The utility of phospholipase A2 receptor autoantibody in membranous nephropathy after kidney transplantation.

Membranous nephropathy (MN) is estimated to cause end-stage renal disease in ∼ 5% of patients, in whom renal transplantation is the therapy of choice. Among patients receiving a transplant for MN, the disease will recur in the graft in 30-50%; among these, graft loss will occur in 50% within 10 years. Several studies have suggested that phospholipase A2 receptor autoantibody (aPLA2R) levels before transplantation might be useful in predicting recurrence, and their titration after transplantation is clinically relevant to assess the risk of recurrence and progression, to guide treatment indications and to monitor treatment response. In this review we describe the evolving role of aPLA2R as a biomarker in primary MN and its current usefulness in predicting recurrence of this autoimmune podocytopathy after renal transplantation.

Over-expression of muscle glycogen synthase in human diabetic nephropathy.

Diabetic nephropathy (DN) is a major complication of diabetic patients and the leading cause of end-stage renal disease. Glomerular dysfunction plays a critical role in DN, but deterioration of renal function also correlates with tubular alterations. Human DN is characterized by glycogen accumulation in tubules. Although this pathological feature has long been recognized, little information exists about the triggering mechanism. In this study, we detected over-expression of muscle glycogen synthase (MGS) in diabetic human kidney. This enhanced expression suggests the participation of MGS in renal metabolic changes associated with diabetes. HK2 human renal cell line exhibited an intrinsic ability to synthesize glycogen, which was enhanced after over-expression of protein targeting to glycogen. A correlation between increased glycogen amount and cell death was observed. Based on a previous transcriptome study on human diabetic kidney disease, significant differences in the expression of genes involved in glycogen metabolism were analyzed. We propose that glucose, but not insulin, is the main modulator of MGS activity in HK2 cells, suggesting that blood glucose control is the best approach to modulate renal glycogen-induced damage during long-term diabetes.

Should we be using kidneys from hepatitis C virus-infected donors?

PURPOSE OF REVIEW: Transplantation of kidneys from donors with a positive serology for hepatitis C virus (HCVD positive) remains controversial. RECENT FINDINGS: Registry studies reported that the use of HCVD positive kidneys into HCV positive recipients is associated with shorter time awaiting transplantation but with a small increase in hazard for death and graft loss compared with HCVD negative. Notably, patients who received kidneys from HCVD positive have better survival than those who remain in the waitlist. A collaborative study using HCVD positive kidneys into HCVRNA positive recipients showed that HCV serology was not an independent risk factor for liver disease, graft survival, and patient survival in the long term. The safety of this approach can be improved by matching donors and recipients according to HCV genotypes. Because the incidence and prevalence of HCV infection in dialysis patients are decreasing, kidneys from HCVD positive are becoming surplus organs due to the lack of appropriate recipients in the waitlist. To improve the underutilization of these kidneys, organizational measures, including the offer of these kidneys for preemptive transplantation, are suggested. SUMMARY: The use of kidneys from HCVD positive into HCVR positive seems to be a safe approach in the long term, showing a better patient survival than that of HCV positive patients on the waitlist.

KCNQ1 gene variants and risk of new-onset diabetes in tacrolimus-treated renal-transplanted patients.

Recent genome-wide association studies identified single-nucleotide polymorphisms (SNPs) in the gene encoding the pore-forming subunit of the voltage-gated K+ channel (KCNQ1) as a risk factor for type 2 diabetes. Tacrolimus (Tac) increased the risk of new-onset diabetes after transplantation (NODAT). The aim of this study was to analyze the association between KCNQ1 variants and the risk for NODAT in kidney-transplanted patients who received Tac as primary immunosuppressor. We genotyped three common KCNQ1 SNPs in 145 Spanish patients who received a cadaveric kidney graft and developed NODAT in the first-year post-transplant (the NODAT group), and 260 patients who remained non-diabetics (non-NODAT). In addition, we searched for DNA variants in the whole KCNQ1 coding exons in these patients. SNP rs2237895 (genotype CC) was associated with an increased risk for NODAT in our population (p = 0.008; OR = 1.83, 95% CI = 1.14-2.93), independently of other risk factors as body mass index, recipient age, or tacrolimus dosage. Other KCNQ1 variants were not associated with NODAT in our patients. Our work supported a role for KCNQ1 gene variants as determinants of the risk of developing NODAT among Tac-treated patients.

Effect of cinacalcet on hypercalcemia and bone mineral density in renal transplanted patients with secondary hyperparathyroidism.

BACKGROUND: Persistent secondary hyperparathyroidism (SHP) is the most frequent cause of hypercalcemia observed in approximately 10% of renal transplanted (RT) patients 1 year after surgery. Persistent SHP with hypercalcemia is an important factor of bone loss after renal transplantation. This study prospectively evaluates the effects of cinacalcet therapy on serum calcium (SCa) and parathyroid hormone (PTH) blood levels, and basically on bone mineral density (BMD) in RT patients with persistent hyperparathyroidism. METHODS: Nine RT patients (eight women, one man) with allograft function more than 6 months were included based on total SCa more than 10.5 mg/dL and intact parathyroid hormone (iPTH) concentration more than 65 pg/mL. After inclusion, patients started on a single daily oral dose of 30 mg of cinacalcet. At inclusion and every study visit blood levels of creatinine, Ca, P, alkaline phosphatase, iPTH 1,25- dihydroxyvitamin D3, and 25-hydroxyvitamin D3 were assessed. Baseline and at the end of study radial BMD were measured. Study follow-up was 12 months. RESULTS: During the study period, SCa decreased from 11.72+/-0.39 to 10.03+/-0.54 mg/dL (P<0.001). iPTH decreased from 308.85+/-120.12 to 214.66+/-53.75 mg/dL (P<0.05). The mean serum creatinine decreased from 1.58+/-0.34 to 1.25+/-0.27 mg/dL (P=0.03) and the mean radial BMD increased from 0.881+/-0.155 to 0.965+/-0.123 gr/cm2 (P<0.05). There were no significant changes in the other parameters assessed. One patient was excluded for gastrointestinal intolerance. CONCLUSIONS: In RT patients with hypercalcemia secondary to persistent SHP, cinacalcet corrects hypercalcemia and PTH, simultaneously improving BMD.

Effect of thymoglobulin induction on HIV-infected renal transplant recipients: differences between HIV-positive and HIV-negative patients.

The best immunosuppressive regimen in HIV-infected renal transplant recipients has not been established. Thymoglobulin has been associated with an increased risk of serious bacterial infections in HIV-negative patients and, for this reason, there is some concern over its use in the HIV-infected population. We describe three consecutive HIV-infected renal transplant recipients who received thymoglobulin as induction therapy, and we compared their progress with a cohort of 23 HIV-negative recipients. Median follow-up was 24 and 11 months, respectively. Nadir lymphocytopenia was observed at 1 week in both groups, and their absolute lymphocyte count recovery was similar. An early and deep (<30 cells/mm(3)) CD4(+) T cell lymphocytopenia was seen in two of the three HIV-infected patients. No opportunistic infections were diagnosed in HIV-positive patients. One HIV-positive patient had a bacterial infection and five HIV-negative patients had one or more bacterial infections. Thymoglobulin was safe in our three HIV-infected renal transplant recipients. Until those data are confirmed in larger studies, close monitoring is recommended during the thymoglobulin-induced CD4(+) T cell lymphocytopenia period.

Beta 2 microglobulin serum levels and prediction of survival in AL amyloidosis.

To study the relation between beta 2 microglobulin (beta 2M) and survival in AL amyloidosis, we measured the serum level of beta 2M in 80 patients with AL amyloidosis diagnosed within 1 year of evaluation, who had received no therapy. Patients had a median age of 61 years and 52% were male. Major clinical manifestations were renal disease in 25 patients (31%), cardiomyopathy in 23 patients (29%), and neuropathy or other organ involvement in 32 patients (41%). The beta 2M level, measured by an ELISA assay in serum samples collected at the time of evaluation, ranged from 1.69 to 10 mg/ml (mean = 4.57); in 56% of the patients beta 2M > 4 mg/ml. The patients with a beta 2M < or = 4 mg/ml had serum creatinine levels lower than those with beta 2M > 4 (1.43 vs 2.67 mg/dl; p = 0.02). Survival from study entry was analyzed overall by the level of beta 2M, adjusting for creatinine level and clinical stratum. We found the beta 2M level to be predictive of survival (median survival 16.1 months for beta 2M < or = 4 mg/ml vs 8.0 months for beta 2M > 4 mg/ml, p = 0.044). Thus a beta 2M level less than 4 mg/ml indicated a longer time of survival.

The in vitro effect of calcitriol on parathyroid cell proliferation and apoptosis.

Calcitriol treatment is used to reduce parathyroid hormone levels in azotemic patients with secondary hyperparathyroidism (HPT). Whether long-term calcitriol administration reduces parathyroid gland size in patients with severe secondary hyperparathyroidism is not clear. The aim of the study was to evaluate in vitro the effect of calcitriol on parathyroid cell proliferation and apoptosis in normal parathyroid glands and in adenomatous and hyperplastic human parathyroid glands. Freshly harvested parathyroid glands from normal dogs and hyperplastic and adenomatous glands from patients with secondary (2 degrees) and primary (1 degree) HPT undergoing parathyroidectomy were studied. Flow cytometry was used to quantify the cell cycle and apoptosis of parathyroid cells. Apoptosis was also evaluated by DNA electrophoresis and light and electron microscopy. In normal dog parathyroid glands, culture with calcitriol (10(-10) to 10(-7) M) for 24 h produced a dose-dependent inhibitory effect on the progression of cells into the cell cycle and into apoptosis. When glands from patients with 2 degrees HPT were cultured for 24 h, only high calcitriol concentrations (10(-7) M) inhibited the progression through the cell cycle and the induction of apoptosis. In parathyroid adenomas (1 degrees HPT), even a high concentration of calcitriol (10(-7) M) had no significant effect on the cell cycle or apoptosis. The present study shows that in vitro, calcitriol inhibits in a dose-dependent manner in normal parathyroid glands both parathyroid cell proliferation and apoptosis. However, in secondary hyperplasia, only high concentrations of calcitriol inhibited cell proliferation and apoptosis. In 1 degree HPT, even high concentrations of calcitriol had no effect. Because calcitriol simultaneously inhibits both cell proliferation and apoptosis, a reduction in the parathyroid gland mass may not occur as a direct effect of calcitriol treatment.