Analysis of T Cell Subsets in Adult Primary/Idiopathic Minimal Change Disease: A Pilot Study

Aim. To characterise infiltrating T cells in kidneys and circulating lymphocyte subsets of adult patients with primary/idiopathic minimal change disease. Methods. In a cohort of 9 adult patients with primary/idiopathic minimal change recruited consecutively at disease onset, we characterized (1) infiltrating immune cells in the kidneys using immunohistochemistry and (2) circulating lymphocyte subsets using flow cytometry. As an exploratory analysis, association of the numbers and percentages of both kidney-infiltrating immune cells and the circulating lymphocyte subsets with kidney outcomes including deterioration of kidney function and proteinuria, as well as time to complete clinical remission up to 48 months of follow-up, was investigated. Results. In the recruited patients with primary/idiopathic minimal change disease, we observed (a) a dominance of infiltrating T helper 17 cells and cytotoxic cells, comprising cytotoxic T cells and natural killer cells, over Foxp3+ Treg cells in the renal interstitium; (b) an increase in the circulating total CD8+ T cells in peripheral blood; and (c) an association of some of these parameters with kidney function and proteinuria. Conclusions. In primary/idiopathic minimal change disease, a relative numerical dominance of effector over regulatory T cells can be observed in kidney tissue and peripheral blood. However, larger confirmatory studies are necessary

Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation

Sphingosine- 1- phosphate (S1P) lyase is a vitamin B6- dependent enzyme that degrades sphingosine- 1- phosphate in the final step of sphingolipid metabolism. In 2017, a new inherited disorder was described caused by mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). This condition is referred to as SPL insufficiency syndrome (SPLIS) or alternatively as nephrotic syndrome type 14 (NPHS14). Patients with SPLIS exhibit lymphopenia, nephrosis, adrenal insufficiency, and/or neurological defects. No targeted therapy for SPLIS has been reported. Vitamin B6 supplementation has therapeutic activity in some genetic diseases involving B6- dependent enzymes, a finding ascribed largely to the vitamin’s chaperone function. We investigated whether B6 supplementation might have activity in SPLIS patients. We retrospectively monitored responses of disease biomarkers in patients supplemented with B6 and measured SPL activity and sphingolipids in B6- treated patient- derived fibroblasts. In two patients, disease biomarkers responded to B6 supplementation. S1P abundance and activity levels increased and sphingolipids decreased in response to B6. One responsive patient is homozygous for an SPL R222Q variant present in almost 30% of SPLIS patients. Molecular modeling suggests the variant distorts the dimer interface which could be overcome by cofactor supplementation. We demonstrate the first potential targeted therapy for SPLIS and suggest that 30% of SPLIS patients might respond to cofactor supplementation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162713/2/jimd12238.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162713/1/jimd12238_am.pd

The Banff Conferences on renal allograft pathology – the latest 2013 report

The Banff Conference diagnostic categories and their criteria for renal biopsy interpretation were created in 1991 by a group comprising nephrologists, pathologists, transplant surgeons and immunologists. These guidelines are widely used in many countries. Every two years, participants at these meetings present and discuss research findings that have added to our knowledge of allograft pathology. From the start, features of T-cell mediated rejection were established. This was followed by discovery of C4d staining in biopsy tissue and better characterisation of antibody mediated rejection. The formation of working groups to look into problematic areas has allowed better refinements to be made to the classification scheme. The latest Banff 2013 report is significant for the inclusion of a C4d-negative category under humoral rejection. Together with the realisation that endarteritis may be antibody mediated, this latest report will greatly impact how pathologists interpret the allograft biopsy

Angiomotin mutation causes glomerulopathy and renal cysts by upregulating hepatocyte nuclear factor transcriptional activity

10.1002/ctm2.904Clinical and Translational Medicine12

Risk score model for kidney biopsy

10.1038/s41390-019-0277-zPediatric Research854477-48

Cellular actions of opioids on periaqueductal grey neurons from C57B16/J mice and mutant mice lacking MOR-1

1. Patch clamp recordings were made from periaqueductal grey (PAG) neurons in vitro to investigate the cellular actions of opioids in wild-type C57B16/J mice and mutant mice lacking the first exon of the μ-opioid (MOP) receptor. 2. In wild-type mice, the κ-(KOP) agonist U-69593 (300 nM) and the mixed μ/δ-opioid agonist met-enkephalin (10 μM), but not the δ-(DOP) agonist deltorphin (300 nM), reduced the amplitude of evoked GABA(A)-mediated inhibitory postsynaptic currents (IPSCs). Met-enkephalin and U-69593 also reduced the rate of spontaneous miniature IPSCs, but had no effect on their amplitude and kinetics. In μ-receptor-deleted mice, only U-69593 (300 nM) reduced the amplitude of evoked IPSCs. 3. In wild-type mice, the MOP agonist DAMGO (3 μM) produced an outward current in 76% of the neurons. Deltorphin and U-69593 produced outward currents in 24 and 32% of the neurons, respectively. In μ-receptor-deleted mice, deltorphin and U-69593 produced similar outward currents in 32 and 27% of the neurons, respectively, while DAMGO was without effect. All neurons in both the wild-type and μ-receptor-deleted mice responded with similar outward currents to either the GABA(B) receptor agonist baclofen (10 μM), or the opioid-like receptor ORL1 (NOP) agonist nociceptin (300 nM). 4. The DAMGO-, deltorphin-, U-69593-, baclofen- and nociceptin-induced currents displayed inward rectification and reversed polarity at −109 to −116 mV. 5. These findings indicate that μ-, δ- and κ-opioid receptor activation has complex pre- and postsynaptic actions within the mouse PAG. This differs to the rat PAG where only μ-opioid receptor actions have been observed

The Value of Renal Biopsy in Non-Insulin-Dependent Diabetes Mellitus in Singapore over the Past Two Decades

10.1159/000505624Kidney Diseases64284–29

Multicenter study on the genetics of glomerular diseases among southeast and south Asians: Deciphering Diversities - Renal Asian Genetics Network (DRAGoN)

10.1111/cge.14116CLINICAL GENETIC