk we genotyped the RCC patients for 8 different genes (50 genotypes). A significant relationship was observed for several combinations of alleles including CYP1A1 ("variant"), NAT2 and NAT1 (slow) and GSTM1 (null allele). Associations between specific mutational profiles and at risk genotypes at different tumoral stages should allow us to: 1) define more precisely the nature of specific patterns of mutations in relation with the deficiency or overexpression of such or such enzymes in presence of particular carcinogens; 2) demonstrate that certain combinations of genotypes confer a particular risk to develop a specific type of tumor in VHL patients. Thus tracking of potentially carcinogenic substances, through their footprints and through identification of conditionally detrimental genotypes of genes participating in their detoxification should permit a better prevention through an appropriate nutrition adapted to each individual.

Pancreatic involvement in von Hippel-Lindau disease. The Groupe Francophone d'Etude de la Maladie de von Hippel-Lindau.

BACKGROUND & AIMS: Pancreatic involvement in von Hippel-Lindau (VHL) disease, a genetic disorder with a dominant mode of inheritance affecting various organs, has rarely been studied. We assessed the prevalence, type of lesions, natural history, and impact of pancreatic involvement in patients with VHL. METHODS: A total of 158 consecutive patients from 94 families with VHL disease were studied in a prospective French collaborative study. All patients underwent systematic screening for VHL lesions, including computerized tomography (CT) scanning of the pancreas reviewed by an experienced radiologist. Clinical data, investigations, and treatments performed were also reviewed. RESULTS: Pancreatic involvement was observed in 122 patients (77.2%) and included true cysts (91.1%), serous cystadenomas (12.3%), neuroendocrine tumors (12.3%), or combined lesions (11.5%). The pancreas was the only organ affected in 7.6% of patients. Patients with pancreatic lesions had fewer pheochromocytomas than those without (14/122 vs. 16/36; P<0.0001), and patients with neuroendocrine pancreatic tumors had renal involvement less often than those without (8/99 vs. 6/20; P = 0.013). None of the patients with neuroendocrine tumors had symptoms of hormonal hypersecretion. Pancreatic lesions evolved in half of patients but required specific treatment in only 10 (8.2%) when they were symptomatic or for the resection of large neuroendocrine tumors. CONCLUSIONS: Pancreatic involvement is seen in most patients with VHL disease. Although symptoms are rare, specific treatment of pancreatic lesions is required in selected patients, mainly those with neuroendocrine tumors.