Multiparametric Monitoring of Disease Progression in Contemporary Patients with Wild-Type Transthyretin Amyloid Cardiomyopathy Initiating Tafamidis Treatment.

BACKGROUND: Recently, a disease modifying therapy has become available for transthyretin amyloid cardiomyopathy (ATTR-CM). A validated monitoring concept of treatment is lacking, but a current expert consensus recommends three clinical domains (clinical, biomarker and ECG/imaging) assessed by several measurable features to define disease progression. METHODS: We retrospectively analyzed data of wild-type ATTR-CM patients initiating tafamidis therapy assessed within our local routine protocol at baseline and 6-months follow-up with respect to the frequency of values beyond the proposed thresholds defining disease progression. Additionally, associations of cardiac magnetic resonance (CMR) tomography with clinical domains were examined within a subgroup. RESULTS: Sixty-two ATTR-CM patients were included (88.7% male, mean age 79 years). In total, 16.1% of patients had progress in the clinical and functional domain, 33.9% in the biomarker domain and 43.5% in the imaging/electrocardiography (ECG) domain, with the latter driven by deterioration of the diastolic dysfunction grade and global longitudinal strain. In total, 35.5% of patients showed progress in none, 35.5% in one, 29.0% in two and no patient in three domains, the latter indicating overall disease progression. A subgroup analysis of twenty-two patients with available baseline and follow-up CMR data revealed an increase in CMR-based extracellular volume by more than 5% in 18.2% of patients, with no significant correlation with progress in one of the clinical domains. CONCLUSIONS: We provide first frequency estimates of the markers of disease progression according to a recent expert consensus statement, which might help refine the multiparametric monitoring concept in patients with ATTR-CM.

A case report of recurrent membranoproliferative glomerulonephritis after kidney transplantation due to ventriculoatrial shunt infection.

BACKGROUND: Transplant failure requires the consideration of numerous potential causes including rejection, acute tubular necrosis, infection, and recurrence of the original kidney disease. Kidney biopsy is generally required to approach these differential diagnoses. However, the histopathological findings on their own do not always lead to a definite diagnosis. Consequently, it is crucial to integrate them with clinical findings and patient history when discussing histopathological patterns of injury. The histopathologic finding of a membranoproliferative glomerulonephritis (MPGN) is one of the most challenging constellations since it does not refer to a specific disease entity but rather reflects a pattern of injury that is the result of many different causes. Whilst MPGN is occasionally classified as immune complex mediated, careful evaluation usually reveals an underlying disorder such as chronic infection, plasma cell dyscrasia, complement disorders, and autoimmune disease. CASE PRESENTATION: We describe the case of a 43-year-old woman who was referred to us because of a slowly rising serum creatinine 4 years after kidney transplantation. As in the native kidney, the biopsy revealed an MPGN pattern of injury. The cause of this finding had not been established prior to transplantation leading to a classification as idiopathic MPGN in the past. Further workup at the time of presentation and allograft failure revealed chronic infection of a ventriculoatrial shunt as the most probable cause. CONCLUSION: This case underlines the fact that MPGN is not a disease but a histopathological description. Consequently, the causative disorder needs to be identified to avoid kidney failure and recurrence after transplantation.

Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression.

Mutations affecting the integrity and function of cilia have been identified in various genes over the last decade accounting for a group of diseases called ciliopathies. Ciliopathies display a broad spectrum of phenotypes ranging from mild manifestations to lethal combinations of multiple severe symptoms and most of them share cystic kidneys as a common feature. Our starting point was a consanguineous pedigree with three affected fetuses showing an early embryonic phenotype with enlarged cystic kidneys, liver and pancreas and developmental heart disease. By genome-wide linkage analysis, we mapped the disease locus to chromosome 17q11 and identified a homozygous nonsense mutation in NEK8/NPHP9 that encodes a kinase involved in ciliary dynamics and cell cycle progression. Missense mutations in NEK8/NPHP9 have been identified in juvenile cystic kidney jck mice and in patients suffering from nephronophthisis (NPH), an autosomal-recessive cystic kidney disease. This work confirmed a complete loss of NEK8 expression in the affected fetuses due to nonsense-mediated decay. In cultured fibroblasts derived from these fetuses, the expression of prominent polycystic kidney disease genes (PKD1 and PKD2) was decreased, whereas the oncogene c-MYC was upregulated, providing potential explanations for the observed renal phenotype. We furthermore linked NEK8 with NPHP3, another NPH protein known to cause a very similar phenotype in case of null mutations. Both proteins interact and activate the Hippo effector TAZ. Taken together, our study demonstrates that NEK8 is essential for organ development and that the complete loss of NEK8 perturbs multiple signalling pathways resulting in a severe early embryonic phenotype.

Conditional loss of kidney microRNAs results in congenital anomalies of the kidney and urinary tract (CAKUT).

MicroRNAs have emerged as essential regulators of gene expression and may play important roles in a variety of human disorders. To understand the role of microRNA-mediated gene regulation in the kidney, we deleted the microRNA-processing enzyme Dicer in developing renal tubules and parts of the ureteric bud in mice. Genetic deletion of Dicer resulted in renal failure and death of the animals at 4-6 weeks of age. Interestingly, the kidneys of microRNA-deficient animals were small due to a reduced number of nephrons and showed massive hydronephrosis due to ureteropelvic junction obstruction. This phenotype is reminiscent of congenital anomalies of the kidney and urinary tract (CAKUT), an important group of human disorders characterized by a combination of renal hypoplasia with congenital abnormalities of the urinary tract. We used metanephric kidney cultures to examine the developmental defects underlying these pathologies. Dicer knockout kidneys showed a significant reduction of tubular branching explaining renal hypoplasia. Moreover, the ureters of these kidneys showed an altered morphology and impaired motility. These functional changes went along with altered expression of smooth muscle actin implying a defect in the differentiation of ureteric smooth muscle cells. In addition, we show the polycystic kidney disease gene Pkd1 to be a target of miR-20 implying that this interaction may contribute to the molecular basis for the cystogenesis in our model. In conclusion, these data demonstrate an essential role for microRNA-dependent gene regulation in mammalian kidney development and suggest that deregulation of microRNAs may underlie CAKUT, the most important group of renal disorders in humans.

Survival and distribution of injected haematopoietic stem cells in acute kidney injury.

BACKGROUND: Endogenous bone marrow-derived cells are known to incorporate into renal epithelium at a low rate. Haematopoietic stem cells (HSCs) rather than mesenchymal stem cells (MSC) are responsible for this phenomenon. MSCs have the potential to ameliorate kidney function after acute kidney injury (AKI) without directly repopulating the tubules. However, little is known about the short-term effect of HSCs. METHODS: In this article, we analysed the survival rate and organ distribution of isolated rat HSCs injected into the renal artery after ischaemic renal injury, using quantitative real-time PCR, as well as their impact on renal function and histomorphology. RESULTS: Intra-arterially injected Lin(-)CD90(+) HSCs were detected in the kidney at significant amounts only within the first 24 h after injection and were virtually absent by Day 2. Compared with control animals, no differences were seen after HSC administration with respect to kidney function or histomorphologic changes of AKI. At Day 7 HSCs were again readily detectable in the kidney suggesting a redistribution of cells at later time points. Of note, HSCs did not seem to have an exclusive tropism for the injured kidney but were detectable in the lungs, liver, spleen, heart and brain at all time points. CONCLUSIONS: Injected HSCs do not appear to significantly contribute to tubular repair or ameliorate renal damage in ischaemic AKI although they may show considerable engraftment in various organs. These data further challenge the concept that injection of HSCs may be used as a therapeutic approach in treating AKI.