Afección renal en el síndrome de MELAS: descripción de 2 casos / Kidney involvement in MELAS syndrome: Description of 2 cases

Introducción: El síndrome MELAS -miopatía, encefalopatía, acidosis láctica y episodios similares a ictus- es una citopatía mitocondrial relacionada con varias mutaciones del ADN mitocondrial, siendo la substitución A3243G en el gen tARNLeu la más frecuentemente asociada. Pacientes y métodos: Aparte de su sintomatología habitual, los pacientes presentan historia de sordera neurosensorial y diabetes tipo 2 (DM2). Además, estudios recientes muestran que algunos pacientes tienen también afección renal, normalmente en forma de glomeruloesclerosis focal y segmentaria (GFS). Resultados: En este artículo se discute la afección renal de 2 pacientes no emparentados portadores de la mutación A3243G. Los 2 presentan sordera neurosensorial y DM2. Se realizó estudio anatomopatológico en ambos. Uno de ellos desarrolló proteinuria en rango nefrótico e insuficiencia renal terminal, con cambios de GFS en la biopsia, mientras que el otro presentaba proteinuria leve e insuficiencia renal, sin cambios histológicos reseñables en la microscopia óptica. Conclusión: La presencia de GFS u otra afección glomerular o tubular renal, acompañada de sordera neurosensorial y DM2, podría ser indicativa de la existencia de la mutación A3243G y estos hallazgos deberían propiciar un estudio genético y una evaluación de posible afección extrarrenal (AU)

Introduction: MELAS syndrome -myopathy, encephalopathy, lactic acidosis and stroke-like episodes- is a maternally-inherited mitochondrial cytopathy related to several mitochondrial DNA mutations, with the A3243G mutation in tRNALeu gene being the most frequent of them. Patients and methods: Apart from its typical symptomatology, patients usually exhibit a maternally-inherited history of neurosensory deafness and insulin-dependent type 2 diabetes mellitus (T2DM). Recent studies have shown that few patients carrying a A3243G mutation also suffer from renal dysfunction, usually in form of focal segmental glomerulosclerosis (FSGS). Results: In this study we examine kidney involvement in 2 unrelated patients with a A3243G mutation by genetic testing. Both have a maternally-inherited neurosensory deafness and insulin-dependent T2DM. A renal biopsy was performed in both patients. One patient developed nephrotic proteinuria and renal insufficiency, with FSGS findings being observed in the kidney biopsy, whereas the other suffered from mild proteinuria and renal insufficiency, with non-specific glomerular changes. Conclusion: The presence of FSGS or other kidney involvement accompanied by hereditary neurosensory deafness and T2DM could be suggestive of a A3243G tRNALeu mutation and should prompt a genetic testing and an evaluation of potential extrarenal involvement (AU)

Kidney involvement in MELAS syndrome: Description of 2 cases. / Afección renal en el síndrome de MELAS: descripción de 2 casos.

INTRODUCTION: MELAS syndrome -myopathy, encephalopathy, lactic acidosis and stroke-like episodes- is a maternally-inherited mitochondrial cytopathy related to several mitochondrial DNA mutations, with the A3243G mutation in tRNALeu gene being the most frequent of them. PATIENTS AND METHODS: Apart from its typical symptomatology, patients usually exhibit a maternally-inherited history of neurosensory deafness and insulin-dependent type 2 diabetes mellitus (T2DM). Recent studies have shown that few patients carrying a A3243G mutation also suffer from renal dysfunction, usually in form of focal segmental glomerulosclerosis (FSGS). RESULTS: In this study we examine kidney involvement in 2 unrelated patients with a A3243G mutation by genetic testing. Both have a maternally-inherited neurosensory deafness and insulin-dependent T2DM. A renal biopsy was performed in both patients. One patient developed nephrotic proteinuria and renal insufficiency, with FSGS findings being observed in the kidney biopsy, whereas the other suffered from mild proteinuria and renal insufficiency, with non-specific glomerular changes. CONCLUSION: The presence of FSGS or other kidney involvement accompanied by hereditary neurosensory deafness and T2DM could be suggestive of a A3243G tRNALeu mutation and should prompt a genetic testing and an evaluation of potential extrarenal involvement.

Accuracy of unenhanced magnetic resonance angiography for the assessment of renal artery stenosis.

PURPOSE: To evaluate the accuracy of unenhanced magnetic resonance angiography (U-MRA) using balanced steady-state free precession (SSFP) sequences with inversion recovery (IR) pulses for the evaluation of renal artery stenosis. MATERIALS AND METHODS: U-MRA was performed in 24 patients with suspected main renal artery stenosis. Two radiologists evaluated the quality of the imaging studies and the ability of U-MRA to identify hemodynamically significant main renal artery stenosis (RAS) defined as a stenosis ≥50% when compared to gold standard tests: contrast-enhanced magnetic resonance angiography (CE-MRA) (18 patients) or digital subtraction arteriography (DSA) (6 patients). RESULTS: A total of 44 main renal arteries were evaluated. Of them, 32 renal arteries could be assessed with U-MRA. When CE-MRA or DSA was used as the reference standard, nine renal arteries had hemodynamically significant RAS. U-MRA correctly identified eight out of nine arteries as having ≥50% RAS, and correctly identified 22 out of 23 arteries as not having significant RAS, with a sensitivity of 88.8%, a specificity of 95.65%, positive and negative predictive value of 88.8% and 95.65%, respectively, and an accuracy of 93.75%. Renal artery fibromuscular dysplasia (FMD) was observed in the two misclassified arteries. CONCLUSION: U-MRA is a reliable diagnostic method to depict normal and stenotic main renal arteries. U-MRA can be used as an alternative to contrast-enhanced magnetic resonance angiography or computer tomography angiography in patients with renal insufficiency unless FMD is suspected.

Implication of chromosome 18 in hypertension by sibling pair and association analyses: putative involvement of the RKHD2 gene.

This study aims to test the implication of regions on chromosomes 9, 17, and 18 in essential hypertension (EH) by combining sibling-pair linkage analysis and case-control association studies. The selection of these chromosomal regions is based on previous evidence of their implication in EH or in related phenotypes by comparative genomics in several rat models and from genome-wide linkage studies in humans. For the affected sibling-pair linkage analysis, 27 microsatellite markers were genotyped in 56 pedigrees from Spain with hypertensive sibling pairs. Linkage analysis showed significant excess allele sharing at the D18S474 marker on 18q21.1, as shown by maximum likelihood of allele sharing methods (logarithm of odds=3.24; P=0.00011) and nonparametric linkage calculations (nonparametric linkage=3.32; P=0.00044). On the contrary, no significant results with any of the markers analyzed on chromosomes 9 and 17 were obtained. We further focused on the Ring finger and KH domain containing 2 (RKHD2) gene located 6 Kb distal from D18S474 and performed a case-control association study based on linkage disequilibrium in 112 hypertensive patients and 156 control subjects. We selected 2 RKHD2-tagged single nucleotide polymorphisms, rs1941958 and rs1893379, covering, in terms of linkage disequilibrium, the entire gene, and observed a significant overrepresentation of the rs1941958G-rs1893379T RKHD2 haplotype in the group of hypertensive patients in comparison with controls (2P=0.0004; odds ratio: 2.32). We also detected epistatic effects between the 2 RKHD2 single nucleotide polymorphisms (2P=0.002; odds ratio: 2.48). Our data confirm the implication of chromosome 18 in EH and support a contribution of RKHD2 to the genetic susceptibility of this complex phenotype.

Association of TGF-beta1 polymorphisms with chronic renal disease.

BACKGROUND: Transforming growth factor beta1 (TGF-beta1) plays an important role in tissue fibrosis and has been found to participate in cardiovascular disease (CVD). This study aimed to evaluate the association of TGF-beta1 polymorphisms with chronic renal disease (CRD), and its progression to dialysis in a retrospective longitudinal study of an end-stage renal disease (ESRD) cohort. METHODS: The Arg/Pro (codon 25) and Leu/Pro (codon 10) polymorphisms were genotyped in 104 ESRD patients aged 64 +/- 14 yrs (mean +/- SD), 62 males, and in 104 matched controls. RESULTS: The genotype distribution of Leu10Pro and Arg25Pro polymorphisms was different between patients and controls: Leu/Leu, Leu/Pro, Pro/Pro: 0.35, 0.50, 0.15 vs. 0.30, 0.24, 0.46 (p=0.001) and Arg/Arg, Arg/Pro, Pro/Pro: 0.79, 0.21, 0 vs. 0.87, 0.10, 0.03 (p=0.019). Similarly, haplotypes constructed with the combination of both polymorphisms were different among groups. There were no differences in CRD progression rate among genotypes. Codon 10 Leu allele was associated with the presence of clinical CVD in the ESRD patients (Leu/Leu, Leu/Pro, Pro/Pro: with CVD 0.49, 0.49, 0.02 vs. without CVD 0.27, 0.51, 0.22 (p=0.01). Combined polymorphism haplotypes were also significantly different between ESRD patients with and without CVD. This association was independent from other risk factors. CONCLUSIONS: TGF-beta1 polymorphisms are associated with ESRD, particularly in patients with associated clinical CVD, and could be useful as genetic markers of CRD and higher cardiovascular risk.

Acute renal failure secondary to imatinib mesylate treatment in chronic myeloid leukemia.

A 58-year-old woman with chronic myeloid leukemia (CML), and previous intolerance to interferon was treated with the BCR-ABL tyrosine kinase protein inhibitor imatinib mesylate. Coincidentally, with the start of treatment, the patient developed acute renal failure, with acute tubular necrosis being observed on histopathology. Imatinib was stopped and three hemodialysis sessions were performed, which was followed by a progressive improvement of the renal function and normalization of the urine output. One year later the patient still has mild chronic renal failure and remains in chronic phase of CML on hydroxyurea treatment.

Association between the A1166C polymorphism of the angiotensin II receptor type 1 and progression of chronic renal insufficiency.

BACKGROUND: In some studies genetic variation in the renin-angiotensin-aldosterone system (RAAS) has been associated with hypertension and rapid progression of renal insufficiency to end-stage renal disease (ESRD). Most of these studies do not take into account covariables influencing progression. We studied retrospectively the role of angiotensinogen (AGT) M235T, angiotensin converting enzyme (ACE) insertion/deletion (I/D), angiotensin II type 1 receptor (AT1R) A1166C, aldosterone syntase (CYP11B2) -344C/T and intron 2 W/C polymorphisms in conjunction with clinical and biochemical covariables on the rate of progression of renal insufficiency in a group of patients with ESRD of various etiologies. METHODS: Genotyping was performed by polymerase chain reaction (PCR) in 104 ESRD patients (62 males and 42 females), aged 64 +/- 14 years (mean +/- SD) with mean initial serum creatinine of 2.6 +/- 1.1 mg/dL and a mean time to reach ESRD of 52 +/- 38 months. RESULTS: The univariate analysis showed that there was a significant difference in the values of the slopes among the AT1R A1166C polymorphism genotypes: AA -4.87 +/- 0.22, AC -5.09 +/- 0.65 and CC -5.52 +/- 0.66 (p<0.05). None of the remainder polymorphisms showed significant association with progression. Stepwise multiple regression analysis including all the clinical, biochemical and genetic variables showed that only systolic blood pressure (SBP), serum PTHi and AT1R genotype were independently associated with the rate of progression, excluding the other variables from the model. CONCLUSIONS: These results indicate that susceptibility to faster progression to ESRD is associated with the AT1R A1166C polymorphism. This association remains significant after adjustment for relevant covariates, highlighting the importance of analyzing genetic risk factors in the context of clinical and biochemical variables.

Rapid decline in renal function reflects reversibility and predicts the outcome after angioplasty in renal artery stenosis.

Percutaneous transluminal renal angioplasty (PTRA) has a beneficial effect on renal function in some, but not all, patients with atheromatous renal artery stenosis. Our aim is to identify factors influencing clinical success after PTRA in this group of patients. Seventy-three patients undergoing PTRA were studied; 14 patients were excluded from final analysis because of restenosis. All patients had chronic renal failure secondary to vascular nephropathy and renal artery stenosis. The diagnosis of renal artery stenosis was based on carbon dioxide digital angiography showing greater than 60% luminal narrowing. The rate of renal failure progression was assessed by the slope of the regression line of serum creatinine versus time. At least three consecutive creatinine measurements before and after angioplasty were required for study entry. Response to PTRA was made by comparison of the slope before and after PTRA. The association of age, serum creatinine level, proteinuria, renal size, pre-PTRA slope value, diabetes, ischemic heart disease, peripheral vascular disease, and cerebrovascular disease with response to PTRA was assessed by multiple regression analysis, with changes in slope values as the dependent variable. Renal function improved in 34 of 59 patients (57.6%). Mean follow-up was 627 +/- 284 (SD) days. The slope of the reciprocal serum creatinine plot before PTRA was significantly associated with a favorable change in progression rate after PTRA (beta = -0.012; P = 0.004). A scatter plot showed a statistically significant inverse correlation between pre-PTRA slope values and post-PTRA slope changes (r = -0.46; P = 0.000). Rapidly progressive renal failure is associated with a favorable response on renal failure progression after PTRA in patients with vascular nephropathy and renal artery stenosis.