Sporadic cases of apolipoprotein A-IV medullary amyloidosis have been reported. Here we describe five families found to have autosomal dominant medullary amyloidosis due to two different pathogenic APOA4 variants. A large family with autosomal dominant chronic kidney disease (CKD) and bland urinary sediment underwent whole genome sequencing with identification of a chr11:116692578 G>C (hg19) variant encoding the missense mutation p.L66V of the ApoA4 protein. We identified two other distantly related families from our registry with the same variant and two other distantly related families with a chr11:116693454 C>T (hg19) variant encoding the missense mutation p.D33N. Both mutations are unique to affected families, evolutionarily conserved and predicted to expand the amyloidogenic hotspot in the ApoA4 structure. Clinically affected individuals suffered from CKD with a bland urinary sediment and a mean age for kidney failure of 64.5 years. Genotyping identified 48 genetically affected individuals; 44 individuals had an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73 m2, including all 25 individuals with kidney failure. Significantly, 11 of 14 genetically unaffected individuals had an eGFR over 60 ml/min/1.73 m2. Fifteen genetically affected individuals presented with higher plasma ApoA4 concentrations. Kidney pathologic specimens from four individuals revealed amyloid deposits limited to the medulla, with the mutated ApoA4 identified by mass-spectrometry as the predominant amyloid constituent in all three available biopsies. Thus, ApoA4 mutations can cause autosomal dominant medullary amyloidosis, with marked amyloid deposition limited to the kidney medulla and presenting with autosomal dominant CKD with a bland urinary sediment. Diagnosis relies on a careful family history, APOA4 sequencing and pathologic studies.
- MeSH
- amyloidóza * MeSH
- apolipoproteiny A * MeSH
- chronická renální insuficience * diagnóza genetika komplikace MeSH
- intersticiální nefritida * diagnóza genetika komplikace MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Amyloid A amyloidosis is a serious clinical condition resulting from the systemic deposition of amyloid A originating from serum amyloid A proteins with the kidneys being the most commonly and earliest affected organ. Previously described amyloid A amyloidosis is linked to increased production and deposition of serum amyloid A proteins secondary to inflammatory conditions arising from infectious, metabolic, or genetic causes. Here we describe a family with primary amyloid A amyloidosis due to a chr11:18287683 T>C (human genome version19) mutation in the SAA1 promoter linked to the amyloidogenic SAA1.1 haplotype. This condition leads to a doubling of the basal SAA1 promoter activity and sustained elevation of serum amyloid A levels that segregated in an autosomal dominant pattern in 12 genetically affected and in none of six genetically unaffected relatives, yielding a statistically significant logarithm of odds (LOD) score over 5. Affected individuals developed proteinuria, chronic kidney disease and systemic deposition of amyloid composed specifically of the SAA1.1 isoform. Tocilizumab (a monoclonal antibody against the interleukin-6 receptor) had a beneficial effect when prescribed early in the disease course. Idiopathic forms represent a significant and increasing proportion (15-20%) of all diagnosed cases of amyloid A amyloidosis. Thus, genetic screening of the SAA1 promoter should be pursued in individuals with amyloid A amyloidosis and no systemic inflammation, especially if there is a positive family history.
- MeSH
- amyloidóza * komplikace MeSH
- lidé MeSH
- mutace MeSH
- promotorové oblasti (genetika) MeSH
- sérový amyloid A genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
- MeSH
- alely MeSH
- jednonukleotidový polymorfismus MeSH
- lidé MeSH
- membranózní glomerulonefritida * diagnóza genetika MeSH
- receptory pro fosfolipasy A2 genetika MeSH
- retrospektivní studie MeSH
- transplantace ledvin * škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases is an update to the KDIGO 2012 guideline. The aim is to assist clinicians caring for individuals with glomerulonephritis (GN), both adults and children. The scope includes various glomerular diseases, including IgA nephropathy and IgA vasculitis, membranous nephropathy, nephrotic syndrome, minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), infection-related GN, antineutrophil cytoplasmic antibody (ANCA) vasculitis, lupus nephritis, and anti-glomerular basement membrane antibody GN. In addition, this guideline will be the first to address the subtype of complement-mediated diseases. Each chapter follows the same format providing guidance related to diagnosis, prognosis, treatment, and special situations. The goal of the guideline is to generate a useful resource for clinicians and patients by providing actionable recommendations based on evidence syntheses, with useful infographics incorporating views from experts in the field. Another aim is to propose research recommendations for areas where there are gaps in knowledge. The guideline targets a broad global audience of clinicians treating GN while being mindful of implications for policy and cost. Development of this guideline update followed an explicit process whereby treatment approaches and guideline recommendations are based on systematic reviews of relevant studies, and appraisal of the quality of the evidence and the strength of recommendations followed the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. Limitations of the evidence are discussed, with areas of future research also presented.
- MeSH
- dítě MeSH
- dospělí MeSH
- glomerulonefritida * diagnóza terapie MeSH
- IgA nefropatie * diagnóza terapie MeSH
- ledviny MeSH
- lidé MeSH
- lipoidní nefróza * MeSH
- membranózní glomerulonefritida * diagnóza farmakoterapie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- směrnice pro lékařskou praxi MeSH
BACKGROUND: Diverse adipose lesions can affect peripheral nerves, including an intrinsic disorder known as lipomatosis of nerve (LN). This condition leads to massive nerve enlargement and has often been associated with nerve territory overgrowth. Although LN has been well documented as a peripheral lesion, it is uncertain whether LN can occur or extend intradurally. METHODS: In the present 2-part study, we searched our institutional database and the world literature to identify any case of LN occurring or extending intradurally. Strict pathognomonic imaging and histopathologic features of LN were required to be present. RESULTS: We did not identify any case of LN that had occurred or extended intradurally in our institution. Specifically, in our database, we found no case of intradural LN, and an evaluation of the imaging studies of proximal examples of LN did not show any extension proximal to the spinal foramen. Our literature search identified 208 reports of potential interest, of which only 3 had reported on spinal LN. Although 2 of the 3 cases showed some similarities to LN, none had demonstrated features diagnostic for LN and none had demonstrated nerve territory overgrowth. A review of 16 cases of LN in proximal locations summarized in a recently reported systematic review did not reveal any cases with LN proximal to the foramen or in an intradural location. CONCLUSION: A review of our institutional cases and reported cases did not show any example of LN extending or occurring intradurally. It appears that LN is a benign tumor-like nerve lesion that is without a central location, unlike more well-known tumors such as schwannomas.
- MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipomatóza diagnostické zobrazování patologie MeSH
- magnetická rezonanční tomografie MeSH
- mladý dospělý MeSH
- periferní nervy diagnostické zobrazování patologie MeSH
- retrospektivní studie MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Perineural spread (PNS) is an unusual mechanism of tumor extension and has been typically reported in squamous cell carcinoma, adenocystic carcinoma, and desmoplastic melanoma. Our group has previously demonstrated PNS in rectal, prostate, bladder, and cervical cancer from the primary site along the autonomic nerves to the major somatic nerves and even intradurally. We believe similar principles apply to renal cell carcinoma (RCC) as well, despite the different anatomy. CASE DESCRIPTION: We performed a retrospective search to identify cases of intradural-extramedullary metastases of RCC caused by PNS. Strict anatomic and imaging inclusion criteria were defined: only lesions located between T6 and L3 were included, and PNS as a potential cause had to be supported by imaging evidence. Although 3 cases of spinal intradural metastases were identified, only one met our strict inclusion criteria. A 61-year-old woman developed a late intradural-extramedullary metastasis of RCC 16 years after the original diagnosis that we believe represents an example of visceral organ PNS. CONCLUSIONS: RCC can propagate via PNS from the primary tumor along the autonomic nerves to the aorticorenal, celiac, and mesenteric ganglia and then along the thoracic and lumbar splanchnic nerves to the corresponding spinal nerves and intradurally. We present radiologic evidence together with the review of the literature to support the premise that PNS of RCC not only occurs but goes unrecognized.
- MeSH
- databáze bibliografické statistika a číselné údaje MeSH
- karcinom z renálních buněk komplikace patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- míšní nervy diagnostické zobrazování MeSH
- nádory ledvin komplikace patologie MeSH
- nádory míchy diagnostické zobrazování sekundární MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- přehledy MeSH
Sedmapadesátiletá žena s progresivní amyotrofickou laterální sklerózou (ALS) byla opakovaně během čtyř let vyšetřena pro atypické bolesti na hrudi. Její vstupně normální koncentrace srdečního troponinu T (cTnT) byla progresivně více elevována během jednotlivých dalších hospitalizací, aniž by bylo přítomno zjevné srdeční onemocnění nebo bylo k dispozici jiné vysvětlení pro zvýšení cTnT. V případě této jedné pacientky se zdálo, že zvyšující se koncentrace cTnT korelují s progresí ALS.
A 57-year-old woman with progressive amyotrophic lateral sclerosis (ALS) presented repeatedly with atypical chest pain over a period of 4 years. Her initially normal cardiac troponin T (cTnT) value became progressively elevated during subsequent visits in the absence of clinically overt heart disease, and in the absence of alternative explanations for cTnT elevation. In this one patient there appeared to be a relationship between her rising levels of cTnT and increasing severity of ALS.
- MeSH
- amyotrofická laterální skleróza * diagnóza patofyziologie MeSH
- bolesti na hrudi * diagnóza etiologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- progrese nemoci MeSH
- senzitivita a specificita MeSH
- troponin C analýza MeSH
- troponin I analýza MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
