Mutant polycystin-2 induces proliferation in primary rat tubular epithelial cells in a STAT-1/p21-independent fashion accompanied instead by alterations in expression of p57KIP2 and Cdk2

Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the formation of multiple fluid-filled cysts that destroy the kidney architecture resulting in end-stage renal failure. Mutations in genes PKD1 and PKD2 account for nearly all cases of ADPKD. Increased cell proliferation is one of the key features of the disease. Several studies indicated that polycystin-1 regulates cellular proliferation through various signaling pathways, but little is known about the role played by polycystin-2, the product of PKD2. Recently, it was reported that as with polycystin-1, polycystin-2 can act as a negative regulator of cell growth by modulating the levels of the cyclin-dependent kinase inhibitor, p21 and the activity of the cyclin-dependent kinase 2, Cdk2.

Methods

Here we utilized different kidney cell-lines expressing wild-type and mutant PKD2 as well as primary tubular epithelial cells isolated from a PKD transgenic rat to further explore the contribution of the p21/Cdk2 pathway in ADPKD proliferation.

Results

Surprisingly, over-expression of wild-type PKD2 in renal cell lines failed to inactivate Cdk2 and consequently had no effect on cell proliferation. On the other hand, expression of mutated PKD2 augmented proliferation only in the primary tubular epithelial cells of a rat model but this was independent of the STAT-1/p21 pathway. On the contrary, multiple approaches revealed unequivocally that expression of the cyclin-dependent kinase inhibitor, p57^KIP2, is downregulated, while p21 remains unchanged. This p57 reduction is accompanied by an increase in Cdk2 levels.

Conclusion

Our results indicate the probable involvement of p57^KIP2 on epithelial cell proliferation in ADPKD implicating a new mechanism for mutant polycystin-2 induced proliferation. Most importantly, contrary to previous studies, abnormal proliferation in cells expressing mutant polycystin-2 appears to be independent of STAT-1/p21.     

Effects of pyrrolidine dithiocarbamate on proliferation and nuclear factor-κB activity in autosomal dominant polycystic kidney disease cells

Background

Pyrrolidine dithiocarbamate (PDTC) reduces renal cyst growth in a rodent model of polycystic kidney disease (PKD) but the mechanism of action is not clear. Here, we investigated the hypothesis that PDTC reduces the proliferation of cystic epithelial cells in vitro in a nuclear factor (NF)-κB-dependent manner.

Methods

Immortalized autosomal dominant PKD (ADPKD) cells that are heterozygous (WT9-7) and homozygous (WT-9-12) for a truncating Pkd1 mutation, and immortalized normal human tubular cells (HK-2), were exposed to NF-κB-inducing agents with or without PDTC. Cell proliferation and apoptosis were assessed by bromodeoxyuridine assay and Annexin V flow cytometry, respectively. NF-κB activity was assessed by luciferase reporter assay and western blotting for nuclear p65, p50, and RelB subunits and cytoplasmic phosphorylated-IκBα.

Results

Serum-induced proliferation was similar in all cell lines over 72 h. PDTC demonstrated anti-proliferative effects that were delayed in ADPKD cells compared to HK-2. Basal NF-κB-dependent luciferase reporter activity was lower in ADPKD cells compared to normal cells. Classical NF-κB stimulants, lipopolysaccharide (LPS) and tumor necrosis factor (TNF)-α, increased NF-κB luciferase activity in HK-2, whereas in PKD cell lines, NF-κB activity was only induced by TNF-α. However, neither stimulant altered proliferation in any cell line. PDTC reduced TNF-α-stimulated NF-κB activity in HK-2 only.

Conclusions

PDTC reduced proliferation in ADPKD cells but did not consistently alter NF-κB activation, suggesting that other signalling pathways are likely to be involved in its ability to attenuate renal cyst growth in vivo.

     

Simultaneous clinical resolution of focal segmental glomerulosclerosis associated with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab

Background

Severe hypokalemia is known to cause muscle paralysis, and renal tubular acidosis is a recognized cause. Cystic disease of the kidney is associated with severe hypokalemia.

Case presentation

We report a 33-year-old male patient who presented with generalized limb weakness caused by severe hypokalemia due to renal tubular acidosis, who was found to have renal medullary cysts.

Conclusion

The association of cystic renal disease with hypokalemia, and the possible pathophysiological basis of the development of renal cysts in patients with severe hypokalemia, are discussed.     

Kyste hydatique primitif de la rate: deux cas. Peut-on être conservateurs ?

Introduction

Via two cases of hydatid cyst of the spleen, we discuss the management of this rare disease. The choice of open surgery or laparoscopy depends on the size of the cyst and its location.

Cases

The first case was a hydatid cyst type 1 occurring in a young patient, which was operated by celioscopy with splenic conservation. The second case was a modified multilocular cyst in a patient aged 38 years, where a splenectomy was necessary.

Results

In both cases, the evolution was satisfactory, except the splenectomy needed a ten-day hospitalization, whereas the length of hospitalization for the conservative approach was five days and did not require postsplenectomy immune care.

Conclusion

Hydatid cyst of the spleen should be treated surgically because of the high-risk of rupture, the most widely used approach in adults is standard splenectomy but the surgical technique should be chosen according to the size of the cyst and its location. In our opinion splenic conservation should be implemented in all cases of single, superficial cysts.     

Place de la fenestration dans la prise en charge des kystes biliaires simples

Introduction

Simple hepatic cysts must be differenciated from cystadenoma and from cystadenocarcinoma. The treatment is different and surgical indications are restricted. We want to enhance the superiority of fenestration in the management of simple hepatic cysts through clinical cases and review of the literature.

Observation

We report two cases of simple hepatic cyst the clinical presentation of which were pain and superinfection of the cyst. Initial diagnosis was made after ultrasonography and computed tomography scan. The first case was a recurrent cyst of segments IV-V, 3 years after a surgical drainage and was treated with aspiration, surgical drainage and alcohol sclerotherapy. Subcutaneous and intracystic abscesses occurred four months later treated with multiple percutaneous radiological drainage then with fenestration of the cyst and partial pericystectomy. The long-term outcomes was good. The second case was a huge cyst of the right lobe of the liver treated with fenestration with a good outcome.

Conclusion

The diagnosis of simple hepatic cysts is easily done at radiology. Surgery is only indicated when the cyst is symptomatic or complicated. In these two cases, fenestration of the cyst was curative and it remains the recommended technique.     

Biliary atresia type I cyst and choledochal cust: can we differentiate or not?

Background/purpose

It is difficult to discriminate between choledochal cust with obstructive jaundice and biliary atresia with a cyst at the porta hepatis in neonates or young infants. This review evaluates whether it is possible to differentiate between these two diseases. We here also provide an overview of our experience with type I cyst biliary atresia patients.

Methods

Among all the biliary atresia infants who we treated, the infants who were diagnosed with type I cyst biliary atresia were identified and reviewed for their management and outcome. The clinical course and management in different reports were reviewed and compared to the cases presented to our institution.

Results

Among the 220 biliary atresia cases, 11 (5 %; male/female: 4/7) were diagnosed to be type I cyst biliary atresia. Two received hepaticoenterostomy and nine received hepatic portoenteros. Three patients had severe late complications; overall, nine (81.8 %) were alive with their native liver and without jaundice.

Conclusions

Patient with choledochal cust are likely to represent larger cysts and inversely, smaller, static, anechoic cysts are more likely to represent cystic biliary atresia. However, exceptional cases were yet presented, and a definitive diagnosis may not be reached. Thus a complete differentiation between choledochal cust from type I cyst biliary atresia is yet hard to reach.     

Type IV-A choledochal cysts: a challenge

Background/Purpose

Type IV-A choledochal cysts are characterized by congenital cystic dilatation of the biliary tree extending to involve the intrahepatic biliary channels also. A single-center experience of the management of type IV-A choledochal cysts is presented.

Methods

Thirty-five out of 105 (33%) patients with choledochal cysts, who underwent surgery at a tertiary care center in northern India from January 1989 to December 2002, were found to have a type IV-A (Todani’s classification) cyst. The mean age of the patients was 24 years (range, 3 months to 60 years); 17 patients in the group were adults and 22 were females. Presenting features were abdominal pain, jaundice, cholangitis, and abdominal lump, in various combinations.

Results

Excision of the extrahepatic part of the cyst and a wide bilio-enteric anastomosis was achieved in 32 (91%) patients, while internal drainage of the cyst was necessitated in 3 patients, for technical reasons: collaterals due to portal hypertension (1 patient) and dense adhesions (2 patients). Six (17%) patients developed postoperative complications: 3 had bilio-enteric anastomosis leaks, with 2 requiring a percutaneous proximal biliary diversion; 2 had intraabdominal bleeds requiring re-exploration, and 1 had external pancreatic fistula that closed spontaneously. Follow-up information was available for 28 (80%) patients. Mean duration of follow up was 25 months (median, 12 months; range, 6 months to 9 years). Three patients required re-operation, for anastomotic stricture (n = 2) and hepatolithiasis and recurrent cholangitis (n = 1) during follow up.

Conclusions

Excision of the extrahepatic part of the cyst and drainage of the intrahepatic part by a wide hilar or subhilar anastomosis gave satisfactory results in the majority of patients with type IV-A choledochal cysts. Close long-term follow up of these patients is essential, because they are likely to present with complications related to the residual intrahepatic part of the disease.     

Systemic Effect of Endoscopic Ultrasonography-Guided Pancreatic Cyst Ablation with Ethanol and Paclitaxel

Background

Endoscopic ultrasonography (EUS)-guided pancreatic cyst ablation is a minimally invasive treatment modality. Local injection of ablative agents may rarely cause systemic effects in patients.

Aims

This study aimed to evaluate the systemic effect of ablative agents by analyzing the plasma drug concentration.

Methods

Ten patients with pancreatic cysts were enrolled. Cyst ablation was performed by 99 % ethanol lavage (2.5–70 mL) and paclitaxel (Genexol-polymeric micelle, 6.0–24.0) injection. Blood samples were collected at 0, 2, 4, 7 and 24 h. Plasma paclitaxel concentration was analyzed by a liquid chromatography-tandem mass spectrometry with the lowest limit of quantitation of 0.1 ng/mL. Procedure-related complications were closely monitored.

Results

Pancreatic cysts were located at the head in two, body in seven and tail in one patient. Eight cysts were septated. Median diameter and original volume were 39.5 mm (range 2.7–21.8) and 14.79 mL (3.42–343.30). Median cyst fluid CEA and amylase values were 17.10 ng/mL (0.5–14127.5) and 73.50 U/L (3.1–91,590). Peak plasma paclitaxel concentration values were observed between 2 and 7 h, ranging from 0.45 to 14.73 ng/mL. The highest concentration (17.10 ng/mL at 0 h) was observed in a patient who had intracystic bleeding. Mild abdominal pain occurred in five patients and vomiting in one patient during the first 48-h monitoring.

Conclusion

Plasma paclitaxel concentration after EUS-guided pancreatic cyst ablation was nearly as low as the undetectable value and rarely caused systemic side-effect.     

Severity of diverticulitis in patients with polycystic kidney disease without transplantation

Background

Patients with polycystic kidney disease (PKD) who have had a kidney transplant have an increased risk of diverticular disease and complicated diverticulitis. Literature is limited regarding the severity of diverticulitis in patients with PKD who have not had a transplant. We aim to assess whether patients with PKD, with and without renal transplant, have a similar course of diverticulitis.

Methods

A retrospective review of all adult PKD patients at our institution diagnosed with diverticulitis between 2000 and 2016 was conducted. Patients without documented PKD and diverticulitis were excluded. We compared PKD patients with and without renal transplantation.

Results

A total of 41 patients were identified. Mean age was 60 (± 12), and 56% were female. Fourteen patients had undergone renal transplantation. Five (19%) non-transplant patients had complicated diverticulitis, compared to 43% (n = 6) transplanted (p = 0.33). Fifteen (56%) non-transplant and 8 (57%) transplant patients had recurrent diverticulitis (p = 1.00). Three (11%) non-transplant and 5 (36%) transplanted patients had recurrent complicated diverticulitis. Eight (30%) non-transplant and 7 (50%) transplant patients underwent surgery (p = 0.31). All 8 non-transplant patients underwent sigmoid resection with primary anastomosis without diversion. In the transplant group, 3 Hartmann procedures and 1 sigmoid resection with and 3 without diversion were performed. There was one in-hospital death in each group.

Conclusion

In our group of patients, there was no difference in rate of recurrent diverticulitis, diverticulitis complications, or operative intervention in patients with PKD with and without renal transplant. The renal transplant group had a higher rate of recurrent, complicated diverticulitis.

     

Molecular Diagnostics in Autosomal Dominant Polycystic Kidney Disease: Utility and Limitations

Background and objectives: Gene-based mutation screening is now available and has the potential to provide diagnostic confirmation or exclusion of autosomal dominant polycystic kidney disease. This study illustrates its utility and limitations in the clinical setting.Design, setting, participants, & measurements: Using a molecular diagnostic service, genomic DNA of one affected individual from each study family was screened for pathologic PKD1 and PKD2 mutations. Bidirectional sequencing was performed to identify sequence variants in all exons and splice junctions of both genes and to confirm the specific mutations in other family members. In two multiplex families, microsatellite markers were genotyped at both PDK1 and PKD2 loci, and pair-wise and multipoint linkage analysis was performed.Results: Three of five probands studied were referred for assessment of renal cystic disease without a family history of autosomal dominant polycystic kidney disease, and two others were younger at-risk members of families with autosomal dominant polycystic kidney disease being evaluated as living-related kidney donors. Gene-based mutation screening identified pathogenic mutations that provided confirmation or exclusion of disease in three probands, but in the other two, only unclassified variants were identified. In one proband in which mutation screening was indeterminate, DNA linkage studies provided strong evidence for disease exclusion.Conclusions: Gene-based mutation screening or DNA linkage analysis should be considered in individuals in whom the diagnosis of autosomal dominant polycystic kidney disease is uncertain because of a lack of family history or equivocal imaging results and in younger at-risk individuals who are being evaluated as living-related kidney donors.Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease worldwide affecting one in 500 to 1000 live births (1,2). It is characterized by focal and sporadic development and progressive enlargement of renal cysts, leading to ESRD in late middle age. Typically, only a few renal cysts are detected in most affected individuals before 30 yr of age; however, by the fifth decade of life, hundreds to thousands of renal cysts will be found in the majority of patients. Overall, it accounts for 5 to 8% of ESRD in developed countries (1,2). ADPKD is a systemic disorder associated with multiple extrarenal complications, such as cysts in nonrenal organs, valvular heart disease, colonic diverticula, inguinal hernias, and intracranial arterial aneurysms. It is genetically heterogeneous, with most cases arising from mutations in PKD1 (MIM 601313) and PKD2 (MIM 173910), located on chromosome 16p13.3 and 4q21–23, respectively (1–4). In a linkage-characterized European sample, PKD1 accounts for approximately 85% of the cases, whereas PKD2 accounts for most of the remainder (3,4). Although the clinical manifestations of the two gene types overlap completely, a strong locus effect is evident with more severe renal disease in PKD1 than PKD2 (median age at ESRD 54 versus 74, respectively) (5). In addition, both environmental and genetic modifiers have been implicated to account for the significant intrafamilial renal disease variability observed (6–8), and a mild allelic effect has been suggested for PKD1 but not PKD2 (7,8).PKD1 is a large gene consisting of 46 exons with an open reading frame of approximately 13 kb and is predicted to encode a protein of 4302 amino acids. Its entire 5′ region up to exon 33 has been duplicated six times more proximally on chromosome 16p, and the presence of these highly homologous pseudogenes has made genetic analysis of PKD1 difficult (1,2). Recent availability of protocols for long-range and locus-specific amplification of PKD1 has enabled the complete mutation screening of this complex gene (9–11). By contrast, PKD2 is a single-copy gene that consists of 15 exons with an open reading frame of approximately 3 kb and is predicted to encode a protein of 968 amino acids (1,2). Marked allelic heterogeneity is evident for ADPKD, with more than 200 different PKD1 and more than 50 different PKD2 mutations reported to date (2,9–11). The majority of these mutations are unique and scattered throughout both genes. Most of them are also predicted to be protein truncating (as a result of frame-shift deletion/insertion, nonsense changes, or splice defects), although a significant number of unclassified variants (UCV; e.g., in-frame deletions, missense changes) have been reported (9–11). Despite sequencing of all of the coding regions and exon-intron splice junctions in both genes only 45 to 63% of pathogenic mutations could be identified in three large clinical series (9–11).The diagnosis of ADPKD is generally straightforward when affected individuals present with a positive family history and enlarged kidneys with multiple cysts (12). Renal ultrasound is a sensitive method for this purpose, and age-dependant criteria based on cyst number have been derived for individuals who are born with 50% risk for PKD1 (13); however, because cyst formation is an age-dependent process, the false-negative rate of ultrasound-based diagnosis is higher in younger at-risk individuals or in those who are affected by PKD2, which is associated with later onset disease (14). Equivocal imaging results can be a source of diagnostic uncertainty in the clinic because the underlying gene type for most patients is unknown. In addition, renal cystic disease without a family history of ADPKD and evaluation of younger at-risk individuals as living-related kidney donors are clinical scenarios that often pose diagnostic challenges (12). Using a case series, we illustrate the utility and limitations of molecular diagnostics for ADPKD in the clinical setting.     

Une localisation exceptionnelle du kyste hydatique: à propos de deux cas

Introduction

The hydatid cyst is a cosmopolitan parasitic infection that constitutes a problem of public health in developing countries’ areas of breeding.

Material and methods

The aim of this work is to report on the condition of extraordinary location. We report two cases of hydatid cyst of the right buttock. The diagnosis was confirmed by ultrasound scan of the soft parts. The treatment was surgical.

Discussion

The muscle hydatic cyst is a rare disease and achievement of the buttock is exceptional, so you must always think of it in subjects living in high endemic countries. The eradication of this disease is based on prophylaxis.

Conclusion

The hydatid cyst of soft parts is a rare tumor that grows slow, with local extension. You have to think of this diagnosis, especially in subjects from high endemic countries and seek explorations needed to make the diagnosis in time and avoid therapeutic errors.     

Endoscopic biliary drainage for children with persistent or exacerbated symptoms of choledochal cysts

Background

Symptoms of choledochal cysts sometimes persist or become exacerbated. As preoperative management for patients with these cysts, we prospectively employed endoscopic drainage, based on the theory that protein plugs cause symptoms by obstructing the pancreatobiliary ducts.

Methods

Children with choledochal cysts underwent endoscopic retrograde cholangiopancreatography (ERCP). When ERCP showed compaction with filling defects in patients with persistent or worsening symptoms (study patients), the placement of a short biliary stent tube was attempted for drainage. The clinical and ERCP findings of the study patients were compared with those of patients who were asymptomatic at ERCP (asymptomatic patients).

Results

There were 13 study patients (median age 2.9 years) and 41 asymptomatic patients (4.7 years) enrolled in the study between August 2005 and February 2011. Study patients more frequently had jaundice and elevated transaminase levels. ERCP showed that all study patients had obstruction or compacted filling defects in the common channel or the narrow segment distal to the cyst. Insertion of a stent tube was successful in 11 patients. Symptoms were relieved soon after biliary drainage. Surgery revealed that the obstructing materials were protein plugs, except in one case, which involved fatty acid calcium stones.

Conclusions

These results support the protein plug theory. Endoscopic short-tube stenting is adequate and effective as preoperative management.     

Evidence for Pathogenicity of Atypical Splice Mutations in Autosomal Dominant Polycystic Kidney Disease

Background and objectives: Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by locus and allelic heterogeneity, large multi-exon gene structure and duplication in PKD1, and a high level of unclassified variants. Comprehensive screening of PKD1 and PKD2 by two recent studies have shown that atypical splice mutations account for 3.5% to 5% of ADPKD. We evaluated the role of bioinformatic prediction of atypical splice mutations and determined the pathogenicity of an atypical PKD2 splice variant from a multiplex ADPKD (TOR101) family.Design, setting, participants, & measurements: Using PubMed, we identified 17 atypical PKD1 and PKD2 splice mutations. We found that bioinformatics analysis was often useful for evaluating the pathogenicity of these mutations, although RT-PCR is needed to provide the definitive proof.Results: Sequencing of both PKD1 and PKD2 in an affected subject of TOR101 failed to identify a definite mutation, but revealed several UCVs, including an atypical PKD2 splice variant. Linkage analysis with microsatellite markers indicated that TOR101 was PKD2-linked and IVS8 + 5G→A was shown to cosegregate only with affected subjects. RT-PCR of leukocyte mRNA from an affected subject using primers from exons 7 and 9 revealed six splice variants that resulted from activation of different combinations of donor and acceptor cryptic splice sites, all terminating with premature stop codons.Conclusions: The data provide strong evidence that IVS8 + 5G→A is a pathogenic mutation for PKD2. This case highlights the importance of functional analysis of UCVs.Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder worldwide, affecting approximately one in 500 live births. It is characterized by focal development and progressive enlargement of renal cysts, leading to end-stage renal disease (ESRD) in late middle age. Typically, only a few renal cysts are detected in most affected subjects before 30 yr of age. However, by the fifth decade of life, hundreds to thousands of renal cysts are found in most patients. Overall, ADPKD accounts for 5% to 8% of end-stage renal disease (ESRD) in developed countries (1,2). Extrarenal complications of ADPKD are variable and include inguinal hernias, colonic diverticulae, valvular heart disease, and intracranial arterial aneurysms (1).Mutations of two genes, PKD1 (MIM 601313) and PKD2 (MIM 173910), account for approximately 85% and 15% of all cases of ADPKD in linkage-characterized European populations (3,4). Although the clinical manifestations of PKD1 and PKD2 overlap completely, a strong locus effect on renal disease severity is evident with more severe renal disease in PKD1 than PKD2 (median age at ESRD: 54 yr versus 74, respectively) (5). PKD1 is a large gene consisting of 46 exons with an open reading frame of approximately 13 kb and is predicted to encode a protein of 4302 amino acids. Its entire 5′ region up to exon 33 has been duplicated six times proximally on chromosome 16p, and the presence of these highly homologous pseudogenes has made genetic analysis of PKD1 difficult (1,2). Recent availability of protocols for long-range and locus-specific amplification of PKD1 has enabled the complete mutation screening of this complex gene (6–9). In contrast, PKD2 is a single-copy gene consisting of 15 exons with an open reading frame of approximately 3 kb and is predicted to encode a protein of 968 amino acids (1,2).The diagnosis of ADPKD is straightforward in affected subjects with a positive family history and enlarged kidneys with multiple cysts (6). Renal ultrasound is a useful method for this purpose, and age-dependant criteria based on cyst number have been derived for subjects born with 50% risk of PKD1 or PKD2 (6,10). However, ultrasound diagnosis of ADPKD in younger at-risk subjects with equivocal or negative findings and in subjects affected by PKD2 or de novo disease remains a challenge (6). For these reasons, molecular screening is a useful tool in the clinical setting. However, marked allelic heterogeneity is evident, with over 200 different PKD1 and over 50 different PKD2 mutations reported to date (2,6–9,11–13). The majority of these mutations are unique and scattered throughout both genes. Although the majority of these mutations are predicted to be protein truncating (frame-shift deletion/insertion, nonsense or canonical splice changes), a large number of unclassified variants (UCVs; in-frame deletions, mis-sense and atypical splice changes) has also been reported (7–9). Comprehensive screening of both PKD1 and PKD2 by two recent studies identified definitive and probable mutations in 42% to 63% and 26% to 37% of patients, respectively (8,9). These two studies also reported that atypical splice mutations account for approximately 3.5% to 5% of ADPKD (8,9). In the current study, we performed and evaluated the utility of bioinformatics analysis on 17 reported atypical PKD1 and PKD2 splice mutations. We also determine the pathogenicity of an atypical splice variant found in a family affected by PKD2 and highlight the importance of functional analysis of UCVs in molecular diagnostic testing.     

Natural course of Fabry disease and the effectiveness of enzyme replacement therapy: a systematic review and meta-analysis

Objective

Current available evidence on long-term effectiveness of enzyme replacement therapy (ERT) for Fabry disease is limited. More insight is needed whether ERT effectiveness differs in patients with and without baseline end-organ damage.

Design

Through a systematic review, untreated and ERT treated males and females with Fabry disease were compared for main clinical outcomes: renal function, left ventricular mass (LVmass), cerebral white matter lesions (WMLs) and end-organ complications. Through a meta-analysis ERT effectiveness was estimated in different disease stages.

Data extraction

Two reviewers assessed quality of the included studies according to guidelines for prognosis research. Data were synthesized using a random effects meta-analysis.

Results

Thirty-one studies were systematically reviewed while six studies were included in the meta-analysis. In patients with a GFR?>?60 ml/min/1.73 m², decline of renal function was similar for treated and untreated patients. Only ERT treated males with a GFR?<?60 ml/min/1.73 m² had a slower rate of decline in renal function, possibly attributable to anti-proteinuric therapy. Regardless of left ventricular hypertrophy (LVH) at baseline, LVmass remained stable or increased in males despite ERT, however at a slower rate compared to untreated male patients. In ERT treated females with LVH LVmass decreased, and remained stable in females without LVH. WMLs can not be prevented by ERT. Stroke, cardiac and end-stage renal complications develop, though the incidence of new complications seems to be reduced during ERT.

Conclusion

ERT is effective in reducing LVH, but has a limited effect on renal function. Improved treatment options are needed for Fabry disease.     

Syndrome de Budd-Chiari : complication rare du kyste hydatique du foie : �� propos de trois cas

Introduction

Hydatid disease is a parasitic infestation due to the development of Echinococcus granulosus in the organism. This disease is particularly frequent in Tunisia where echinococcosis is endemic. Liver is the most common organ to be affected by hydatidosis, and several complications have been described. Vascular complications secondary to hepatic echinococcosis such as Budd-Chiari syndrome have rarely been reported.

Case reports

We report three rare cases of hydatid cyst complicated by Budd-Chiari syndrome. The cyst occupied at least two segments of the hepatic dome in all patients, and its diameter was 12.5, 21 and 12.5 cm, respectively. According to the Gharbi classification, the cysts were type III in one case and type IV in the other two cases. The Budd-Chiari syndrome was chronic in one patient and asymptomatic in other cases. The diagnosis was established by abdominal ultrasound (US) in two cases, confirmed by Doppler US and CT angiogram in one patient and by CT angiogram in the other. The diagnosis was established only by CT angiogram in the third case. The Budd-Chiari syndrome was due to the compression of two hepatic veins in one case, compression of inferior vena cava in one case and compression of one hepatic vein and inferior vena cava in another case. Laparotomy was performed in all patients. The surgical procedure comprised the resection of the protruding hepatic tissue after puncture aspiration of the cyst in all the three cases. The postoperative period was complicated by abscess formation in residual cavity, requiring drainage, and by the development of ascites in one case.

Conclusion

Hydatid cyst should be suspected amongst the causes of Budd-Chiari syndrome in countries where the disease is endemic. Conversely, this vascular complication should be looked for routinely in patients with hydatid disease of the liver.     

High-risk Diabetic Patients in Medicare Part D Programs: Are They Getting the Recommended ACEI/ARB Therapy?

BACKGROUND

Diabetes patients with hypertension and/or renal disease are at an increased risk of cardiovascular morbidity and mortality. Clinical evidence suggests that the use of ACEI/ARB for these patients improves patient outcomes.

OBJECTIVE

To describe ACEI/ARB utilization among high-risk patients with diabetes and to identify patient characteristics that predict suboptimal utilization of ACEI/ARB.

DESIGN

A retrospective cohort study.

PATIENTS

Diabetic patients with coexisting hypertension and/or renal disease with continuous Medicare coverage from October 1, 2005 through June 30, 2006 in six states (Alabama, California, Florida, Mississippi, New York, and Ohio).

INTERVENTIONS AND MEASUREMENTS

Any ACEI/ARB use during the first 6 months of 2006.

RESULTS

A total of 1,250,466 Medicare Part D enrollees met our inclusion criteria. ACEI/ARB utilization rates were 63%, 58.3%, and 43.1% among diabetic patients with hypertension and renal disease, hypertension without renal disease, and renal involvement without hypertension, respectively. After adjusting for all other characteristics studied, patients in the hypertension only (OR 0.83; 95% CI: 0.82–0.84) and renal disease only (OR: 0.48; 95% CI: 0.46–0.50) risk groups were less likely to use ACEI/ARB compared to diabetes patients with both hypertension and renal disease. Several demographics, including male gender, age older than 65, and white race, were all predictors of suboptimal ACEI/ARB use. Results from state-specific analyses are consistent with those for all six states.

CONCLUSION

In this cohort, less than 60% of high-risk patients with diabetes were receiving the recommended ACEI/ARB therapy. Several patient demographic and clinical characteristics are strongly associated with suboptimal ACEI/ARB use.     

Autosomal-dominante polyzystische Nierenerkrankung

Background

Patients with autosomal dominant polycystic kidney disease (ADPKD) have a varying risk for progression to renal failure and the necessity for dialysis depending on the individual risk profile. This review summarizes the current knowledge on the genetics and pathophysiology relevant for individual disease progression and currently available treatment strategies for ADPKD are assessed.

Methods

Literature search for articles on the pathophysiology and treatment of ADPKD.

Results

Renal scanning with magnetic resonance imaging (MRI) represents the most sensitive tool for establishing both the diagnosis and prognosis for estimation of the risk of progression. Strict blood pressure control, preferably with angiotensin-converting enzyme (ACE) inhibitors, is the most crucial component of treatment. Selected patients with chronic kidney disease (CKD) stages I–III and a high probability of rapid progression to end-stage renal disease can benefit from treatment with tolvaptan, which has been shown to delay cyst growth and to reduce loss of the estimated glomerular filtration rate (eGFR).

Conclusion

In addition to non-specific treatment approaches, tolvaptan represents a treatment option for high risk ADPKD patients to inhibit progression of cyst growth and loss of eGFR.

     

Offspring of parents with Balkan Endemic Nephropathy have higher C-reactive protein levels suggestive of inflammatory processes: a longitudinal study

Background

Despite the characteristic extensive tubulointerstitial fibrosis, Balkan Endemic Nephropathy (BEN) is usually considered a non-inflammatory disease.

Methods

We examined a marker of inflammation, C-reactive protein (CRP), in the offspring of patients with BEN, a population at risk for BEN, prior to development of established disease to determine if an inflammatory process could be identified in the early stages of the disease. In 2003/04, 102 adult offspring whose parents had BEN and a control group of 99 adult offspring of non-BEN patients were enrolled in this prospective study. This cohort was re-examined yearly for four consecutive years. Levels of serum CRP were measured in years 3 and 4 and compared between groups. The data were analyzed with mixed models.

Results

Compared to controls, offspring of BEN parents had statistically higher CRP levels in two consecutive years, suggestive of early inflammatory reactivity. Whenever the mother was affected by BEN (both parents, or mother only), serum CRP was significantly increased, but not if only the father had BEN. CRP was inversely related to kidney cortex width but not to markers or renal function.

Conclusion

Early stages of BEN may involve inflammatory processes. The observation of a maternal involvement supports the concept of fetal programming, which has been implicated in the pathogenesis of other chronic kidney diseases.     

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

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.     

Inflammatory Bowel Disease and Systemic AA Amyloidosis

Background

Systemic AA amyloidosis is a recognised complication of inflammatory bowel disease. AA amyloidosis is a potential cause of end-stage renal failure and mortality but little is known of the natural history of this condition in inflammatory bowel disease.

Methods

We evaluated the clinical phenotype, disease progression and outcome amongst 26 patients with inflammatory bowel disease and AA amyloidosis followed prospectively at a single center between 1989 and 2010.

Results

Twenty-two patients had Crohn’s disease and four had ulcerative colitis. Fistulae and abscesses occurred in ten cases, all of whom had Crohn’s disease. Amyloidotic proteinuric renal dysfunction occurred in all of the cases. It resolved in five patients with well-controlled inflammation, but was progressive in all of the other patients. Fifteen patients reached end-stage renal disease after a median time of 6.3 years from development of renal dysfunction (by Kaplan–Meier estimate), six of whom subsequently proceeded to renal transplantation. There were five functioning grafts at census 0.8, 3.2, 4.2, 20.1 and 24.6 years after transplantation. One graft failed 14.5 years after renal transplantation because of amyloid recurrence in a patient with sustained chronic inflammatory activity.

Conclusions

AA amyloidosis remains a serious complication of both Crohn’s disease and ulcerative colitis, and is characterized by proteinuric renal dysfunction that may resolve following suppression of inflammatory activity. Patient and graft survival are excellent in patients who undergo renal transplantation.