Allograft and patient survival after sequential HSCT and kidney transplantation from the same donor-A multicenter analysis.

Tolerance induction through simultaneous hematopoietic stem cell and renal transplantation has shown promising results, but it is hampered by the toxicity of preconditioning therapies and graft-versus-host disease (GVHD). Moreover, renal function has never been compared to conventionally transplanted patients, thus, whether donor-specific tolerance results in improved outcomes remains unanswered. We collected follow-up data of published cases of renal transplantations after hematopoietic stem cell transplantation from the same donor and compared patient and transplant kidney survival as well as function with caliper-matched living-donor renal transplantations from the Austrian dialysis and transplant registry. Overall, 22 tolerant and 20 control patients were included (median observation period 10 years [range 11 months to 26 years]). In the tolerant group, no renal allograft loss was reported, whereas 3 were lost in the control group. Median creatinine levels were 85 µmol/l (interquartile range [IQR] 72-99) in the tolerant cohort and 118 µmol/l (IQR 99-143) in the control group. Mixed linear-model showed around 29% lower average creatinine levels throughout follow-up in the tolerant group (P < .01). Our data clearly show stable renal graft function without long-term immunosuppression for many years, suggesting permanent donor-specific tolerance. Thus sequential transplantation might be an alternative approach for future studies targeting tolerance induction in renal allograft recipients.

Primary membranous nephropathy: comprehensive review and historical perspective.

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in non-diabetic Caucasian adults over 40 years of age. It has an estimated incidence of 8-10 cases per 1 million. Fifty per cent of patients diagnosed with primary MN continue to have nephrotic syndrome and 30% of patients may progress to end-stage renal disease over 10 years. Although it was recognised as a distinct clinic-pathological entity in 1940s by immunofluorescence and electron microscopy, the pathogenesis and treatment have become more apparent only in the last decade. Discovery of M-type phospholipase A2 receptor (PLA2R) antibodies and thrombospondin type 1 domain-containing 7A antibodies has given new perspectives in understanding the pathogenesis of the disease process. Anti-PLA2R antibody is the first serologic marker that has promising evidence to be used as a tool to prognosticate the course of the disease. More importantly, therapeutic agents such as rituximab and adrenocorticotropic hormone analogues are the newer therapeutic options that should be considered in the therapy of primary MN.

A single center's approach to discriminating donor versus host origin of renal neoplasia in the allograft kidney.

Renal cell carcinoma (RCC) in the allograft of kidney transplant recipient (KTR) patients is rare and may represent a de novo process arising from the transplanted organ or metastasis from a clinically undetectable host primary. Determination of host versus donor origin is important for staging and management. We report our experience utilizing Penta-C (PC) and Penta-D (PD) short-tandem repeat (STR) microsatellite analysis to discriminate between host and donor origin of RCC identified in renal allografts. We identified 5 KTR patients with RCC in the allograft kidney. The PC and PD microsatellite analysis was applied to tumor, host, and donor formalin-fixed, paraffin-embedded tissue sections and/or fresh blood leukocytes to identify the origin of the neoplastic cells. The PC and PD microsatellite alleles were robustly amplified in all samples. Each case showed one or more informative alleles indicating that the neoplastic cells originate from donor tissue. Allele frequency data indicate that by using both PC and PD markers, we will be able to discriminate between host and donor cell of origin in over 99% of cases. The PC and PD microsatellite analysis is a convenient, robust, and efficient strategy to determine donor versus host origin or RCC in transplant kidney specimens.

PKC{delta} is activated in a dietary model of steatohepatitis and regulates endoplasmic reticulum stress and cell death.

Hepatic steatosis can progress to the clinical condition of non-alcoholic steatohepatitis (NASH), which is a precursor of more serious liver diseases. The novel PKC isoforms δ and ε are activated by lipid metabolites and have been implicated in lipid-induced hepatic disease. Using a methionine- and choline-deficient (MCD) dietary model of NASH, we addressed the question of whether hepatic PKCδ and PKCε are activated. With progression from steatosis to steatohepatitis, there was activation and increased PKCδ protein content coincident with hepatic endoplasmic reticulum (ER) stress parameters. To examine whether similar changes could be induced in vitro, McA-RH 7777 (McA) hepatoma cells were used. We observed that McA cells stored triglyceride and released alanine aminotransferase (ALT) when treated with MCD medium in the presence of fatty acids. Further, MCD medium with palmitic acid, but not oleic or linoleic acids, maximally activated PKCδ and stimulated ER stress. In PKCδ knockdown McA cells, MCD/fatty acid medium-induced ALT release and ER stress induction were completely blocked, but triglyceride storage was not. In addition, a reduction in the uptake of propidium iodide and the number of apoptotic nuclei and a significant increase in cell viability and DNA content were observed in PKCδ knockdown McA cells incubated in MCD medium with palmitic acid. Our studies show that PKCδ activation and protein levels are elevated in an animal model of steatohepatitis, which was recapitulated in a cell model, supporting the conclusion that PKCδ plays a role in ALT release, the ER stress signal, and cell death.