Longitudinal study of living kidney donor glomerular dynamics after nephrectomy

j o u rna l c lu b

http://www.kidney-international.org © 2015 International Society of Nephrology

Kidney International (2015) 88, 932–933. doi:10.1038/ki.2015.329

Living-donor kidneys are a mainstay of kidney transplantation. Early physiological changes include an approximately 40% increase in renal plasma flow (RPF) and glomerular filtration rate (GFR). There are few data on the long-term effects on glomerular dynamics in solitary kidneys after donation. The study by Lenihan et al. included 21 kidney donors who underwent detailed long-term clinical, physiological, and radiological evaluation before and after kidney donation. A morphometric analysis of glomeruli obtained at the time of surgery was also done. Donors showed parallel increases in single-kidney RPF, renocortical volume, and GFR early after the procedure (median 0.8 years), and these changes were sustained through to the late post-donation period (median 6.3 years) (Figure). The glomerular ultrafiltration coefficient (Kf) increased early and then remained constant through the late post-donation study. Using the above assumptions, the 40% elevation in remnant kidney GFR was from the increase in Kf. Hypertension was seen in 14% in the early postdonation period to 57% in the late post-donation period. Abnormal levels of albuminuria were not seen at any time. In summary, adaptive hyperfiltration that occurs in the kidney after donor nephrectomy is mainly a result of hyperperfusion and hypertrophy without glomerular hypertension of the remaining glomeruli. Hypertension was a common occurrence post-donation.

mediators. IL-18 is upregulated in many diseases, including atherosclerosis, and has been detected in macrophages, T cells, endothelial cells, and smooth muscle cells (SMCs) in human aorta. Moreover, previous studies demonstrated that blocking IL-18 signaling ameliorates atherosclerosis while administration of IL-18 exacerbates atherosclerosis in Apoe knockout (Apoe–/–) mice. Wang et al. studied the effect of IL18 receptor knockout (Il18r–/–) on atherosclerosis in Apoe–/– mice. Surprisingly, Apoe–/–Il18r–/– mice were not protected from atherosclerosis, and IL-18 binding to endothelial cells from Apoe–/–Il18r–/– mice versus Apoe–/–Il18r+/+ mice was similar. Using immunoprecipitation and mass spectroscopy, the authors identified the Na-Cl cotransporter (NCC) as a novel IL-18-binding protein. NCC was found to be expressed highly in kidney but also at low levels in heart, lung, and liver. Though NCC was not expressed in normal aorta, it was detected in atherosclerotic aortic lesions and colocalized with IL18r and macrophage, SMC, and endothelial-cell markers. Moreover, incubation with IL-18, IL-1b, and tumor necrosis factor-a (TNF-a) increased NCC expression. To test the role of NCC in promoting atherogenesis in vivo, the investigators studied the effect of knocking out Ncc (Ncc–/–) on atherosclerosis in Apoe–/– mice. Though neither Apoe–/–Ncc–/– nor Apoe–/–Il18r–/– mice were protected from atherosclerosis, Apoe–/–Ncc–/–Il18r–/– mice developed less aortic atherosclerosis, suggesting that IL18r and NCC together mediate the effects of IL-18. Consistent with this interpretation, treatment with a thiazide diuretic (NCC blocker) had reduced atherosclerosis in Apoe–/–Il18r–/– but not in Apoe–/– mice. To examine whether the protective effects of Ncc and Il18 deletion in Apoe–/– mice were mediated by effects on bone marrow-derived cells and not by alteration of electrolyte levels, bone marrow transplant studies were performed that demonstrated that transplantation of Apoe–/– or Apoe–/–Il18r–/– bone marrow into Apoe–/– mice was not protective but Apoe–/–Ncc–/–Il18r–/– bone marrow was. Finally, the authors delineated amino acid residues in NCC that were critical for its role in intracellular signal transduction after binding of IL-18. This study identified a novel role for NCC as a mediator of IL-18 signaling and atherogenesis, and additional studies are needed to determine whether these findings are relevant to the effects of thiazide diuretics in preventing cardiovascular disease in humans.

Interleukin-18 function in atherosclerosis is mediated by the interleukin-18 receptor and the Na-Cl cotransporter

The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development

Wang et al., Nat Med 2015; 21: 820–826; doi:10.1038/nm.3890

Lin et al., Sci Signal 2015; 8: ra88; doi:10.1126/scisignal.aaa5157

Interleukin-18 (IL-18) is a cytokine that induces polarization of Th1 cells and causes upregulation of several proinflammatory

In normal conditions, B cells exposed to antigens differentiate to antibody-producing plasma cells. Multiple myeloma, a

Longitudinal study of living kidney donor glomerular dynamics after nephrectomy

Change in single-kidney RPF (%)

Change in single-kidney GFR (%)

Adapted from Lenihan et al./J Clin Invest

Lenihan et al., J Clin Invest 2015; 125: 1311–1318; doi:10.1172/JCI78885

Years after donation

Years after donation

Left: Percentage of single-kidney GFR change over time, plotted separately for each individual (n = 21). Right: Percentage of RPF change over time, plotted separately for each individual (n = 21).

Jai Radhakrishnan

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Michael Ross

Kidney International (2015) 88

jo urn a l c l u b

Maria Pia Rastaldi

Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury Huang et al., Hepatology 2015; 62: 600–614; doi:10.1002/hep.27841

Damage-associated molecular patterns (DAMPs), such as HMGB1, are released from injured cells and promote inflammation and organ injury through the activation of Toll-like receptors (TLRs). Histone proteins and nuclear and mitochondrial DNA are also released from injured cells and may activate inflammation. Neutrophils can release DNA to form extracellu-

Kidney International (2015) 88



Sham

Overlay

GFP (Neu)

SYTOX (NETs)

Adapted from Huang et al./Hepatology

malignant disorder of plasma cells, is a very severe, mainly untreatable condition that affects the kidney in about 40% of cases. Renal involvement significantly influences patients’ survival and includes immunoglobulin light-chain (AL) amyloidosis, monoclonal immunoglobulin deposition disease, myeloma cast nephropathy, and acute tubular necrosis. About 12% of tumor samples from subjects with multiple myeloma present loss-of-function mutations in tumor necrosis factor receptorassociated factor 3 (TRAF3), an adaptor protein involved in different signaling pathways, depending on the cell type and the engaged receptors. Mice with a B cell-specific deletion of TRAF3 display increased B-cell survival and develop B-cell malignancies. Therefore, human and mouse data implicate TRAF3 as an important player in restraining B-cell survival, but its mechanism of action remained elusive. Now, Lin and co-workers have shown by a coordinated series of in vivo and in vitro experiments that absence of TRAF3 specifically in B cells causes augmented sensitivity to interleukin-6 (IL-6), a cytokine responsible for development and survival of plasma cells. By binding to the IL-6 receptor complex, IL-6 recruits signal transducer and activator of transcription 3 (STAT3) and determines its activation by Janus-activated kinase 1 (Jak1). Activated STAT3 translocates to the nucleus and promotes the expression of genes initiating the plasma-cell differentiation program. The authors were able to demonstrate that the presence of TRAF3 in B cells is necessary because its association with the phosphatase PTPN22 (protein tyrosine phosphatase nonreceptor type 22) inhibits the IL-6–STAT3 pathway and limits plasma-cell accumulation. Collectively, these results have important implications for future therapeutic strategies in B-cell malignancies, and specifically in multiple myeloma.

I/R (60 min)

Demonstration of DNA extravasation from neutrophils (NET formation) in liver after ischemia/reperfusion. GFP-labeled neutrophils were imaged in vivo by multiphoton microscopy while DNA was stained with SYTOX dye.

lar webs, denoted as neutrophil extracellular traps (NETs). NETs play a protective role against infections by killing pathogens but also have been implicated in organ injury in both infectious and sterile models of inflammation. Although DAMPs are well known to mediate organ injury, including ischemic acute kidney injury, the role of NETs in ischemic or toxic organ injury is less clear. Peptidyl arginine deiminase 4 (PAD4) is an enzyme expressed in neutrophils that modifies arginine residues in histones to produce citrullinated residues. PAD4 is also essential for the production of NETs. Huang et al. examined the role of NETs, PAD4, and HMGB1 in a model of murine hepatic ischemia/reperfusion injury (IRI). They found that hepatic IRI resulted in the formation of NETs within the liver and release of histone/DNA into the circulation. The significance of this phenomenon was explored with the use of DNase1, which degrades extracellular DNA, and inhibitors of PAD4, both of which reduced circulating DNA and reduced liver damage. Using neutrophils, which lack either TLR4 or TLR9, the authors showed that histones and HMGB1 induce NET formation via these receptors. Together, the results weave an interesting story wherein cell stress initiates the release of DAMPs, which then activate neutrophils to form NETs, which, in turn, amplify inflammation and organ injury. PAD4 and NETs have also been implicated in myocardial ischemia, suggesting that this may be a general mechanism. In this regard, although the role of neutrophils in kidney IRI remains unclear, inhibitors of PAD4 reduced kidney injury. The role of NETs in ischemic kidney injury and the possibility that PAD4 has neutrophil-independent actions in ischemic injury have not been critically evaluated. PAD4 inhibitors are in development for cancer treatment, and DNase1 is FDA approved (albeit for inhaled use) for cystic fibrosis, offering the potential for translation to clinical use. W. Brian Reeves

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