Role of de novo donor-specific anti-HLA antibodies in kidney graft failure: A case-control study.

The role of de novo donor-specific anti-human leukocyte antigen (anti-HLA) antibodies (dnDSA) within the pathways leading to graft failure remains not fully understood. We investigated 56 patients who were transplanted between 2002 and 2014 with kidney graft failure (cases), for a possible association of development of dnDSA with graft failure. The 56 patients with failed transplants were matched with 56 patients with a functioning graft at present for the variables deceased or living donor, transplant number, transplant year, recipient age and gender, donor age and gender, dialysis vintage time, transplant induction therapy. All patients had at least one serum collected 1 year before failure (in cases) or end of follow-up (in controls). Cases and controls were very well-matched in several baseline characteristics. Post-transplant anti-HLA antibodies were found in 84% of cases and only 36% of controls (P < .001), with 54% of cases and 16% of controls (P < .001) having dnDSA at time of detection. Chronic active antibody-mediated rejection was significantly more common (P < .001) in patients with dnDSA (61% vs 12%), in 53 (47%) patients that had at least one graft biopsy performed during follow-up. dnDSA was a significant risk factor (odds ratio [OR] = 6.06; P = .003) for graft failure in a multivariable conditional logistic regression model. dnDSA as a time-dependent variable, was also an independent predictor [hazard ratio (HR) = 2.46; P = .002] of graft failure in a multivariable Cox regression analysis. In both statistical approaches, only dnDSA-II (OR = 11.90; P = .006) (HR = 2.30; P = .014) was significantly associated with graft failure. Post-transplant dnDSA was clearly associated with graft loss, particularly if against HLA class II antigens. dnDSA detection should be a tool for post-transplant monitoring of kidney graft recipients, allowing for the identification of those with a higher risk of graft failure.

Characterization of end-stage renal disease after liver transplantation in transthyretin amyloidosis (ATTR V30M).

Transthyretin (TTR) amyloidosis, an autosomal-dominant disease, is characterized by peripheral and autonomic neuropathy--familial amyloidotic polyneuropathy (FAP). End-stage renal disease (ESRD) occurs at 10 years after the onset of neuropathy. Orthotopic liver transplantation (OLT) is the usual treatment of choice. We evaluated FAP patients, ATTR V30M, before and after OLT who started dialysis within 3 months after surgery. The 11 patients had an age at the onset of neuropathy of 31.9 ± 6.3 years with a mean evolution of disease to OLT of 4.54 ± 2.5 years. The glomerular filtration rate was <60 mL/min in 2 patients, 2 displayed nephrotic range proteinuria, and 3 had microalbuminuria. Elective pacemaker implantation was necessary in 8 subjects. Post-OLT 3 patients developed proteinuria, 2 of whom showed increasing nephrotic syndrome. Dysautonomia worsened leading to bladder catheterization in 6. In patients with previous normal renal function and proteinuria <3 g/d, the evolution of neuropathy to the first dialysis was 14.6 ± 4.2 years versus 7.5 ± 1.1 among the other subjects. Overall, dialysis was implemented at 7.4 ± 4.9 years after surgery. There was no liver graft dysfunction. The heart evaluation post-OLT showed the following: 3 patients with de novo dysrhythmias requiring pacemaker implantation and 3 with N-terminal pro-natriuretic peptide levels >10,000 pg/mL. Death occurred in 4 subjects at an average of 26 months after initiation of dialysis. Concerning ESRD, there was no clear benefit of transplantation in the early stages. Patients with normal renal function and lower levels of proteinuria showed slower progression to ESRD, irrespective of their duration of neuropathy.

Erythropoietin production by distal nephron in normal and familial amyloidotic adult human kidneys.

BACKGROUND/AIM: the kidney is the major site of erythropoietin production. Many efforts have been made to identify renal erythropoietin-producing cells. Previous studies showed conflicting results, but the predominant localization reported was the peritubular interstitial and tubular epithelial cells. This study was conducted to identify the erythropoietin-producing cells in renal biopsies from 10 cadaveric donors and 45 patients with familial amyloidosis ATTR V30M, thirteen of them with anemia. Familial amyloidosis Type I (FAP-I) is a genetic disorder caused by a transthyretin (TTR) protein variant presenting a single amino acid substitution of methionine for valine at position 30 of the polypeptide chain (TTR V30M). Anemia in FAP-I is associated with inappropriately low serum erythropoietin levels. METHODS: erythropoietin expression was detected by in situ hybridization (ISH) and confirmed by laser capture microdissection followed by PCR. Renal segments were identified by immunohistochemistry. RESULTS: erythropoietin was mainly expressed by epithelial distal tubular cells and collecting tubules and additionally, in a few biopsies, by glomerular cells. A similar expression pattern was observed in donors and FAP-I patients. No increased mRNA erythropoietin expression was found in anemic patients, all of them presenting only a slight expression in medulla and cortex. CONCLUSIONS: these results suggest the distal nephron as the major site of erythropoietin production, and support the notion that an inappropriate erythropoietin production is the cause of anemia in familial amyloidosis ATTR V30M.

[Contralateral occlusion of the internal carotid artery in the study of carotid stenosis using Doppler ultrasonography]. / Oclusión contralateral de la arteria carótida interna en el estudio por ecografía Doppler de las estenosis carotídeas.

INTRODUCTION AND AIMS: The degree of stenosis measured by Doppler ultrasonography in patients with contralateral occlusion of the internal carotid artery (ICA) is assumed to be overestimated. We propose to measure the extent to which this phenomenon affects the capacity of Doppler ultrasonography to classify stenoses. PATIENTS AND METHODS: A retrospective study of 47 patients was conducted using Doppler ultrasonography and digital subtraction angiography; all subjects had confirmed unilateral occlusion of the ICA and stenoses of the contralateral ICA. Curves were traced plotting the degree of stenosis against the peak systolic velocity (PSV) and its ratio in the ICA and in the common carotid artery (VICA/VCCA). The curves were compared with their equivalents with no contralateral occlusion found in the literature. Later, the cases of stenosis were classified into groups of less than 50, 50-69 and more than 70%, and the main statistical values were calculated. RESULTS: The PSV in the stenoses between 40-50% presents more than 1 standard deviation (SD) above the mean. There were no significant deviations in other degrees of stenosis (p > 0.4). The VICA/VCCA showed a similar parallelism, but with deviations lower than 1 SD (p = 0.56). Seventeen per cent of the stenoses were over-classified, and this conditioned a sensitivity of 84, 71 and 100%, and a specificity of 100, 94 and 88% for the groups of less than 50, 50-69 and over 70%, respectively. The VICA/VCCA over-classified 41% of the stenoses; sensitivity was seen to be 56, 43 and 100% and specificity was 90, 64 and 87%. Diagnostic accuracy of the PSV and VICA/VCCA stands at 83 and 57%, respectively. CONCLUSIONS: Contralateral occlusion leads to over-classification of the PSV. There is a tendency to over-classify, although this does not affect the overall diagnostic accuracy. The VICA/VCCA does not offer greater diagnostic accuracy in classifying stenoses with contralateral occlusion.

Oclusión contralateral de la arteria carótida interna en el estudio por ecografía Doppler de las estenosis carotídeas / Contralateral occlusion of the internal carotid artery in the study of carotid stenosis using doppler ultrasonography

Introducción y objetivo. Se presupone una sobreestimación del grado de estenosis medida por ecografía Doppler en pacientes con oclusión contralateral de la arteria carótida interna (ACI). Proponemos cuantificar el efecto de este fenómeno sobre la capacidad de la ecografía Doppler para clasificar las estenosis. Pacientes y métodos. Se estudiaron retrospectivamente 47 pacientes mediante ecografía Doppler y angiografía de sustracción digital, todos con oclusión unilateral de la ACI confirmada y estenosis de la ACI contralateral. Se crearon curvas que relacionan el grado de estenosis con la velocidad máxima sistólica (VMS) y su razón en la ACI y en la arteria carótida común (VACI/VACC). Las contrastamos con sus equivalentes sin oclusión contralateral anteriormente publicadas. Posteriormente, las estenosis se clasificaron en grupos de < 50, 50-69 y > 70%, y se calcularon los principales valores estadísticos. Resultados. La VMS en las estenosis entre el 40-50% presenta más de una desviación estándar sobre la media. No hay desviaciones significativas en otros grados de estenosis (p > 0,4). La VACI/VACC muestra un paralelismo semejante, pero inferior a una desviación estándar (p = 0,56). El 17% de las estenosis se sobreestimó, lo que condicionó una sensibilidad del 84, 71 y 100%, y una especificidad del 100, 94 y 88% para los grupos de < 50, 50-69 y > 70%, respectivamente. La VACI/VACC sobreestimó el 41% de las estenosis; así, mostró una sensibilidad del 56, 43 y 100% y una especificidad del 90, 64 y 87% en los respectivos grupos. La exactitud diagnóstica de la VMS y de la VACI/VACC se sitúa en el 83 y el 57%, respectivamente. Conclusiones. La oclusión contralateral provoca una sobrestimación de la VMS. Existe una tendencia a la sobreestimación, aunque sin repercusión en la exactitud diagnóstica global. La VACI/VACC no presenta mayor exactitud diagnóstica en la clasificación de las estenosis con oclusión contralateral (AU)

Introduction and aims. The degree of stenosis measured by Doppler ultrasonography in patients with contralateral occlusion of the internal carotid artery (ICA) is assumed to be overestimated. We propose to measure the extent to which this phenomenon affects the capacity of Doppler ultrasonography to classify stenoses. Patients and methods. A retrospective study of 47 patients was conducted using Doppler ultrasonography and digital subtraction angiography; all subjects had confirmed unilateral occlusion of the ICA and stenoses of the contralateral ICA. Curves were traced plotting the degree of stenosis against the peak systolic velocity (PSV) and its ratio in the ICA and in the common carotid artery (VICA/VCCA). The curves were compared with their equivalents with no contralateral occlusion found in the literature. Later, the cases of stenosis were classified into groups of less than 50, 50-69 and more than 70%, and the main statistical values were calculated. Results. The PSV in the stenoses between 40-50% presents more than 1 standard deviation (SD) above the mean. There were no significant deviations in other degrees of stenosis (p > 0.4). The VICA/VCCA showed a similar parallelism, but with deviations lower than 1 SD (p = 0.56). Seventeen per cent of the stenoses were over-classified, and this conditioned a sensitivity of 84, 71 and 100%, and a specificity of 100, 94 and 88% for the groups of less than 50, 50-69 and over 70%, respectively. The VICA/VCCA over-classified 41% of the stenoses; sensitivity was seen to be 56, 43 and 100% and specificity was 90, 64 and 87%. Diagnostic accuracy of the PSV and VICA/VCCA stands at 83 and 57%, respectively. Conclusions. Contralateral occlusion leads to over-classification of the PSV. There is a tendency to over-classify, although this does not affect the overall diagnostic accuracy. The VICA/VCCA does not offer greater diagnostic accuracy in classifying stenoses with contralateral occlusion (AU)

Chylous ascites in a renal transplant recipient under sirolimus (rapamycin) treatment.

Ascites is a rare complication of renal transplantation. Ascites has been reported after kidney transplantation due to rejection, decapsulation of the graft, urinary or vascular leak, lymphocele, transudation, or infection. While technical complications of the procedure are the most frequent cause, portal hypertension and graft rejection are other causes. Ascites can occur after renal transplantation independent of kidney function. Usually, a time relation can be made between the surgical procedure and ascites development. Chylous ascites is still more uncommon; it is usually related to traumatic lymphatic injury. Drugs are rarely associated with the genesis of ascites. Sirolimus has been associated with a high rate of lymphoceles, lymphedema, and pulmonary alveolar proteinosis. The exact mechanisms remain unknown. The risk for lymphocele formation with sirolimus is 12% to 15%. Ascites is an adverse effect with an incidence between 3% and 20%, but no relation between sirolimus and chylous ascites was previously established. We present a clinical report of chylous ascites in a renal transplant patient under sirolimus therapy; our investigation pointed to sirolimus as the cause.

Ineffectiveness of dialysis in transthyretin (TTR) clearance in familial amyloid polyneuropathy type I, in spite of lower stability of the TTR Met30 variant.

BACKGROUND: Familial Amyloid Polyneuropathy (FAP) is an hereditary form of systemic amyloidosis related to a mutant transthyretin (TTR). The renal disease ranges from proteinuria to end-stage renal failure (ESRF), with replacement of renal function by dialysis. In comparison with FAP patients with normal renal function, the progression of the neurologic disease seems to be retarded in FAP patients on dialysis. PATIENTS AND METHODS: We evaluated the influence of hemodialysis and hemodiafiltration on plasma TTR levels in 6 FAP patients with ESRF, which were on regular hemodialysis for 4 months to 6 years, prior to this study. Hemodialysis was performed over a two-week period, one week with a cellulose triacetate membrane and the other with a polysulfone membrane. In the third week, patients were submitted to hemodiafiltration. Plasma TTR levels were measured at the beginning, 60 min, 120 min, and at the end of each session. We also evaluated the TTR adsorbed by the membrane and in the dialysate. RESULTS: TTR levels did not change significantly with the dialysis. The total amount of TTR adsorbed to the membrane was always < 2 mg and found in the dialysate < 1 mg. Hemodialysis and hemodiafiltration were ineffective in removing TTR, in spite of lower stability of the TTR Met30 variant. CONCLUSION: The protective feature of hemodialysis on the progression of the amyloidosis is not due to the clearance of this abnormal protein from plasma.

Familial amyloid polyneuropathy type I (Portuguese): distribution and characterization of renal amyloid deposits.

Renal amyloidosis has been considered rare and late in the evolution of the transthyretin (TTR) familial amyloid polyneuropathy (FAP) of the Portuguese type (type I). Renal biopsy has been performed systematically in 14 patients with FAP type I before liver transplantation. In all patients, TTR Met30 mutation was shown. Seven had proteinuria or abnormal microalbuminuria, whereas seven others had no urinary abnormalities. All had renal amyloid deposition predominantly in the medulla. Glomerular and vascular involvement was more prominent in patients with urinary abnormalities. Patients with the most extensive renal lesions represented a subgroup with a low score of polyneuropathy disability, a high prevalence of nephropathy in the proband generation, or a late onset for relatives with nephropathy. Immunohistochemistry studies showed that the amyloid substance corresponded to transthyretin. We have shown that renal TTR-derived amyloid deposition is common in patients with FAP type I, even in the absence of urinary abnormalities. The clinical presentation of nephropathy is not a late occurrence in the disease.