Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition.

Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SNF2H (SMARCA5) or SNF2L (SMARCA1) ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 were previously implicated in NDDs. Here, we describe 40 individuals from 30 families with de novo or maternally inherited pathogenic variants in SMARCA1. This novel NDD was associated with mild to severe ID/DD, delayed or regressive speech development, and some recurrent facial dysmorphisms. Individuals carrying SMARCA1 loss-of-function variants exhibited a mild genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptfsingle and double mouse knockouts revealed the importance of NURF composition and dosage for proper forebrain development. Finally, we propose that genetic alterations affecting different NURF components result in a NDD with a broad clinical spectrum.

Variants in PTEN Are Associated With a Diverse Spectrum of Cortical Dysplasia.

BACKGROUND: Inactivating mutations in PTEN are among the most common causes of megalencephaly. Activating mutations in other nodes of the PI3K/AKT/MTOR signaling pathway are recognized as a frequent cause of cortical brain malformations. Only recently has PTEN been associated with cortical malformations, and analyses of their prognostic significance have been limited. METHODS: Retrospective neuroimaging analysis and detailed chart review were conducted on 20 participants identified with pathogenic or likely pathogenic mutations in PTEN and a cortical brain malformation present on brain magnetic resonance imaging. RESULTS: Neuroimaging analysis revealed four main cerebral phenotypes-hemimegalencephaly, focal cortical dysplasia, polymicrogyria (PMG), and a less severe category, termed "macrocephaly with complicated gyral pattern" (MCG). Although a high proportion of participants (90%) had neurodevelopmental findings on presentation, outcomes varied and were favorable in over half of participants. Consistent with prior work, 39% of participants had autism spectrum disorder and 19% of participants with either pure-PMG or pure-MCG phenotypes had epilepsy. Megalencephaly and systemic overgrowth were common, but other systemic features of PTEN-hamartoma tumor syndrome were absent in over one-third of participants. CONCLUSIONS: A spectrum of cortical dysplasias is present in individuals with inactivating mutations in PTEN. Future studies are needed to clarify the prognostic significance of each cerebral phenotype, but overall, we conclude that despite a high burden of neurodevelopmental disease, long-term outcomes may be favorable. Germline testing for PTEN mutations should be considered in cases of megalencephaly and cortical brain malformations even in the absence of other findings, including cognitive impairment.

Acute kidney injury and chronic kidney disease in umbilical cord blood transplant recipients.

Introduction: Acute kidney injury (AKI) is a frequent early complication post hematopoietic stem cell transplant (HSCT), associated with high morbidity and mortality. Cord blood transplant (CBT) recipients are potentially exposed to more nephrotoxic insults, compared to patients undergoing HSCT from other donor sources. We aimed to identify risk factors for AKI in patients undergoing CBT. We also aimed to identify the impact of AKI on chronic kidney disease (CKD) and survival outcomes by one-year post-CBT. Methods: Adults and children who underwent a first CBT at our Institution were retrospectively evaluated. AKI was staged according to Kidney Disease Improving Global Outcomes (KDIGO) definitions. Cox regression models were used to estimate the association of demographic factors and post-CBT parameters with the cause-specific hazard of AKI. Results: We identified 276 patients. Median age was 32 years, 28% (77/276) were children (<18 years) and 129 (47%) were white. A myeloablative conditioning regimen was administered to 243 patients (88%) and 248 (90%) received cyclosporine for GVHD prophylaxis. One-hundred and eighty-six patients (67%) developed AKI by day 60 post-transplant, with 72 (26%) developing severe AKI (stage 2 and 3). In a multivariable analysis, each increase in bilirubin level of 1 mg/dL was associated with a 23% increase in the risk of severe AKI (adjusted HR 1.23, 95% CI 1.13 - 1.34, p<.0001). Conversely, systemic steroid administration appeared to be protective of severe AKI (unadjusted HR 0.36, 95% CI 0.18 - 0.72, p=.004) in a univariate model . Two-hundred-forty-seven patients were evaluable at the one-year time point. Among those, 100 patients (40%) developed CKD one-year post-CBT. Severe AKI was associated with a higher hazard of non-relapse mortality (adjusted HR=3.26, 95% CI 1.65-6.45, p=.001) and overall mortality (adjusted HR=2.28, 95% CI 1.22-4.27, p=.01). Discussion: AKI is a frequent complication after CBT and is associated with worse outcomes. Questions remain as to the mechanism of the protective role of steroids on kidney function in the setting of CBT.

Clinical, neuroimaging and molecular characteristics of PPP2R5D-related neurodevelopmental disorders: an expanded series with functional characterisation and genotype-phenotype analysis.

BACKGROUND: Variants in PPP2R5D, affecting the regulatory B56δ subunit of protein phosphatase 2A (PP2A), have been identified in individuals with neurodevelopmental abnormalities. However, the molecular and clinical spectra remain incompletely understood. METHODS: Individuals with PPP2R5D variants were enrolled through Simons Variation in Individuals Project/Simons Searchlight. Data were collected from medical history interviews, medical record review, online validated instruments and neuroimaging review. Genetic variants were biochemically characterised. RESULTS: We studied 76 individuals with PPP2R5D variants, including 68 with pathogenic de novo variants, four with a variant of uncertain significance (VUS) and four siblings with a novel dominantly inherited pathogenic variant. Among 13 pathogenic variants, eight were novel and two (p.Glu198Lys and p.Glu200Lys) were highly recurrent. Functional analysis revealed impaired PP2A A/C-subunit binding, decreased short linear interaction motif-dependent substrate binding or both-with the most severe phenotypes associated with variants that completely retained one of these binding characteristics and lost the other-further supporting a dominant-negative disease mechanism. p.Glu198Lys showed the highest C-binding defect and a more severe clinical phenotype. The inherited p.Glu197Gly variant had a mild substrate binding defect, and three of four VUS had no biochemical impact. Common clinical phenotypes were language, intellectual or learning disabilities (80.6%), hypotonia (75.0%), macrocephaly (66.7%), seizures (45.8%) and autism spectrum disorder (26.4%). The mean composite Vineland score was 59.8, and most participants were in the 'moderate to low' and 'low' adaptive levels in all domains. CONCLUSION: Our study delineates the most common features of PPP2R5D-related neurodevelopmental disorders, expands the clinical and molecular spectrum and identifies genotype-phenotype correlations.

ANKLE2-related microcephaly: A variable microcephaly syndrome resembling Zika infection.

OBJECTIVE: This study delineates the clinical and molecular spectrum of ANKLE2-related microcephaly (MIC), as well as highlights shared pathological mechanisms between ANKLE2 and the Zika virus. METHODS: We identified 12 individuals with MIC and variants in ANKLE2 with a broad range of features. Probands underwent thorough phenotypic evaluations, developmental assessments, and anthropometric measurements. Brain imaging studies were systematically reviewed for developmental abnormalities. We functionally interrogated a subset of identified ANKLE2 variants in Drosophila melanogaster. RESULTS: All individuals had MIC (z-score ≤ -3), including nine with congenital MIC. We identified a broad range of brain abnormalities including simplified cortical gyral pattern, full or partial callosal agenesis, increased extra-axial spaces, hypomyelination, cerebellar vermis hypoplasia, and enlarged cisterna magna. All probands had developmental delays in at least one domain, with speech and language delays being the most common. Six probands had skin findings characteristic of ANKLE2 including hyper- and hypopigmented macules. Only one individual had scalp rugae. Functional characterization in Drosophila recapitulated the human MIC phenotype. Of the four variants tested, p.Val229Gly, p.Arg236*, and p.Arg536Cys acted as partial-loss-of-function variants, whereas the c.1421-1G>C splicing variant demonstrated a strong loss-of-function effect. INTERPRETATION: Deleterious variants in the ANKLE2 gene cause a unique MIC syndrome characterized by congenital or postnatal MIC, a broad range of structural brain abnormalities, and skin pigmentary changes. Thorough functional characterization has identified shared pathogenic mechanisms between ANKLE2-related MIC and congenital Zika virus infection. This study further highlights the importance of a thorough diagnostic evaluation including molecular diagnostic testing in individuals with MIC.

The utility of cerebrospinal fluid-derived cell-free DNA in molecular diagnostics for the PIK3CA-related megalencephaly-capillary malformation (MCAP) syndrome: a case report.

The megalencephaly-capillary malformation (MCAP) syndrome is an overgrowth disorder caused by mosaic gain-of-function variants in PIK3CA It is characterized by megalencephaly or hemimegalencephaly, vascular malformations, somatic overgrowth, among other features. Epilepsy is commonly associated with MCAP, and a subset of individuals have cortical malformations requiring resective epilepsy surgery. Like other mosaic disorders, establishing a molecular diagnosis is largely achieved by screening lesional tissues (such as brain or skin), with a low diagnostic yield from peripheral tissues (such as blood). Therefore, in individuals with MCAP in whom lesional tissues are scarce or unavailable or those ineligible for epilepsy surgery, establishing a molecular diagnosis can be challenging. Here we report on the utility of cerebrospinal fluid (CSF)-derived cfDNA for the molecular diagnosis of an individual with MCAP syndrome harboring a mosaic PIK3CA variant (c.3139C > T, p.His1047Tyr). The proband presented with asymmetric megalencephaly without significant dysgyria. He did not have refractory epilepsy and was therefore not a candidate for epilepsy surgery. However, he developed diffuse large B-cell lymphoma (DLBCL) in late childhood, with four CSF samples obtained via lumbar puncture for cancer staging during which one sample was collected for cfDNA extraction and sequencing. PIK3CA variant allele fractions in CSF cell-free DNA (cfDNA), skin fibroblasts, and peripheral blood were 3.08%, 37.31%, and 2.04%, respectively. This report illustrates the utility of CSF-derived cfDNA in MCAP syndrome. Minimally invasive-based molecular diagnostic approaches utilizing cfDNA not only facilitate accurate genetic diagnosis but also have important therapeutic implications for individuals with refractory epilepsy as repurposed PI3K-AKT-MTOR pathway-inhibitors become more widely available.

Profiling PI3K-AKT-MTOR variants in focal brain malformations reveals new insights for diagnostic care.

Focal malformations of cortical development including focal cortical dysplasia, hemimegalencephaly and megalencephaly, are a spectrum of neurodevelopmental disorders associated with brain overgrowth, cellular and architectural dysplasia, intractable epilepsy, autism and intellectual disability. Importantly, focal cortical dysplasia is the most common cause of focal intractable paediatric epilepsy. Gain and loss of function variants in the PI3K-AKT-MTOR pathway have been identified in this spectrum, with variable levels of mosaicism and tissue distribution. In this study, we performed deep molecular profiling of common PI3K-AKT-MTOR pathway variants in surgically resected tissues using droplet digital polymerase chain reaction (ddPCR), combined with analysis of key phenotype data. A total of 159 samples, including 124 brain tissue samples, were collected from 58 children with focal malformations of cortical development. We designed an ultra-sensitive and highly targeted molecular diagnostic panel using ddPCR for six mutational hotspots in three PI3K-AKT-MTOR pathway genes, namely PIK3CA (p.E542K, p.E545K, p.H1047R), AKT3 (p.E17K) and MTOR (p.S2215F, p.S2215Y). We quantified the level of mosaicism across all samples and correlated genotypes with key clinical, neuroimaging and histopathological data. Pathogenic variants were identified in 17 individuals, with an overall molecular solve rate of 29.31%. Variant allele fractions ranged from 0.14 to 22.67% across all mutation-positive samples. Our data show that pathogenic MTOR variants are mostly associated with focal cortical dysplasia, whereas pathogenic PIK3CA variants are more frequent in hemimegalencephaly. Further, the presence of one of these hotspot mutations correlated with earlier onset of epilepsy. However, levels of mosaicism did not correlate with the severity of the cortical malformation by neuroimaging or histopathology. Importantly, we could not identify these mutational hotspots in other types of surgically resected epileptic lesions (e.g. polymicrogyria or mesial temporal sclerosis) suggesting that PI3K-AKT-MTOR mutations are specifically causal in the focal cortical dysplasia-hemimegalencephaly spectrum. Finally, our data suggest that ultra-sensitive molecular profiling of the most common PI3K-AKT-MTOR mutations by targeted sequencing droplet digital polymerase chain reaction is an effective molecular approach for these disorders with a good diagnostic yield when paired with neuroimaging and histopathology.

Thrombotic Microangiopathy Increases the Risk of Chronic Kidney Disease but Not Overall Mortality in Long-term Transplant Survivors.

Thrombotic microangiopathy (TMA) after allogeneic hematopoietic cell transplant (HCT) is associated with acute kidney injury (AKI) and increased mortality. The impact of TMA on chronic kidney disease (CKD) and long-term mortality among HCT survivors has not been fully examined. To assess the risk of CKD and mortality in HCT survivors with and without history of TMA, we conducted a retrospective cohort study among adult allogeneic HCT recipients who survived to at least 1 year post-transplantation. We examined the association between the history of TMA within 1 year and the onset of CKD longitudinally for 5 years with generalized estimating equation (GEE) while adjusting for other key confounders. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 using the CKD-EPI formula with outpatient creatinine values collected during the annual long-term follow-up unit follow-up visits. Kaplan Meier curves landmarked at 1 year were used for survival analyses. Among 2091 adult patients who underwent allogeneic HCT, we identified 1151 patients who survived at least 1 year and had available long-term follow-up data. Among them, 57 patients developed TMA within 1 year and 1094 did not have TMA. There was no pretransplantation baseline difference in eGFR between groups. After adjusting for confounders, history of TMA was associated with an odds ratio of 2.83 (95% confidence interval 1.33-6.03) for CKD development over 5 years after transplantation. The conditional 5-year survival was 78% in the TMA survivors and 80% in the non-TMA survivors (log rank P = .122). HCT survivors with a history of TMA had increased risk of CKD development. Although TMA was associated with high risk of mortality within 1 year after transplantation, long-term survival was comparable with non-TMA survivors. Future therapeutic interventions should focus on not only short-term mortality outcomes, but also short- and long-term kidney outcomes for HCT patients with TMA.

Prognostic Biomarkers for Thrombotic Microangiopathy after Acute Graft-versus-Host Disease: A Nested Case-Control Study.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a complication of allogeneic hematopoietic cell transplantation (HCT) that often occurs following the development of acute graft-versus-host disease (aGVHD). In this study, we aimed to identify early TMA biomarkers among patients with aGVHD. We performed a nested-case-control study from a prospective cohort of allogeneic HCT recipients, matching on the timing and severity of antecedent aGVHD. We identified 13 TMA cases and 25 non-TMA controls from 208 patients in the cohort. Using multivariable conditional logistic regression, the odds ratio for TMA compared with non-TMA was 2.65 (95% confidence interval [CI], 1.00 to 7.04) for every 100 ng/mL increase in terminal complement complex sC5b9 and 2.62 (95% CI, 1.56 to 4.38) for every 1000 pg/mL increase in angiopoietin-2 (ANG2) at the onset of aGVHD. ADAMTS13 and von Willebrand factor (VWF) antigens were not appreciably associated with TMA. Using a Cox regression model incorporating sC5b9 >300 ng/mL and ANG2 >3000 pg/mL at the onset of aGVHD, the adjusted hazard ratio for mortality was 5.33 (95% CI, 1.57 to 18.03) for the high-risk group (both elevated) and 4.40 (95% CI, 1.60 to 12.07) for the intermediate-risk group (one elevated) compared with the low-risk group (neither elevated). In conclusion, we found that elevated sC5b9 and ANG2 levels at the onset of aGVHD were associated with the development of TMA and possibly mortality after accounting for the timing and severity of aGVHD. The results suggest important roles of complement activation and endothelial dysfunction in the pathogenesis of TMA. Measurement of these biomarkers at the onset of aGVHD may inform prognostic enrichment for preventive trials and improve clinical care.

Ambulatory Blood Pressure and Endothelial Dysfunction in Hematopoietic Cell Transplantation Recipients.

Hematopoietic cell transplantation (HCT) is a common treatment for many disorders. Albuminuria post-HCT, which may represent endothelial injury or inflammation from graft- versus-host disease, increases the risk of chronic kidney disease and nonrelapse mortality at 1 year. HCT recipients also have abnormal blood pressure (BP) and increased rates of cardiovascular complications. We sought to determine the relationships among albuminuria, endothelial dysfunction, and BP in HCT recipients. Patients age ≥12 years who underwent their first allogeneic HCT between 2012 and 2015 and survived through day 80 post-HCT were eligible. Peripheral endothelial function was assessed using the EndoPAT2000 device at day 80 along with 24-hour ambulatory BP monitoring (ABPM). Clinical and laboratory data were collected along with a urine sample for calculation of the albumin-to-creatinine ratio. Both logistic and linear regression analyses were used to identify associations between EndoPAT score and clinical variables. Sixty patients (median age, 48 years; range, 14 to 69 years) completed the study. The median EndoPAT score was 2.05 (range, 1.02 to 4.45), and 17 patients (28%) had abnormal endothelial function. Forty-two patients (72%) had ambulatory hypertension (HTN), and 38 (63%) had blunted nocturnal dipping. HTN on ABPM (P = .045) and blunted nocturnal dipping (P = .04) were associated with a lower EndoPAT score. Albuminuria was not associated with EndoPAT score. There was a lack of agreement between our clinical definition of HTN (office BP and/or use of medications) and ABPM results (P = .04). We did not find an association between lower EndoPAT scores and albuminuria, but did find an association between an abnormal nocturnal dip and HTN diagnosed by ABPM. This suggests that albuminuria may reflect local endothelial injury and inflammation rather than a systemic process. Office BP readings do not accurately reflect true BP, suggesting that 24-hour ABPM studies are needed to diagnose and treat HTN appropriately.

Changes in Glomerular Filtration Rate and Impact on Long-Term Survival among Adults after Hematopoietic Cell Transplantation: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: Kidney injury is a significant complication for patients undergoing hematopoietic cell transplantation (HCT), but few studies have prospectively examined changes in GFR in long-term survivors of HCT. We described the association between changes in GFR and all-cause mortality in patients up to 10 years after HCT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a prospective, observational cohort study of adult patients undergoing HCT at the Fred Hutchinson Cancer Center in Seattle, Washington from 2003 to 2015. Patients were followed from baseline, before conditioning therapy, until a maximum of 10 years after transplant. We used Cox proportional hazard models to examine the association between creatinine eGFR and all-cause mortality. We used time-dependent generalized estimating equations to examine risk factors for decreases in eGFR. RESULTS: A total of 434 patients (median age, 52 years; range, 18-76 years; 64% were men; 87% were white) were followed for a median 5.3 years after HCT. The largest decreases in eGFR occurred within the first year post-transplant, with the eGFR decreasing from a median of 98 ml/min per 1.73 m2 at baseline to 78 ml/min per 1.73 m2 by 1 year post-HCT. Two thirds of patients had an eGFR<90 ml/min per 1.73 m2 at 1 year after transplant. When modeled as a continuous variable, as eGFR declined from approximately 60 ml/min per 1.73 m2, the hazard of mortality progressively increased relative to a normal eGFR of 90 ml/min per 1.73 m2 (P<0.001). For example, when compared with an eGFR of 90 ml/min per 1.73 m2, the hazard ratios for eGFR of 60, 50, and 40 ml/min per 1.73 m2 are 1.15 (95% confidence interval, 0.87 to 1.53), 1.68 (95% confidence interval, 1.26 to 2.24), and 2.67 (95% confidence interval, 1.99 to 3.60), respectively. Diabetes, hypertension, acute graft versus host disease, and cytomegalovirus infection were independently associated with a decline in GFR, whereas calcineurin inhibitor levels, chronic graft versus host disease, and albuminuria were not. CONCLUSIONS: Adult HCT recipients have a high risk of decreased eGFR by 1 year after HCT. Although eGFR remains fairly stable thereafter, a decreased eGFR is significantly associated with higher risk of mortality, with a progressively increased risk as eGFR declines.

Estimating GFR in adult patients with hematopoietic cell transplant: comparison of estimating equations with an iohexol reference standard.

BACKGROUND AND OBJECTIVES: Formal evaluation of kidney function before and after hematopoietic cell transplant is important to determine conditioning regimens, type of transplant, and medication dosing. Serum creatinine and estimating equations may not accurately assess kidney function. DESIGN, STUDY, PARTICIPANTS, & MEASUREMENTS: Existing estimating equations for GFR were compared with an iohexol measure of GFR in a prospective cohort study of 50 patients undergoing hematopoietic cell transplant and subsequent care at the Fred Hutchinson Cancer Research Institute from 2009 to 2013. Patients underwent iohexol GFR, serum creatinine, and cystatin C determination at baseline and day 100 posthematopoietic cell transplant. Iohexol GFR measurements were compared with the CKD Epidemiology Collaboration, Inker CKD Epidemiology Collaboration cystatin C with and without serum creatinine, Modification of Diet in Renal Disease, and Cockcroft-Gault estimating equations using Bland-Altman analysis and McNemar's test. The iohexol measurements were also compared with blood samples collected simultaneously on filter paper. RESULTS: Mean differences between iohexol GFR and eGFR on the basis of Bland-Altman analyses ranged from -20.6 to +15.4 ml/min per 1.73 m(2) at baseline and -12.7 to +12.9 ml/min per 1.73 m(2) at day 100. The CKD Epidemiology Collaboration and Modification of Diet in Renal Disease estimating equations classified 64% of patients with a GFR<90 at baseline compared with 38% by iohexol GFR (P=0.003 and P<0.01, respectively). No statistically significant differences were seen at day 100. The filter paper GFR had a mean difference of 0 at baseline and 5.9 at day 100. Additionally, 21%-37% and 57%-89% of eGFRs were within 10% and 30%, respectively, of the iohexol GFR at baseline, and 16%-34% and 72%-84% were within 10% and 30%, respectively, of the iohexol GFR at day 100; 98% of the filter paper estimates at baseline were within 30%, and 46% were within 10% of iohexol GFR. CONCLUSIONS: The estimating equations are neither accurate nor precise in the hematopoietic cell transplant population, and clinical decision may require measurement of GFR.

Urinary elafin and kidney injury in hematopoietic cell transplant recipients.

BACKGROUND AND OBJECTIVES: Graft-versus-host disease (GVHD) is associated with kidney injury after hematopoietic cell transplantation (HCT). Because plasma elafin levels correlate with skin GVHD, this study examined urinary elafin as a potential marker of renal inflammation and injury. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Urine was collected prospectively on 205 patients undergoing their first HCT from 2003 to 2010. Collections were done at baseline, weekly through day 100, and monthly through year 1 to measure elafin and urine albumin-to-creatinine ratio (ACR). Associations between urinary elafin levels and microalbuminuria, macroalbuminuria, AKI and CKD, and mortality were examined using Cox proportional hazards or linear regression models. Available kidney biopsy specimens were processed for immunohistochemistry. RESULTS: Mean urinary elafin levels to day 100 were higher in patients with micro- or macroalbuminuria (adjusted mean difference, 529 pg/ml; P=0.03) at day 100 than in those with a normal ACR (adjusted mean difference, 1295 pg/ml; P<0.001). Mean urinary elafin levels were higher in patients with AKI compared with patients without AKI (adjusted mean difference, 558 pg/ml; P<0.01). The average urinary elafin levels within the first 100 days after HCT were higher in patients who developed CKD at 1 year than in patients without CKD (adjusted mean difference, 894 pg/ml; P=0.002). Among allogeneic recipients, a higher proportion of patients with micro- or macroalbuminuria at day 100 also had grade II-IV acute GVHD (80% and 86%, respectively) compared with patients with a normal ACR (58%; global P<0.01). Each increase in elafin of 500 pg/ml resulted in a 10% increase in risk of persistent macroalbuminuria (hazard ratio, 1.10; 95% confidence interval [95% CI], 1.06 to 1.13; P<0.001) and a 7% increase in the risk of overall mortality (95% CI, 1.02 to 1.13, P<0.01). Renal biopsy specimens from a separate cohort of HCT survivors demonstrated elafin staining in distal and collecting duct tubules. CONCLUSION: Higher urinary elafin levels are associated with an increased risk of micro- and macroalbuminuria, AKI and CKD, and death after HCT.