Nefropatía falciforme. Manifestaciones clínicas y nuevos mecanismos implicados en el daño renal / Sickle cell nephropathy. Clinical manifestations and new mechanisms involved in kidney injury

Las complicaciones renales se encuentran entre las más frecuentes de la enfermedad falciforme (EF), aparecen tempranamente desde la infancia, y constituyen uno de los principales factores relacionados con la mortalidad en estos pacientes. La vasooclusión y la hemólisis son los principales mecanismos patogénicos subyacentes. La médula renal reúne condiciones ideales para la falciformación de los hematíes debido a su baja presión parcial de oxígeno, elevada osmolaridad y pH ácido. Inicialmente, la falciformación en los vasa recta de la médula renal es la causa de hipostenuria, que es universal, y aparece en la infancia temprana. Existe también hematuria, microscópica y macroscópica, en parte relacionada con la necrosis papilar renal cuando los infartos son extensos. La liberación en la médula renal de prostaglandinas debido a la isquemia se relaciona con el aumento del filtrado glomerular (FG). De forma adaptativa, aumenta la reabsorción de sodio en el túbulo proximal, que se acompaña de un aumento de la secreción de creatinina. Por ello, el FG estimado a partir de la creatinina puede estar sobreestimado. La glomeruloesclerosis focal y segmentaria es la glomerulopatía más común. La albuminuria es muy frecuente, y se ha observado reducción en el 72,8% de los sujetos tratados con IECA o ARA-II. Recientes evidencias sugieren que la hemoglobina libre tiene efectos nocivos sobre los podocitos, pudiendo ser un mecanismo implicado en la alteración de la función renal que presentan estos enfermos. Estos efectos han de ser mejor estudiados en la EF, ya que podrían constituir una alternativa terapéutica en la nefropatía falciforme. (AU)

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. (AU)

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.

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.

Guía de práctica clínica sobre la detección y el manejo de la enfermedad renal crónica / Clinical practice guideline on the detection and management of chronic kidney disease

Objetivos: Esta GPC sobre Enfermedad Renal Crónica (ERC) responde a preguntas clínicas concernientes a su detección precoz, derivación a atención especializada y manejo, tanto mediante tratamiento farmacológico como con medidas higiénico dietéticas, estilos de vida e intervenciones educativas. Así como informar al paciente y cuidadores para facilitar la toma de decisiones compartidas. En esta GPC no se abordan los siguientes aspectos: Tratamiento de las causas específicas o modificables de ERC, tratamiento sustitutivo renal y tratamiento de las complicaciones de la ERC (anemia, acidosis metabólica, insuficiencia cardiaca, enfermedad renal ósea, insuficiencia renal aguda). ERC en población pediátrica.

Effects of rapamycin on angiomyolipomas in patients with tuberous sclerosis.

BACKGROUND: Tuberous sclerosis (TS) is a systemic disease, with an autosomal dominant pattern of inheritance caused by mutations in two genes (TSC1 and TSC2) that cause tumours (angiomyolipomas [AML], angiofibromas, astrocytomas). Constant and inadequate proliferation occurring in TS may be blocked by mTOR inhibitors (mammalian target of rapamycin), such as rapamycin. MATERIAL AND METHODS: At present, our study includes 17 patients with TS. All had at least one AML greater than 2cm in diameter diagnosed by MRI. They received rapamycin during 12 months. Plasma levels remained stable between 4-8ng/dl. The AML size was monitored every six months by abdominal MRI. RESULTS: At 12 months of inclusion, MRI indicated a decrease in the size of AML in all patients showing at least a 50% reduction in 82.4% (14/17, 95% CI [56.57%, 96.20%]). The mean percent reduction was 66.3% (95% CI [56.9%, 75.6%], P<.0001). The major side effects observed were: oral aphthous ulcers (5/17); hypertriglyceridemia (3/17); microcytosis and hypochromia (3/17); diarrhea (2/17); acne (1/17); acute pyelonephritis (1/17); and proteinuria (1/17). CONCLUSIONS: These preliminary clinical data suggest that rapamycin can play a beneficial role in the treatment of TS. Our experience in 17 patients treated for 12 months demonstrates safety and efficacy in reducing AML volume.