HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients.

Recurrence of primary membranous nephropathy after transplantation occurs in up to 44% of patients and is driven by PLA2R antibody. Here, we asked whether genetic determinants could improve risk prediction. First, we sequenced PLA2R1 and HLA-D loci in 248 patients with primary membranous nephropathy and identified two independent single nucleotide polymorphisms (SNPs) at risk for primary membranous nephropathy at each locus. These were rs9271188 (intergenic between HLA-DRB1 and HLA-DQA1,) and rs9275086 (intergenic between HLA-DQB1 and HLA-DQA2) at the HLA-D locus along with rs6726925 and rs13018963 at the PLA2R1 locus. Then we investigated whether primary membranous nephropathy at-risk variants were associated with recurrence in a retrospective cohort of 105 donor-recipient pairs and a replication cohort of 40 pairs. Seven SNPs located between HLA-DRB1 and HLA-DQA1 in linkage disequilibrium with rs9271188, and three SNPs in the PLA2R1 region predicted recurrence when presented by the donor, but not when presented by the recipient. The two SNPs in the HLA-D region most strongly associated with recurrence (rs9271705 and rs9271550) were confirmed in the replication cohort. A genetic risk score based on the two best predictors at each locus (rs9271705, rs9271550, rs17830558, and rs3828323) identified a group of patients with high risk of recurrence. Thus, our results suggest that the graft contributes to recurrence of primary membranous nephropathy through the disease susceptibility HLA-D and PLA2R1 SNPs in an autoimmune milieu. Further studies are needed before implementation of genetic testing for these in donor selection.

Sickle cell nephropathy. Clinical manifestations and new mechanisms involved in kidney injury.

Kidney problems are among the most common complications in sickle cell disease (SCD). They occur early in childhood and are one of the main factors related to mortality in these patients. The main underlying pathogenic mechanisms are vaso-occlusion and haemolysis. The renal medulla has ideal conditions for the sickling of red cells due to its low partial pressure of oxygen, high osmolarity and acidic pH. Initially, sickle-cell formation in the vasa recta of the renal medulla causes hyposthenuria. This is universal and appears in early childhood. Microscopic and macroscopic haematuria also occur, in part related to renal papillary necrosis when the infarcts are extensive. Release of prostaglandins in the renal medulla due to ischaemia leads to an increase in the glomerular filtration rate (GFR). Adaptively, sodium reabsorption in the proximal tubule increases, accompanied by increased creatinine secretion. Therefore, the GFR estimated from creatinine may be overestimated. Focal segmental glomerulosclerosis is the most common glomerular disease. Albuminuria is very common and reduction has been found in 72.8% of subjects treated with ACE inhibitors or ARB. Recent evidence suggests that free haemoglobin has harmful effects on podocytes, and may be a mechanism involved in impaired kidney function in these patients. These effects need to be better studied in SCD, as they could provide a therapeutic alternative in sickle cell nephropathy.