Progressive nephropathy associated with mitochondrial tRNA gene mutation

Mitochondrial DNA plays a crucial role in oxidative production of energy. Thus, defects in mitochondrial DNA can affect virtually all organ systems. The point mutation A --> G at position 3243 in the mitochondrial tRNAleu(UUR) gene is the cause of several distinct types of mitochondrial cytopathy and several clinical phenotypes, including encephalomyopathy with lactic acidosis and stroke-like episodes and maternally inherited diabetes and deafness. This mutation has been recently described also in association with kidney disease, mainly focal and segmental glomerulosclerosis. At present, little is known about the prevalence of this mitochondrial nephropathy, its clinical course and the pathogenesis of glomerular damage. We describe 2 unrelated patients, who presented with proteinuria and progressed to end-stage renal failure. Other clinical features were short stature, severe headache, hearing loss, diabetes mellitus and hypertrophic cardiomyopathy. The main histological finding was an increased number of abnormal mitochondria in tubular cells and podocytes. Analysis of mitochondrial DNA from leukocytes and urine sediment revealed heteroplasmy for the A3243G mutation in tRNAleu(UUR) gene in both patients. Recognition of the characteristic clinical and histological features of the mitochondrial A3243G mutation-associated glomerulopathy will enable correct diagnosis and better management of a disease which is likely to be underdiagnosed.     

Prevalence of Japanese dialysis patients with an A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene.

BACKGROUND: A high prevalence of an A-to-G mutation at nucleotide 3243 of the mitochondrial genome in patients with diabetes mellitus (DM) and/or deafness has been reported previously. We investigated the prevalence of this mutation in Japanese dialysis patients with associated DM and/or deafness. METHODS: We studied 106 dialysis patients with DM, 26 with DM and deafness, and 26 with deafness alone, using peripheral leucocytes to detect an A-to-G transition at nucleotide 3243 of the mitochondrial gene. RESULTS: We identified this transition in 1 of 26 patients with DM and deafness. None of the 106 DM or 26 dialysis patients with deafness but no DM was positive for this mutation. A 42-year-old male patient on continuous ambulatory peritoneal dialysis (CAPD) who carried this mutation had a 20-year history of sensory hearing loss as well as hypertrophic cardiomyopathy. CONCLUSION: We found that a mitochondrial gene mutation at nucleotide 3243 was present in one dialysis patient with NIDDM and deafness. The prevalence of this mutation was found to be below 1% in diabetic end-stage renal disease patients in Japan.     

系统性硬化症的肾脏损害

目的了解系统性硬化症肾脏损害的临床特点及病理特点。方法对我院９３例确诊的系统性硬化症（ＳＳｃ）患者进行回顾性临床分析，并对５例患者进行了肾组织病理学检查。结果有１９４％（１８例）患者有临床肾脏损害，肾功能衰竭发生率为５４％，本组病死率为１２９％，其中死于肾衰者占４１７％。４例患者和１例尸检的肾组织学显示ＳＳｃ的肾脏血管改变为多样性；４例显示有不同程度的小叶间动脉和弓动脉、入球动脉的受累，表现为血管内膜增厚，纤维组织呈“洋葱皮”样同心圆状排列，其中２例并无肾脏损害临床表现。另１例病程长达２２年的患者的肾脏病理表现主要为慢性肾小球肾炎。结论ＳＳｃ患者肾脏损害是一严重并发症，是其主要死亡原因。肾脏病理改变主要为肾脏血管病变，可发生在出现肾脏损害临床表现之前。对ＳＳｃ患者应密切加强随访。     

Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation

BACKGROUND: Several families have been described in which an A to G transition mutation at position 3243 (A3243G) of the mitochondrial DNA (mtDNA) is associated with focal and segmental glomerulosclerosis (FSGS). However, the prevalence, clinical features, and pathophysiology of FSGS carrying mtDNA mutations are largely undefined. METHODS: Among 11 biopsy-proven primary FSGS patients of unknown etiology, we examined seven FSGS patients to determine whether any of the clinical and pathological features of FSGS were associated with an A3243G mtDNA mutation. In four subjects in whom the A3243G mtDNA mutation was discovered in blood leukocytes, as well as in urine sediments, we retrospectively reviewed the medical records and re-evaluated the renal biopsy specimen using light and electron microscopy. We further screened the patient's family members for the presence and degree of heteroplasmy for this mtDNA mutation and obtained medical histories that were consistent with mitochondrial cytopathy. RESULTS: The four individuals identified with the A3243G mtDNA mutation were female. Proteinuria was diagnosed in these individuals during a routine annual health checkup in their teenage years. None of the patients showed any symptoms related to mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode, whereas diabetes mellitus in two of the patients and a hearing disturbance in one patient became manifest within a 3- to 13-year follow-up period. Strict maternal transmitted inheritance was confirmed by pedigree studies in all of these patients. Steroid therapy was ineffective in all four patients. In two of these patients, renal function declined slowly to end-stage renal failure. Histologic examination of biopsy specimens revealed that glomeruli were not hypertrophied, while electron microscopic examination identified severely damaged, multinucleated podocytes containing extremely dysmorphic abnormal mitochondria in all patients. CONCLUSIONS: FSGS may belong to the spectrum of renal involvement in A3243G mtDNA mutation in humans. Severely injured podocytic changes containing abnormal mitochondria may explain the pathogenesis of FSGS in association with the A3243G mtDNA mutation.     

Clinical and pathological analysis of patients presenting renal lesion and monoclonal gammopathy

Objectives To analyze the spectrum of renal diseases associated with monoclonal gammopathy and unrelated renal diseases. Methods Hospitalized patients in Peking Union Medical College Hospital who underwent renal biopsy between January, 2013 and December, 2015. They had monoclonal gammopathy on serum protein electrophoresis (SPE), serum immunofixation electrophoresis (IFE), urine IFE and/or serum free light chain (FLC). 64 patients met the inclusion criteria and were classified as monoclonal gammopathy of renal significance (MGRS) (n=36), monoclonal gammopathy of undetermined significance (MGUS) (n=17) and hematologic malignancy (n=11). Results Renal lesions in MGRS subgroup included light chain amyloidosis (n=28, 77.8%), light chain deposition disease (n=7, 19.4%), and fibrillary glomerulopathy (n=1, 2.8%). eGFR in light chain amyloidosis subgroup differed significantly, compared with light chain deposition disease [eGFR 93 ml?min-1?(1.73 m2)-1 vs 28 ml?min-1?(1.73 m2)-1, P＜0.01], as well as HTN incidence (35.7% vs 100.0%, P＜0.01). Renal diseases in MGUS subgroup included membranous nephropathy (n=10, 58.8%), focal segmental glomerulosclerosis (n=3, 17.6%), diabetic glomerulopathy (n=1, 5.9%), Henoch-Schonlein purpura nephritis (n=1, 5.9%), anti-glomerular basement membrane disease concurrent with membranous nephropathy (n=1, 5.9%) and glomerulomegaly (n=1, 5.9%). Various renal lesions related/unrelated to hematologic malignancy were seen in third subgroup, including light chain cast nephropathy (n=3, 27.3%), tubulo-interstitial lesions (n=2, 18.2%), light chain amyloidosis (n=1, 9.1%), light chain deposition disease(n=1, 9.1%), IgA nephropathy (n=1, 9.1%), mesangial proliferative glomerulonephritis (n=1, 9.1%), endocapillary proliferative glomerulonephritis (n=1, 9.1%) and acute tubular necrosis (n=1, 9.1%). Positive rates of SPE, serum IFE and urine IFE in MGRS subgroup were 40.6%, 52.8% and 69.4%, respectively. Positive rates of SPE, serum IFE and urine IFE in MGUS subgroup were 68.8%, 100.0% and 37.5%, respectively. Positive rates of SPE, serum IFE and urine IFE in hematologic malignancy subgroup were 54.5%, 72.7% and 81.8% respectively. MGRS and MGUS subgroups differed significantly in positive rate of serum IFE (P＜0.001). Abnormal rates of serum FLC ratio in above three subgroups were 83.3%, 17.6% and 90.9%, respectively, with that in MGUS group being significantly lower than the rates in other two groups (P＜0.001, respectively). Conclusions The significance of monoclonal gammopathy in patients with renal disease should be evaluated by other clinical data, as well as renal pathology.     

Evidence that the mitochondrial leucyl tRNA synthetase (LARS2) gene represents a novel type 2 diabetes susceptibility gene

Previously, we have shown that a mutation in the mitochondrial DNA-encoded tRNA(Leu(UUR)) gene is associated with type 2 diabetes. One of the consequences of this mutation is a reduced aminoacylation of tRNA(Leu(UUR)). In this study, we have examined whether variants in the leucyl tRNA synthetase gene (LARS2), involved in aminoacylation of tRNA(Leu(UUR)), associate with type 2 diabetes. Direct sequencing of LARS2 cDNA from 25 type 2 diabetic subjects revealed eight single nucleotide polymorphisms. Two of the variants were examined in 7,836 subjects from four independent populations in the Netherlands and Denmark. A -109 g/a variant was not associated with type 2 diabetes. Allele frequencies for the other variant, H324Q, were 3.5% in type 2 diabetic and 2.7% in control subjects, respectively. The common odds ratio across all four studies was 1.40 (95% CI 1.12-1.76), P = 0.004. There were no significant differences in clinical variables between carriers and noncarriers. In this study, we provide evidence that the LARS2 gene may represent a novel type 2 diabetes susceptibility gene. The mechanism by which the H324Q variant enhances type 2 diabetes risk needs to be further established. This is the first report of association between an aminoacyl tRNA synthetase gene and disease. Our results further highlight the important role of mitochondria in glucose homeostasis.     

Incomplete distal renal tubular acidosis coinherited with a mutation in the band 3 (AE1) gene

Background. Band 3 (anion exchanger 1, AE1) is one of the most abundant proteins of the erythrocyte membrane. We have previously characterized twenty AE1 gene defects underlying spherocytic haemolytic anaemia with band 3 deficiency. Since AE1 is also expressed in the intercalated cells of renal cortical collecting ducts where it is thought to participate in urine acidification, we asked whether the spherocytogenic AE1 mutations also affect the regulation of urine acidity. Methods. We examined 10 patients from seven unrelated families with hereditary spherocytosis with band 3 deficiency using the short urine acidification test with CaCl2 administration at a dose of 0.2 g/g b.w. To assess the ability of the nephron to secrete protons, 400 mol of NaHCO3 were infused over a period of 2 h. Results. While we detected no significant abnormalities in eight patients, we have diagnosed incomplete distal renal tubular acidosis (dRTA) in two patients from one family whose urinary pH 5 h after a CaCl2 administration were 6.65 and 6.89. Administration of bicarbonate in these two patients resulted in high urinary HCO3^- concentration. The patients carry the previously characterized mutation band 3^PRIBRAM that encodes a C-terminally truncated band 3 containing only the cytoplasmic domain and the first three putative transmembrane segments. Conclusions. This finding shows an association of a band 3 defect with abnormal urinary acidification perhaps secondary to Cl^-/HCO3 exchange in the basolateral membrane of &agr;-intercalated cells of cortical collecting ducts.     

The position of the polycystic kidney disease 1 (PKD1) gene mutation correlates with the severity of renal disease

The severity of renal cystic disease in the major form of autosomal dominant polycystic kidney disease (PKD1) is highly variable. Clinical data was analyzed from 324 mutation-characterized PKD1 patients (80 families) to document factors associated with the renal outcome. The mean age to end-stage renal disease (ESRD) was 54 yr, with no significant difference between men and women and no association with the angiotensin-converting enzyme polymorphism. Considerable intrafamilial variability was observed, reflecting the influences of genetic modifiers and environmental factors. However, significant differences in outcome were also found among families, with rare examples of unusually late-onset PKD1. Possible phenotype/genotype correlations were evaluated by estimating the effects of covariants on the time to ESRD using proportional hazards models. In the total population, the location of the mutation (in relation to the median position; nucleotide 7812), but not the type, was associated with the age at onset of ESRD. Patients with mutations in the 5' region had significantly more severe disease than the 3' group; median time to ESRD was 53 and 56 yr, respectively (P = 0.025), with less than half the chance of adequate renal function at 60 yr (18.9% and 39.7%, respectively). This study has shown that the position of the PKD1 mutation is significantly associated with earlier ESRD and questions whether PKD1 mutations simply inactivate all products of the gene.     

幼年系统性红斑狼疮神经精神症候群的临床研究

目的:探讨幼年系统性红斑狼疮(JSLE)神经系统表现的临床特征.方法:选择本院风湿科1999年1月至2007年1月JSLE患者47例的临床资料作回顾性分析,分析其神经系统表现的临床特征.结果:神经精神症侯群29例(61.7%):癫痫发作17例(36.2%),狼疮性头痛7例(14.9%),情绪失调5例(10.6%),脑血管病4例(8.5%),急性精神错乱3例(6.4%),无菌性脑膜支3例(6.4%),精神障碍3饲(6.4%),运动障碍3饲(6.4%),格林-巴利综合征2例(4.3%),颅神经病变1例(2.1%).系统性红斑狼疮疾病活动指教(SLEDAL)和系统性红斑狼疮损伤指教(SLICC)与无神经表现的JSLE患者相比,有显著性差异.结论:幼年系统性红斑狼疮病人的神经精神症候群普遍高发.     

The spectrum of renal involvement in epidermolysis bullosa dystrophica hereditaria: report of two cases

Epidermolysis bullosa dystrophica Hallopeau-Siemens (EBDH) is one of the most severe inherited epidermolyses, a group of mechanobullous dermatological disorders. We observed two patients presenting with a severely multilating type of EBDH who developed biopsy-proven renal disease, which substantially altered the evolution and pathogenesis of their disease. In a boy, chronic postinfectious glomerulonephritis developed, most probably due to recurring superinfections of bullous skin lesions. He also experienced acute oliguric renal failure due to severe diarrhea during exacerbation of EBDH. A female patient developed a nephrotic syndrome due to secondary amyloidosis. Hypoalbuminemia caused further fluid losses through bullous skin lesions, aggravating intravascular hypovolemia and leading to rapid renal failure secondary to bilateral renal vein thrombosis. The study shows that, although rare, renal complications may alter the natural course of EBDH.     

Complement factor H mutation in familial thrombotic thrombocytopenic purpura with ADAMTS13 deficiency and renal involvement

Thrombotic thrombocytopenic purpura is a rare disorder of small vessels that is associated with deficiency of the von Willebrand factor-cleaving protease ADAMTS13, which favors platelet adhesion and aggregation in the microcirculation. The disease manifests mainly with central nervous system symptoms, but cases of renal insufficiency have been reported. Presented are findings of the genetic basis of phenotype heterogeneity in thrombotic thrombocytopenic purpura in two sisters within one family. The patients had ADAMTS13 deficiency as a result of two heterozygous mutations (causing V88M and G1239V changes). In addition, a heterozygous mutation (causing an S890I change) in factor H of complement was found in the patient who developed chronic renal failure but not in her sister, who presented with exclusive neurologic symptoms.     

The spectrum of renal abnormalities in patients with psoriasis

Objective  

Kidney involvement secondary to psoriasis is a controversial issue. In this study, we evaluated the prevalence of urinary abnormalities in patients with psoriasis.     

肾细胞癌伴静脉癌栓15例临床分析

１９８５～１９９４年治疗肾细胞癌伴静脉癌栓１５例。按癌栓水平分为肾型１０例，肝下型４例，肝上型１例。Ｂ超和ＣＴ检查总确诊率７３％。手术１４例均完整取出癌栓，术后１３例接受５－ＦＵ加ＭＭＣ方案化疗。随访３个月～５年，１例肝下型和２例肾型无瘤存活分别３６、４３、５２个月，余均在术后２年内死亡。认为Ｂ超与ＣＴ互补应用可基本确诊静脉癌栓，除肝上型和已有血管壁浸润者外大部分癌栓可采用松解游离同时渐渐拉出的方式取出，癌栓水平除肝上型外对预后影响不大。     

The effect of diuretics on systemic and renal hemodynamics in patients with renal insufficiency

Diuretics have been used in acute renal failure in an attempt to increase urine flow and ameliorate the reduction in glomerular filtrate rate. A beneficial response occurs in some experimental models of acute renal failure when diuretics are administered prophylactically or very early in the course of renal failure and may require a renal vascular bed capable of responding partially, at least, to vasodilating stimuli. In chronic renal insufficiency the most important indications for diuretic use are for the treatment of systemic hypertension and for the correction of the congested state. However, the precise effect of diuretic therapy under these conditions is unpredictable and dependent on the functional state of the renal vessels. Diuretic administration may at times prove detrimental, resulting in a deterioration of glomerular filtration rate. In hemodynamically unstable conditions the slow removal of extracellular fluid by continuous arteriovenous hemofiltration may prove preferable to diuretic administration or standard forms of dialysis.     

Glomerular involvement in adults with sickle cell hemoglobinopathies: Prevalence and clinical correlates of progressive renal failure

Patients with sickle cell anemia (SCA) may develop a glomerulopathy with proteinuria and progressive renal insufficiency, leading to ESRD. Albuminuria is a sensitive marker of glomerular damage in this population and precedes the development of renal insufficiency. For determination of the prevalence of glomerular damage in SCA and the clinical correlates of renal insufficiency, 300 adult patients with SCA were studied (hemoglobin SS = 184; and 116 with other sickling hemoglobinopathies: SC, SD, and S-beta thalassemia); albumin excretion rates (AER) and renal function (Cockroft-Gault formula) were determined, and clinical and hematologic evaluations were conducted. In hemoglobin SS disease, increased AER (micro- and macroalbuminuria) occurred in 68% of adult patients, and macroalbuminuria occurred in 26%. In other sickling disorders, increased AER occurs in 32% of adults, and macroalbuminuria occurs in 10%. The development of graded albuminuria was age dependent, so at 40 yr, 40% of patients with SS disease had macroalbuminuria. There were no differences in hematologic parameters (hemoglobin levels, white blood cell count, percentage of reticulocytes, platelet counts, or lactate dehydrogenase levels) between patients with normoalbuminuria and those with micro- or macroalbuminuria. By multivariate analysis, albuminuria correlated with age and serum creatinine in SS disease but not with BP or hemoglobin levels. In other sickling disorders, albuminuria tended to be associated with age but not with hemoglobin or BP levels. The diastolic BP was lower in patients with SCA than in African American control subjects, and the development of renal insufficiency, which was present in 21% of adults with SS disease, was not accompanied by significant hypertension. It is concluded that glomerular damage in adults with SCA is very common, and a majority of patients with SS disease are at risk for the development of progressive renal failure. The development of micro- and macroalbuminuria is not related to the degree of anemia, suggesting that sickle cell glomerulopathy is not solely related to hemodynamic adaptations to chronic anemia. In contrast to other glomerulopathies, the development of systemic hypertension is uncommon in SS disease with renal insufficiency.