Kidneys have a high energy demand to facilitate the reabsorption of the glomerular filtrate. For this reason, renal cells have a high density of mitochondria. Mitochondrial cytopathies can be the ...result of a mutation in both mitochondrial and nuclear DNA. Mitochondrial dysfunction can lead to a variety of renal manifestations. Examples of tubular manifestations are renal Fanconi Syndrome, which is often found in patients diagnosed with Kearns-Sayre and Pearson’s marrow-pancreas syndrome, and distal tubulopathies, which result in electrolyte disturbances such as hypomagnesemia. Nephrotic syndrome can be a glomerular manifestation of mitochondrial dysfunction and is typically associated with focal segmental glomerular sclerosis on histology. Tubulointerstitial nephritis can also be seen in mitochondrial cytopathies and may lead to end-stage renal disease. The underlying mechanisms of these cytopathies remain incompletely understood; therefore, current therapies focus mainly on symptom relief. A better understanding of the molecular disease mechanisms is critical in order to improve treatments.
Bartter syndrome is a rare inherited salt-losing renal tubular disorder characterized by secondary hyperaldosteronism with hypokalemic and hypochloremic metabolic alkalosis and low to normal blood ...pressure. The primary pathogenic mechanism is defective salt reabsorption predominantly in the thick ascending limb of the loop of Henle. There is significant variability in the clinical expression of the disease, which is genetically heterogenous with 5 different genes described to date. Despite considerable phenotypic overlap, correlations of specific clinical characteristics with the underlying molecular defects have been demonstrated, generating gene-specific phenotypes. As with many other rare disease conditions, there is a paucity of clinical studies that could guide diagnosis and therapeutic interventions. In this expert consensus document, the authors have summarized the currently available knowledge and propose clinical indicators to assess and improve quality of care.
GGGGCC repeat expansions of C9orf72 represent the most common genetic variant of amyotrophic lateral sclerosis and frontotemporal degeneration, but the mechanism of pathogenesis is unclear. Recent ...reports have suggested that the transcribed repeat might form toxic RNA foci that sequester various RNA processing proteins. Consensus as to the identity of the binding partners is missing and whole neuronal proteome investigation is needed. Using RNA fluorescence in situ hybridization we first identified nuclear and cytoplasmic RNA foci in peripheral and central nervous system biosamples from patients with amyotrophic lateral sclerosis with a repeat expansion of C9orf72 (C9orf72+), but not from those patients without a repeat expansion of C9orf72 (C9orf72-) or control subjects. Moreover, in the cases examined, the distribution of foci-positive neurons correlated with the clinical phenotype (t-test P < 0.05). As expected, RNA foci are ablated by RNase treatment. Interestingly, we identified foci in fibroblasts from an asymptomatic C9orf72+ carrier. We next performed pulldown assays, with GGGGCC5, in conjunction with mass spectrometry analysis, to identify candidate binding partners of the GGGGCC repeat expansion. Proteins containing RNA recognition motifs and involved in splicing, messenger RNA nuclear export and/or translation were significantly enriched. Immunohistochemistry in central nervous system tissue from C9orf72+ patients with amyotrophic lateral sclerosis demonstrated co-localization of RNA foci with SRSF2, hnRNP H1/F, ALYREF and hnRNP A1 in cerebellar granule cells and with SRSF2, hnRNP H1/F and ALYREF in motor neurons, the primary target of pathology in amyotrophic lateral sclerosis. Direct binding of proteins to GGGGCC repeat RNA was confirmed in vitro by ultraviolet-crosslinking assays. Co-localization was only detected in a small proportion of RNA foci, suggesting dynamic sequestration rather than irreversible binding. Additional immunohistochemistry demonstrated that neurons with and without RNA foci were equally likely to show nuclear depletion of TDP-43 (χ(2) P = 0.75) or poly-GA dipeptide repeat protein inclusions (χ(2) P = 0.46). Our findings suggest two non-exclusive pathogenic mechanisms: (i) functional depletion of RNA-processing proteins resulting in disruption of messenger RNA splicing; and (ii) licensing of expanded C9orf72 pre-messenger RNA for nuclear export by inappropriate association with messenger RNA export adaptor protein(s) leading to cytoplasmic repeat associated non-ATG translation and formation of potentially toxic dipeptide repeat protein.
SS is a prevalent and underdiagnosed systemic disease that primarily affects epithelial tissue. It may affect renal function either as epithelial disease causing tubulointerstitial nephritis or as an ...immune complex-mediated glomerulopathy. These lesions may cause a variety of clinical features, both overt and occult. The epithelial disease is mediated by B and T cells, notably the Th17 subtype. We review the prevalence of renal SS, its presentation, likely pathogenesis and treatment.
Nephrocalcinosis describes the ectopic deposition of calcium salts in the kidney parenchyma. Nephrocalcinosis can result from a number of acquired causes but also an even greater number of genetic ...diseases, predominantly renal but also extrarenal. Here we provide a review of the genetic causes of nephrocalcinosis, along with putative mechanisms, illustrated by human and animal data.
Calcineurin inhibitors (CNIs) are immunosuppressive drugs that are used widely to prevent rejection of transplanted organs and to treat autoimmune disease. Hypertension and renal tubule dysfunction, ...including hyperkalemia, hypercalciuria and acidosis, often complicate their use. These side effects resemble familial hyperkalemic hypertension, a genetic disease characterized by overactivity of the renal sodium chloride cotransporter (NCC) and caused by mutations in genes encoding WNK kinases. We hypothesized that CNIs induce hypertension by stimulating NCC. In wild-type mice, the CNI tacrolimus caused salt-sensitive hypertension and increased the abundance of phosphorylated NCC and the NCC-regulatory kinases WNK3, WNK4 and SPAK. We demonstrated the functional importance of NCC in this response by showing that tacrolimus did not affect blood pressure in NCC-knockout mice, whereas the hypertensive response to tacrolimus was exaggerated in mice overexpressing NCC. Moreover, hydrochlorothiazide, an NCC-blocking drug, reversed tacrolimus-induced hypertension. These observations were extended to humans by showing that kidney transplant recipients treated with tacrolimus had a greater fractional chloride excretion in response to bendroflumethiazide, another NCC-blocking drug, than individuals not treated with tacrolimus; renal NCC abundance was also greater. Together, these findings indicate that tacrolimus-induced chronic hypertension is mediated largely by NCC activation, and suggest that inexpensive and well-tolerated thiazide diuretics may be especially effective in preventing the complications of CNI treatment.
•Solid organ transplantation is a well-recognized risk factor for aspergillosis.•Diagnosis is often challenging, especially in the comorbid patient.•Voriconazole is the first-line antifungal ...agent.•Prompt therapy and removal of infected tissue where possible are essential.•The prognosis for invasive Aspergillus is extremely poor.
A renal transplant recipient aged 68 years experienced multiple complications after an initial good graft function from a deceased donor transplant. Late in the first week, the patient was oliguric with hematuria; the graft failed in week 2 after the development of a hematoma from a rupture of a renal artery aneurysm. He had a recurrent bleed from the internal iliac graft site and subsequently developed painful dark patches on his leg, distal to where the transplant had been. Histology from the explanted graft and skin biopsies demonstrated Aspergillus flavus; this was also grown in the culture of the external iliac artery tissue. Systemic aspergillosis is rare but well recognized, especially in the immunocompromised. Presentations include mycotic aneurysms and secondary cutaneous aspergillosis from hematogenous spread. Diagnosis requires confirmation by histology or direct culture, but a high β-glucan concentration and positive galactomannan antigen can suggest invasive fungal infection in the early stages of the disease. Cases should be managed with systemic antifungals and involvement of local microbiology services; unfortunately, the prognosis is poor.
ABSTRACT
Approval of the vasopressin V2 receptor antagonist tolvaptan—based on the landmark TEMPO 3:4 trial—marked a transformation in the management of autosomal dominant polycystic kidney disease ...(ADPKD). This development has advanced patient care in ADPKD from general measures to prevent progression of chronic kidney disease to targeting disease-specific mechanisms. However, considering the long-term nature of this treatment, as well as potential side effects, evidence-based approaches to initiate treatment only in patients with rapidly progressing disease are crucial. In 2016, the position statement issued by the European Renal Association (ERA) was the first society-based recommendation on the use of tolvaptan and has served as a widely used decision-making tool for nephrologists. Since then, considerable practical experience regarding the use of tolvaptan in ADPKD has accumulated. More importantly, additional data from REPRISE, a second randomized clinical trial (RCT) examining the use of tolvaptan in later-stage disease, have added important evidence to the field, as have post hoc studies of these RCTs. To incorporate this new knowledge, we provide an updated algorithm to guide patient selection for treatment with tolvaptan and add practical advice for its use.
Global grain production is under threat from the escalating evolution of herbicide-resistant weed populations. Worldwide, herbicide-reliant grain crop production systems have driven the proliferation ...of herbicide resistant populations of major weed species. Alternatives or adjuncts to herbicides are needed for sustainable control of crop weeds in grain crops worldwide. Here we introduce and prove the ability of a new weed control tool, the Harrington Seed Destructor (HSD), to intercept and destroy weed seeds during grain crop harvest. The interception and destruction of weed seeds exiting the grain harvester in the chaff fraction during grain crop harvest is a hitherto unrealized opportunity. We have developed a cage mill-based chaff processing unit that consistently destroys weed seed infesting grain crop chaff fractions. The subsequent construction of the HSD incorporating this unit had >95% weed seed destruction efficacy when used during commercial harvest of three major grain crops, wheat (Triticum aestivum L.), barley (Hordeum vulgare L.), and lupin (Lupinus angustifolius L.). The HSD system has the potential for a dramatic impact on global grain production by providing the unique combination of effective weed control with complete retention of grain crop harvest residues. Only herbicides offer this same combination of highly effective weed control and complete residue retention in large scale grain crop production systems.
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