Renal sarcoma and associated malignant pulmonary embolism: a report of 2 cases

Renal sarcoma with venous tumour thrombus is usually an aggressive malignancy that necessitates complete surgical extirpation to achieve cure. Due to the rarity of these tumours, clinicians rely on case reports to better understand and treat patients with this disease. We recently encountered 2 patients with renal sarcoma who developed malignant pulmonary embolus. Our cases, combined with those previously published, suggest renal sarcoma tumour thrombus is at high risk for spontaneous and intraoperative embolization. This report details our experience and outlines measures that may decrease the rate of venous tumour embolization in patients with sarcoma.Sarcomas represent approximately 1% of primary renal neoplasms. To our knowledge, there are only 10 cases in the medical literature of postpubertal patients with primary renal sarcoma associated with inferior vena cava (IVC) tumour thrombus.^1–10 Of these cases, 3 suffered a malignant pulmonary embolus (PE).^4,6,8 We present 2 additional cases of renal sarcomas with IVC thrombus and malignant PE.     

Subsequent prostate cancer detection in patients with prostatic intraepithelial neoplasia or atypical small acinar proliferation

Introduction:

To evaluate the predictors of prostate cancer in follow-up of patients diagnosed on initial biopsy with high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP).

Methods:

We studied 201 patients with HGPIN and 22 patients with ASAP on initial prostatic biopsy who had subsequent prostatic biopsies. The mean time of follow-up was 17.3 months (range 1–62). The mean number of biopsy sessions was 2.5 (range 2–6), and the median number of biopsy cores was 10 (range 6–14).

Results:

On subsequent biopsies, the rate of prostate cancer was 21.9% (44/201) in HGPIN patients. Of these, 32/201 patients (15.9%), 9/66 patients (13.6%) and 3/18 patients (16.6%) were found to have cancer on the first, second and third follow-up biopsy sessions, respectively. In ASAP patients, the cancer detection rate was 13/22 (59.1%), all of whom were found on the first follow-up biopsy. There was a statistically significant difference between the cancer detection rate in ASAP and HGPIN patients (p < 0.001). Multivariate analysis showed that the independent predictors of cancer were the number of cores in the initial biopsy, the number of cores (> 10) in the follow-up biopsy and a prostate specific antigen (PSA) density of ≥ 0.15 (odds ratio 0.77, 3.46 and 2.7,8 respectively; p < 0.04). Conversely, in ASAP patients none of these variables were found to be associated with cancer diagnosis.

Conclusion:

ASAP is a strong predictive factor associated with cancer when compared with HGPIN. The factors predictive of cancer on follow-up biopsy of HGPIN are number of cores on initial biopsy, more than 10 cores in rebiopsy and elevated PSA density. As the cancer detection rate on repeated biopsy of HGPIN patients is the same as that of patients without HGPIN, perhaps the standard of repeat biopsy in all patients with HGPIN should be revisited.Owing to the widespread use of prostate specific antigen (PSA) as a screening tool for prostate cancer associated with increasing use of transrectal ultrasound (TRUS) guided prostate needle biopsy and the increasing number of sampling cores per biopsy, the histological findings of high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP) has also increased.The detection rate of HGPIN in TRUS-guided needle biopsies performed owing to an elevated PSA level or an abnormal digital rectal examination (DRE), was found to be between 4% and 25% of patients^1–4 and the cancer detection rate on repeated biopsy was reported from 2% to 47% of patients.^1,3,5,6,7 Conversely, the rate of ASAP on initial biopsy was reported to range from 2.4% to 3.7%^3,8,9 the cancer detection rate on repeated biopsy was found to be as high as 52% in isolated ASAP^3,8,10 and 72% in ASAP associated with HGPIN.^3,11The management of patients found to have HGPIN on initial biopsy varies considerably, ranging from immediate rebiopsy to close observation at varying intervals.^12–15 Our aim was to examine our experience with prostatic rebiopsy in patients with HGPIN, ASAP or both.     

Renal Dendritic Cells Ameliorate Nephrotoxic Acute Kidney Injury

Inflammation contributes to the pathogenesis of acute kidney injury. Dendritic cells (DCs) are immune sentinels with the ability to induce immunity or tolerance, but whether they mediate acute kidney injury is unknown. Here, we studied the distribution of DCs within the kidney and the role of DCs in cisplatin-induced acute kidney injury using a mouse model in which DCs express both green fluorescence protein and the diphtheria toxin receptor. DCs were present throughout the tubulointerstitium but not in glomeruli. We used diphtheria toxin to deplete DCs to study their functional significance in cisplatin nephrotoxicity. Mice depleted of DCs before or coincident with cisplatin treatment but not at later stages experienced more severe renal dysfunction, tubular injury, neutrophil infiltration and greater mortality than nondepleted mice. We used bone marrow chimeric mice to confirm that the depletion of CD11c-expressing hematopoietic cells was responsible for the enhanced renal injury. Finally, mixed bone marrow chimeras demonstrated that the worsening of cisplatin nephrotoxicity in DC-depleted mice was not a result of the dying or dead DCs themselves. After cisplatin treatment, expression of MHC class II decreased and expression of inducible co-stimulator ligand increased on renal DCs. These data demonstrate that resident DCs reduce cisplatin nephrotoxicity and its associated inflammation.Innate immune responses are pathogenic in both ischemic and toxic acute renal failure. In response to renal injury, inflammatory chemokines and cytokines are produced both by renal parenchymal cells, such as proximal tubule epithelial cells, and resident or infiltrating leukocytes.^1–4 The elaborated chemokines and cytokines, including TNF-α, IL-18, keratinocyte-derived chemokine, and monocyte chemoattractant protein 1, subsequently recruit additional immune cells to the kidney, such as neutrophils, T cells, monocytes, and inflammatory dendritic cells (DCs), which may cause further injury through pathways that are not fully defined.^2,5–12 DCs are sentinels of the immune system and under steady-state conditions induce tolerance by various mechanisms, including production of TGF-β, IL-10, or indoleamine 2,3-dioxygenase^13–16; expression of PDL-1, PDL-2, or FcγR2B^17,18; clonal deletion of autoreactive T cells¹⁹; and induction of T regulatory cells via the inducible co-stimulator (ICOS) pathway.^20–23 In response to pathogens or products of tissue injury, DCs mature and initiate immunity or inflammatory diseases.^24,25 Monocytes recruited to inflamed tissue can also differentiate into inflammatory DCs and mediate defense against pathogens or contribute to inflammatory tissue responses.^12,26–28Although DCs represent a major population of immune cells in the kidney,²⁹ their role in renal disease is poorly defined. Liposomal clodronate has been used to study the pathophysiologic role of phagocytic cells, which include DCs and macrophages.^3,30–32 An alternative DC-specific approach uses expression of the simian diphtheria toxin receptor (DTR) driven by the CD11c promoter to target DCs for DT-mediated cell death.²⁴ This model has been used extensively to study the role of DCs in various physiologic and pathophysiologic contexts^32,33; however, its application in kidney disease has been limited to recent studies of immune complex–mediated glomerulonephritis.^12,23We have reported that inflammation plays an important role in the pathogenesis of cisplatin-induced acute kidney injury (AKI).^1,4,5,34 Given the dearth of information regarding the role of renal DCs in AKI, this study examined the renal DC population and the impact of its depletion on cisplatin nephrotoxicity. We show that DCs are the most abundant population of renal resident leukocytes and form a dense network throughout the tubulointerstitium. Renal DCs displayed surface markers that distinguished them from splenic DCs. Using a conditional DC depletion model, we determined that DC ablation markedly exacerbates cisplatin-induced renal dysfunction, structural injury, and infiltration of neutrophils.     

Glucagon-Like Peptide 1/Glucagon Receptor Dual Agonism Reverses Obesity in Mice

OBJECTIVE

Oxyntomodulin (OXM) is a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide that reduces body weight in obese subjects through increased energy expenditure and decreased energy intake. The metabolic effects of OXM have been attributed primarily to GLP1R agonism. We examined whether a long acting GLP1R/GCGR dual agonist peptide exerts metabolic effects in diet-induced obese mice that are distinct from those obtained with a GLP1R-selective agonist.

RESEARCH DESIGN AND METHODS

We developed a protease-resistant dual GLP1R/GCGR agonist, DualAG, and a corresponding GLP1R-selective agonist, GLPAG, matched for GLP1R agonist potency and pharmacokinetics. The metabolic effects of these two peptides with respect to weight loss, caloric reduction, glucose control, and lipid lowering, were compared upon chronic dosing in diet-induced obese (DIO) mice. Acute studies in DIO mice revealed metabolic pathways that were modulated independent of weight loss. Studies in Glp1r^−/− and Gcgr^−/− mice enabled delineation of the contribution of GLP1R versus GCGR activation to the pharmacology of DualAG.

RESULTS

Peptide DualAG exhibits superior weight loss, lipid-lowering activity, and antihyperglycemic efficacy comparable to GLPAG. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were more pronounced upon chronic treatment with DualAG than with GLPAG. Dual receptor agonism also increased fatty acid oxidation and reduced hepatic steatosis in DIO mice. The antiobesity effects of DualAG require activation of both GLP1R and GCGR.

CONCLUSIONS

Sustained GLP1R/GCGR dual agonism reverses obesity in DIO mice and is a novel therapeutic approach to the treatment of obesity.Obesity is an important risk factor for type 2 diabetes, and ∼90% of patients with type 2 diabetes are overweight or obese (1). Among new therapies for type 2 diabetes, peptidyl mimetics of the gut-derived incretin hormone glucagon-like peptide 1 (GLP-1) stimulate insulin biosynthesis and secretion in a glucose-dependent manner (2,3) and cause modest weight loss in type 2 diabetic patients. The glucose-lowering and antiobesity effects of incretin-based therapies for type 2 diabetes have prompted evaluation of the therapeutic potential of other glucagon-family peptides, in particular oxyntomodulin (OXM). The OXM peptide is generated by post-translational processing of preproglucagon in the gut and is secreted postprandially from l-cells of the jejuno-ileum together with other preproglucagon-derived peptides including GLP-1 (4,5). In rodents, OXM reduces food intake and body weight, increases energy expenditure, and improves glucose metabolism (6–8). A 4-week clinical study in obese subjects demonstrated that repeated subcutaneous administration of OXM was well tolerated and caused significant weight loss with a concomitant reduction in food intake (9). An increase in activity-related energy expenditure was also noted in a separate study involving short-term treatment with the peptide (10).OXM activates both, the GLP-1 receptor (GLP1R) and glucagon receptor (GCGR) in vitro, albeit with 10- to 100-fold reduced potency compared with the cognate ligands GLP-1 and glucagon, respectively (11–13). It has been proposed that OXM modulates glucose and energy homeostasis solely by GLP1R agonism, because its acute metabolic effects in rodents are abolished by coadministration of the GLP1R antagonist exendin(9–39) and are not observed in Glp1r^−/− mice (7,8,14,15). Other aspects of OXM pharmacology, however, such as protective effects on murine islets and inhibition of gastric acid secretion appear to be independent of GLP1R signaling (14). In addition, pharmacological activation of GCGR by glucagon, a master regulator of fasting metabolism (16), decreases food intake in rodents and humans (17–19), suggesting a potential role for GCGR signaling in the pharmacology of OXM. Because both OXM and GLP-1 are labile in vivo (T_1/2 ∼12 min and 2–3 min, respectively) (20,21) and are substrates for the cell surface protease dipeptidyl peptidase 4 (DPP-4) (22), we developed two long-acting DPP-4–resistant OXM analogs as pharmacological agents to better investigate the differential pharmacology and therapeutic potential of dual GLP1R/GCGR agonism versus GLP1R-selective agonism. Peptide DualAG exhibits in vitro GLP1R and GCGR agonist potency comparable to that of native OXM and is conjugated to cholesterol via a Cys sidechain at the C-terminus for improved pharmacokinetics. Peptide GLPAG differs from DualAG by only one residue (Gln³→Glu) and is an equipotent GLP1R agonist, but has no significant GCGR agonist or antagonist activity in vitro. The objective of this study was to leverage the matched GLP1R agonist potencies and pharmacokinetics of peptides DualAG and GLPAG in comparing the metabolic effects and therapeutic potential of a dual GLP1R/GCGR agonist with a GLP1R-selective agonist in a mouse model of obesity.     

Distinct Functions of Activated Protein C Differentially Attenuate Acute Kidney Injury

Administration of activated protein C (APC) protects from renal dysfunction, but the underlying mechanism is unknown. APC exerts both antithrombotic and cytoprotective properties, the latter via modulation of protease-activated receptor-1 (PAR-1) signaling. We generated APC variants to study the relative importance of the two functions of APC in a model of LPS-induced renal microvascular dysfunction. Compared with wild-type APC, the K193E variant exhibited impaired anticoagulant activity but retained the ability to mediate PAR-1-dependent signaling. In contrast, the L8W variant retained anticoagulant activity but lost its ability to modulate PAR-1. By administering wild-type APC or these mutants in a rat model of LPS-induced injury, we found that the PAR-1 agonism, but not the anticoagulant function of APC, reversed LPS-induced systemic hypotension. In contrast, both functions of APC played a role in reversing LPS-induced decreases in renal blood flow and volume, although the effects on PAR-1-dependent signaling were more potent. Regarding potential mechanisms for these findings, APC-mediated PAR-1 agonism suppressed LPS-induced increases in the vasoactive peptide adrenomedullin and infiltration of iNOS-positive leukocytes into renal tissue. However, the anticoagulant function of APC was responsible for suppressing LPS-induced stimulation of the proinflammatory mediators ACE-1, IL-6, and IL-18, perhaps accounting for its ability to modulate renal hemodynamics. Both variants reduced active caspase-3 and abrogated LPS-induced renal dysfunction and pathology. We conclude that although PAR-1 agonism is solely responsible for APC-mediated improvement in systemic hemodynamics, both functions of APC play distinct roles in attenuating the response to injury in the kidney.Acute kidney injury (AKI) leading to renal failure is a devastating disorder,¹ with a prevalence varying from 30 to 50% in the intensive care unit.² AKI during sepsis results in significant morbidity, and is an independent risk factor for mortality.^3,4 In patients with severe sepsis or shock, the reported incidence ranges from 23 to 51%^5–7 with mortality as high as 70% versus 45% among patients with AKI alone.^1,8The pathogenesis of AKI during sepsis involves hemodynamic alterations along with microvascular impairment.⁴ Although many factors change during sepsis, suppression of the plasma serine protease, protein C (PC), has been shown to be predictive of early death in sepsis models,⁹ and clinically has been associated with early death resulting from refractory shock and multiple organ failure in severe sepsis.¹⁰ Moreover, low levels of PC have been highly associated with renal dysfunction and pathology in models of AKI.¹¹ During vascular insult, PC becomes activated by the endothelial thrombin-thrombomodulin complex, and the activated protein C (APC) exhibits both antithrombotic and cytoprotective properties. We have previously demonstrated that APC administration protects from renal dysfunction during cecal ligation and puncture and after endotoxin challenge.^11,12 In addition, recombinant human APC [drotrecogin alfa (activated)] has been shown to reduce mortality in patients with severe sepsis at high risk of death.¹³ Although the ability of APC to protect from organ injury in vivo is well documented,^11,14,15 the precise mechanism mediating the response has not been ascertained.APC exerts anticoagulant properties via feedback inhibition of thrombin by cleavage of factors Va and VIIIa.¹⁶ However, APC bound to the endothelial protein C receptor (EPCR) can also exhibit direct potent cytoprotective properties by cleaving protease-activated receptor-1 (PAR-1).¹⁷ Various cell culture studies have demonstrated that the direct modulation of PAR-1 by APC results in cytoprotection by several mechanisms, including suppression of apoptosis,^18,19 leukocyte adhesion,^19,20 inflammatory activation,²¹ and suppression of endothelial barrier disruption.^22,23 In vivo, the importance of the antithrombotic activity of APC is well established in model systems^24,25 and in humans.²⁶ However, the importance of PAR-1-mediated effects of APC also has been clearly defined in protection from ischemic brain injury²⁷ and in sepsis models.²⁸ Hence, there has been significant debate whether the in vivo efficacy of APC is attributed primarily to its anticoagulant (inhibition of thrombin generation) or cytoprotective (PAR-1-mediated) properties.^17,29The same active site of APC is responsible for inhibition of thrombin generation by the cleavage of factor Va and for PAR-1 agonism. Therefore, we sought to generate point mutations that would not affect catalytic activity, but would alter substrate recognition to distinguish the two functions. Using these variants, we examined the relative role of the two known functions of APC in a model of LPS-induced renal microvascular dysfunction.     

Racial Composition of Residential Areas Associates with Access to Pre-ESRD Nephrology Care

Referral to a nephrologist before initiation of chronic dialysis occurs less frequently for blacks than whites, but the reasons for this disparity are incompletely understood. Here, we examined the contribution of racial composition by zip code on access and quality of nephrology care before initiation of renal replacement therapy (RRT). We retrospectively studied a cohort study of 92,000 white and black adults who initiated RRT in the United States between June 1, 2005, and October 5, 2006. The percentage of patients without pre-ESRD nephrology care ranged from 30% among those who lived in zip codes with <5% black residents to 41% among those who lived in areas with >50% black residents. In adjusted analyses, as the percentage of blacks in residential areas increased, the likelihood of not receiving pre-ESRD nephrology care increased. Among patients who received nephrology care, the quality of care (timing of care and proportion of patients who received a pre-emptive renal transplant, who initiated therapy with peritoneal dialysis, or who had a permanent hemodialysis access) did not differ by the racial composition of their residential area. In conclusion, racial composition of residential areas associates with access to nephrology care but not with quality of the nephrology care received.Clinical practice guidelines for chronic kidney disease emphasize the importance of timely referral to a nephrologist for patients expected to require renal replacement therapy.^1–3 Nevertheless, approximately 33% of end-stage renal disease (ESRD) patients in the United States do not see a nephrologist before initiation of chronic dialysis.^4,5 Lack of timely access to nephrology care is associated with several adverse outcomes after initiation of dialysis including higher mortality rates,^6–9 higher rates of hospitalization,¹⁰ lower rates of renal transplantation,^11,12 delayed creation of arteriovenous fistulae,¹³ lower rates of achievement of dialysis treatment targets,^14,15 and a lower likelihood of receiving home-based dialysis therapies such as peritoneal dialysis and home hemodialysis.^3,16–18In the United States, black dialysis patients are less likely than white patients to have received nephrology care before onset of ESRD.^9,19–21 They are also less likely to receive a pre-emptive kidney transplant,^22,23 select peritoneal dialysis over hemodialysis,²⁴ and have a vascular access in place at onset of hemodialysis.^25,26 Several factors may contribute to these disparities including differences in insurance status, level of education, physician knowledge or biases, and patient preferences.^9,27–29 In addition, geographic factors such as proximity to dialysis facilities and degree of urbanization also affect access to nephrology care.^30–33A substantial proportion of black patients are also more likely to live in areas where most other residents are black. A recent study demonstrated that both black and white dialysis patients living in predominantly black zip codes were less likely to receive a kidney transplant than patients living in other areas.³⁴ Although levels of income, wealth and education tended to be lower among residents of predominantly black zip codes, lower transplant rates among dialysis patients living in these areas were not completely explained by these measures. Patients who live in predominantly black zip codes may face unique barriers to care that are not explained by measured socioeconomic characteristics of those zip codes. We therefore hypothesized that dialysis patients living in zip codes with a greater proportion of black residents would be less likely to have received pre-ESRD care and less likely to have received high-quality nephrology care than patients living in other zip codes. We also hypothesized that these relationships would not be completely explained by differences in zip code socioeconomic status or patient race.     

Connexin 30 Deficiency Impairs Renal Tubular ATP Release and Pressure Natriuresis

In the renal tubule, ATP is an important regulator of salt and water reabsorption, but the mechanism of ATP release is unknown. Several connexin (Cx) isoforms form mechanosensitive, ATP-permeable hemichannels. We localized Cx30 to the nonjunctional apical membrane of cells in the distal nephron and tested whether Cx30 participates in physiologically important release of ATP. We dissected, partially split open, and microperfused cortical collecting ducts from wild-type and Cx30-deficient mice in vitro. We used PC12 cells as ATP biosensors by loading them with Fluo-4/Fura Red to measure cytosolic calcium and positioning them in direct contact with the apical surface of either intercalated or principal cells. ATP biosensor responses, triggered by increased tubular flow or by bath hypotonicity, were approximately three-fold greater when positioned next to intercalated cells than next to principal cells. In addition, these responses did not occur in preparations from Cx30-deficient mice or with purinergic receptor blockade. After inducing step increases in mean arterial pressure by ligating the distal aorta followed by the mesenteric and celiac arteries, urine output increased 4.2-fold in wild-type mice compared with 2.6-fold in Cx30-deficient mice, and urinary Na⁺ excretion increased 5.2-fold in wild-type mice compared with 2.8-fold in Cx30-deficient mice. Furthermore, Cx30-deficient mice developed endothelial sodium channel–dependent, salt-sensitive elevations in mean arterial pressure. Taken together, we suggest that mechanosensitive Cx30 hemichannels have an integral role in pressure natriuresis by releasing ATP into the tubular fluid, which inhibits salt and water reabsorption.It is well established that renal tubular epithelial cells release ATP,^1–4 which then binds to purinergic receptors along the nephron and collecting ducts to regulate salt and water reabsorption^5–12; however, the molecular mechanism of ATP release and the identity of ATP channels are less clear. The possible mechanisms include vesicular release,^1,2 pannexin or connexin hemichannels,^13–16 ATP-permeable anion channels such as the cystic fibrosis transmembrane conductance regulator,¹⁷ or the maxi anion channel.¹⁸ Previous work also suggested that the release of ATP in epithelia may be triggered by mechanical stimulation,^19–21 including elevations in tubular fluid flow rates. For example, tubular flow–dependent ATP release resulting in purinergic calcium signaling has been well characterized in the cortical collecting duct (CCD)^21–23; however, the ATP release mechanism has not been identified.Connexin 30 (Cx30) is a member of the connexin (Cx) family of transmembrane proteins (more than 20 isoforms). Various Cx proteins can form large pores in the nonjunctional plasma membrane of cells (gap junction hemichannels) before the assembly of two Cx hemichannels into complete gap junction channels between adjacent cells.¹⁴ Cx hemichannels are large, mechanosensitive ion channels that allow the passage of a variety of small molecules and metabolites, including ATP.^14–16 Our laboratory localized Cx30 in the nonjunctional apical plasma membrane of cells in the distal nephron,²⁴ suggesting that Cx30 may function as an ATP-releasing, luminal membrane hemichannel in this nephron segment. To address this hypothesis, we applied a recently developed ATP biosensor technique¹⁸ combined with a Cx30 knockout mouse model²⁵ to show tubular flow–induced ATP release through luminal Cx30 hemichannels in the renal collecting duct. The physiologic significance of this mechanically induced Cx30-mediated luminal ATP release was further studied by assessing its involvement in pressure natriuresis, a multifactorial, multimechanistic intrarenal phenomenon that causes diuresis and natriuresis in response to elevations in systemic BP.²⁶ Pressure natriuresis involves proximal and distal nephron components; hemodynamic factors such as medullary blood flow and renal interstitial hydrostatic pressure; and renal autocoids such as nitric oxide, prostaglandins, kinins, and angiotensin II.^26–32 Because pressure natriuresis is related to mechanical factors and Cx hemichannels are mechanosensitive, we hypothesized that Cx30-mediated ATP release is involved, at least in part, in pressure natriuresis, a critically important phenomenon in the maintenance of body fluid balance and BP.     

Activation of p53 Promotes Renal Injury in Acute Aristolochic Acid Nephropathy

Ingestion of aristolochic acid (AA) can cause AA nephropathy (AAN), in which excessive death of tubular epithelial cells (TECs) characterize the acute phase. AA forms adducts with DNA, which may lead to TEC apoptosis via p53-mediated signaling. We tested this hypothesis both by studying p53-deficient mice and by blocking p53 in TECs with its inhibitor pifithrin-α. AA induced acute AAN in wild-type mice, resulting in massive apoptotic and necrotic TEC death and acute renal failure; p53 deficiency or pharmacologic inhibition attenuated this injury. In vitro, AA induced apoptotic and necrotic death of TEC in a time- and dosage-dependent manner, with apoptosis marked by a 10-fold increase in cleaved caspase-3 and terminal deoxynucleotidyl transferase–mediated digoxigenin-deoxyuridine nick-end labeling–positive/Annexin V-positive propidium iodide–negative TECs (all P < 0.001). AA induced dephosphorylation of STAT3 and the subsequent activation of p53 and TEC apoptosis. In contrast, overexpression of STAT3, p53 inhibition, or p53 knockdown with small interfering RNA all attenuated AA-induced TEC apoptosis. Taken together, these results suggest that AA induces TEC death via apoptosis by dephosphorylation of STAT3 and posttranslational activation of p53, supporting the hypothesis that p53 promotes renal injury in acute AAN.Chinese herb nephropathy was first reported in Belgium in patients with prolonged intake of Chinese herbs during a slimming regimen and is recognized as one of the most severe complications caused by traditional Chinese medicine.^1–3 It is now clear that the major substance that causes Chinese herb nephropathy is the plant nephrotoxin aristolochic acid and its metabolism products.^4–6 Thus, the term aristolochic acid nephropathy (AAN), instead of Chinese herbal nephropathy, is used today.^7,8 AAN has emerged as an important cause of drug-associated renal failure worldwide.⁹Patients with AAN exhibit a rapidly progressive renal deterioration, resulting in acute renal failure that could lead to ESRD.^1–3,10,11 A similar clinical course was observed in experimental animals treated with AA.^12,13 Pathologically, chronic AAN is characterized by extensive interstitial fibrosis with atrophy and loss of renal tubules.^{1–3,10–13} The lesions of chronic AAN are mainly in the cortex involving proximal tubular epithelial cells (TECs)^10–13; glomeruli are relatively spared with minimal inflammation.^9–12 In contrast, progressive TEC death occurs early in the clinical course with an absence of renal fibrosis and inflammation in experimental models and patients with acute AAN.^10,14,15 Although apoptosis is an important pathologic feature in in vivo and in vitro studies of acute AAN,^16–18 the underlying mechanisms remain unclear.In considering the genotoxic effect of AA with the formation of AA-DNA adducts and the importance of the p53 signaling pathway in DNA damage and cell apoptosis,^19–21 we hypothesized that TEC apoptosis in acute AAN is dependent on p53 signaling. We investigated this by inducing acute AAN in p53 knockout (KO) and p53 wild-type (WT) mice and by blocking the p53 activities with a pharmacologic inhibitor. We further studied the toxicity of AA on TEC apoptosis by examining a panel of apoptotic biomarkers. The mechanism that AA induced TEC apoptosis by activating p53 via a STAT3-dependent posttranslational modification was identified.     

Pregnancy and Maternal Outcomes Among Kidney Transplant Recipients

Fertility rates, pregnancy, and maternal outcomes are not well described among women with a functioning kidney transplant. Using data from the Australian and New Zealand Dialysis and Transplant Registry, we analyzed 40 yr of pregnancy-related outcomes for transplant recipients. This analysis included 444 live births reported from 577 pregnancies; the absolute but not relative fertility rate fell during these four decades. Of pregnancies achieved, 97% were beyond the first year after transplantation. The mean age at the time of pregnancy was 29 ± 5 yr. Compared with previous decades, the mean age during the last decade increased significantly to 32 yr (P < 0.001). The proportion of live births doubled during the last decade, whereas surgical terminations declined (P < 0.001). The fertility rate (or live-birth rate) for this cohort of women was 0.19 (95% confidence interval 0.17 to 0.21) relative to the Australian background population. We also matched 120 parous with 120 nulliparous women by year of transplantation, duration of transplant, age at transplantation ±5 yr, and predelivery creatinine for parous women or serum creatinine for nulliparous women; a first live birth was not associated with a poorer 20-yr graft or patient survival. Maternal complications included preeclampsia in 27% and gestational diabetes in 1%. Taken together, these data confirm that a live birth in women with a functioning graft does not have an adverse impact on graft and patient survival.One of the many perceived benefits of kidney transplantation has been restoration of pituitary-ovarian function and fertility in women of reproductive age. Prenatal advice for women with a functioning kidney transplant has been primarily based on data derived from observational research,^1–13 and the reported live-birth rates achieved in such women range from 43.2¹⁴ to 82%.¹⁵Although an increased pregnancy event number has been reported for women with a functioning kidney transplant,¹⁶ little is actually known about “pregnancy rate changes” during the past 40 yr. More importantly, long-term graft and maternal survival analyses, referred to when advising women who have undergone transplantation and are considering a pregnancy, have been mostly performed without adequate matching,¹² or, alternatively, matching has been used but outcomes followed up for only brief intervals^14,17,18 and in small cohorts.^19–22 Published graft matching studies to date suggest no adverse impact 10 yr after a live birth.¹⁴In most instances, pregnancies in women with a kidney graft have been encouraged. Historically, renal function,^8,15,17,18 baseline proteinuria,²³ intercurrent hypertension,^1,24 and time from transplantation^{1,3,5,8,14,15,18,24,25} have been used to predict adverse event risks to the mother, kidney, and offspring. To this are added the often unquantifiable inherent risks for genetically transmitted diseases or the problems associated with prematurity.^26,27 More recently, epidemiologic evidence suggests low birth weight may be associated with the development of hypertension,²⁸ cardiovascular disease,²⁹ insulin resistance,³⁰ and end-stage renal failure.³¹ Moreover, low birth weight is associated with an increased risk for hypertension, independent of genetic and shared environmental factors.³²Series published to date have not captured all pregnancy events or their outcomes. Limitations of some of the published studies include short duration of follow-up and studies with no adequate or long-term matching for decade and renal function.We examined fertility rates, pregnancy rates, and pregnancy outcomes over 40 yr in an at-risk population, defined as women who were aged between 15 and 49 and had a functioning kidney transplant, using ANZDATA registry data. In addition, maternal and graft outcomes were analyzed, and, uniquely, a matched cohort analysis of 120 nulliparous and 120 parous women who had undergone transplantation enabled analysis of outcomes at 20 yr.     

Active Vitamin D Treatment for Reduction of Residual Proteinuria: A Systematic Review

Despite renin-angiotensin-aldosterone system blockade, which retards progression of CKD by reducing proteinuria, many patients with CKD have residual proteinuria, an independent risk factor for disease progression. We aimed to address whether active vitamin D analogs reduce residual proteinuria. We systematically searched for trials published between 1950 and September of 2012 in the Medline, Embase, and Cochrane Library databases. All randomized controlled trials of vitamin D analogs in patients with CKD that reported an effect on proteinuria with sample size≥50 were selected. Mean differences of proteinuria change over time and odds ratios for reaching ≥15% proteinuria decrease from baseline to last measurement were synthesized under a random effects model. From 907 citations retrieved, six studies (four studies with paricalcitol and two studies with calcitriol) providing data for 688 patients were included in the meta-analysis. Most patients (84%) used an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker throughout the study. Active vitamin D analogs reduced proteinuria (weighted mean difference from baseline to last measurement was −16% [95% CI, −13% to −18%]) compared with controls (+6% [95% CI, 0% to +12%]; P<0.001). Proteinuria reduction was achieved more commonly in patients treated with an active vitamin D analog (204/390 patients) than control patients (86/298 patients; OR, 2.72 [95% CI, 1.82 to 4.07]; P<0.001). Thus, active vitamin D analogs may further reduce proteinuria in CKD patients in addition to current regimens. Future studies should address whether vitamin D therapy also retards progressive renal functional decline.CKD is a worldwide health burden, affecting about 15% of the Western adult population.¹ CKD is associated with premature death, cardiovascular disease, infection, and cancer, and it consumes disproportionate health care resources.^2–4 The mainstay of current CKD treatment is pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Although these drugs may retard progression of both renal and cardiovascular disease^5–9 partly through their capacity to reduce proteinuria,^10,11 progression to ESRD and cardiovascular complications cannot be prevented in many CKD patients.A recent single-level meta-analysis including over 2 million participants showed that albuminuria is independently associated with mortality and ESRD, regardless of age.¹² The amount of residual albuminuria/proteinuria under RAAS blockade is a strong predictor of both long-term renal disease progression^13,14 and cardiovascular complications,¹⁵ and an absent or blunted proteinuria response to the use of RAAS blockers is an especially strong predictor.¹⁶ The efficacy of RAAS blockade intensification in an attempt to further reduce residual proteinuria is, however, limited by side effects, such as hyperkalemia and hypotension.^17,18 Adjunctive therapies, which can offer the lowering of residual proteinuria but without these drawbacks, may improve renal and cardiovascular protection.Studies in animal models of CKD suggested that proteinuria, renal fibrosis, and renal function loss may be reduced by treatment with an active vitamin D analog not only as monotherapy but also when given as adjunctive therapy to conventional RAAS blockade.^19–21 In CKD patients, lower vitamin D concentrations have been associated with an increased risk of mortality,^22,23 cardiovascular complications,²⁴ and renal disease progression.²⁵ These findings have resulted in a number of small- to medium-sized prospective randomized controlled trials (RCTs) with the use of active vitamin D analogs targeting reduction of (residual) proteinuria in CKD patients. So far, results have been inconclusive, with studies reporting significant,^26–28 borderline significant,^29–31 or nonsignificant^32,33 effects. We performed a systematic review and meta-analysis of all available RCTs to address the effect of active vitamin D analogs on residual proteinuria in patients with CKD.     

The NLRP3 Inflammasome Promotes Renal Inflammation and Contributes to CKD

Inflammation significantly contributes to the progression of chronic kidney disease (CKD). Inflammasome-dependent cytokines, such as IL-1β and IL-18, play a role in CKD, but their regulation during renal injury is unknown. Here, we analyzed the processing of caspase-1, IL-1β, and IL-18 after unilateral ureteral obstruction (UUO) in mice, which suggested activation of the Nlrp3 inflammasome during renal injury. Compared with wild-type mice, Nlrp3^−/− mice had less tubular injury, inflammation, and fibrosis after UUO, associated with a reduction in caspase-1 activation and maturation of IL-1β and IL-18; these data confirm that the Nlrp3 inflammasome upregulates these cytokines in the kidney during injury. Bone marrow chimeras revealed that Nlrp3 mediates the injurious/inflammatory processes in both hematopoietic and nonhematopoietic cellular compartments. In tissue from human renal biopsies, a wide variety of nondiabetic kidney diseases exhibited increased expression of NLRP3 mRNA, which correlated with renal function. Taken together, these results strongly support a role for NLRP3 in renal injury and identify the inflammasome as a possible therapeutic target in the treatment of patients with progressive CKD.Chronic kidney disease (CKD) is a significant cause of morbidity and mortality in the general population.^1,2 In nondiabetic CKD, the progression from mild/moderate kidney disease to ESRD is a complex process that involves many factors, including tubulointerstitial inflammation and fibrosis. The involvement of mononuclear inflammatory cells in the damaged renal interstitium is a universal finding in failing kidneys and correlates inversely with renal function.^3–9 The molecular mechanisms that regulate inflammation in CKD, however, remain unclear.An inflammatory response is induced during cellular injury such as necrosis.¹⁰ Cellular contents that are inappropriately released after loss of plasma membrane, integrity are endogenous adjuvants or danger-associated molecular patterns (DAMPs).^11–13 These DAMPs alert the innate immune system to cellular injury and produce a proinflammatory response to aid the repair of damaged tissues. Although beneficial in the case of pathogens, the reaction to endogenous (nonmicrobial) injury can contribute to tissue damage and disease progression.The NOD-like receptors (NLRs) compose a group of pattern recognition receptors involved in a wide variety of host innate immune responses to microbial and nonmicrobial stimuli.¹⁴ The best understood members include NOD2 (NLRC2, implicated in Crohn''s disease)¹⁵ and NLRP3 (also known as NALP3 or cryopyrin). Upon activation, the NLRP3 proteins oligomerize and recruit via homotypic molecular interactions, the adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and the protease caspase-1 to form a protein complex termed “the inflammasome.”¹⁶ The formation of the inflammasome induces caspase-1 autoprocessing and activation that results in the processing of cellular substrates including the cytokines pro-IL-1β and pro-IL-18.^17,18 In the case of IL-1β, caspase-1 cleaves the 35-kD pro-IL-1β to generate the mature and secreted 17-kD cytokine.Recent reports have implicated the NLRP3 inflammasome in the recognition of endogenous danger signals released from damaged and dying cells. DAMPs capable of activating the NLRP3 inflammasome include reactive oxygen species, extracellular ATP, monosodium urate crystals, nucleic acids, and extracellular matrix components including hyaluronan and biglycan.^19–24 Consistent with these observations, the NLRP3 inflammasome has been implicated in the pathogenesis of various nonmicrobial diseases, including diabetes, gout, silicosis, and acetaminophen liver toxicity.^19,20,25,26 The coexistence of cellular injury and inflammation suggests that the NLRP3 inflammasome may also play a role in regulating inflammation in CKD. Furthermore, the NLRP3 agonist biglycan and cytokines such as IL-1β, IL-18, and the IL-1 receptor all contribute to renal inflammation and fibrosis.^24,27–30 In this study, we demonstrated that the Nlrp3 inflammasome regulates renal inflammation and fibrosis during unilateral ureteral obstruction (UUO) in mice. In addition, studies of humans demonstrated increased NLRP3 in a variety of nondiabetic kidney diseases and CKD. These data provide valuable insight into the processes driving renal inflammation and CKD progression and identify NLRP3 as a novel target for therapeutic intervention.     

Depression,Pain Intensity,and Interference in Acute Spinal Cord Injury

Background:

The high prevalence of pain and depression in persons with spinal cord injury (SCI) is well known. However the link between pain intensity, interference, and depression, particularly in the acute period of injury, has not received sufficient attention in the literature.

Objective:

To investigate the relationship of depression, pain intensity, and pain interference in individuals undergoing acute inpatient rehabilitation for traumatic SCI.

Methods:

Participants completed a survey that included measures of depression (PHQ-9), pain intensity (“right now”), and pain interference (Brief Pain Inventory: general activity, mood, mobility, relations with others, sleep, and enjoyment of life). Demographic and injury characteristics and information about current use of antidepressants and pre-injury binge drinking also were collected. Hierarchical multiple regression was used to test depression models in 3 steps: (1) age, gender, days since injury, injury level, antidepressant use, and pre-injury binge drinking (controlling variables); (2) pain intensity; and (3) pain interference (each tested separately).

Results:

With one exception, pain interference was the only statistically significant independent variable in each of the final models. Although pain intensity accounted for only 0.2% to 1.2% of the depression variance, pain interference accounted for 13% to 26% of the variance in depression.

Conclusion:

Our results suggest that pain intensity alone is insufficient for understanding the relationship of pain and depression in acute SCI. Instead, the ways in which pain interferes with daily life appear to have a much greater bearing on depression than pain intensity alone in the acute setting.Key words: depression, pain, spinal cord injuriesThe high incidence and prevalence of pain following spinal cord injury (SCI) is well established^1–6 and associated with numerous poor health outcomes and low quality of life (QOL).^1,7,8 Although much of the literature on pain in SCI focuses on pain intensity, there is emerging interest in the role of pain interference or the extent to which pain interferes with daily activities of life.^7,9 With prevalence as high as 77% in SCI, pain interference impacts life activities such as exercise, sleep, work, and household chores.^2,7,10–13 Pain interference also has been associated with disease management self-efficacy in SCI.¹⁴ There is a significant relationship between pain intensity and interference in persons with SCI.⁷ Like pain, the high prevalence of depression after SCI is well-established.^15–17 Depression and pain often co-occur,^18,19 and their overlap ranges from 30% to 60%.¹⁹ Pain is also associated with greater duration of depressed mood.²⁰ Pain and depression share common biological pathways and neurotransmitter mechanisms,¹⁹ and pain has been shown to attenuate the response to depression treatment.^21,22Despite the interest in pain and depression after SCI and implications for the treatment of depression, their co-occurrence has received far less attention in the literature.²³ Greater pain has been associated with higher levels of depression in persons with SCI,^16,24 although this is not a consistent finding.²⁵ Similarly, depression in persons with SCI who also have pain appears to be worse than for persons with non-SCI pain, suggesting that the link between pain and depression may be more intense in the context of SCI.²⁶ In one of the few studies of pain intensity and depression in an acute SCI rehabilitation setting, Cairns et al ²⁷ found a co-occurrence of pain and depression in 22% to 35% of patients. This work also suggested an evolution of the relationship between pain and depression over the course of the inpatient stay, such that they become associated by discharge. Craig et al²⁸ found that pain levels at discharge from acute rehabilitation predicted depression at 2-year follow-up. Pain interference also has been associated with emotional functioning and QOL in persons with SCI^1,7,29,30 and appears to mediate the relationship between ambulation and depression.³¹Studies of pain and depression in person with SCI are often limited methodologically to examine the independent contributions of pain intensity and interference to depression in an acute setting. For example, they include only pain intensity^{16,23,25,28,30}; classify subjects by either pain plus depression²³ or pain versus no pain^8,28,30; use pain intensity and interference as predictor and outcome, respectively¹; collapse pain interference domains into a single score¹; or use only univariate tests (eg, correlations).^7,8,25,30 In addition, the vast majority focus on the chronic period of injury. To fill a gap in knowledge, we examined the independent contributions of pain intensity and pain interference to depression, while accounting for injury and demographic characteristics, antidepressant treatment, and pre-injury binge drinking in a sample of persons with acute SCI. We hypothesized that when accounting for both pain intensity and interference in the model, interference would have an independent and significant relationship with depression, above and beyond pain intensity.     

Combination of Peritubular C4d and Transplant Glomerulopathy Predicts Late Renal Allograft Failure

The histologic associations and clinical implications of peritubular capillary C4d staining from long-term renal allografts are unknown. We identified 99 renal transplant patients who underwent an allograft biopsy for renal dysfunction at least 10 yr after transplantation, 25 of whom were C4d-positive and 74 of whom were C4d-negative. The average time of the index biopsy from transplantation was 14 yr in both groups. Compared with C4d-negative patients, C4d-positive patients were younger at transplantation (29 ± 13 versus 38 ± 12 yr; P < 0.05) and were more likely to have received an allograft from a living donor (65 versus 35%; P < 0.001). C4d-positive patients had more inflammation, were more likely to have transplant glomerulopathy, and had worse graft outcome. The combined presence of C4d positivity, transplant glomerulopathy, and serum creatinine of >2.3 mg/dl at biopsy were very strong predictors of rapid graft loss. C4d alone did not independently predict graft loss. Retrospective staining of historical samples from C4d-positive patients demonstrated C4d deposition in the majority of cases. In summary, these data show that in long-term renal allografts, peritubular capillary staining for C4d occurs in approximately 25% of biopsies, can persist for many years after transplantation, and strongly predicts graft loss when combined with transplant glomerulopathy.Advances in understanding immunologic mechanisms underlying acute renal allograft rejection have enabled the development of efficient diagnostic tools and therapeutic strategies directed against early immune-mediated graft loss. This led to an increase of 1-yr graft survival rates to >90%; however, long-term graft survival has not improved to a similar degree.^1,2 A steady decline of renal function over years is still the rule in the majority of cases after renal transplantation. Multiple factors can influence graft outcome in the late posttransplantation setting, including acute and or chronic rejection; patient compliance with immunosuppressive therapy; and other medical conditions, such as cardiovascular disease, hypertension, diabetes, infections, drug toxicities, and recurrent disease. Evaluation of renal biopsies may reveal changes related to calcineurin inhibitor toxicity, immune-mediated injury, BK nephropathy, thrombotic microangiopathy, hypertension, diabetes, and recurrent disease, which can help guide appropriate therapy.There is a growing awareness of the contribution of chronic immune-mediated injury and alloantibodies in late renal allograft dysfunction. Immunohistochemical detection of the complement degradation product C4d in peritubular capillaries (PTCs) of renal allograft biopsies has gained considerable attention because of its diagnostic and prognostic importance in early acute antibody-mediated rejection (AMR). Detection of C4d is regarded as indirect evidence (a “footprint”) of a host''s antibody response to a renal allograft and is one of the key criteria used to diagnose AMR.³ C4d deposition has also been implicated in more chronic immune injury of allograft kidneys. Transplant glomerulopathy (TG), a cause of renal dysfunction in longstanding renal allografts, has an estimated prevalence of 1.6 to 12% in renal transplant populations.^4–9 TG is often associated with evidence of AMR, such as the presence of donor-specific antibodies (DSAs) and positive PTC C4d staining, and is considered to be a hallmark of chronic AMR.^4,9–13 The combination of circulating alloantibodies, glomerular and PTC basement membrane multilamination, PTC C4d, and duplication of the glomerular basement membrane has been termed the “ABCD tetrad” of late AMR by Halloran et al.⁴Many reports have diffused that PTC C4d deposition predicts poor graft survival in both early (<1 yr) and late (>1 yr) posttransplantation periods.^12,14–23 Several reports also have shown C4d staining has little impact on graft survival. Satoskar et al.²⁴ examined 80 cases of late allograft rejection that occurred >1 yr after transplantation. They followed patients for 20 mo and found no difference in outcome between C4d⁺ and C4d⁻ groups. Nickeleit et al.²⁵ analyzed 400 transplant biopsies, at a median of 38 d after transplantation (range 7 to 5646 d) and found no differences between C4d⁺ and C4d⁻ groups in serum creatinine or graft survival at 1 yr of follow-up. A European study including protocol biopsy samples from early and late time points found no reduction in allograft survival in C4d⁺ versus C4d⁻ biopsy samples.¹³ Recently, a study by Haas et al.²⁶ of ABO-incompatible renal allografts showed that diffuse PTC C4d deposition without histologic evidence of AMR or cellular rejection in their initial protocol biopsies was associated with a lower risk for scarring at 1 yr. Several factors may explain the conflicting conclusions in these studies, including limitations as a result of highly selected patient groups,¹² short follow-up,^24–26 and the inclusion of both early and late allograft biopsies.^13,22,23,25In this study, we identified a unique cohort of renal transplant recipients with allografts surviving ≥10 yr after transplantation with biopsies performed for evaluation of graft dysfunction with or without proteinuria at these later time points. The aim of this study was to assess the prevalence of C4d staining and to clarify the clinical and pathologic significance of C4d positivity in long-term renal allografts.     

Albuminuria and Estimated Glomerular Filtration Rate Independently Associate with Acute Kidney Injury

Acute kidney injury (AKI) is increasingly common and a significant contributor to excess death in hospitalized patients. CKD is an established risk factor for AKI; however, the independent graded association of urine albumin excretion with AKI is unknown. We analyzed a prospective cohort of 11,200 participants in the Atherosclerosis Risk in Communities (ARIC) study for the association between baseline urine albumin-to-creatinine ratio and estimated GFR (eGFR) with hospitalizations or death with AKI. The incidence of AKI events was 4.0 per 1000 person-years of follow-up. Using participants with urine albumin-to-creatinine ratios <10 mg/g as a reference, the relative hazards of AKI, adjusted for age, gender, race, cardiovascular risk factors, and categories of eGFR were 1.9 (95% CI, 1.4 to 2.6), 2.2 (95% CI, 1.6 to 3.0), and 4.8 (95% CI, 3.2 to 7.2) for urine albumin-to-creatinine ratio groups of 11 to 29 mg/g, 30 to 299 mg/g, and ≥300 mg/g, respectively. Similarly, the overall adjusted relative hazard of AKI increased with decreasing eGFR. Patterns persisted within subgroups of age, race, and gender. In summary, albuminuria and eGFR have strong, independent associations with incident AKI.It has long been recognized that an episode of acute kidney injury (AKI) can have serious health consequences.^1–4 Even a relatively small degree of renal injury increases a patient''s risk of a prolonged hospital stay, chronic kidney disease (CKD), ESRD, and death.^2,5–10 Over the last 2 decades, the incidence of hospitalized AKI has increased dramatically.^11–14 Precise estimations vary depending on population and method of case identification, but a recent community-based study of AKI estimated the incidence of nondialysis requiring AKI at 522 per 100,000 population per year and dialysis-requiring AKI at 30 per 100,000,¹³ which is well over that of ESRD.¹⁴ This increase in the burden of disease, taken with the associated poor long-term outcomes, has established AKI as a major public health issue.¹⁴Beyond routine supportive care, there exists little established medical therapy for AKI.¹⁵ Many current lines of research are focused on the prevention of AKI. However, few prospective, population-based studies have evaluated the development of AKI.^3,13,16 Hsu et al.,^13,17 along with multiple observational series in various clinical settings, have clearly established older age and CKD as risk factors for AKI.^18–24 Other observed associations with AKI include black race and male gender.^11,18,25 Proteinuria, an established risk factor in the development of cardiovascular disease,^26,27 ESRD,²⁸ and death,²⁹ is less studied in its role in the development of AKI. Hsu and colleagues demonstrated the prospective association of proteinuria with dialysis-requiring AKI; however, the proteinuria classification was binary and based on dipstick measurement.¹⁷ To our knowledge, no study has quantified the independent dose response of albuminuria with AKI hospitalization, including less severe AKI. Our study''s objective was thus to characterize prospectively the association between baseline urine albumin-to-creatinine ratio (UACR) and hospitalizations for AKI, controlling for established and potential risk factors such as CKD, age, and cardiovascular comorbidities.