Kayla J. Erspamer, M.D.

All Publications

• Practices, attitudes and barriers faced by internists and pediatricians in transitioning young adult patients to adult medicine. International journal of adolescent medicine and health Erspamer, K. J., Jacob, H., Hasan, R. 2019; 34 (3)

  Abstract

  To assess perspectives of clinicians at an academic medical center regarding current practices, barriers and possible interventions in transitioning young adult patients to adult care.Electronic survey results from licensed independent providers in the Departments of Internal Medicine (n = 87) and Pediatrics (n = 49) were analyzed.The majority of providers at our institution are unaware of and do not follow national transition guidelines. Seventy-seven percent of pediatricians provide the majority of preparation and support in transition care of young adults with complex medical conditions without involvement of other interprofessional team members. Ninety-six percent of internists report not receiving formal training related to transition care and only 44% are comfortable caring for young adults with medical complexity. Eighty-eight percent of pediatricians and internists support a standard transition process, yet significant gaps in this process exist.Despite the existence of national society-supported recommendations for transitions of care processes, lack of awareness among providers regarding national transition guidelines has led to uncertainty when it comes to managing the transition of young adult patients. There is lack of communication between pediatricians and internists, and internists are not as confident in caring for young adult patients. The scope of work of the interprofessional team is not utilized adequately. Providers agree on the importance of developing a standardized pediatric to adult transition process. These results help inform possible future interventions to improve care for this population.

  View details for DOI 10.1515/ijamh-2019-0129

  View details for PubMedID 31883368

• Salt-sensitive transcriptome of isolated kidney distal tubule cells. Physiological genomics Swanson, E. A., Nelson, J. W., Jeng, S., Erspamer, K. J., Yang, C. L., McWeeney, S., Ellison, D. H. 2019; 51 (4): 125-135

  Abstract

  In the distal kidney tubule, the steroid hormone aldosterone regulates sodium reabsorption via the epithelial sodium channel (ENaC). Most studies seeking to identify ENaC-regulating aldosterone-induced proteins have used transcriptional profiling of cultured cells. To identify salt-sensitive transcripts in an in vivo model, we used low-NaCl or high-NaCl diet to stimulate or suppress endogenous aldosterone, in combination with magnetic- and fluorescence-activated cell sorting to isolate distal tubule cells from mouse kidney for transcriptional profiling. Of the differentially expressed transcripts, 162 were more abundant in distal tubule cells isolated from mice fed low-NaCl diet, and 161 were more abundant in distal tubule cells isolated from mice fed high-NaCl diet. Enrichment analysis of Gene Ontology biological process terms identified multiple statistically overrepresented pathways among the differentially expressed transcripts that were more abundant in distal tubule cells isolated from mice fed low-NaCl diet, including ion transmembrane transport, regulation of growth, and negative regulation of apoptosis. Analysis of Gene Ontology molecular function terms identified differentially expressed transcription factors, transmembrane transporters, kinases, and G protein-coupled receptors. Finally, comparison with a recently published study of gene expression changes in distal tubule cells in response to administration of aldosterone identified 18 differentially expressed genes in common between the two experiments. When expression of these genes was measured in cortical collecting ducts microdissected from mice fed low-NaCl or high-NaCl diet, eight were differentially expressed. These genes are likely to be regulated directly by aldosterone and may provide insight into aldosterone signaling to ENaC in the distal tubule.

  View details for DOI 10.1152/physiolgenomics.00119.2018

  View details for PubMedID 30875275

  View details for PubMedCentralID PMC6485379

• Dual gain and loss of cullin 3 function mediates familial hyperkalemic hypertension. American journal of physiology. Renal physiology Cornelius, R. J., Zhang, C., Erspamer, K. J., Agbor, L. N., Sigmund, C. D., Singer, J. D., Yang, C. L., Ellison, D. H. 2018; 315 (4): F1006-F1018

  Abstract

  Familial hyperkalemic hypertension is caused by mutations in with-no-lysine kinases (WNKs) or in proteins that mediate their degradation, kelch-like 3 (KLHL3) and cullin 3 (CUL3). Although the mechanisms by which WNK and KLHL3 mutations cause the disease are now clear, the effects of the disease-causing CUL3Δ403-459 mutation remain controversial. Possible mechanisms, including hyperneddylation, altered ubiquitin ligase activity, decreased association with the COP9 signalosome (CSN), and increased association with and degradation of KLHL3 have all been postulated. Here, we systematically evaluated the effects of Cul3Δ403-459 using cultured kidney cells. We first identified that the catalytically active CSN subunit jun activation domain-binding protein-1 (JAB1) does not associate with the deleted Cul3 4-helix bundle domain but instead with the adjacent α/β1 domain, suggesting that altered protein folding underlies the impaired binding. Inhibition of deneddylation with JAB1 siRNA increased Cul3 neddylation and decreased KLHL3 abundance, similar to the Cul3 mutant. We next determined that KLHL3 degradation has both ubiquitin ligase-dependent and -independent components. Proteasomal KLHL3 degradation was enhanced by Cul3Δ403-459; however, autophagic degradation was also upregulated by this Cul3 mutant. Finally, to evaluate whether deficient substrate adaptor was responsible for the disease, we restored KLHL3 to wild-type (WT) Cul3 levels. In the absence of WT Cul3, WNK4 was not degraded, demonstrating that Cul3Δ403-459 itself cannot degrade WNK4; conversely, when WT Cul3 was present, as in diseased humans, WNK4 degradation was restored. In conclusion, deletion of exon 9 from Cul3 generates a protein that is itself ubiquitin-ligase defective but also capable of enhanced autophagocytic KLHL3 degradation, thereby exerting dominant-negative effects on the WT allele.

  View details for DOI 10.1152/ajprenal.00602.2017

  View details for PubMedID 29897280

  View details for PubMedCentralID PMC6230741

• With no lysine kinase 4 modulates sodium potassium 2 chloride cotransporter activity in vivo. American journal of physiology. Renal physiology Terker, A. S., Castañeda-Bueno, M., Ferdaus, M. Z., Cornelius, R. J., Erspamer, K. J., Su, X. T., Miller, L. N., McCormick, J. A., Wang, W. H., Gamba, G., Yang, C. L., Ellison, D. H. 2018; 315 (4): F781-F790

  Abstract

  With no lysine kinase 4 (WNK4) is essential to activate the thiazide-sensitive NaCl cotransporter (NCC) along the distal convoluted tubule, an effect central to the phenotype of familial hyperkalemic hypertension. Although effects on potassium and sodium channels along the connecting and collecting tubules have also been documented, WNK4 is typically believed to have little role in modulating sodium chloride reabsorption along the thick ascending limb of the loop of Henle. Yet wnk4-/- mice (knockout mice lacking WNK4) do not demonstrate the hypocalciuria typical of pure distal convoluted tubule dysfunction. Here, we tested the hypothesis that WNK4 also modulates bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) function along the thick ascending limb. We confirmed that w nk4-/- mice are hypokalemic and waste sodium chloride, but are also normocalciuric. Results from Western blots suggested that the phosphorylated forms of both NCC and NKCC2 were in lower abundance in wnk4-/- mice than in controls. This finding was confirmed by immunofluorescence microscopy. Although the initial response to furosemide was similar in wnk4-/- mice and controls, the response was lower in the knockout mice when reabsorption along the distal convoluted tubule was inhibited. Using HEK293 cells, we showed that WNK4 increases the abundance of phosphorylated NKCC2. More supporting evidence that WNK4 may modulate NKCC2 emerges from a mouse model of WNK4-mediated familial hyperkalemic hypertension in which more phosphorylated NKCC2 is present than in controls. These data indicate that WNK4, in addition to modulating NCC, also modulates NKCC2, contributing to its physiological function in vivo.

  View details for DOI 10.1152/ajprenal.00485.2017

  View details for PubMedID 29412704

  View details for PubMedCentralID PMC6230736

• Direct and Indirect Mineralocorticoid Effects Determine Distal Salt Transport. Journal of the American Society of Nephrology : JASN Terker, A. S., Yarbrough, B., Ferdaus, M. Z., Lazelle, R. A., Erspamer, K. J., Meermeier, N. P., Park, H. J., McCormick, J. A., Yang, C. L., Ellison, D. H. 2016; 27 (8): 2436-45

  Abstract

  Excess aldosterone is an important contributor to hypertension and cardiovascular disease. Conversely, low circulating aldosterone causes salt wasting and hypotension. Aldosterone activates mineralocorticoid receptors (MRs) to increase epithelial sodium channel (ENaC) activity. However, aldosterone may also stimulate the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC). Here, we generated mice in which MRs could be deleted along the nephron to test this hypothesis. These kidney-specific MR-knockout mice exhibited salt wasting, low BP, and hyperkalemia. Notably, we found evidence of deficient apical orientation and cleavage of ENaC, despite the salt wasting. Although these mice also exhibited deficient NCC activity, NCC could be stimulated by restricting dietary potassium, which also returned BP to control levels. Together, these results indicate that MRs regulate ENaC directly, but modulation of NCC is mediated by secondary changes in plasma potassium concentration. Electrolyte balance and BP seem to be determined, therefore, by a delicate interplay between direct and indirect mineralocorticoid actions in the distal nephron.

  View details for DOI 10.1681/ASN.2015070815

  View details for PubMedID 26712527

  View details for PubMedCentralID PMC4978056

• Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis. Kidney international Terker, A. S., Zhang, C., Erspamer, K. J., Gamba, G., Yang, C. L., Ellison, D. H. 2016; 89 (1): 127-34

  Abstract

  Dietary potassium deficiency activates thiazide-sensitive sodium chloride cotransport along the distal nephron. This may explain, in part, the hypertension and cardiovascular mortality observed in individuals who consume a low-potassium diet. Recent data suggest that plasma potassium affects the distal nephron directly by influencing intracellular chloride, an inhibitor of the with-no-lysine kinase (WNK)-Ste20p-related proline- and alanine-rich kinase (SPAK) pathway. As previous studies used extreme dietary manipulations, we sought to determine whether the relationship between potassium and NaCl cotransporter (NCC) is physiologically relevant and clarify the mechanisms involved. We report that modest changes in both dietary and plasma potassium affect NCC in vivo. Kinase assay studies showed that chloride inhibits WNK4 kinase activity at lower concentrations than it inhibits activity of WNK1 or WNK3. Also, chloride inhibited WNK4 within the range of distal cell chloride concentration. Mutation of a previously identified WNK chloride-binding motif converted WNK4 effects on SPAK from inhibitory to stimulatory in mammalian cells. Disruption of this motif in WNKs 1, 3, and 4 had different effects on NCC, consistent with the three WNKs having different chloride sensitivities. Thus, potassium effects on NCC are graded within the physiological range, which explains how unique chloride-sensing properties of WNK4 enable it to mediate effects of potassium on NCC in vivo.

  View details for DOI 10.1038/ki.2015.289

  View details for PubMedID 26422504

  View details for PubMedCentralID PMC4814375