Protocol for a randomized controlled multicenter trial assessing the efficacy of leuprorelin for severe polycystic liver disease: the AGAINST-PLD study.

BACKGROUND: In patients with severe polycystic liver disease (PLD), there is a need for new treatments. Estrogens and possibly other female sex hormones stimulate growth in PLD. In some patients, liver volume decreases after menopause. Female sex hormones could therefore be a target for therapy. The AGAINST-PLD study will examine the efficacy of the GnRH agonist leuprorelin, which blocks the production of estrogen and other sex hormones, to reduce liver growth in PLD. METHODS: The AGAINST-PLD study is an investigator-driven, multicenter, randomized controlled trial. Institutional review board (IRB) approval was received at the University Medical Center of Groningen and will be collected in other sites before opening these sites. Thirty-six female, pre-menopausal patients, with a very large liver volume for age (upper 10% of the PLD population) and ongoing liver growth despite current treatment options will be randomized to direct start of leuprorelin or to 18 months standard of care and delayed start of leuprorelin. Leuprorelin is given as 3.75 mg subcutaneously (s.c.) monthly for the first 3 months followed by 3-monthly depots of 11.25 mg s.c. The trial duration is 36 months. MRI scans to measure liver volume will be performed at screening, 6 months, 18 months, 24 months and 36 months. In addition, blood will be drawn, DEXA-scans will be performed and questionnaires will be collected. This design enables comparison between patients on study treatment and standard of care (first 18 months) and within patients before and during treatment (whole trial). Main outcome is annualized liver growth rate compared between standard of care and study treatment. Secondary outcomes are PLD disease severity, change in liver growth within individuals and (serious) adverse events. The study is designed as a prospective open-label study with blinded endpoint assessment (PROBE). DISCUSSION: In this trial, we combined the expertise of hepatologist, nephrologists and gynecologists to study the effect of leuprorelin on liver growth in PLD. In this way, we hope to stop liver growth, reduce symptoms and reduce the need for liver transplantation in severe PLD. Trial registration Eudra CT number 2020-005949-16, registered at 15 Dec 2020. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-005949-16 .

Autosomal dominant policystic kidney disease, more than a renal disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder mainly involving the kidney. It affects one in 400-1000 live births. Early hypertension and progressive renal failure due to massive enlargement of cysts and fibrosis are hallmarks of the disease. ADPKD accounts for ~5-10% of cases requiring renal replacement therapy. But not only the kidneys are affected in ADPKD: cysts also occur in other organs such as the liver, pancreas, arachnoid membrane and seminal vesicles. Non-cystic manifestations of the diseases are intracranial aneurysms, hernias and valvular abnormalities. Complications in ADPKD usually result from kidney involvement and include cyst bleeding and cyst infection. However, serious extrarenal features such as subarachnoid haemorrhage can also occur. There is no specific treatment for ADPKD currently, but many molecules targeting up- or downregulated molecules in the renal epithelial cells are being tested. A clinical trial using tolvaptan (a vasopressin receptor antagonist) has demonstrated efficacy, while mTOR inhibitors have shown no positive effect in ADPKD. ACEIs and ARBs are the drugs of choice for treating hypertension in ADPKD. Until a specific therapy becomes available, early treatment of hypertension and lifestyle changes are encouraged.

WT1 mutations may be a cause of severe renal failure due to nephroblastomatosis in Wilms' tumor patients.

Wilms' tumor suppressor gene (WT1) encodes a transcription factor required for normal development of the genitourinary system. Germline WT1 mutations have been described in a wide spectrum of pathological conditions, including kidney diseases, genital abnormalities and Wilms' tumor. Here we report a 4-year-old male patient who presented with bilateral cryptorchidism, Wilms' tumor, nephroblastomatosis and renal failure without nephrotic proteinuria. Sequence analysis of the WT1 gene demonstrated a constitutional heterozygous nonsense mutation in exon 7, which leads to a truncation of the WT1 protein at the zinc-finger 1. In the DNA of the tumor, we observed the same mutation in homo/hemizygosity. Given the requirement of WT1 for normal development, the WT1 mutation is likely to be responsible for the nephroblastomatosis and, in consequence, for the severe renal failure observed in our patient. This finding extends the spectrum of kidney diseases related to WT1 mutations and points to the need to screen for this gene in children with genitourinary abnormalities and Wilms' tumor because of the associated risk of nephroblastomatosis and renal failure in those carrying WT1 mutations.

Post-pancreaticoduodenectomy hemorrhage. Incidence, diagnosis, and treatment.

BACKGROUND: Although mortality post-pancreaticoduodenectomy (PD) has decreased, morbidity rates continue to be high, ranging from 30% to 50%. Among complications, hemorrhage stands out; it is associated with high mortality and there is no standard management. The aim of the present study was to analyze the incidence, diagnosis, and treatment of hemorrhage post-cephalic PD at our center. METHODS: From January 2005 to December 2008, 107 PDs were performed. A retrospective review of characteristics of patients with postoperative hemorrhage was made from our prospective database. Demographic data, diagnosis, treatment (medical, laparotomy, interventional radiology), association with fistula (pancreatic or biliary), intra- or extraluminal hemorrhage, bleeding time (early or late), severity (moderate/severe), and mortality were analyzed. RESULTS: Eighteen patients (18/107; 16.82%) hemorrhaged after PD. Hemorrhage appeared early (< 24 h) in 4 of these 18 patients (22.2%), and it was severe in 13/18 (72%). Hemorrhage-related mortality was 11% (2/18) and hospital mortality was 22.2% (4/18). Arteriography was performed in 8/18 patients (44.4%) and was effective in 6/8 (75%); laparotomy was performed in 8/18 (44.4%). Re-bleeding occurred in 5 of these 18 patients after the first treatment (27.8%). An association between hemorrhage and fistula was observed. CONCLUSIONS: Hemorrhage after pancreatic resection must be considered a complication with relatively high mortality. Diagnosis should be established and treatment applied rapidly. Pancreatic and/or biliary fistulae were significantly associated with a higher risk of postoperative hemorrhage. Interventional radiology is a good therapeutic option.

[Relationship between renal size and blood pressure profile in patients with autosomal dominant polycystic kidney disease without renal failure]. / Relación entre el tamaño renal y el perfil de presión arterial en pacientes con poliquistosis renal autosómica dominante sin insuficiencia renal.

BACKGROUND: Enlargement of renal size plays an important role in the development of hypertension in patients with autosomic dominant polycystic kidney disease (ADPKD) and normal renal function. METHODS: A 24h blood pressure monitoring (ABPM) and a renal echography have been performed in 37 patients with ADPKD and estimated glomerular filtration rate > 60 ml/min/1.73 m(2) to study the relationship between renal size and an altered blood pressure profile in prehypertension stages. RESULTS: 13 patients had normal blood pressure, 11 were diagnosed of masked hypertension, 4 had white coat hypertension and 9 had hypertension. We have found in the normotensive group with a dipper blood pressure profile a positive and statistically significant relationship between renal size and diastolic blood pressure variability. CONCLUSIONS: ABPM helps to make an early diagnosis of hypertension and to identify those patients with masked hypertension. This study suggests a relationship between renal size and a blood pressure profile linked to a major cardiovascular risk in normotensive patients with ADPKD.

Preservation of renal function in a patient with Fabry nephropathy on enzyme replacement therapy.

Fabry disease is an X-linked recessive inborn error of glycosphingolipid metabolism caused by the deficient activity of the lysosomal enzyme, alpha-galactosidase A. Enzyme replacement therapy (ERT) for this disorder has been available in Europe since 2001. However, its effect on advanced renal failure remains controversial. We report the case of a patient whose decline in renal function was reduced by the administration of ERT (agalsidase-alpha). This reduction was more pronounced after doubling the dose of the enzyme. The rate of deterioration of eGFR went from 6.3 ml/min/year prior to the start of ERT (0.2 mg/kg) to 2 ml/min/year (0.4 mg/kg). To our knowledge, this is the first reported case of a patient with moderately impaired renal function treated with high doses of ERT and follow-up of 6 years. The data shown here suggest that ERT may have a very positive impact on renal function even in advanced stages. The role of proteinuria and its control seem to have a clear responsibility for this favorable outcome.

PrEFiNe Plan: Strategic plan for Fabry diseases in Nephrology. / Plan PrEFiNE: Plan estratégico para la enfermedad de Fabry en Nefrología.

BACKGROUND: Renal failure is one of the main causes of death in patients with Fabry disease (FD). Due to the low prevalence of FD, delayed diagnosis and misdiagnosis, often the correct diagnosis is made when organ damage is already present. Early recognition of the disease would allow the prevention of severe complications and the premature death of patients with FD. OBJECTIVE: We present here the PrEFiNE project, which includes a wide spectrum of activities with the aim of improve knowledge and diagnosis of FD. The project is sponsored by Shire Iberia (http://shireiberica.com/) METHODS: From January 2016 to the end of 2017 several activities will be carried out, starting with a survey to evaluate current FD knowledge among nephrologists; in addition some studies to assess prevalence of this disease will be performed. One study will include patients receiving dialysis, another study will cover kidney transplant patients, and a pilot study in chronic kidney disease in stage 3-5 predialysis. Also planned is a pharmacoeconomic study to focus on burden of FD. At the same time medical education activities will be conducted both on line and on site. Plan for dissemination will include medical publications and diffusion to media. PrEFiNE Project will finish with the publication of a compilation book on FD in Nephrology including all planned activities and proposing recommendations based on results and detected unmet needs. PrEfiNE Plan will be coordinated by severa scientific committees, one at national level and 10 other regionals comittees, tha will be responsible to ensure the maximum scientific quality of proposed activities. An advisory board will supervise the project. DISCUSSION: PrEfiNE project will evaluate an action plan focused on improving FD knowledge to make necessary recommendations for an early recognition of the disease. In addition will generate a plan to improve previously undetected needs.

[Collagen IV (alpha3-alpha4) nephropathy]. / La nefropatía del coláigeno IV (aalpha3-alpha4).

Recent evidence has shown that the COL4A3, COL4A4 and COL4A5 genes are involved in different renal manifestations. Mutations in these collagen type IV genes affect the glomerular basement membrane (GBM) giving rise to a nephropathy whose symptoms range from isolated hematuria to severe renal failure. This disorder has been traditionally considered to be different entities: Autosomal Dominant Alport syndrome, Familial Benign Hematuria, Autosomal Recessive Alport Syndrome carriers. But the increased knowledge of the molecular basis of this clinical diversity prompted us to agglutinate these entities under the name of "collagen type IV nephropathy". This fact has relevant implications in diagnosis, prognosis and management.

Loss of heterozygosity in renal and hepatic epithelial cystic cells from ADPKD1 patients.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the commonest genetic diseases in man, affecting 1:1000 individuals in the Caucasian population. It is caused by mutations in the PKD1 or PKD2 genes. Recently, controversial data regarding the mutational mechanism underlying cyst initiation have been reported: genetic analyses have shown that second somatic mutations may lead to cyst formation (detected as microsatellite loss of heterozygosity, LOH, and point mutations), but immunohistochemical studies show strong immunoreactivity for polycystin in some cysts. In order to further characterise this matter we have analysed 211 cysts from seven different patients for LOH, we have detected a 13.3% LOH for PKD1. This loss was specific to PKD1 as no LOH was detected when other chromosomal regions were studied. Whenever linkage analysis has been possible, it has been proved that the lost allele corresponded to the wild-type. Our data supports previous results in the two-hit theory for ADPKD due to the large number of cysts studied. ADPKD would occur through a recessive cellular mechanism. The probability of cyst development would depend on the probability of mutation in the second allele. The different phenotypical expression of the same mutation reported in ADPKD could be due to the different tendency of inactivation in the second allele in each individual.

Influence of the ACE gene polymorphism in the progression of renal failure in autosomal dominant polycystic kidney disease.

The recent description of a polymorphism in the gene for angiotensin-converting enzyme (ACE), with the D allele associated with greater plasma levels of ACE, allows us to perform studies of the relationship between this polymorphism and chronic renal diseases in which the renin-angiotensin system could be implicated. We examined 155 patients with autosomal dominant polycystic kidney disease (ADPKD) with linkage to the PKD1 locus. The ACE insertion/deletion (I/D) polymorphism was amplified with the previously published flanking primers, and the polymerase chain reaction product was separated, sized on a 2% agarose gel, and visualized by ultraviolet transillumination. The ACE genotype distributions were 11.6%, 63.8%, and 24.5% for II, ID, and DD, respectively. There were no significant differences among the three genotypes with respect to mean age, sex distribution, and prevalence of hypertension. The ACE genotype distribution in patients with end-stage renal failure at the time of data compilation was similar to that of the entire study population. In the subgroup of patients who received renal replacement therapy before the age of 50 years, we found a significant association between DD genotype and onset of end-stage renal disease (ESRD) before the age of 50 years compared with II and ID (P = 0.017). We calculated the estimated median renal survival time as 51 years for the II genotype, 53 years for the ID genotype, and 48 years for the DD genotype. There were statistically significant differences between DD and ID patients (P = 0.025). In conclusion, we found DD genotype implies a worse renal prognosis based on both the significantly lower median renal survival time and significantly greater percentage of patients who reach ESRD before the age of 50 years, without implying a greater prevalence of hypertension.

Facilitated diagnosis of the contiguous gene syndrome: tuberous sclerosis and polycystic kidneys by means of haplotype studies.

Tuberous sclerosis (TSC) and autosomal dominant polycystic kidney disease (ADPKD) are genetically heterogeneous diseases. The major gene for ADPKD (PKD1) lies adjacent to the TSC2 gene on chromosome 16p13. Some reports in the literature referred to an unusual presentation of TSC with enlarged cystic kidneys at birth, but it was not until the localization of the TSC2 and PKD1 genes that it was possible to analyze the interaction between both genes. We describe a case of a child with TSC and enlarged cystic kidneys. The study of genetic marker segregation in the family pointed to the presence of a deletion involving the 3' region of PKD1. A further study of the region showed a deletion of 40 kb involving both PKD1 and TSC2. We suggest that an additive or synergistic effect between PKD1 and TSC2 may cause this renal phenotype. A contiguous gene syndrome involving PKD1 and TSC2 should be suspected in children with TSC and enlarged polycystic kidneys at birth. The first approach to identify a deletion of both genes could be the analysis of the segregation of PKD1 and TSC2 markers in the family.

Increased prevalence of polycystic kidney disease type 2 among elderly polycystic patients.

Autosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous, with at least three chromosomal loci (PKD1, PKD2, and PKD3) accounting for the disease. Mutations in the PKD2 gene, on the long arm of chromosome 4, are estimated to be responsible for 15% of the cases of ADPKD, based on linkage studies. PKD2 is a milder form of the disease, with a mean age of end-stage renal disease (ESRD) approximately 20 years later than PKD1. The object of this study is to determine the proportion of elderly patients with ADPKD with ESRD who harbor mutations in the PKD2 gene. We analyzed all exons and intron-exon boundaries of the PKD2 gene by single-strand conformation polymorphism analysis and silver staining technique in 46 patients with ADPKD who reached ESRD after the age of 63 years or were not yet undergoing renal replacement therapy (RRT) by that age. We performed exactly the same studies in a control group of 40 patients with ADPKD with unknown gene status aged younger than 63 years. In 22 patients, a mutation in the PKD2 gene was defined: 18 of 46 patients from the elderly group and 4 of 40 patients from the control group. We identified 14 different mutations: 4 nonsense mutations, 1 missense mutation, 5 small deletions, 2 insertions, 1 deletion of the whole PKD2 gene, and 1 splicing mutation. Five of these mutations previously were described by our group. Three of the mutations reported in the present study are recurrent. The prevalence of PKD2 disease among elderly patients with ADPKD undergoing RRT is 39.1%, almost three times the prevalence of the disease in the general ADPKD population.

Ultrasonographic study of pancreatic cysts in autosomal dominant polycystic kidney disease.

Pancreatic cysts are an uncommon extrarenal clinical feature of autosomal dominant polycystic kidney disease (ADPKD). The prevalence of pancreatic cysts, sonographically assessed in ADPKD and in the different typs of ADPKD (PKD1 and PKD2) has not been reported. We have studied 173 ADPKD patients and 160 non-affected family members and found a prevalence of pancreatic cysts, of 9% in ADPKD patients over 30 years of age. The presence of pancreatic cysts was related to the increasing age, to the female sex and to the type of ADPKD, found exclusively in PKD1 patients. No complications related to pancreatic cysts were recorded. Pancreatic cysts are an unusual feature of ADPKD and do not appear to contribute to morbidity or mortality.

Successful pregnancy in a patient with hemolytic-uremic syndrome during the second trimester of pregnancy.

BACKGROUND: Hemolytic uremic syndrome (HUS) is a rare, well-characterized complication of the puerperium constituting a cause of acute renal failure after an uncomplicated delivery. However, its presentation during pregnancy is unusual, with only four cases before the 20th week of gestation reported. CASE: A case of HUS occurred at 18 weeks' gestation. Despite the initial severity of the clinical presentation, therapy, consisting of corticosteroids and plasmapheresis, resulted in complete recovery of renal function, with a rapid improvement in thrombocytopenia and hemolysis. No remarkable events occurred after this episode, and a full-term pregnancy with a normal fetal outcome was achieved. CONCLUSION: We are aware of no other reports of successful pregnancy after the development of HUS during the first half of pregnancy. This provides evidence that continuation of pregnancy until term is possible. Rapid diagnosis and intensive treatment with plamapheresis, corticosteroids and dialysis, when required, may improve the maternal and fetal prognosis.

[Heterozygosity loss and somatic mutations in type I and II dominant autosomal renal polycystic kidney disease: evidence of a recessive mechanism at a cell level in cystogenesis]. / Estudio de pérdidas de heterozigosidad y mutaciones somáticas en la poliquistosis renal autosómica dominante tipos I y II: demostración de un mecanismo recesivo a nivel celular en la cistogénesis.

Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder mainly characterized by renal cyst formation. Cysts in ADPKD are focal in nature, since only a small fraction of nephrons become cystic. The hypothesis that a second hit may be required for cyst formation has been proposed. This hypothesis suggests that inactivation of the inherited wild-type allele by a somatic mutation triggers cyst formation. In some cases, this second hit eliminates the normal allele and the affected cells remain with a single allele, which is the inherited mutated copy, and we only visualize one allele after the amplification by polymerase chain reaction; this is called loss of heterozygosity (LOH). In this study we have analysed the DNA isolated from epitehlial cells from 164 cysts of 8 kidneys affected by ADPKD type I and 30 cysts form a kidney affected by ADPKD type II. We have demonstrated the presence of LOH in 20.1% of PKD1 cysts and in 10% of PKD2 cysts. We have also found eight other different mutations in PKD2 cysts without LOH; so the percentage of somatic mutations in the PKD2 kidney reaches 36.6% of cysts. In conclusion, our data suggest that a recessive mechanism at the cellular level is implicated in cyst formation in the PKD1 and the PKD2 disease. The loss of both copies of the gene triggers the proliferation of a single cell, resulting in the cyst formation.

[Mutational analysis of the PKD1 and PKD2 (type 1 and 2 dominant autosomal polycystic kidney) genes]. / Estudio mutacional de los genes PKD1 y PKD2 (poliquistosis renal autosómica dominante tipo 1 y 2).

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. It is caused by mutations in at least two different genes: PKD1 and PKD2. The study of mutations in these genes is very difficult nowadays. In this study we have analyzed the non reiterated region of the PKD1 gene and all the exons and intron exon boundaries of the PKD2 gene. The technique used to study these genes have been single strand conformation analysis and heteroduplex. We have found 25 differences within the DNA sequence of the PKD1 gene with respect to the published sequence. Seven of these changes correspond to nonsense, missense, frameshifting and splicing mutations. The rest of changes correspond to polymorphisms or rare DNA variants. In the PKD2 gene we have identified 8 new mutations and one polymorphism. Six of these mutations are frameshifting, one is missense and the other one is a large deletion of the PKD2 gene. The rate of mutation detection within the PKD1 gene has been 4% and the rate for PKD2 has been 100%. We have not observed any correlation between genotype and phenotype either in the PKD1 nor in the PKD2 gene. The mutation analysis of ADPKD genes is very difficult, specially for the PKD1 gene. The rate of mutation detection is higher in the PKD2 gene but the global efficacy of the technique is very low as PKD2 represents only 15% of ADPKD patients. Nowadays linkage analysis is still the most useful technique for the molecular diagnosis of ADPKD patients.

[Clinical, genetic and molecular studies on autosomal dominant polycystic kidney disease]. / Estudio Clínico, genético y molecular de la poliquistosis renal autosómica dominate tipos 1 y 2.

BACKGROUND: Two genes causing autosomal dominant polycystic kidney disease (ADPKD), PKD1 and PKD2, have been described. In the present work we study, by means of linkage analysis, the genetic heterogeneity in our population as well as the clinical differences between PKD1 and PKD2. SUBJECTS AND METHODS: 316 subjects belonging to 49 unrelated ADPKD families have been studied by means of 3 microsatellites for PKD1 and 3 for PKD2 to differentiate if they have ADPKD type 1 or 2. The techniques used to analyze the microsatellites have been the chemiluminescence and the silver satining techniques. All the subjects underwent a complete physical examination and a sonographic scan. Clinical and molecular results have been correlated. RESULTS: Genetic heterogeneity has been proved, with 85% of families linked to PKD1 and 15% to PKD2. The disease is more severe in PKD1, with an earlier age at diagnosis (27.4 vs. 41.4 years; p = 0.0002), a younger age at the onset of end stage renal disease (53.4 vs. 72.7 years, p < 0.00001), and earlier age at diagnosis of hypertension (34.8 vs. 49.7 years; p = 0.001) and a higher prevalence of hypertension for all groups of age. In both forms of ADPKD there were families showing anticipation (8/44 for PKD1 and 2/5 for PKD2) but this was not a widespread phenomenon. Our data do not support the phenomenon of genetic imprinting for this disease. CONCLUSION: In the population of Catalonia, Spain, PKD1 accounts for 85% of families with autosomal dominant polycystic kidney disease and PKD2 accounts for the remaining 15%. PKD1 form is more severe than PKD2.

[Cystic lymphangioma of the stomach. Report of a new case]. / Linfangioma quístico de estómago. Aportación de un nuevo caso.

Cystic lymphangioma are rare benign tumours which are manifested as unilocular o multilocular masses containing chylous or serous material. Its origin is generally accepted to be a congenital lymphatic inflammation. It is difficult to make a preoperative diagnosis. Occasionally, when these lesions are suspected, they may be diagnosed by lymphography. We describe one case which underwent subtotal gastrectomy. At the microscopic examination dilated lymphatic channels were present with some lymphatic inflammation.

[Usefulness of erythromycin in severe postoperative gastroparesis]. / Utilidad de la eritromicina en la gastroparesia postquirúrgica severa.

Erythromycin has recently been shown to exert a great effect on gastroduodenal motor activity. This prokinetic action may be clinically useful in patients with gastrointestinal hypomotility such as diabetic or postsurgical gastroparesis. The case of a diabetic patient who underwent antrectomy Billroth II for gastric cancer is presented. Severe gastroparesis appeared after surgery and nasogastric aspiration could not be removed, although the patient was treated with metoclopramide, and glucose levels, hydroelectrolytic balance and nutritional status were corrected. Forty-one days after the first operation, a second gastrectomy with Bilroth II reconstruction was performed because of supposed anastomotic narrowing, which was not confirmed at surgery. Fourteen days later, i.v. erythromycin (200 mg/4h) was started owing to gastroparesis persistence. Six days after treatment the patient tolerated oral ingestion. Prokinetic drugs constitute the specific therapy for gastroparesis. Metoclopramide is the most used, although its efficacy is limited. In the last few years, erythromycin has proved to have a powerful effect on gastroduodenal motility. This effect is mediated, at least in part, by its motilin stimulating activity accelerating gastric emptying. Our patient completely recovered from gastroparesis after erythromycin treatment. Recent results of erythromycin therapy in these patients have been promising, despite the difficult management involved.