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Purpose Limited data are available on venovenous extracorporeal membrane oxygenation (ECMO) in patients with severe hypoxemic respiratory failure from coronavirus disease 2019 (COVID-19). Methods We examined the clinical features and outcomes of 190 patients treated with ECMO within 14 days of ICU admission, using data from a multicenter cohort study of 5122 critically ill adults with COVID-19 admitted to 68 hospitals across the United States. To estimate the effect of ECMO on mortality, we emulated a target trial of ECMO receipt versus no ECMO receipt within 7 days of ICU admission among mechanically ventilated patients with severe hypoxemia (PaO2/FiO2

Objective To determine whether surge conditions were associated with increased mortality. Design Multicenter cohort study. Setting U.S. ICUs participating in STOP-COVID. Patients Consecutive adults with COVID-19 admitted to participating ICUs between March 4 and July 1, 2020. Interventions None Measurements and Main Results The main outcome was 28-day in-hospital mortality. To assess the association between admission to an ICU during a surge period and mortality, we used two different strategies: (1) an inverse probability weighted difference-in-differences model limited to appropriately matched surge and non-surge patients and (2) a meta-regression of 50 multivariable difference-in-differences models (each based on sets of randomly matched surge- and non-surge hospitals). In the first analysis, we considered a single surge period for the cohort (March 23 – May 6). In the second, each surge hospital had its own surge period (which was compared to the same time periods in matched non-surge hospitals). Our cohort consisted of 4342 ICU patients (average age 60.8 [sd 14.8], 63.5% men) in 53 U.S. hospitals. Of these, 13 hospitals encountered surge conditions. In analysis 1, the increase in mortality seen during surge was not statistically significant (odds ratio [95% CI]: 1.30 [0.47-3.58], p = .6). In analysis 2, surge was associated with an increased odds of death (odds ratio 1.39 [95% CI, 1.34-1.43], p Conclusions Admission to an ICU with COVID-19 in a hospital that is experiencing surge conditions may be associated with an increased odds of death. Given the high incidence of COVID-19, such increases would translate into substantial excess mortality.

Rationale & Objective Acute kidney injury treated with kidney replacement therapy (AKI-KRT) occurs frequently in critically ill patients with COVID-19. We examined the clinical factors that determine kidney recovery in this population. Study Design Multicenter cohort study. Setting & Participants 4221 adults with COVID-19 not receiving kidney replacement therapy who were admitted to intensive care units at 68 US hospitals with COVID-19 from March 1 to June 22, 2020 (the “ICU cohort”). Among these, 876 developed AKI-KRT after admission to the ICU (the “AKI-KRT subcohort”). Exposure(s) The ICU cohort was analyzed using AKI severity as the exposure. For the AKI-KRT subcohort, exposures included demographics, comorbidities, initial mode of KRT, and markers of illness severity at the time of dialysis initiation. Outcome(s) The outcome for the ICU cohort was estimated glomerular filtration rate (GFR) at hospital discharge. A three-level outcome including death, kidney nonrecovery, and kidney recovery at discharge, was analyzed for the AKI-KRT subcohort. Analytical approach The ICU cohort was characterized using descriptive analyses. The AKI-KRT subcohort was characterized with both descriptive analyses and multinomial logistic regression to assess factors associated with kidney nonrecovery while accounting for death. Results Among a total of 4221 patients in the ICU cohort, 2361 (56%) developed AKI, including 876 (21%) who received KRT. More severe AKI was associated with higher mortality. Among survivors, more severe AKI was associated with an increased rate of kidney nonrecovery and lower kidney function at discharge. Among the 876 patients with AKI-KRT, 588 (67%) died, 95 (11%) had kidney nonrecovery, and 193 (22%) had kidney recovery by the time of discharge. The odds of kidney nonrecovery was greater for lower estimated GFR with odds ratios (ORs) of 2.09 (95% CI, 1.09-4.04), 4.27 (95% CI, 1.99-9.17), and 8.69 (95% CI, 3.07-24.55) for CKD GFR categories 3, 4, and 5, respectively, compared to estimated GFR > 60 mL/min/1.73 m2. Oliguria at the time of KRT initiation was also associated with nonrecovery (OR 2.10 [95% CI, 1.14-3.88] and 4.02 [95% CI, 1.72-9.39] for patients with 50-499 and, Critically ill patients with COVID-19 often develop acute kidney injury (AKI). This study of 4221 patients demonstrated that more severe AKI was associated with greater in-hospital mortality and poorer kidney function at hospital discharge. Among the 876 patients who required dialysis for AKI, almost two-thirds died. Among those who survived to discharge, about two-thirds recovered kidney function and were discharged without the need for dialysis. Lower baseline kidney function and reduced urine output were associated with non-recovery of kidney function. Identification of such predictors is important in assessing prognosis among these critically ill patients and has implications for clinical care of individuals critically ill with COVID-19.

Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived circulating signaling molecule that has been implicated in chronic kidney disease, such as focal segmental glomerulosclerosis (FSGS). Typically, native uPAR (isoform 1) translates to a 3-domain protein capable of binding and activating integrins, yet the function of additional isoforms generated by alternative splicing is unknown. Here, we characterized mouse uPAR isoform 2 (msuPAR2), encoding domain I and nearly one-half of domain II, as a dimer in solution, as revealed by 3D electron microscopy structural analysis. In vivo, msuPAR2 transgenic mice exhibited signs of severe renal disease characteristic of FSGS with proteinuria, loss of kidney function, and glomerulosclerosis. Sequencing of the glomerular RNAs from msuPAR2-Tg mice revealed a differentially expressed gene signature that includes upregulation of the suPAR receptor Itgb3, encoding β3 integrin. Crossing msuPAR2-transgenic mice with 3 different integrin β3 deficiency models rescued msuPAR2-mediated kidney function. Further analyses indicated a central role for β3 integrin and c-Src in msuPAR2 signaling and in human FSGS kidney biopsies. Administration of Src inhibitors reduced proteinuria in msuPAR2-transgenic mice. In conclusion, msuPAR2 may play an important role in certain forms of scarring kidney disease.

Soluble urokinase receptor (suPAR) is a circulatory molecule that activates αvβ3 integrin on podocytes, causes foot process effacement, and contributes to proteinuric kidney disease. While active integrin can be targeted by antibodies and small molecules, endogenous inhibitors haven't been discovered yet. Here we report what we believe is a novel renoprotective role for the inducible costimulator ligand (ICOSL) in early kidney disease through its selective binding to podocyte αvβ3 integrin. Contrary to ICOSL's immune-regulatory role, ICOSL in nonhematopoietic cells limited the activation of αvβ3 integrin. Specifically, ICOSL contains the arginine-glycine-aspartate (RGD) motif, which allowed for a high-affinity and selective binding to αvβ3 and modulation of podocyte adhesion. This binding was largely inhibited either by a synthetic RGD peptide or by a disrupted RGD sequence in ICOSL. ICOSL binding favored the active αvβ3 rather than the inactive form and showed little affinity for other integrins. Consistent with the rapid induction of podocyte ICOSL by inflammatory stimuli, glomerular ICOSL expression was increased in biopsies of early-stage human proteinuric kidney diseases. Icosl deficiency in mice resulted in an increased susceptibility to proteinuria that was rescued by recombinant ICOSL. Our work identified a potentially novel role for ICOSL, which serves as an endogenous αvβ3-selective antagonist to maintain glomerular filtration.

Background COVID‐19 epidemiologic studies comparing immunosuppressed and immunocompetent patients may provide insight into the impact of immunosuppressants on outcomes. Methods In this retrospective cohort study, we assembled kidney or kidney‐pancreas transplant recipients who underwent transplant from January 1, 2010, to June 30, 2020, and kidney or kidney‐pancreas waitlisted patients who were ever on the waitlist from January 1, 2019, to June 30, 2020. We identified laboratory‐confirmed COVID‐19 until January 31, 2021, and tracked its outcomes by leveraging informatics infrastructure developed for an outcomes research network. Results COVID‐19 was identified in 62 of 887 kidney or kidney‐pancreas transplant recipients and 20 of 434 kidney or kidney‐pancreas waitlisted patients (7.0% vs. 4.6%, p = .092). Of these patients with COVID‐19, hospitalization occurred in 48 of 62 transplant recipients and 8 of 20 waitlisted patients (77% vs. 40%, p = .002); intensive care unit admission occurred in 18 of 62 transplant recipients and 2 of 20 waitlisted patients (29% vs. 10%, p = .085); and 7 transplant recipients were mechanically ventilated and died, whereas no waitlisted patients were mechanically ventilated or died (11% vs. 0%, p = .116). Conclusions Our study provides single‐center data and an informatics approach that can be used to inform the design of multicenter studies.

Variation in hospital mortality has been described for coronavirus disease 2019 (COVID-19), but the factors that explain these differences remain unclear.Our objective was to utilize a large, nationally representative dataset of critically ill adults with COVID-19 to determine which factors explain mortality variability.In this multicenter cohort study, we examined adults hospitalized in intensive care units with COVID-19 at 70 United States hospitals between March and June 2020. The primary outcome was 28-day mortality. We examined patient-level and hospital-level variables. Mixed-effects logistic regression was used to identify factors associated with interhospital variation. The median odds ratio (OR) was calculated to compare outcomes in higher- vs. lower-mortality hospitals. A gradient boosted machine algorithm was developed for individual-level mortality models.A total of 4,019 patients were included, 1537 (38%) of whom died by 28 days. Mortality varied considerably across hospitals (0-82%). After adjustment for patient- and hospital-level domains, interhospital variation was attenuated (OR decline from 2.06 [95% CI, 1.73-2.37] to 1.22 [95% CI, 1.00-1.38]), with the greatest changes occurring with adjustment for acute physiology, socioeconomic status, and strain. For individual patients, the relative contribution of each domain to mortality risk was: acute physiology (49%), demographics and comorbidities (20%), socioeconomic status (12%), strain (9%), hospital quality (8%), and treatments (3%).There is considerable interhospital variation in mortality for critically ill patients with COVID-19, which is mostly explained by hospital-level socioeconomic status, strain, and acute physiologic differences. Individual mortality is driven mostly by patient-level factors. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Summary: Many US states published crisis standards of care (CSC) guidelines for allocating scarce critical care resources during the COVID-19 pandemic. However, the performance of these guidelines in maximizing their population benefit has not been well tested. In 2,272 adults with COVID-19 requiring mechanical ventilation drawn from the Study of the Treatment and Outcomes in Critically Ill Patients with COVID-19 (STOP-COVID) multicenter cohort, we test the following three approaches to CSC algorithms: Sequential Organ Failure Assessment (SOFA) scores grouped into ranges, SOFA score ranges plus comorbidities, and a hypothetical approach using raw SOFA scores not grouped into ranges. We find that area under receiver operating characteristic (AUROC) curves for all three algorithms demonstrate only modest discrimination for 28-day mortality. Adding comorbidity scoring modestly improves algorithm performance over SOFA scores alone. The algorithm incorporating comorbidities has modestly worse predictive performance for Black compared to white patients. CSC algorithms should be empirically examined to refine approaches to the allocation of scarce resources during pandemics and to avoid potential exacerbation of racial inequities.

Rationale & Objective Underlying kidney disease is an emerging risk factor for more severe COVID-19 illness. We examined the clinical courses of critically ill COVID-19 patients with and without pre-existing kidney disease and investigated the association between degree of underlying kidney disease and in-hospital outcomes. Study Design Retrospective cohort study Settings & Participants 4,264 critically ill COVID-19 patients (143 dialysis patients, 521 chronic kidney disease [CKD] patients, and 3,600 patients without CKD) admitted to ICUs at 68 hospitals in the United States. Predictor(s) Presence (versus absence) of pre-existing kidney disease Outcome(s) In-hospital mortality (primary); respiratory failure, shock, ventricular arrhythmia/ cardiac arrest, thromboembolic event, major bleed, and acute liver injury (secondary) Analytical Approach We used standardized differences to compare patient characteristics (values >0.10 indicate a meaningful difference between groups) and multivariable adjusted Fine and Gray survival models to examine outcome associations. Results Dialysis patients had a shorter time from symptom onset to ICU admission compared to other groups (median [quartile 1-quartile 3] days: 4 [2-9] for dialysis patients; 7 [3-10] for CKD patients; 7 [4-10] for patients without pre-existing kidney disease). More dialysis patients (25%) reported altered mental status than those with CKD (20%, standardized difference = 0.12) and no kidney disease (12%, standardized difference = 0.36). Half of dialysis and CKD patients died within 28-days of ICU admission versus 35% of patients without pre-existing kidney disease. Compared to patients without pre-existing kidney disease, dialysis patients had a higher risk of 28-day in-hospital death (adjusted HR 1.41; 95% CI 1.09, 1.81), while patients with CKD had an intermediate risk (adjusted HR 1.25; 95% CI 1.08, 1.44). Limitations Potential residual confounding Conclusions Findings highlight the high mortality of individuals with underlying kidney disease and severe COVID-19, underscoring the importance of identifying safe and effective COVID-19 therapies for this vulnerable population., Individuals with underlying kidney disease may be particularly vulnerable to severe COVID-19 illness, marked by multi-system organ failure, thrombosis, and a heightened inflammatory response. Among 4,264 critically ill adults with COVID-19 admitted to 68 intensive care units across the U.S., we found that both chronic kidney disease and dialysis patients had a ∼50% 28-day in-hospital mortality rate. Patients with underlying kidney disease had higher in-hospital mortality than patients without kidney disease, with patients on maintenance dialysis having the highest risk. As evidenced by differences in symptoms and clinical trajectories, patients with pre-existing kidney disease may have unique susceptibility to COVID-19-related complications which warrants additional study and special consideration in the pursuit and development of targeted therapies.

Hypercoagulability may be a key mechanism of death in patients with COVID-19. This cohort study evaluated the incidence of venous thromboembolism and major bleeding in critically ill patients with COVID-19 and examined the observational effect of early therapeutic anticoagulation on survival., Visual Abstract. Early Anticoagulation in COVID-19 Hypercoagulability may be a key mechanism of death in patients with COVID-19. This cohort study evaluated the incidence of venous thromboembolism and major bleeding in critically ill patients with COVID-19 and examined the observational effect of early therapeutic anticoagulation on survival. Visual Abstract. Early Anticoagulation in COVID-19 Hypercoagulability may be a key mechanism of death in patients with COVID-19. This cohort study evaluated the incidence of venous thromboembolism and major bleeding in critically ill patients with COVID-19 and examined the observational effect of early therapeutic anticoagulation on survival., Background: Hypercoagulability may be a key mechanism of death in patients with coronavirus disease 2019 (COVID-19). Objective: To evaluate the incidence of venous thromboembolism (VTE) and major bleeding in critically ill patients with COVID-19 and examine the observational effect of early therapeutic anticoagulation on survival. Design: In a multicenter cohort study of 3239 critically ill adults with COVID-19, the incidence of VTE and major bleeding within 14 days after intensive care unit (ICU) admission was evaluated. A target trial emulation in which patients were categorized according to receipt or no receipt of therapeutic anticoagulation in the first 2 days of ICU admission was done to examine the observational effect of early therapeutic anticoagulation on survival. A Cox model with inverse probability weighting to adjust for confounding was used. Setting: 67 hospitals in the United States. Participants: Adults with COVID-19 admitted to a participating ICU. Measurements: Time to death, censored at hospital discharge, or date of last follow-up. Results: Among the 3239 patients included, the median age was 61 years (interquartile range, 53 to 71 years), and 2088 (64.5%) were men. A total of 204 patients (6.3%) developed VTE, and 90 patients (2.8%) developed a major bleeding event. Independent predictors of VTE were male sex and higher D-dimer level on ICU admission. Among the 2809 patients included in the target trial emulation, 384 (11.9%) received early therapeutic anticoagulation. In the primary analysis, during a median follow-up of 27 days, patients who received early therapeutic anticoagulation had a similar risk for death as those who did not (hazard ratio, 1.12 [95% CI, 0.92 to 1.35]). Limitation: Observational design. Conclusion: Among critically ill adults with COVID-19, early therapeutic anticoagulation did not affect survival in the target trial emulation. Primary Funding Source: None.

Background: As percutaneous renal biopsies (PRBs) are increasingly performed by radiologists, an increase in the use of 18-gauge automated needle stands to compromise adequacy. We compare the adequacy and safety of PRB with 14-, 16-, and 18-gauge automated needles. Methods: PRB of native (N-592) and transplant (T-1,023) kidneys was performed from January 2002 to December 2019 using real-time ultrasound. Baseline clinical and laboratory data, biopsy data (number of cores, total glomeruli, and total glomeruli per core), and outcome (hematoma on renal US at 1-h, complications, and transfusion) were collected prospectively. PRB with N14g (337) versus N16g (255) and T16g (892) versus T18g (131) needles were compared. A p value of Results: PRB with an 18-g needle yielded the lowest number of total glomeruli per biopsy (N14g vs. N16g: 33 ± 13 vs. 29 ± 12, p < 0.01 and T16g vs. T18g: 34 ± 16 vs. 21 ± 11, p < 0.0001), significantly fewer total glomeruli per core (T16g vs. T18g: 12.7 ± 6.4 vs. 9.6 ± 5.0, p < 0.001 and N16g vs. T18g: 14.2 ± 6.3 vs. 9.6 ± 5.0, p < 0.001). A hematoma by renal US 1-h post-PRB was similar for native (14g–35% vs. 16g–29%, p = 0.2), and transplant biopsies (16g–10% vs. 18g–9%, p = 0.9) and the complication rate for native (14g–8.9% vs. 16g–7.1%, p = 0.5), transplant biopsies (16g–4.6% vs. 18g–1.5%, p = 0.2) and transfusion rate for native (14g–7.7% vs. 16g–5.8%, p = 0.4), and transplant biopsies (16g–3.8% vs. 18g–0.8%, p = 0.1) were similar irrespective of needle size. Conclusions: PRB of native and transplant kidneys with the use of a 16-gauge needle provides an optimal sample. However, our experience in transplant biopsies suggests the use of an 18-gauge needle stands to jeopardize the diagnostic accuracy of the PRB while not improving safety.

Comparative COVID-19 epidemiologic studies between immunosuppressed and immunocompetent patients may provide insight into the impact of immunosuppressive medications on clinical outcomes. In this retrospective cohort pilot study, we determined the incidence and outcomes of COVID-19 in kidney or kidney-pancreas transplant recipients and kidney or kidney-pancreas waitlisted patients in our center. COVID-19 testing was performed in 63 of 537 kidney or kidney-pancreas transplanted patients, versus 43 of 383 kidney or kidney-pancreas waitlisted patients as of June 4, 2020 (12% versus 11%, p=0.81). COVID-19 was identified in 14 of 537 kidney or kidney-pancreas transplanted patients, versus 9 of 383 kidney or kidney-pancreas waitlisted patients (2.6% versus 2.3%, p=0.81). Hospitalization occurred in 11 of 14 transplanted patients, and 4 of 9 waitlisted patients with COVID-19 (79% versus 44%, p=0.18). Intensive care unit admission occurred in 5 of 14 transplanted patients, and 1 of 9 waitlisted patients with COVID-19 (36% versus 11%, p=0.34). Two transplanted patients with COVID-19 were mechanically ventilated and died, whereas no waitlisted patients with COVID-19 died or were mechanically ventilated. Our study provides preliminary data that can be used for power calculations to inform multicenter studies designed to validate these findings.

The kidney is an organ involved in cross talk with many human organs. The link between the immune system and the kidney has been studied in some detail, although data precisely elucidating their interaction are sparse, in particular with regard to the function of the kidney filter apparatus. Current research suggests that an understanding of the impairment of this cross talk between the bone marrow, as a fundament of the immune system and the kidney will provide meaningful insights into the pathophysiological mechanisms of impaired kidney filter function. Circulating factors have long been implicated in the pathogenesis of idiopathic nephrotic syndrome, particularly focal segmental glomerulosclerosis (FSGS) and its recurrence. Soluble urokinase receptor (suPAR) has emerged as a circulating factor responsible for FSGS and also as an early predictive marker for the development of various renal diseases. The bone marrow has recently been revealed as a predominant source of suPAR with deleterious effects on the kidney filter. These new findings have led to bone marrow or hematopoietic stem cell transplants being considered as potential therapeutic options for preventing the post-transplantation recurrence of FSGS or even as a treatment for the original disease associated with high suPAR levels. Whereas bone marrow transplantation for patients with pre-existing chronic kidney disease is challenging, recent clinical trials have demonstrated the promising outcome of combined bone marrow and kidney transplantation in patients with kidney failure. In this review, with its brief update on suPAR, we describe the critical new role of the bone marrow in the pathogenesis of the kidney disease process and the functional connection between these two organs through the soluble mediator, suPAR. We also comment on the feasibility of bone marrow transplants for the treatment of patients with chronic renal failure arising from recurrent FSGS.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide. DN typically manifests by glomerular hyperfiltration and microalbuminuria; then, the disease progresses to impaired glomerular filtration rate, which leads to ESRD. Treatment options for DN include the strict control of blood glucose levels and pressure (e.g., intraglomerular hypertension). However, the search for novel therapeutic strategies is ongoing. These include seeking specific molecules that contribute to the development and progression of DN to potentially interfere with these “molecular targets” as well as with the cellular targets within the kidney such as podocytes, which play a major role in the pathogenesis of DN. Recently, podocyte membrane protein urokinase receptor (uPAR) and its circulating form (suPAR) are found to be significantly induced in glomeruli and sera of DN patients, respectively, and elevated suPAR levels predicted diabetic kidney disease years before the occurrence of microalbuminuria. The intent of this review is to summarize the emerging evidence of uPAR and suPAR in the clinical manifestations of DN. The identification of specific pathways that govern DN will help us build a more comprehensive molecular model for the pathogenesis of the disease that can inform new opportunities for treatment.

Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and αvβ3 integrin, whereby APOL1 protein variants G1 and G2 exhibited higher affinity for suPAR-activated avb3 integrin than APOL1 G0. APOL1 G1 or G2 augments αvβ3 integrin activation and causes proteinuria in mice in a suPAR-dependent manner. The synergy of circulating factor suPAR and APOL1 G1 or G2 on αvβ3 integrin activation is a mechanism for CKD.

Dyslipidemia, malnutrition and inflammation are common in patients with chronic kidney disease (CKD) and are strongly associated with cardiovascular disease (CVD) and increased mortality. The epidemiology of dyslipidemia and its interactions with malnutrition and inflammation in CKD patients have been the subject of much interest in the past decade. Recent clinical trials have explored the effects of statins on CVD specifically in CKD patients.Whereas the risk relationship between total cholesterol level and CVD morbidity and mortality is direct, strong and progressive in CKD patients without malnutrition and inflammation, it is inconsistent and often paradoxical in those with malnutrition and inflammation. Accumulating evidence demonstrates that statins reduce significantly the risk of CVD in CKD patients before the initiation of dialysis. However, the beneficial effect of statins in CKD patients on dialysis is uncertain. In CKD patients on dialysis, malnutrition and inflammation pose a higher risk for CVD than dyslipidemia.In CKD patients, the risk of CVD associated to dyslipidemia is complex and is modified by malnutrition and inflammation.

Soluble uPAR is known to contribute to certain types of chronic kidney disease, and myeloid cells from the bone marrow have now been shown to be a key source of this factor. Excess levels of protein in urine (proteinuria) is a hallmark of kidney disease that typically occurs in conjunction with diabetes, hypertension, gene mutations, toxins or infections but may also be of unknown cause (idiopathic)1. Systemic soluble urokinase plasminogen activator receptor (suPAR) is a circulating factor implicated in the onset and progression of chronic kidney disease (CKD)2, such as focal segmental glomerulosclerosis (FSGS)3,4. The cellular source(s) of elevated suPAR associated with future and progressing kidney disease is unclear, but is likely extra-renal, as the pathological uPAR is circulating and FSGS can recur even after a damaged kidney is replaced with a healthy donor organ. Here we report that bone marrow (BM) Gr-1lo immature myeloid cells are responsible for the elevated, pathological levels of suPAR, as evidenced by BM chimera and BM ablation and cell transfer studies. A marked increase of Gr-1lo myeloid cells was commonly found in the BM of proteinuric animals having high suPAR, and these cells efficiently transmit proteinuria when transferred to healthy mice. In accordance with the results seen in suPAR-associated proteinuric animal models, in which kidney damage is caused not by local podocyte-selective injury but more likely by systemic insults, a humanized xenograft model of FSGS resulted in an expansion of Gr-1lo cells in the BM, leading to high plasma suPAR and proteinuric kidney disease. Together, these results identify suPAR as a functional connection between the BM and the kidney, and they implicate BM immature myeloid cells as a key contributor to glomerular dysfunction.

Soluble urokinase plasminogen activator receptor (suPAR) independently predicts chronic kidney disease (CKD) incidence and progression. Apolipoprotein L1 (APOL1) gene variants G1 and G2, but not the reference allele (G0), are associated with an increased risk of CKD in individuals of recent African ancestry. Here we show in two large, unrelated cohorts that decline in kidney function associated with APOL1 risk variants was dependent on plasma suPAR levels: APOL1-related risk was attenuated in patients with lower suPAR, and strengthened in those with higher suPAR levels. Mechanistically, surface plasmon resonance studies identified high-affinity interactions between suPAR, APOL1 and α

Late referral of patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) for evaluation of kidney transplantation is common. Even though renal transplantation offers a clear survival benefit to patients with advanced CKD and ESRD and should be considered the renal replacement therapy of choice, numerous barriers to early renal transplant referral have been observed. Some of these barriers can be overcome by improving the communication between the referring providers and the transplant centers. Furthermore, providing more intensive education to both patients and referring providers with regard to the eligibility of CKD and ESRD patients for a transplant will likely result in higher referral rates. This in turn will lead to improved survival outcomes in this group of patients with otherwise significantly increased morbidity and mortality.

Kidney podocytes are highly differentiated epithelial cells that form interdigitating foot processes with bridging slit diaphragms (SDs) that regulate renal ultrafiltration. Podocyte injury results in proteinuric kidney disease, and genetic deletion of SD-associated CD2-associated protein (CD2AP) leads to progressive renal failure in mice and humans. Here, we have shown that CD2AP regulates the TGF-β1–dependent translocation of dendrin from the SD to the nucleus. Nuclear dendrin acted as a transcription factor to promote expression of cytosolic cathepsin L (CatL). CatL proteolyzed the regulatory GTPase dynamin and the actin-associated adapter synaptopodin, leading to a reorganization of the podocyte microfilament system and consequent proteinuria. CD2AP itself was proteolyzed by CatL, promoting sustained expression of the protease during podocyte injury, and in turn increasing the apoptotic susceptibility of podocytes to TGF-β1. Our study identifies CD2AP as the gatekeeper of the podocyte TGF-β response through its regulation of CatL expression and defines a molecular mechanism underlying proteinuric kidney disease.

Focal Segmental Glomerulosclerosis (FSGS) can lead to ESRD requiring a renal transplant and the rate of recurrent FSGR (rFSGS) is high. The exact mechanisms of the pathogenesis of FSGS and rFSGS is unclear and both FSGS and rFSGS have similar pathological findings and clinical symptoms. To date there are no good tests that can predict FSGS or rFSGS. A very recent report indicated that antibodies against Angiotensin Receptor Type 1 (AT1R-Ab) could predict rFSGS post-transplant. Angiotensin II (AT II) acts on angiotensin 1 receptor (AT1R) and exerts hemodynamically vital actions. AT1Rs are extensively distributed across various organ systems including renal podocytes. Over-activation of AT1R via AT II or AT1R-Ab could trigger events leading to chronic renal injury. Presence of AT1R-Ab was shown to be associated with vascular rejection and malignant hypertension in the absence of detectable allograft-specific HLA antibodies and also in C4d positive AMR in a zero mismatch (ABDR) renal transplant in the absence of HLA DSAs. We present a case of a 7 year old African American male with biopsy-proven FSGS and typical features of nephrotic syndrome including proteinuria of 13 g/g based on protein to creatinine ratio. Upon initial diagnosis he was treated with steroids. Cessation of the steroids resulted in recurrence of his nephrotic syndrome. Additionally he was diagnosed with hypertension (HTN) and left ventricular hypertrophy both treated with an ACE inhibitor. He unfortunately progressed in terms of his chronic kidney disease to ESRD requiring a cadaveric renal transplant, performed in Jan 2016. His mean AT1 -Ab levels were 266.18 ± 36.06 (n = 7) and 120.72 ± 37.53 U/ML (n = 5) pre and post-transplant respectively (>17 units of AT1R-Ab is considered positive). Currently the patient is doing well on maintenance immunosuppression without recurrence of his original disease. The practice of screening for AT1R-Ab in pre and post renal transplant patients is gradually evolving. Considering the mechanisms of AT1R activation and subsequent downstream events, early monitoring for AT1R antibody levels in similar patients with HTN and idiopathic FSGS may help in appropriate management of preventing multi-organ injuries, malignant HTN, metabolic disorders and eventual ESRD. More patients with pre-transplant FSGS and r FSGS post transplant need to be evaluated for AT1R-Ab.

Diabetes mellitus (DM) is the most common cause of chronic kidney disease (CKD) and end stage renal disease (ESRD). New onset diabetes mellitus after transplant (NODAT) has been described in approximately 30 percent of non-diabetic kidney transplant recipients many years post transplantation. DM in patients with kidney transplantation constitutes a major comorbidity, and has significant impact on the patients and allografts’ outcome. In addition to the major comorbidity and mortality that result from cardiovascular and other DM complications, long standing DM after kidney transplant has significant pathological injury to the allograft, which results in lowering the allografts and the patients’ survivals. In spite of the cumulative body of data on diabetic nephropathy (DN) in the native kidney, there has been very limited data on the DN in the transplanted kidney. In this review, we will shed the light on the risk factors that lead to the development of NODAT. We will also describe the impact of DM on the transplanted kidney, and the outcome of kidney transplant recipients with NODAT. Additionally, we will present the most acceptable data on management of NODAT.