Michael Schultheiss

Patients with Mutations in NPHS2 (Podocin) Do Not Respond to Standard Steroid Treatment of Nephrotic Syndrome

Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroid-resistant NS (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes of ESRD in the first two decades of life. Mutations in the NPHS2 gene represent a frequent cause of SRNS, occurring in approximately 20 to 30% of sporadic cases of SRNS. On the basis of a very small number of patients, it was suspected that children with homozygous or compound heterozygous mutations in NPHS2 might exhibit primary steroid resistance and a decreased risk of FSGS recurrence after kidney transplantation. To test this hypothesis, NPHS2 mutational analysis was performed with direct sequencing for 190 patients with SRNS from 165 different families and, as a control sample, 124 patients with steroid-sensitive NS from 120 families. Homozygous or compound heterozygous mutations in NPHS2 were detected for 43 of 165 SRNS families (26%). Conversely, no homozygous or compound heterozygous mutations in NPHS2 were observed for the 120 steroid-sensitive NS families. Recurrence of FSGS in a renal transplant was noted for seven of 20 patients with SRNS (35%) without NPHS2 mutations, whereas it occurred for only two of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2. None of 29 patients with homozygous or compound heterozygous mutations in NPHS2 who were treated with cyclosporine A or cyclophosphamide demonstrated complete remission of NS. It was concluded that patients with SRNS with homozygous or compound heterozygous mutations in NPHS2 do not respond to standard steroid treatment and have a reduced risk for recurrence of FSGS in a renal transplant. Because these findings might affect the treatment plan for childhood SRNS, it might be advisable to perform mutational analysis of NPHS2, if the patient consents, in parallel with the start of the first course of standard steroid therapy.

No evidence for genotype/phenotype correlation in NPHS1 and NPHS2 mutations

Primary steroid-resistant nephrotic syndrome (SRNS) is characterized by childhood onset of proteinuria and progression to end-stage renal disease. In 26% of cases it is caused by recessive mutations in NPHS2 (podocin). Congenital nephrotic syndrome (CNS) is caused by mutations in NPHS1 (nephrin) or NPHS2. In three families mutations in NPHS1 and NPHS2 had been reported to occur together, and these tri-allelic mutations were implicated in genotype/phenotype correlations. To further test the hypothesis of tri-allelism, we examined a group of 62 unrelated patients for NPHS1 mutations, who were previously shown to have NPHS2 mutations; 15 of 62 patients had CNS. In addition, 12 CNS patients without NPHS2 mutation were examined for NPHS1 mutations. Mutational analysis yielded three different groups. (1) In 48 patients with two recessive NPHS2 mutations (11 with CNS), no NPHS1 mutation was detected, except for 1 patient, who had one NPHS1 mutation only. This patient was indistinguishable clinically and did not have CNS. (2) In 14 patients with one NPHS2 mutation only (4 with CNS), we detected two additional recessive NPHS1 mutations in the 4 patients with CNS. They all carried the R229Q variant of NPHS2. The CNS phenotype may be sufficiently explained by the presence of two NPHS1 mutations. (3) In 12 patients without NPHS2 mutation (all with CNS), we detected two recessive NPHS1 mutations in 11 patients, explaining their CNS phenotype. We report ten novel mutations in the nephrin gene. Our data do not suggest any genotype/phenotype correlation in the 5 patients with mutations in both the NPHS1 and the NPHS2 genes.

Procedural and shunt-related complications and mortality of the transjugular intrahepatic portosystemic shunt (TIPSS).

The implantation of a transjugular intrahepatic portosystemic shunt (TIPSS) is a complex angiographic procedure performed in patients with end‐stage liver disease. Numerous case reports and narrative reviews have been published so far; however, studies systematically investigating procedural and shunt‐related complications are lacking.

Free Hepatic Vein Pressure Is Not Useful to Calculate the Portal Pressure Gradient in Cirrhosis: A Morphologic and Hemodynamic Study.

PURPOSE To systematically evaluate the accuracy of free hepatic vein pressure (FHVP), the internal reference for hepatic venous pressure gradient (HVPG). MATERIALS AND METHODS Diameter and pressure measurements were obtained in multiple locations within the hepatic vein, inferior vena cava (IVC), and right atrium on 30 hepatic venograms in 29 consecutive candidates for transjugular intrahepatic portosystemic shunt creation. RESULTS On angiography, 15 patients (52%) had hepatic veins showing a normal and conical appearance, whereas the other 14 had irregular or narrow (maximal diameter ≤ 6 mm) veins. Diameters of hepatic veins increased from 4.4 mm ± 0.9 (range, 3.3-7 mm) at a peripheral position to 8.7 mm ± 3.0 (range, 5.0-15.5 mm; P < .001) at a central position, and respective pressures decreased from 10.9 mm Hg ± 3.7 (range, 3-17 mm Hg) to 7.4 mm Hg ± 3.7 (range, 0-14 mm Hg; P < .001). Gradients between wedged hepatic vein pressure and central free hepatic vein, IVC, and right atrium pressures were 17.2 mm Hg ± 5.4 (range, 4-33 mm Hg), 18.0 mm Hg ± 5.8 (range, 4-33 mm Hg), and 20.0 mm Hg ± 5.9 (range, 4-33 mm Hg), respectively. Pearson correlation coefficients were 0.679 between the HVPG and hepatic atrial pressure gradient (HAPG) and 0.889 between the wedged hepatic vein/IVC pressure gradient (HCPG) and HAPG. CONCLUSIONS FHVP measurement depends on catheter tip position and vein morphology. Its use to calculate HVPG is not recommended. The high agreement between the HCPG and the HAPG suggests that both gradients may be used if one considers a systemic difference of 2 mm Hg.

Treatment with proton pump inhibitors is associated with increased mortality in patients with pyogenic liver abscess

Proton pump inhibitors (PPI) are often used in patients with gastro‐esophageal reflux and peptic ulcer disease. A higher risk for infectious diseases and for pyogenic liver abscess has been reported in patients with prolonged PPI intake. Although many patients have ongoing PPI treatment after diagnosis of liver abscess, there are no data available that focus on the prognostic impact of PPI treatment in these patients.

Selenium levels in patients with hepatitis C virus-related chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma: a pilot study.

We read with great interest the findings described by Shi et al. They detected high levels of donor-derived CD56þ, CD3þ, and CD14þ T cells in the first explanted liver grafts in both the short and long term after liver transplantation (LT). They concluded that these long-lived intragraft leukocytes in LT patients could cause long-term hematopoietic chimerism, challenging our conclusion that long-term blood chimerism is derived from hematopoietic stem/progenitor cells (HSPCs) in the liver, although they also suggest the possibility that it may result from hematopoiesis of relocated donor HSPCs. The critical issue here is whether the mature leukocytes in the intragraft are really long-lived. Natural killer (NK) cells (CD56þ) are generally considered short-lived effector cells. Although it is still controversial, recent studies have demonstrated that NK cells have the ability to become long-lived memory cells and contribute to secondary immune responses. The mechanisms for NK cell longevity are unclear, but these self-renewing capable NK cells are not just simple mature NK cell proliferation. In liver tissue, CD14þ cells are mostly Kupffer cells with a lifespan of 3.8 days, which are generated and maintained by a high monocyte influx rate or local progenitor proliferation. However, what the local progenitor cells are and where they are derived from are yet to be clarified. Based on the understanding as outlined above, we think high levels of donor-derived T cells in recipient liver are unlikely to result from a simple mature T-cell proliferation to survive for 2 years after LT. Instead, it may generate from an existent small population of donor HSPCs or blood HSPCs in liver grafts (Shi et al. appears to agree with the latter point), which are able to selfrenew and differentiation to maintain the mature leucocyte pool. In this sense, the findings by Shi et al. prove our hypothesis. Regarding the origin of HSPCs, both consistent presences in liver or from blood HSPCs are possible. We prefer the former hypothesis, because the population was maintained in liver grafts after extensive perfusion, but we did not exclude the probability of blood HSPCs in liver grafts. Finally, in 5 of the explanted liver grafts, Shi et al. could not detect donor-derived Lin CD34þ HSPCs, which does not mean the HSPCs do not exist in healthy liver grafts. That Lin CD34þ or Lin CD45þ liver cells isolated from over 30 healthy liver grafts are able to form a hematopoietic colony and engraft in immunodeficient mice are the evidence of the presence of HSPCs in liver grafts. Moreover, Lin CD34þCD38 CD90þ HSPCs only account for 0.03% of total liver cells, whereas the Lin CD34þ population described by Shi et al. was based on different human leukocyte antigen markers, which might further complicate the measurement.

Influence of the transjugular intrahepatic portosystemic stent on firstline treatment of hepatocellular carcinoma

Liver cirrhosis can cause portal hypertension with refractory ascites and variceal bleeding as well as hepatocellular carcinoma (HCC). Therefore, there is a rising patient population previously treated with transjugular intrahepatic portosystemic stent (TIPS) for portal hypertension suffering from HCC. So far a negative influence of TIPS on HCC concerning treatment options has been suspected, since due to reduced portal liver perfusion only transarterial chemotherapy (TAC) instead of additional embolization (TACE) is usually performed. Therefore, the effect of embolization, which has a higher antitumoral potency than intra-arterial chemotherapy itself, is missing. To evaluate treatment modalities in patients with TIPS and HCC we analyzed firstline treatment and overall survival (OS). Between April 1995 and May 2011 we recruited 60 newly diagnosed HCC patients of the Liver Center of the University Hospital Freiburg who previously (>6 months) had been treated with bare metal stent TIPS implantation. For controls we analyzed 60 consecutive HCC patients without previous TIPS implantation. These patients were matched 1:1 for age (65 years), sex, etiology of liver disease, and Child-Pugh score at the time of HCC diagnosis. In all, 51/60 patients (85.0%) in the TIPS group and 42/60 patients (70.0%) in the non-TIPS group died within the observation time. Tumor stages were assessed using the established Barcelona Clinic Liver Cancer (BCLC) classification. In both groups the majority of patients presented with BCLC stage A (48.3% and 44.3%) and BCLC stage B (30.0% and 35.7%) without statistically significant differences (P 5 0.966). TIPS patients had a median OS of 17.0 months (95% confidence interval [CI]: 10.21; 23.79) compared to 24.0 months (95% CI: 9.39; 38.61) of non-TIPS patients (P 5 0.040, Fig. 1A). A multivariate Cox regression model identified multifocal hepatic tumor manifestation (hazard ratio [HR] 2.13, P 5 0.012), TIPS (HR 1.74; P 5 0.040), Child-Pugh B (HR 1.98; P 5 0.008), and C (HR: 3.30; P 5 0.004), alpha-fetoprotein (AFP) >20 ng/mL (HR: 1.94; P 5 0.008), and metastasis (HR 5.20; P 5 0.001) as significant independent negative predictors of OS. Moreover, we analyzed firstline treatment in TIPS and nonTIPS patients. A majority of patients with TIPS were treated by best supportive care (BSC) and did not receive any HCC-specific treatment compared to patients in the non-TIPS group (26.8% versus 6.2%). Interestingly, 28 (46.6%) TIPS patients were treated with TAC compared to 49 (81.6%) non-TIPS patients who had been treated with TACE (P 5 0.002, Fig. 1B). None of the TIPS patients developed severe hepatotoxicity as a possible reason for impaired OS. No statistical differences concerning surgical approaches, percutaneous therapies (radiofrequency ablation [RFA]) and sorafenib application, were found. In conclusion, our findings indicate that TIPS patients have limited therapeutic possibilities concerning HCC-specific therapies, resulting in impaired OS. Especially, transarterial chemotherapies are less often administered in patients with TIPS. Therapy strategies in TIPS patients with HCC should be reassessed, since treatment options are expanded: (super)selective TACE yttrium-90 radioembolization or percutaneous ethanol injection in combination with TACE might be alternative approaches. Therefore, prospective studies are needed to determine the effectiveness and the safety of therapeutic approaches using embolization in patients with TIPS and HCC and to establish treatment guidelines for HCC in these patients.

Stereotactic Body Radiation Therapy as an Alternative Treatment for Patients with Hepatocellular Carcinoma Compared to Sorafenib: A Propensity Score Analysis

Background and Aims: Stereotactic body radiation therapy (SBRT) has emerged as a safe and effective treatment for patients with hepatocellular carcinoma (HCC), but its role in patients with advanced HCC is not yet defined. In this study, we aim to assess the efficacy and safety of SBRT in comparison to sorafenib treatment in patients with advanced HCC. Methods: We included 901 patients treated with sorafenib at six tertiary centers in Europe and Asia and 122 patients treated with SBRT from 13 centers in Germany and Switzerland. Medical records were reviewed including laboratory parameters, treatment characteristics and development of adverse events. Propensity score matching was performed to adjust for differences in baseline characteristics. The primary endpoint was overall survival (OS) and progression-free survival. Results: Median OS of SBRT patients was 18.1 (10.3–25.9) months compared to 8.8 (8.2–9.5) in sorafenib patients. After adjusting for different baseline characteristics, the survival benefit for patients treated with SBRT was still preserved with a median OS of 17.0 (10.8–23.2) months compared to 9.6 (8.6–10.7) months in sorafenib patients. SBRT treatment of intrahepatic lesions in patients with extrahepatic metastases was also associated with improved OS compared to patients treated with sorafenib in the same setting (17.0 vs. 10.0 months, p = 0.012), whereas in patients with portal vein thrombosis there was no survival benefit in patients with SBRT. Conclusions: In this retrospective comparative study, SBRT showed superior efficacy in HCC patients compared to patients treated with sorafenib.

Survival benefit of transarterial chemoembolization in patients with metastatic hepatocellular carcinoma: a single center experience

BackgroundAs prognosis of patients with metastatic hepatocellular carcinoma (HCC) is mainly determined by intrahepatic HCC progression, local treatment with TACE may result in improved OS, although it is not recommended. The purpose of this study was to analyze retrospectively the efficacy of TACE and its impact on OS in patients with metastatic hepatocellular carcinoma (HCC).MethodsTwo hundred and fifteen patients with metastatic HCC who were treated at our Liver Center between 2003 and 2014 were included in this retrospective analysis. Medical records, laboratory parameters and imaging studies were analyzed. Treatment of metastatic HCC and OS were assessedResultsOne hundred and two patients (47.4%) did not receive any HCC specific treatment while 48 patients (22.3%) were treated with sorafenib, 42 patients (19.5%) with TACE and 23 patients (10.7%) received treatment with TACE and sorafenib in combination. Survival analyses and Cox regression models revealed that TACE and a combination therapy of TACE and sorafenib were significant prognostic factors in metastatic HCC. However, further analyses revealed that there was no additional prognostic effect of adding sorafenib to TACE treatment in this patient cohort.ConclusionsIn metastatic HCC, treatment of intrahepatic tumor by TACE may be associated with improved survival. These results support the prognostic importance of treating intrahepatic HCC even in patients with metastatic disease. Therefore, we suggest evaluating the technical feasibility of TACE in all metastatic patients.

Treatment with proton pump inhibitors increases the risk for development of hepatic encephalopathy after implantation of transjugular intrahepatic portosystemic shunt (TIPS)

Background and objective Treatment with proton pump inhibitors (PPIs) has been associated with development of hepatic encephalopathy (HE). As development of HE is a major complication after implantation of a transjugular intrahepatic portosystemic shunt (TIPS), we hypothesized that PPI treatment may be associated with a higher risk of post-TIPS HE. Methods We analyzed data of 397 patients with liver cirrhosis who received de novo TIPS implantation at the University Medical Center Freiburg, Germany. We assessed whether PPI medication and other patient characteristics are predictive factors for the development of post-TIPS HE. Results Patients with PPI treatment at the time of TIPS implantation showed significantly higher rates of post-TIPS HE than those without PPI medication (30.4% vs 11.7%, p < 0.001). The rate of post-TIPS HE increased in a dose-dependent manner. However, PPI medication did not directly affect transplant-free survival. Remarkably, in 59.1% of patients who received PPIs there was no clear indication. Conclusions PPI treatment may be an independent risk factor for the development of post-TIPS HE and the risk increases with PPI dose. Indication for PPI treatment should be assessed carefully prior to TIPS implantation in patients with liver cirrhosis.