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1.  Common genetic variants of the human UMOD gene are functional on transcription and predict plasma uric acid in two distinct populations 
Kidney international  2013;83(4):733-740.
Uromodulin (UMOD) genetic variants cause familial juvenile hyperuricemic nephropathy, characterized by hyperuricemia, decreased renal excretion of UMOD and uric acid; such findings suggest a role for UMOD in the regulation of plasma uric acid. We screened common variants across the UMOD locus in two populations, one from a community-based Chinese population, the other from California twins and siblings. Transcriptional activity of promoter variants was estimated in luciferase reporter plasmids transfected into HEK293 cells and mlMCD3 cells. By variance components in twin pairs, uric acid concentration and excretion were heritable traits. In the primary population from Beijing, we identified that carriers of haplotype GCC displayed higher plasma uric acid, and 3 UMOD promoter variants associated with plasma uric acid. UMOD promoter variants displayed reciprocal effects on urine uric acid excretion and plasma uric acid concentration, suggesting a primary effect on renal tubular handling of urate. These UMOD genetic marker-on-trait associations for uric acid were replicated in an independent American population sample. Site-directed mutagenesis at trait-associated UMOD promoter variants altered promoter activity in transfected luciferase reporter plasmids. These results suggest that UMOD promoter variants seem to initiate a cascade of transcriptional and biochemical changes influencing UMOD secretion, eventuating in elevation of plasma uric acid.
doi:10.1038/ki.2012.449
PMCID: PMC3687544  PMID: 23344472
Uromodulin; uric acid; Tamm-Horsfall protein; UMOD
2.  Angiotensin receptor blockade has protective effects on the post-stenotic porcine kidney 
Kidney international  2013;84(4):767-775.
Angiotensin converting enzyme inhibitors (ACEI)/ angiotensin-II receptor blockers (ARBs) may induce an acute decrease of glomerular filtration rate (GFR) in the stenotic kidney in renal artery stenosis, but most patients tolerate these drugs well. We hypothesized that ACEI/ARBs stabilize stenotic kidney function during prolonged treatment by conferring protective effects. We tested this in control domestic pigs and pigs with renal artery stenosis untreated or treated with valsartan, or triple therapy (7 pigs in each group) for 4 weeks starting 6 weeks after stenosis induction. Renal function, oxygenation, tubular function, and microcirculation were assessed by multi-detector computed tomography (CT), blood-oxygen-level-dependent magnetic-resonance imaging, and micro-CT. Valsartan and triple therapy decreased blood pressure similarly, however, valsartan did not change the GFR of the stenotic kidney compared to renal artery stenosis and was similar to triple therapy. Both valsartan and triple therapy stimulated microvascular density, and improved tubular function. Valsartan also caused a greater increase of angiogenic factors and a decrease in oxidative stress, which were related to higher cortical perfusion and tubular response than triple therapy. Thus, valsartan did not decrease stenotic kidney GFR, but improved cortical perfusion and microcirculation. These beneficial effects may partly offset the hemodynamic GFR reduction in renal artery stenosis and preserve kidney function.
doi:10.1038/ki.2013.144
PMCID: PMC3732527  PMID: 23615504
Renal artery stenosis; angiotensin II type I receptor blockade; microvasculature
3.  Dietary phosphate restriction suppresses phosphaturia but does not prevent FGF23 elevation in a mouse model of chronic kidney disease 
Kidney international  2013;84(4):713-721.
Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that in end-stage renal disease is markedly increased in serum; however, the mechanisms responsible for this increase are unclear. Here, we tested whether phosphate retention in chronic kidney disease (CKD) is responsible for the elevation of FGF23 in serum using Col4α3 knockout mice, a murine model of Alport disease exhibiting CKD. We found a significant elevation in serum FGF23 in progressively azotemic 8 and 12 week-old CKD mice along with an increased fractional excretion of phosphorus. Both moderate and severe phosphate restriction reduced fractional excretion of phosphorus by 8 weeks, yet serum FGF23 levels remained strikingly elevated. By 12 weeks, FGF23 levels were further increased with moderate phosphate restriction, while severe phosphate restriction led to severe bone mineralization defects and decreased FGF23 production in bone. CKD mice on a control diet had low serum 1,25(OH)2D levels and 3-fold higher renal Cyp24α1 gene expression compared to wild-type mice. Severe phosphate restriction increased 1,25(OH)2D levels in CKD mice by 8 weeks and lowered renal Cyp24α1 gene expression despite persistently elevated serum FGF23. Renal klotho gene expression declined in CKD mice on a control diet, but improved with severe phosphate restriction. Thus, dietary phosphate restriction reduces the fractional excretion of phosphorus independent of serum FGF23 levels in mice with CKD.
doi:10.1038/ki.2013.194
PMCID: PMC3758787  PMID: 23698235
4.  Plasma FGF23 levels increase rapidly after acute kidney injury 
Kidney international  2013;84(4):776-785.
Emerging evidence suggests that fibroblast growth factor 23 (FGF23) levels are elevated in patients with acute kidney injury (AKI). In order to determine how early this increase occurs we used a murine folic acid nephropathy model and found that plasma FGF23 levels increased significantly from baseline already after 1 hour of AKI, with an 18-fold increase at 24 hours. Similar elevations of FGF23 levels were found when AKI was induced in mice with osteocyte-specific parathyroid hormone receptor ablation or the global deletion of parathyroid hormone or vitamin D receptor, indicating that the increase in FGF23 was independent of parathyroid hormone and vitamin D signaling. Furthermore, FGF23 levels increased to a similar extent in wild-type mice maintained on normal or phosphate-depleted diets prior to induction of AKI, indicating that the marked FGF23 elevation is at least partially independent of dietary phosphate. Bone production of FGF23 was significantly increased in AKI. The half-life of intravenously administered recombinant FGF23 was only modestly increased. Consistent with the mouse data, plasma FGF23 levels rose 15.9-fold by 24 hours following cardiac surgery in patients who developed AKI. The levels were significantly higher than in those without postoperative AKI. Thus, circulating FGF23 levels rise rapidly during AKI in rodents and humans. In mice this increase is independent of established modulators of FGF23 secretion.
doi:10.1038/ki.2013.150
PMCID: PMC3766419  PMID: 23657144
AKI; fibroblast growth factor 23; phosphate; PTH; vitamin D
5.  Phenotypic characterization of kidney stone formers by endoscopic and histological quantification of intra-renal calcification 
Kidney international  2013;84(4):818-825.
Interstitial Randall’s plaques and collecting duct plugs are distinct forms of renal calcification thought to provide sites for stone retention within the kidney. Here we assessed kidney stone precursor lesions in a random cohort of stone formers undergoing percutaneous nephrolithotomy. Each accessible papilla was endoscopically mapped following stone removal. The percent papillary surface area covered by plaque and plug were digitally measured using image analysis software. Stone composition was determined by micro-computed tomography and infrared analysis. A representative papillary tip was biopsied. Twenty-four hour urine collections were used to measure supersaturation and crystal growth inhibition. The vast majority (99%) of stone formers had Randall’s plaque on at least 1 papilla, while significant tubular plugging (over 1% of surface area) was present in about one-fifth of patients. Among calcium oxalate stone formers the amount of Randall’s plaque correlated with higher urinary citrate levels. Tubular plugging correlated positively with pH and brushite supersaturation but negatively with citrate excretion. Lower urinary crystal growth inhibition predicted the presence of tubular plugging but not plaque. Thus, tubular plugging may be more common than previously recognized among patients with all types of stones, including some with idiopathic calcium oxalate stones.
doi:10.1038/ki.2013.189
PMCID: PMC3784621  PMID: 23698231
Calcium oxalate; calcium phosphate; collecting duct; Randall’s plaque; tubular plug
6.  Host APOL1 genotype is independently associated with proteinuria in HIV infection 
Kidney international  2013;84(4):834-840.
Proteinuria is associated with adverse clinical outcomes in HIV infection. Here we evaluated whether APOL1 risk alleles, previously associated with advanced kidney disease, is independently associated with proteinuria in HIV infection in a cross-sectional study of HIV-infected women in the Women’s Interagency HIV Study. We estimated the percent difference in urine protein excretion and odds of proteinuria (200 mg/g and higher) associated with two versus one or no APOL1 risk allele using linear and logistic regression, respectively. Of 1285 women successfully genotyped, 379 carried one and 80 carried two risk alleles. Proteinuria was present in 124 women; 78 of whom had proteinuria confirmed on a second sample. In women without prior AIDS, two risk alleles were independently associated with a 69% higher urine protein excretion (95% CI: 36%, 108%) and 5-fold higher odds of proteinuria (95% CI: 2.45, 10.37) versus one or no risk allele. No association was found in women with prior AIDS. Analyses in which women with impaired kidney function were excluded and proteinuria was confirmed by a second urine sample yielded similar estimates. Thus, APOL1 risk alleles are associated with significant proteinuria in HIV-infected persons without prior clinical AIDS, independent of clinical factors traditionally associated with proteinuria. Trials are needed to determine whether APOL1 genotyping identifies individuals who could benefit from earlier intervention to prevent overt renal disease.
doi:10.1038/ki.2013.203
PMCID: PMC3788838  PMID: 23715117
7.  Distinct injury markers for the early detection and prognosis of incident acute kidney injury in critically ill adults with preserved kidney function 
Kidney international  2013;84(4):786-794.
The use of novel biomarkers to detect incident acute kidney injury (AKI) in the critically ill is hindered by heterogeneity of injury and the potentially confounding effects of prevalent AKI. Here we examined the ability of urine NGAL (NGAL), L-type Fatty Acid Binding Protein (L-FABP), and Cystatin C to predict AKI development, death, and dialysis in a nested case-control study of 380 critically ill adults with an eGFR over 60 ml/min/1.73 m2. One-hundred thirty AKI cases were identified following biomarker measurement and were compared to 250 controls without AKI. Areas under the receiver-operator characteristic curves (AUC-ROCs) for discriminating incident AKI from non-AKI were 0.58(95%CI: 0.52-0.64), 0.59(0.52-0.65), and 0.50(0.48-0.57) for urine NGAL, L-FABP, and Cystatin C, respectively. The combined AUC-ROC for NGAL and L-FABP was 0.59(56-0.69). Both urine NGAL and L-FABP independently predicted AKI during multivariate regression; however, risk reclassification indices were mixed. Neither urine biomarker was independently associated with death or acute dialysis [NGAL hazard ratio 1.35(95%CI: 0.93-1.96), L-FABP 1.15(0.82-1.61)] though both independently predicted the need for acute dialysis [NGAL 3.44(1.73-6.83), L-FABP 2.36(1.30-4.25)]. Thus, urine NGAL and L-FABP independently associated with the development of incident AKI and receipt of dialysis but exhibited poor discrimination for incident AKI using conventional definitions.
doi:10.1038/ki.2013.174
PMCID: PMC3788840  PMID: 23698227
8.  A comparative effectiveness research study of the change in blood pressure during hemodialysis treatment and survival 
Kidney international  2013;84(4):795-802.
It is not clear to what extent changes in blood pressure (BP) during hemodialysis affect or predict survival. Studying comparative outcomes of BP changes during hemodialysis can have major clinical implications including the impact on management strategies in hemodialysis patients. Here we undertook a retrospective cohort study of 113,255 hemodialysis patients over a 5 year period to evaluate an association between change in BP during hemodialysis and mortality. The change in BP was defined as post- minus pre-hemodialysis BP and mean of BP change values during the hemodialysis session was used as a mortality predictor. The patients averaged 61 years old and consisted of 45% women, 32% African-Americans and 58% diabetics. Over a median follow-up of 2.2 years, a total of 53,461 (47.2%) all-cause and 21,548 (25.7%) cardiovascular deaths occurred. In fully adjusted Cox regression model with restricted cubic splines, there was a U-shaped association between change systolic BP and all-cause mortality. Post-dialytic drops in systolic BP between −30 to 0 mmHg were associated with greater survival, but large decreases of systolic BP (more than −30 mmHg) and any increase in systolic BP (over 0 mmHg) were related to increased mortality. Peak survival was found at a change in systolic BP of −14 mmHg. The U-shaped association was also found for cardiovascular mortality. Thus, modest declines in BP after hemodialysis are associated with the greatest survival, whereas any rise or large decline in BP is associated with worsened survival.
doi:10.1038/ki.2013.237
PMCID: PMC3788841  PMID: 23783241
9.  Progressive endothelin-1 gene activation initiates chronic/end stage renal disease following experimental ischemic-reperfusion injury 
Kidney international  2013;84(4):703-712.
This study assessed whether endothelin-1 (ET1) helps mediate post-ischemic acute kidney injury (AKI) progression to chronic kidney disease (CKD). The impact(s) of potent ETA or ETB receptor-specific antagonists (Atrasentan and BQ-788, respectively) on disease progression were assessed 24 hours or 2 weeks following 30 minutes of unilateral ischemia in CD-1 mice. Unilateral ischemia caused progressive renal ET-1 protein/mRNA increases with concomitant ETA, but not ETB, mRNA elevations. Extensive histone remodeling consistent with gene activation and increased RNA polymerase II binding occurred at the ET-1 gene. Unilateral ischemia produced progressive renal injury as indicated by severe histologic injury and a 40% loss of renal mass. Pre- and post-ischemia or just post-ischemic treatment with Atrasentan conferred dramatic protective effects such as decreased tubule/microvascular injury, normalized tissue lactate, and total preservation of renal mass. Nuclear KI-67 staining was not increased by Atrasentan, implying that increased tubule proliferation was not involved. Conversely, ETB blockade had no protective effect. Thus, our findings provide the first evidence that ET-1 operating through ETA can play a critical role in ischemic AKI progression to CKD. Blockade of ETA provided dramatic protection, indicating the functional significance of these results.
doi:10.1038/ki.2013.157
PMCID: PMC3788861  PMID: 23698233
Endothelin-1; endothelin-1 receptor A; endothelin-1 receptor B; epigenetic modifications; Atrasentan; BQ-788
10.  Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes in both general and high-risk populations 
Kidney international  2011;80(1):93-104.
Both low eGFR and albuminuria are known risk factors for ESRD. This paper focuses on their joint contribution to ESRD and other kidney outcomes.
We performed a collaborative meta-analysis of 9 general population cohorts with 845,125 participants and 8 cohorts with 173,892 participants selected because of high risk for chronic kidney disease. Both eGFR and albuminuria were tested as risk factors for ESRD, acute kidney injury and progressive chronic kidney disease.
In general population cohorts, the risk for ESRD was unrelated to eGFR at values 75–105 ml/min/1.73m2 and increased exponentially at lower eGFR. Hazard ratios (95% confidence interval) at eGFR 60, 45, and 15 (versus 95) ml/min/1.73m2 were 3.69 (2.36–5.76), 29.3 (19.5–44.1) and 454.9 (112.4–1840.2), respectively, after adjustment for albumin-to-creatinine ratio and cardiovascular risk factors. Albuminuria was associated with ESRD risk linearly without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios 30, 300 and 1000 (versus 5) mg/g were 4.87 (2.30–10.3), 13.4 (5.49–32.7) and 28.4 (14.9–54.2), respectively. eGFR and albuminuria were multiplicatively associated with ESRD, without evidence for interaction. Similar, but numerically less pronounced associations were observed for acute kidney injury and progressive chronic kidney disease. The findings in high risk cohorts were generally comparable to those in general population cohorts.
In conclusion, lower eGFR and higher albuminuria are risk factors for ESRD, acute kidney injury and progressive chronic kidney disease independent of each other and of cardiovascular risk factors, both in the general population and high risk cohorts.
doi:10.1038/ki.2010.531
PMCID: PMC3959732  PMID: 21289597
Meta-analysis; eGFR (kidney function); albumin-to-creatinine ratio (albuminuria); dipstick (proteinuria); ESRD (end-stage renal disease); acute kidney injury; progressive chronic kidney disease
11.  White adipose tissue overproduces the lipid-mobilizing factor zinc alpha2-glycoprotein in chronic kidney disease 
Kidney International  2013;83(5):878-886.
Chronic kidney disease (CKD) is frequently associated with protein energy wasting which has been recognized as a strong predictive factor of mortality. Zinc α2-glycoprotein (ZAG) has been proposed as a new adipokine involved in body weight control through its lipid mobilizing activity. We hypothesized that the uremic environment in CKD could alter ZAG production by white adipose tissue and contribute to CKD-associated metabolic disturbances. ZAG protein was quantified in 3T3-L1 adipocytes after incubation with plasma from healthy volunteers and CKD patients (20%, v/v). ZAG was also measured in white adipose tissue (WAT) from 5/6 nephrectomized rodents (Nx5/6) and subcutaneous adipose tissue biopsies from end-stage renal disease patients. Uremic plasma induced a significant increase in ZAG synthesis in 3T3-L1 adipocytes (+124%, p<0.001), associated with an increased basal lipolysis (+31%, p<0.01) and a blunted lipogenesis (−53%, p<0.05). In vivo, Nx5/6 rats and mice exhibited a significant decrease in WAT accretion (−44%, p<0.01 and −43%, p<0.005, respectively) and a higher content of ZAG protein in WAT than control (+498%, p<0.05 and +106%, p<0.01 respectively). Human WAT biopsies from CKD patients exhibited a higher content of ZAG (+573%, p<0.05) than age matched control. This study demonstrated for the first time that ZAG protein content is increased in white adipose tissue from CKD patients or animal models. Overproduction of ZAG in CKD could be a major contributor to dysmetabolism associated with CKD.
doi:10.1038/ki.2013.9
PMCID: PMC3938447  PMID: 23423258
chronic kidney disease, zinc α2-glycoprotein, ZAG, white adipose tissue, lipolysis, lipogenesis
12.  Numerous protein-bound solutes are cleared by the kidney with high efficiency 
Kidney international  2013;84(3):585-590.
The kidney clears numerous solutes from the plasma; however, retention of these solutes causes uremic illness when the kidneys fail. We know remarkably little about which retained solutes are toxic and this limits our ability to improve dialysis therapies. To explore this we employed untargeted mass spectrometry to identify solutes that are efficiently cleared by the kidney. High resolution mass spectrometry detected 1808 features in the urine and plasma ultrafiltrate of 5 individuals with normal renal function. The estimated clearance rates of 1082 peaks were greater than the creatinine clearance indicating tubular secretion. Further analysis identified 90 features representing solutes with estimated clearance rates greater than the renal plasma flow. Quantitative mass spectrometry with stable isotope dilution confirmed that efficient clearance of these solutes is made possible by the combination of binding to plasma proteins and tubular secretion. Tandem mass spectrometry established the chemical identity of 13 solutes including hippuric acid, indoxyl sulfate, and p-cresol sulfate. These 13 efficiently cleared solutes were found to accumulate in the plasma of hemodialysis patients, with free levels rising to more than 20-fold normal for all but two of them. Thus, further analysis of solutes efficiently cleared by secretion in the native kidney may provide a potential route to the identification of uremic toxins.
doi:10.1038/ki.2013.154
PMCID: PMC3758437  PMID: 23636170
13.  The erythropoietin receptor is a downstream effector of Klotho-induced cytoprotection 
Kidney international  2013;84(3):468-481.
Although the role of the erythropoietin (Epo) receptor (EpoR) in erythropoiesis has been known for decades, its role in non-hematopoietic tissues is still not well defined. Klotho has been shown and Epo has been suggested to protect against acute ischemia-reperfusion injury in the kidney. Here we found in rat kidney and in a rat renal tubular epithelial cell line (NRK cells) EpoR transcript and antigen, and EpoR activity signified as Epo-induced phosphorylation of Jak2, ErK, Akt, and Stat5 indicating the presence of functional EpoR. Transgenic overexpression of Klotho or addition of exogenous recombinant Klotho increased kidney EpoR protein and transcript. In NRK cells, Klotho increased EpoR protein, enhanced Epo-triggered phosphorylation of Jak2 and Stat5, the nuclear translocation of phospho-Stat5, and protected NRK cells from hydrogen peroxide cytotoxicity. Knock-down of endogenous EpoR rendered NRK cells more vulnerable, and overexpression of EpoR more resistant to peroxide-induced cytotoxicity, indicating that EpoR mitigates oxidative damage. Knock-down of EpoR by siRNA abolished Epo-induced Jak2, and Stat5 phosphorylation, and blunted the protective effect of Klotho against peroxide-induced cytotoxicity. Thus in the kidney, EpoR and its activity are downstream effectors of Klotho enabling it to function as cytoprotective protein against oxidative injury.
doi:10.1038/ki.2013.149
PMCID: PMC3758776  PMID: 23636173
Cytotoxicity; Erythropoietin; Erythropoietin receptor; Kidney cell line; Klotho; Oxidative stress; Jak2; NRK cell; Stat5
14.  Raising Awareness of Acute Kidney Injury: A Global Perspective of a Silent Killer 
Kidney international  2013;84(3):457-467.
Worldwide, acute kidney injury (AKI) is associated with poor patient outcomes. Over the last few years, collaborative efforts, enabled by a common definition of AKI, have provided a description of the epidemiology, natural history and outcomes of this disease and improved our understanding of the pathophysiology. There is increased recognition that AKI is encountered in multiple settings and in all age groups, and that its course and outcomes are influenced by the severity and duration of the event. The effect of AKI on an individual patient and the resulting societal burden that ensues from the long term effects of the disease, including development of chronic kidney disease (CKD) and end stage renal disease (ESRD), is attracting increasing scrutiny. There is evidence of marked variation in the management of AKI which is, to a large extent, due to a lack of awareness and an absence of standards for prevention, early recognition and intervention. These emerging data point to an urgent need for a global effort to highlight that AKI is preventable, its course modifiable, and its treatment can improve outcomes. In this article, we provide a framework of reference and propose specific strategies to raise awareness of AKI globally, with the goal to ultimately improve outcomes from this devastating disease.
doi:10.1038/ki.2013.153
PMCID: PMC3758780  PMID: 23636171
15.  Activation of hepatocyte growth factor receptor, c-met, in renal tubules is required for renoprotection after acute kidney injury 
Kidney international  2013;84(3):509-520.
Hepatocyte growth factor is a pleiotrophic protein that promotes injury repair and regeneration in multiple organs. Here, we show that after acute kidney injury (AKI), the HGF receptor, c-met, was induced predominantly in renal tubular epithelium. To investigate the role of tubule-specific induction of c-met in AKI, we generated conditional knockout mice, in which the c-met gene was specifically disrupted in renal tubules. These Ksp-met−/−mice were phenotypically normal and had no appreciable defect in kidney morphology and function. However, in AKI induced by cisplatin or ischemia-reperfusion injury, the loss of tubular c-met substantially aggravated renal injury. Compared with controls, Ksp-met−/−mice displayed higher serum creatinine, more severe morphologic lesions, and increased apoptosis, which was accompanied by an increased expression of Bax and Fas ligand and decreased phosphorylation-activation of Akt. In addition, ablation of c-met in renal tubules promoted chemokine expression and renal inflammation after AKI. Consistently, ectopic expression of hepatocyte growth factor in vivo protected the kidneys against AKI in control mice, but not in Ksp-met−/−counterparts. Thus, our results suggest that tubule-specific c-met signaling is crucial in conferring renal protection after AKI, primarily by its anti-apoptotic and anti-inflammatory mechanisms.
doi:10.1038/ki.2013.102
PMCID: PMC3758808  PMID: 23715119
HGF; c-met; acute kidney injury; apoptosis; inflammation
16.  Genotypic variation and outcomes in kidney transplantation: donor and recipient effects 
Kidney international  2013;84(3):431-433.
The genetic composition of a donor impacts long term allograft survival after kidney transplantation. Effects of the recipient’s genetic make-up, particularly variation in immune response pathway genes are less certain. A report in this issue of Kidney International reveals improved graft survival in transplant recipients with lower copy numbers of the complement 4 gene (C4) after receipt of deceased donor kidneys. Genomics breakthroughs in nephrology and immunology will likely revolutionize the field of transplant medicine.
doi:10.1038/ki.2013.167
PMCID: PMC3761401  PMID: 23989355
17.  Upregulation of c-mip is closely related to podocyte dysfunction in membranous nephropathy 
Kidney International  2013;83(3):414-425.
Membranous nephropathy (MN) is a glomerular disease characterized by a nephrotic syndrome without infiltration of inflammatory cells or proliferation of resident cells. Although the cause of the disease is unknown, the primary pathogenic mechanism responsible for the accumulation of immune deposits on the outer aspect of the glomerular basement membrane involves the generation of autoantibodies against antigen targets expressed at the membrane surface of podocyte. The molecular mechanisms of nephrotic proteinuria, which reflects a profound disorder of podocyte function, remain unclear. We show here that induction of c-mip in passive type Heymann nephritis (PHN) coincides with the occurrence of proteinuria. c-mip expression is not detectable in the glomeruli of PHN rats receiving a single dose of anti-megalin polyclonal antibody, yet the immune complexes are readily present but without triggering of proteinuria. Rats reinjected with anti-megalin develop a few days later heavy proteinuria concomitantly with c-mip overproduction in podocytes. We show that overexpression of c-mip is associated with downregulation of synaptopodin in human MN, PHN rats and c-mip transgenic mice, while the abundance of death-associated protein kinase (DAPK) and integrin linked kinase (ILK) is increased. Finally, cyclosporine treatment reduces significantly proteinuria in PHN rats, concomitantly with downregulation of c-mip abundance in podocytes. These results suggest that c-mip plays an active role in podocyte disorders of MN.
doi:10.1038/ki.2012.426
PMCID: PMC3927461  PMID: 23302718
Adult; Apoptosis Regulatory Proteins; physiology; Calcium-Calmodulin-Dependent Protein Kinases; physiology; Carrier Proteins; analysis; genetics; physiology; Cyclosporine; therapeutic use; Glomerulonephritis, Membranous; drug therapy; pathology; Humans; Podocytes; pathology; physiology; Protein-Serine-Threonine Kinases; physiology; Up-Regulation; glomerular disease; Heymann nephritis; membranous nephropathy; nephrotic syndrome; Pathophysiology of Renal Disease and Progression
18.  Serum- and glucocorticoid-regulated kinase 1 is upregulated following unilateral ureteral obstruction causing epithelial–mesenchymal transition 
Kidney international  2010;78(7):668-678.
Obstructive nephropathy leads to chronic kidney disease, characterized by a progressive epithelial-to-mesenchymal cell transition (EMT)-driven interstitial fibrosis. To identify the mechanisms causing EMT, we used the mouse model of unilateral ureteral obstruction and found a rapid and significant increase in serum- and glucocorticoid-regulated kinase-1 (SGK1) expression in the kidneys with an obstructed ureter. Knockout of SGK1 significantly suppressed obstruction-induced EMT, kidney fibrosis, increased glycogen synthase kinase-3β activity, and decreased accumulation of the transcriptional repressor Snail. This caused a reduced expression of the mesenchymal marker α-smooth muscle actin, and collagen deposition in this model. In cultured kidney epithelial cells, mechanical stretch or treatment with transforming growth factor-β not only stimulated the transcription of SGK1, but also stimulated EMT in an SGK1-dependent manner. Activated SGK1 stimulated Snail accumulation and downregulation of the epithelial marker E-cadherin. Hence, our study shows that SGK1 is involved in mediating fibrosis associated with obstructive nephropathy.
doi:10.1038/ki.2010.214
PMCID: PMC3935313  PMID: 20631674
epithelial-to-mesenchymal transition; fibrosis; glycogen synthase kinase; obstructive nephropathy; SGK1; Snail
19.  Diet, but not oral probiotics, effectively reduces urinary oxalate excretion and calciumoxalate supersaturation 
Kidney international  2010;78(11):1178-1185.
We examined the effect of a controlled diet and two probiotic preparations on urinary oxalate excretion, a risk factor for calcium oxalate kidney stone formation, in patients with mild hyperoxaluria. Patients were randomized to a placebo, a probiotic, or a synbiotic preparation. This tested whether these probiotic preparations can increase oxalate metabolism in the intestine and/or decrease oxalate absorption from the gut. Patients were maintained on a controlled diet to remove the confounding variable of differing oxalate intake from food. Urinary oxalate excretion and calcium oxalate supersaturation on the controlled diet were significantly lower compared with baseline on a free-choice diet. Neither study preparation reduced urinary oxalate excretion nor calcium oxalate supersaturation. Fecal lactobacilli colony counts increased on both preparations, whereas enterococcal and yeast colony counts were increased on the synbiotic. Total urine volume and the excretion of oxalate and calcium were all strong independent determinants of urinary calcium oxalate supersaturation. Hence, dietary oxalate restriction reduced urinary oxalate excretion, but the tested probiotics did not influence urinary oxalate levels in patients on a restricted oxalate diet. However, this study suggests that dietary oxalate restriction is useful for kidney stone prevention.
doi:10.1038/ki.2010.310
PMCID: PMC3923490  PMID: 20736987
diet therapy; lactobacilli; nephrolithiasis; probiotic; synbiotic; urolithiasis
20.  Association of estimated glomerular filtration rate and albuminuria with mortality and end-stage renal disease: a collaborative meta-analysis of kidney disease cohorts 
Kidney international  2011;79(12):1331-1340.
Limited data are available on the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end stage renal disease (ESRD) among individuals with chronic kidney disease (CKD). We conducted a collaborative meta-analysis of 21,688 participants selected for CKD from 13 cohorts.
After adjustment for potential confounders and albuminuria, a 15 mL/min/1.73 m2 lower eGFR below 45 mL/min/1.73 m2 was significantly associated with mortality (pooled hazard ratio [HR] 1.47 [95% CI: 1.22–1.79]), and ESRD (pooled HR 6.24 [95% CI: 4.84–8.05]). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eight-fold higher albumin:creatinine ratio (ACR) or protein:creatinine ratio (PCR) was significantly associated with mortality (pooled HR 1.40 [95% CI: 1.27–1.55]), without evidence of significant heterogeneity. An eight-fold higher ACR or PCR was also strongly associated with ESRD (pooled HR 3.04 [95% CI: 2.27–4.08]), with significant heterogeneity between HR estimates.
Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD. The associations are stronger for ESRD than for mortality. The observed associations are consistent with CKD classification based on eGFR stages, and suggest that albuminuria provides additional prognostic information among individuals with CKD.
doi:10.1038/ki.2010.550
PMCID: PMC3917543  PMID: 21289598
21.  Strategies to reverse endothelial dysfunction in diabetic nephropathy 
Kidney international  2012;82(11):1151-1154.
Endothelial dysfunction underlies the basic pathophysiology of microvascular complications of diabetes. Endothelial dysfunction is associated with impaired nitric oxide (NO) availability. Since NO production is tightly regulated by endothelial nitric oxide synthase (eNOS), several therapeutic strategies have been investigated and proposed to improve eNOS bioavailability in the vasculature. The findings of Cheng et al. suggest that increased availability of eNOS may be an effective strategy in restoring endothelial function in patients with diabetic nephropathy.
doi:10.1038/ki.2012.306
PMCID: PMC3914716  PMID: 23151985
22.  Kidney paired donation in the presence of donor-specific antibodies 
Kidney international  2013;84(5):1009-1016.
Incompatible donor/recipient pairs with broadly sensitized recipients have difficulty finding a crossmatch-compatible match, despite a large kidney paired donation pool. One approach to this problem is to combine kidney paired donation with lower-risk crossmatch-incompatible transplantation with intravenous immunoglobulin. Whether this strategy is non-inferior compared with transplantation of sensitized patients without donor-specific antibody (DSA) is unknown. Here we used a protocol including a virtual crossmatch to identify acceptable crossmatch-incompatible donors and the administration of intravenous immunoglobulin to transplant 12 HLA-sensitized patients (median calculated panel reactive antibody 98%) with allografts from our kidney paired donation program. This group constituted the DSA(+) kidney paired donation group. We compared rates of rejection and survival between the DSA(+) kidney paired donation group with a similar group of 10 highly sensitized patients (median calculated panel reactive antibody 85%) that underwent DSA(−) kidney paired donation transplantation without intravenous immunoglobulin. At median follow-up of 22 months, the DSA(+) kidney paired donation group had patient and graft survival of 100%. Three patients in the DSA(+) kidney paired donation group experienced antibody-mediated rejection. Patient and graft survival in the DSA(−) kidney paired donation recipients was 100% at median follow-up of 18 months. No rejection occurred in the DSA(−) kidney paired donation group. Thus, our study provides a clinical framework through which kidney paired donation can be performed with acceptable outcomes across a crossmatch-incompatible transplant.
doi:10.1038/ki.2013.206
PMCID: PMC3913053  PMID: 23715120
desensitization; donor-specific HLA antibodies; kidney paired donation; living-donor kidney transplantation
23.  Long-term clinical consequences of acute kidney injury in the HIV-infected 
Kidney international  2010;78(5):478-485.
To evaluate the long-term consequences of acute kidney injury (AKI) in human immunodeficiency virus (HIV)-infected persons, we studied 17,325 patients in a national HIV registry during their first hospitalization. We determined the association of AKI with risk for heart failure, cardiovascular events, end-stage renal disease (ESRD), and mortality beginning 90 days after discharge. Based on AKI Network criteria, 2453 had stage 1; 273 had stage 2 or 3; and 334 had dialysis-requiring AKI. Over a mean follow-up period of 5.7 years, 333 had heart failure, 673 had cardiovascular diseases (CVDs), 348 developed ESRD, and 8405 deaths occurred. In multivariable-adjusted analyses, AKI stage 1 was associated with death and ESRD, but not heart failure or other CVD. Dialysis-requiring AKI had much stronger and significant associations with increased risk for long-term ESRD, and death in addition to heart failure and cardiovascular events. When AKI was reclassified to account for recovery, stage 1 with recovery was still associated with death, but not ESRD. Thus, in this national sample of HIV-infected persons, we found the clinical repercussions of AKI appear to extend beyond the hospital setting contributing to excess cardiovascular risks, ESRD, and mortality. Additionally, AKI affected almost one of six patients with HIV who survived at least 90 days following discharge.
doi:10.1038/ki.2010.171
PMCID: PMC3913062  PMID: 20520594
acute kidney injury; cardiovascular disease; end-stage renal disease; HIV; mortality
24.  Interleukin-1 Critically Accounts for Intra-renal Th17 Cell Activation in the Obstructed Kidney 
Kidney international  2011;81(4):379-390.
Interleukin 17A-secreting T-helper 17 cells are pathogenic in inflammatory kidney diseases, but their intra-renal regulation is poorly understood. Mouse unilateral ureteral obstruction was examined to better define T-helper 17 cell dynamics during interstitial inflammation. Cell sub-types were analyzed by multi-color flow cytometry, by cell sorting and by their effects on in vitro-generated T-helper 17 cells. Interleukin 17A expression progressively increased in obstructed kidneys and was localised to CCR6+CCR4+/−CD4+ T-cells. Numbers of CCR6+CD4+ T-cells increased >10-fold by 72 hours, were enriched for interleukin 17A production and were highly proliferative by in vivo bromodeoxyuridine labelling. Secreted products from leukocytes of obstructed kidneys enhanced interleukin 17A production by in vitro-generated T-helper 17 cells. The T-helper 17-enhancing activity was identified as interleukin-1 produced by renal dendritic cells and monocytes. The in vivo validity of these findings was confirmed in mice lacking interleulin-1-receptor and in mice treated with a recombinant interleukin-1 receptor antagonist which exhibited reduced intra-renal T-helper 17 activity compared to control animals. Thus, the inflamed kidney accumulates CCR6+ T-helper 17 cells that undergo activation and proliferation. Production of interleukin 1 family cytokines by resident dendritic cells and infiltrating monocytes enhances intra-renal T-helper 17 activation in acute kidney injury.
doi:10.1038/ki.2011.348
PMCID: PMC3913378  PMID: 21975862
Obstructive nephropathy; Lymphocytes; Inflammation; Cytokines; Chemokine Receptor
25.  Has the circulating permeability factor in primary FSGS been found? 
Kidney international  2013;84(2):235-238.
A circulating permeability factor has long been implicated in the pathogenesis of primary focal segmental glomerulosclerosis (FSGS). Recent evidence in animal models, and now in several cohorts of patients with primary FSGS, suggest that the soluble urokinase-type plasminogen-activator receptor (suPAR) might fulfill at least a role as biomarker and perhaps even as contributing factor. Although ongoing studies are needed, confirmation of these findings might lead to new diagnostic and therapeutic strategies for this often resistant glomerular disease, as well as a better understanding of podocyte dysfunction.
doi:10.1038/ki.2013.204
PMCID: PMC3733481  PMID: 23903418

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