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Purpose Typically formulated by investigators from “world centres of excellence,” differentiated thyroid carcinoma (DTC) management guidelines may have more limited applicability in settings of less expert care and fewer resources. Arguably the world’s leading DTC guidelines are those of the American Thyroid Association, revised in 2009 (“ATA 2009”) and 2015 (“ATA 2015”). To further explore the issue of “real-world applicability” of DTC guidelines, we retrospectively compared indications for ablation using ATA 2015 versus ATA 2009 in a two-centre cohort of ablated T1–2, M0 DTC patients ( N  = 336). Based on TNM status and histology, these patients were low–intermediate risk, but many ultimately had other characteristics suggesting elevated or uncertain risk. Methods Working by consensus, two experienced nuclear medicine physicians considered patient and treatment characteristics to classify each case as having “no indication,” a “possible indication,” or a “clear indication” for ablation according to ATA 2009 or ATA 2015. The physicians also identified reasons for classification changes between ATA 2015 versus ATA 2009. Classification was unblinded, but the physicians had cared for only 138/336 patients, and the charts encompassed September 2010–October 2013, several years before the classification was performed. Results One hundred of 336 patients (29.8 %) changed classification regarding indication for ablation using ATA 2015 versus ATA 2009. Most reclassified patients (70/100) moved from “no indication” or “clear indication” to “possible indication.” Reflecting this phenomenon, “possible indication” became the largest category according to the ATA 2015 classification (141/336, 42.0 %, versus 96/336, 28.6 %, according to ATA 2009). Many reclassifications were attributable to multiple clinicopathological characteristics, most commonly, stimulated thyroglobulin or anti-thyroglobulin antibody levels, multifocality, bilateral involvement, or capsular/nodal invasion. Conclusions Regarding indications for ablation, ATA 2015 appears to better “acknowledge grey areas,” i.e., patients with ambiguous or unavailable data requiring individualised, nuanced decision-making, than does ATA 2009.

Purpose We determined the reasons for radioiodine thyroid remnant ablation, and the procedure’s necessity based on postsurgical remnant size, in patients with putatively “low–intermediate-risk” differentiated thyroid carcinoma (DTC). We identified key clinicopathological, treatment and remnant characteristics, and factors associated with remnant size in 336 patients with pT1/2, M0 DTC ablated during the period September 2010 to October 2013 at one Cypriot or one Greek referral centre. Methods Clinicopathological/treatment characteristics were compiled from charts. Experienced nuclear medicine physicians rated the numbers/intensities of uptake foci in the thyroid bed on postablation planar scintigrams using scales of 0–4 points and 0–3 points, respectively. The product of these scores was taken as the “remnant score” that ranged from 0 (no remnant) to 12 (multiple remnants, intense uptake). Results DTC was predominantly papillary. The median [25th–75th percentile] longest primary tumour diameter was 1.0 cm [0.7–1.5 cm]. Despite favourable histotypes and primary tumour classifications, patients often had preablation characteristics suggesting elevated or uncertain risk: 31.0 % of patients (104 of 336) had primary tumour multifocality, 22.0 % (74) had confirmed cervical lymph node metastases, 37.2 % (125) had unknown nodal status, and 38.1 % (128) had antithyroglobulin antibody seropositivity. The median [25th–75th percentile] remnant score was 4 [2–6]; 39.9 % of patients (134 of 336) had scores ≥6. For the entire cohort, T or N stages ( r  ≤ 0.174, P  ≤ 0.05) correlated positively with the remnant score in a univariate Spearman analysis. The numbers of patients referred by the surgeon, cervical lymph nodes excised and metastatic nodes excised correlated negatively ( r  ≤ 0.243, P  ≤ 0.038) with the remnant score, and the first two factors independently predicted the remnant score ( P  ≤ 0.037) in a multivariate analysis. Conclusion Patients with putatively “low–intermediate-risk” DTC frequently had disease characteristics denoting high or uncertain risk, suggesting that “selective” radioiodine ablation in such patients may seldom be applicable outside international centres of excellence. Proxies for surgeon experience and surgical completeness correlated with remnant number/uptake intensity and may aid ablation-related decision-making.

Familial glomerular hematuria(s) comprise a genetically heterogeneous group of conditions which include Alport Syndrome (AS) and thin basement membrane nephropathy (TBMN). Here we investigated 57 Greek-Cypriot families presenting glomerular microscopic hematuria (GMH), with or without proteinuria or chronic kidney function decline, but excluded classical AS. We specifically searched the COL4A3/A4 genes and identified 8 heterozygous mutations in 16 families (28,1%). Eight non-related families featured the founder mutation COL4A3-p.(G1334E). Renal biopsies from 8 patients showed TBMN and focal segmental glomerulosclerosis (FSGS). Ten patients (11.5%) reached end-stage kidney disease (ESKD) at ages ranging from 37-69-yo (mean 50,1-yo). Next generation sequencing of the patients who progressed to ESKD failed to reveal a second mutation in any of the COL4A3/A4/A5 genes, supporting that true heterozygosity for COL4A3/A4 mutations predisposes to CRF/ESKD. Although this could be viewed as a milder and late-onset form of autosomal dominant AS, we had no evidence of ultrastructural features or extrarenal manifestations that would justify this diagnosis. Functional studies in cultured podocytes transfected with wild type or mutant COL4A3 chains showed retention of mutant collagens and differential activation of the unfolded protein response (UPR) cascade. This signifies the potential role of the UPR cascade in modulating the final phenotype in patients with collagen IV nephropathies.

Background About 40–50% of patients with familial microscopic hematuria (FMH) caused by thin basement membrane nephropathy (TBMN) inherit heterozygous mutations in collagen IV genes ( COL4A3 , COL4A4 ). On long follow-up, the full phenotypic spectrum of these patients varies a lot, ranging from isolated MH or MH plus low-grade proteinuria to chronic renal failure of variable degree, including end-stage renal disease (ESRD). Methods Here, we performed Whole Exome Sequencing (WES) in patients of six families, presenting with autosomal dominant FMH, with or without progression to proteinuria and loss of renal function, all previously found negative for severe collagen IV mutations. Hierarchical filtering of the WES data was performed, followed by mutation prediction analysis, Sanger sequencing and genetic segregation analysis. Results In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5 -p.Pro1243Leu and COL4A5- p.Asp654Tyr. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. The phenotypic spectrum of the patients includes hematuria, proteinuria, focal segmental glomerulosclerosis, loss of kidney function and renal cortical cysts. Conclusions A modifier role of LAMA5 on the background of a hypomorphic Alport syndrome causing mutation is a possible explanation of our findings. Digenic inheritance is another scenario, following the concept that mutations at both loci more accurately explain the spectrum of symptoms, but further investigation is needed under this concept. This is the third report linking a LAMA5 variant with human renal disease and expanding the spectrum of genes involved in glomerular pathologies accompanied by familial hematurias. The cystic phenotype overlaps with that of a mouse model, which carried a Lama5 hypomorphic mutation that caused severely reduced Lama5 protein levels and produced kidney cysts.