KDOQI Commentary on the KDIGO 2022 Update to the Clinical Practice Guideline for Diabetes Management in CKD.

The Kidney Disease: Improving Global Outcomes (KDIGO) guideline for diabetes management in chronic kidney disease (CKD) was updated in 2022, just 2 years after the previous update. The need for this rapid update is reflective of the recent and unprecedented positive results of numerous clinical trials aimed at reducing kidney and cardiovascular morbidity and mortality in people with diabetes. The Kidney Disease Outcomes Quality Initiative (KDOQI) work group for diabetes in CKD, convened by the National Kidney Foundation, provides herein a commentary on these changes, particularly the implications for health care in the United States. Changes to the KDIGO guideline mirror the evolution of sodium/glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists from purely antihyperglycemic agents to cardiorenal-metabolic therapeutics, and the lower estimated glomerular filtration rate of≥20mL/min/1.73m2 for SGLT2 inhibitor initiation. New data have also brought the addition of the first-in-class, Federal Drug Administration-approved nonsteroidal mineralocorticoid receptor antagonist finerenone as an agent to reduce cardiorenal end points. While there has been significant progress in innovation, there remain serious challenges to implementation, particularly in the United States where inequities in insurance coverage and high costs limit their use, particularly in vulnerable populations, ultimately widening health care disparities.

Association of Obesity With Kidney and Cardiac Outcomes Among Patients With Glomerular Disease: Findings From the Cure Glomerulonephropathy Network.

RATIONALE & OBJECTIVE: The influence of obesity on cardiorenal outcomes in individuals with glomerular disease is incompletely known. This study examined the association between obesity and kidney and cardiovascular outcomes in children and adults with glomerular kidney disease. STUDY DESIGN: Prospective, multicenter, observational study. SETTING & PARTICIPANTS: Participants in the Cure Glomerulonephropathy Network (CureGN) who were≥5 years of age at enrollment. EXPOSURE: Adult body mass index (BMI) groups: 20-24 (healthy) versus 25-34 (overweight/class 1 obesity) versus≥35 (class 2-3 obesity); and pediatric BMI percentiles: 5th-84th (healthy) versus 85th-94th (overweight) versus≥95th (obese). OUTCOME: A composite kidney outcome (40% estimated glomerular filtration rate [eGFR] decline or kidney failure) and a composite cardiovascular outcome (myocardial infarction, stroke, heart failure, or death). ANALYTICAL APPROACH: Time to composite primary outcomes by BMI strata were estimated using Kaplan-Meier analysis. The adjusted associations between BMI and outcomes were estimated using Cox proportional hazards analysis. RESULTS: The study included 2,301 participants (1,548 adults and 753 children). The incidence of the primary kidney end point was 90.8 per 1,000 person-years in adults with class 2-3 obesity, compared with 58.0 in normal weight comparators. In the univariable analysis, class 2-3 obesity was associated with the primary kidney outcome only in adults (HR, 1.6 [95% CI, 1.1-2.2], P=0.006) compared with the healthy weight groups. In the multivariable adjusted analysis, class 2-3 obesity did not remain significant among adults when controlling for baseline eGFR and proteinuria. Adults with class 2-3 obesity had an incidence of 19.7 cardiovascular events per 1,000 person-years and greater cardiovascular risk (HR, 3.9 [95% CI, 1.4-10.7], P=0.009) in the fully adjusted model. LIMITATIONS: BMI is an imperfect indicator of adiposity. Residual confounding may exist from socioeconomic factors. CONCLUSIONS: Among adult patients in CureGN, class 2-3 obesity is associated with cardiovascular but not kidney outcomes when adjusted for potential confounding factors. PLAIN-LANGUAGE SUMMARY: Obesity is a risk factor for adverse heart and kidney outcomes in patients with chronic kidney disease, but whether it is associated with these outcomes in patients with glomerulonephropathy is not known. This study used existing data from a large sample of adults and children with glomerular diseases to address this question. The findings suggest that obesity increases the risk of cardiovascular but not kidney disease events in adult patients with glomerular disease.

Age of Onset and Disease Course in Biopsy-Proven Minimal Change Disease: An Analysis From the Cure Glomerulonephropathy Network.

RATIONALE & OBJECTIVE: Adolescent- and adult-onset minimal change disease (MCD) may have a clinical course distinct from childhood-onset disease. We characterized the course of children and adults with MCD in the Cure Glomerulonephropathy Network (CureGN) and assessed predictors of rituximab response. STUDY DESIGN: Prospective, multicenter, observational study. STUDY PARTICIPANTS: CureGN participants with proven MCD on biopsy. EXPOSURE: Age at disease onset, initiation of renin-angiotensin-aldosterone system (RAAS) blockade, and immunosuppression including rituximab during the study period. OUTCOME: Relapse and remission, change in estimated glomerular filtration rate (eGFR), and kidney failure. ANALYTICAL APPROACH: Remission and relapse probabilities were estimated using Kaplan-Meier curves and gap time recurrent event models. Linear regression models were used for the outcome of change in eGFR. Cox proportional hazards models were used to estimate the association between rituximab administration and remission. RESULTS: The study included 304 childhood- (≤12 years old), 49 adolescent- (13-17 years old), and 201 adult- (≥18 years) onset participants with 2.7-3.2 years of follow-up after enrollment. Children had a longer time to biopsy (238 vs 23 and 36 days in adolescent- and adult-onset participants, respectively; P<0.001) and were more likely to have received therapy before biopsy. Children were more likely to be treated with immunosuppression but not RAAS blockade. The rate of relapse was higher in childhood- versus adult-onset participants (HR, 1.69 [95% CI, 1.29-2.21]). The probability of remission was also higher in childhood-onset disease (HR, 1.33 [95%CI, 1.02-1.72]). In all groups eGFR loss was minimal. Children were more likely to remit after rituximab than those with adolescent- or adult-onset disease (adjusted HR, 2.1; P=0.003). Across all groups, glucocorticoid sensitivity was associated with a greater likelihood of achieving complete remission after rituximab (adjusted HR, 2.62; P=0.002). LIMITATIONS: CureGN was limited to biopsy-proven disease. Comparisons of childhood to nonchildhood cases of MCD may be subject to selection bias, given that childhood cases who undergo a biopsy may be limited to patients who are least responsive to initial therapy. CONCLUSIONS: Among patients with MCD who underwent kidney biopsy, there were differences in the course (relapse and remission) of childhood-onset compared with adolescent- and adult-onset disease, as well as rituximab response. PLAIN-LANGUAGE SUMMARY: Minimal change disease is a biopsy diagnosis for nephrotic syndrome. It is diagnosed in childhood, adolescence, or adulthood. Patients and clinicians often have questions about what to expect in the disease course and how to plan therapies. We analyzed a group of patients followed longitudinally as part of the Cure Glomerulonephropathy Network (CureGN) and describe the differences in disease (relapse and remission) based on the age of onset. We also analyzed rituximab response. We found that those with childhood-onset disease had a higher rate of relapse but also have a higher probability of reaching remission when compared with adolescent- or adult-onset disease. Children and all steroid-responsive patients are more likely to achieve remission after rituximab.

Design of the COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with chronic kidney disease and type 2 diabetes using a UACR Endpoint study (CONFIDENCE).

BACKGROUND: Despite available interventions, people with type 2 diabetes (T2D) remain at risk of chronic kidney disease (CKD). Finerenone, a potent and selective nonsteroidal mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitors (SGLT2is) can reduce both kidney and cardiovascular risks in people with CKD and T2D. Here we outline the design of a study to investigate whether dual therapy with finerenone and an SGLT2i is superior to either agent alone. METHODS: CONFIDENCE (NCT05254002) is a randomized, controlled, double-blind, double-dummy, international, multicenter, three-armed, parallel-group, 7.5 - to 8.5-month, Phase 2 study in 807 adults with T2D, stage 2-3 CKD and a urine albumin:creatinine ratio (UACR) ≥300-<5000 mg/g. The primary objective is to demonstrate that 6 months of dual therapy comprising finerenone and the SGLT2i empagliflozin is superior for reducing albuminuria versus either agent alone. Interventions will be once-daily finerenone 10 mg or 20 mg (target dose) plus empagliflozin 10 mg, or empagliflozin 10 mg alone, or finerenone 10 mg or 20 mg (target dose) alone. RESULTS: The primary outcome is a relative change from baseline in UACR among the three groups. Secondary outcomes will further characterize efficacy and safety, including changes in estimated glomerular filtration rate and incident hyperkalemia. CONCLUSIONS: CONFIDENCE is evaluating the safety, tolerability and efficacy of dual use of finerenone and an SGLT2i in adults with CKD and T2D. Should an additive effect be shown, early and efficient intervention with dual finerenone and SGLT2i therapy could slow disease progression and provide long-term benefits for people with CKD and T2D.

Diabetes complications and cognitive function in young adults with youth-onset type 1 or type 2 diabetes: the SEARCH for Diabetes in Youth Study.

Aims/hypotheses: People with type 1 (T1D) or type 2 diabetes (T2D) who also have diabetes complications can have pronounced cognitive deficits. It remains unknown, however, whether and how multiple diabetes complications co-occur with cognitive dysfunction, particularly in youth-onset diabetes. Methods: Using data from the SEARCH for Diabetes in Youth study cohort, a prospective longitudinal cohort, we examined clustering of complications and their underlying clinical factors with performance on cognitive tests in young adults with youth-onset T1D or T2D. Cognition was assessed via the NIH Toolbox Cognition Battery. The main cognitive variables were age-corrected scores for composite fluid cognition and associated cognitive subdomains. Diabetes complications included retinopathy, microalbuminuria, and peripheral neuropathy (PN). Lipids, systolic blood pressure (SBP), hemoglobin A1c, and other clinical factors were included in the analyses. Clustering was applied separately to each group (T1D=646; T2D=165). A three-cluster(C) solution was identified for each diabetes type. Mean values and frequencies of all factors were compared between resulting clusters. Results: The average age-corrected score for composite fluid cognition differed significantly across clusters for each group (p<0.001). People with T1D and the lowest average fluid cognition scores had the highest frequency of self-reporting at least one episode of hypoglycemia in the year preceding cognitive testing and the highest prevalence of PN. Persons with T2D and the lowest average fluid cognition scores had the highest SBP, the highest central systolic and diastolic blood pressures, and highest prevalence of PN. Conclusions/interpretations: These findings highlight shared (PN) and unique factors (hypoglycemia in T1D; SBP in T2D) that could be targeted to potentially mitigate cognitive issues in young people with youth-onset diabetes.

Glomerular Hematuria and the Utility of Urine Microscopy: A Review.

Evaluation of hematuria and microscopic examination of urine sediment are commonly used tools by nephrologists in their assessment of glomerular diseases. Certain morphological aspects of urine red blood cells (RBCs) seen by microscopy may help in identifying the source of hematuria as glomerular or not. Recognized signs of glomerular injury are RBC casts or dysmorphic RBCs, in particular acanthocytes (ring-shaped RBCs with protruding blebs). Despite being a highly operator-dependent test, urine sediment examination revealing these signs of glomerular hematuria has demonstrated specificities and positive predictive values ranging between 90%-100% for diagnosing glomerular disease, although sensitivity can be quite variable. Hematuria is a commonly used tool for diagnosing patients with proliferative glomerulonephritis such as IgA nephropathy, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and lupus nephritis, sometimes even as a surrogate for kidney involvement. Studies examining the role for hematuria in monitoring and predicting adverse outcomes in these diseases have shown inconsistent results, possibly due to inconsistent definitions that often fail to consider specific markers of glomerular hematuria such as dysmorphic RBCs, acanthocytes, or RBC casts. A consensus definition of what constitutes glomerular hematuria would help standardize use in future studies and likely improve the diagnostic and prognostic value of hematuria as a marker of glomerulonephritis.

KDOQI US Commentary on the KDIGO 2020 Clinical Practice Guideline for Diabetes Management in CKD.

In October 2020, KDIGO (Kidney Disease: Improving Global Outcomes) published its first clinical practice guideline directed specifically to the care of patients with diabetes and chronic kidney disease (CKD). This commentary presents the views of the KDOQI (Kidney Disease Outcomes Quality Initiative) work group for diabetes in CKD, convened by the National Kidney Foundation to provide an independent expert perspective on the new guideline. The KDOQI work group believes that the KDIGO guideline takes a major step forward in clarifying glycemic targets and use of specific antihyperglycemic agents in diabetes and CKD. The purpose of this commentary is to carry forward the conversation regarding optimization of care for patients with diabetes and CKD. Recent developments for prevention of CKD progression and cardiovascular events in people with diabetes and CKD, particularly related to sodium/glucose cotransporter 2 (SGLT2) inhibitors, have filled a longstanding gap in nephrology's approach to the care of persons with diabetes and CKD. The multifaceted benefits of SGLT2 inhibitors have facilitated interactions between nephrology, cardiology, endocrinology, and primary care, underscoring the need for innovative approaches to multidisciplinary care in these patients. We now have more interventions to slow kidney disease progression and prevent or delay kidney failure in patients with diabetes and kidney disease, but methods to streamline their implementation and overcome barriers in access to care, particularly cost, are essential to ensuring all patients may benefit.

SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio>300mg/g, and estimated glomerular filtration rate of 30 to<90mL/min/1.73m2. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.

High risk of acute kidney injury in Malawian trauma patients: a prospective observational cohort study.

BACKGROUND: Trauma is a common cause of acute kidney injury (AKI). Yet little data exist regarding trauma-related-AKI in low-resourced settings, where the majority of deaths from AKI and trauma occur. We prospectively evaluated epidemiology of AKI in hospitalized Malawian trauma patients. METHODS: AKI was defined by creatinine-only Kidney Disease Improving Global Outcomes (KDIGO) criteria. Those with AKI were followed up 3-6 months later to determine persistent kidney abnormalities. We calculated univariate statistics with Wilcoxon rank sum tests, Fisher's exact, and chi-square tests to compare those with and without AKI. Multivariate log-risk regression modelling was used to determine risk ratios (RR) and 95% confidence intervals (CI) for AKI development. RESULTS: Of 223 participants, 14.4% (n = 32) developed AKI. Most patients were young (median age 32) males (n = 193, 86.5%) involved in road traffic injuries (n = 120, 53.8%). After adjusting for confounders, those with severe anemia during their admission were 1.4 times (RR 1.4, 95% CI 1.1-1.8) more likely to develop AKI than those without. Overall mortality was 7.6% (n = 17), and those who developed AKI were more likely to die than those who did not (18.8% vs 5.6%, p-value = 0.02). Almost half of those with AKI (n = 32) either died (n = 6) or had persistent kidney dysfunction at follow-up (n = 8). CONCLUSION: In one of the few African studies on trauma-related AKI, we found a high incidence of AKI (14.4%) in Malawian trauma patients with associated poor outcomes. Given AKI's association with increased mortality and potential ramifications on long-term morbidity, urgent attention is needed to improve AKI-related outcomes.

UBD modifies APOL1-induced kidney disease risk.

People of recent African ancestry develop kidney disease at much higher rates than most other groups. Two specific coding variants in the Apolipoprotein-L1 gene APOL1 termed G1 and G2 are the causal drivers of much of this difference in risk, following a recessive pattern of inheritance. However, most individuals with a high-risk APOL1 genotype do not develop overt kidney disease, prompting interest in identifying those factors that interact with APOL1 We performed an admixture mapping study to identify genetic modifiers of APOL1-associated kidney disease. Individuals with two APOL1 risk alleles and focal segmental glomerulosclerosis (FSGS) have significantly increased African ancestry at the UBD (also known as FAT10) locus. UBD is a ubiquitin-like protein modifier that targets proteins for proteasomal degradation. African ancestry at the UBD locus correlates with lower levels of UBD expression. In cell-based experiments, the disease-associated APOL1 alleles (known as G1 and G2) lead to increased abundance of UBD mRNA but to decreased levels of UBD protein. UBD gene expression inversely correlates with G1 and G2 APOL1-mediated cell toxicity, as well as with levels of G1 and G2 APOL1 protein in cells. These studies support a model whereby inflammatory stimuli up-regulate both UBD and APOL1, which interact in a functionally important manner. UBD appears to mitigate APOL1-mediated toxicity by targeting it for destruction. Thus, genetically encoded differences in UBD and UBD expression appear to modify the APOL1-associated kidney phenotype.

The association of low-density lipoprotein cholesterol with elevated arterial stiffness in adolescents and young adults with type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth study.

AIM: Our aim was to explore the relationship of Low-Density Lipoprotein Cholesterol (LDL-C) with subclinical cardiovascular disease (CVD) in youth with T1D and T2D. We hypothesized the association of LDL-C with elevated arterial stiffness (AS) would be partially accounted by the co-occurrence of other CVD factors. METHOD: We included 1376 youth with T1D and 157 with T2D from the SEARCH study. CVD risk factors including LDL-C, waist to height ratio (WHtR), mean arterial pressure (MAP), HbA1c, albumin to creatinine ratio (ACR), and insulin sensitivity (IS) score were measured at both visits. At follow up, elevated carotid-femoral AS was defined as levels above 6.8 m/s. Multivariable logistic regression evaluated the odds of elevated AS as a function of the average CVD risk factors. RESULTS: At follow up, age was 18.0 ± 4.1 and 21.6 ± 3.5 years and duration of diabetes was 7.8 ± 1.9 and 7.7 ± 1.9 years in T1D and T2D, respectively. Elevated AS was found in 8.4% of T1D and 49.0% of T2D participants. Each SD increase in LDL-C was associated with 1.28 increased odds (95% CI 1.05-1.54, P = .013) of elevated AS in youth with T1D. The association was similar but not statistically significant in T2D. WHtR, IS, and MAP were associated with elevated AS in both groups. Adjustment for WHtR or IS attenuated to non-significance the relationship between LDL-C and AS in T1D. CONCLUSIONS: Obesity and insulin resistance attenuate the association of high LDL-C with AS suggesting they partially account for the adverse effects of LDL-C on cardiovascular health in youth with T1D.

Racial and health insurance disparities in pediatric acute kidney injury in the USA.

BACKGROUND: Acute kidney injury (AKI) significantly increases morbidity and mortality for hospitalized children, yet sociodemographic risk factors for pediatric AKI are poorly described. We examined sociodemographic differences in pediatric AKI amongst a national cohort of hospitalized children. METHODS: Secondary analysis of the most recent (2012) Kids' Inpatient Database (KID) from the Agency for Healthcare Research and Quality. Study sample weights were used to obtain national estimates of AKI (defined by administrative data). KID is a nationally representative sample of pediatric discharges throughout the USA. Linear risk regression models were used to assess the relationship between our primary exposures (race/ethnicity, health insurance, household urbanization, gender, and age) and the diagnosis of AKI, adjusting for comorbidities. RESULTS: A total of 1,699,841 hospitalizations met our study criteria. In 2012, AKI occurred in approximately 12.3/1000 pediatric hospitalizations, which translates to almost 30,000 children nationally. Asian/Pacific Islander, African-American, and Hispanic children were at slightly increased risk for AKI compared to Caucasian children (adjusted risk difference (RD) 4.5 per 1000 hospitalizations, 95% confidence interval (CI) 2.9-6.0; 2.5/1000 hospitalizations, 95% CI 1.7-3.3; and 1.7/1000 hospitalizations, 95% CI 0.9-2.5, respectively). Uninsured children were more likely to suffer AKI compared to children with any health insurance (e.g., no insurance versus Medicaid: adjusted RD 14.4/1000 hospitalizations, 95% CI 12.7-16.2). Based on these national estimates, one episode of AKI might be prevented if 70 (95% CI 62-79) hospitalized children without insurance were provided with Medicaid. CONCLUSIONS: Pediatric AKI occurs more frequently in racial minority and uninsured children, factors linked to lower socioeconomic status.

Incidence and epidemiology of acute kidney injury in a pediatric Malawian trauma cohort: a prospective observational study.

BACKGROUND: Acute kidney injury (AKI) is highly associated with mortality risk in children worldwide. Trauma can lead to AKI and is a leading cause of pediatric death in Africa. However, there is no information regarding the epidemiology of pediatric, trauma-associated AKI in Africa. METHODS: Prospective cohort study of pediatric trauma patients admitted to a tertiary referral hospital in Malawi. Participants enrolled at admission were followed prospectively throughout their hospitalization. AKI was defined by creatinine-only Kidney Disease Improving Global Outcomes criteria. We calculated descriptive statistics and univariate relative risks (RR) for hypothesis-generation of potential risk factors associated with AKI. RESULTS: We analyzed data from 114 participants. Depending on baseline creatinine definition, AKI incidence ranged from 4 to 10%. The new Schwartz equation estimated baseline creatinine values best and yielded an AKI incidence of 9.7%. Almost one in ten children died during hospitalization, but those with AKI (n = 4) were at significantly higher risk of death compared to those without AKI (40.0% vs 6.2%; RR 6.5, 95% CI 2.2-19.1). Burn injuries were most commonly associated with AKI (63.6%). Other potential AKI risk factors included multiple injuries, trunk or facial injuries, and recent consumption of herbal remedies. CONCLUSIONS: AKI occurs in up to 10% of admitted pediatric trauma patients in Malawi and increases the risk of death 7-fold compared to those without AKI. This large unrecognized burden in trauma requires further investment by researchers, clinicians and policymakers to develop evidenced-based triage, recognition, and management approaches to prevent the associated sequelae and potential mortality from AKI.

Segmental Sclerosis and Extracapillary Hypercellularity Predict Diabetic ESRD.

Pathogenetic markers of diabetic kidney disease (DKD) progression to ESRD are lacking. We characterized the prognostic value of histologic findings in DKD for time to ESRD in native kidney specimens from biopsies performed from 1995 to 2011 with diabetic glomerulosclerosis as the only glomerular disease diagnosis (n=109). Biopsy specimens were analyzed according to standard methods, including determination of diabetic nephropathy class, as defined by the Renal Pathology Society. Clinical data were extracted from electronic medical records. We used competing risk models, with death as the competing risk, to estimate subdistribution hazard ratios (HRs) for ESRD. All multivariable models included age, sex, black race, baseline eGFR, and baseline proteinuria. Pathologic characteristics achieving P<0.1 were added into successively complex models. ESRD occurred in 56% of patients, and 26% of patients died before reaching ESRD. In univariate analyses, diabetic nephropathy class was not statistically significant in predicting time to ESRD. The final multivariable model (n=106) showed a borderline association between mild mesangial expansion and decreased risk for ESRD (subdistribution HR, 0.64; 95% confidence interval, 0.40 to 1.00). Poor prognostic factors in the final model included segmental sclerosis and extracapillary hypercellularity (subdistribution HR, 2.04; 95% confidence interval, 1.36 to 3.05; and subdistribution HR, 2.21; 95% confidence interval, 1.19 to 4.11, respectively). In conclusion, we identified segmental sclerosis and extracapillary hypercellularity as novel, poor prognostic indicators of time from DKD to ESRD. Whether these indicators represent a distinct pathogenetic phenotype of DKD will require a large study with a broad spectrum of disease severity.

Association of Type 1 Diabetes vs Type 2 Diabetes Diagnosed During Childhood and Adolescence With Complications During Teenage Years and Young Adulthood.

Importance: The burden and determinants of complications and comorbidities in contemporary youth-onset diabetes are unknown. Objective: To determine the prevalence of and risk factors for complications related to type 1 diabetes vs type 2 diabetes among teenagers and young adults who had been diagnosed with diabetes during childhood and adolescence. Design, Setting, and Participants: Observational study from 2002 to 2015 in 5 US locations, including 2018 participants with type 1 and type 2 diabetes diagnosed at younger than 20 years, with single outcome measures between 2011 and 2015. Exposures: Type 1 and type 2 diabetes and established risk factors (hemoglobin A1c level, body mass index, waist-height ratio, and mean arterial blood pressure). Main Outcomes and Measures: Diabetic kidney disease, retinopathy, peripheral neuropathy, cardiovascular autonomic neuropathy, arterial stiffness, and hypertension. Results: Of 2018 participants, 1746 had type 1 diabetes (mean age, 17.9 years [SD, 4.1]; 1327 non-Hispanic white [76.0%]; 867 female patients [49.7%]), and 272 had type 2 (mean age, 22.1 years [SD, 3.5]; 72 non-Hispanic white [26.5%]; 181 female patients [66.5%]). Mean diabetes duration was 7.9 years (both groups). Patients with type 2 diabetes vs those with type 1 had higher age-adjusted prevalence of diabetic kidney disease (19.9% vs 5.8%; absolute difference [AD], 14.0%; 95% CI, 9.1%-19.9%; P < .001), retinopathy (9.1% vs 5.6%; AD, 3.5%; 95% CI, 0.4%-7.7%; P = .02), peripheral neuropathy (17.7% vs 8.5%; AD, 9.2%; 95% CI, 4.8%-14.4%; P < .001), arterial stiffness (47.4% vs 11.6%; AD, 35.9%; 95% CI, 29%-42.9%; P < .001), and hypertension (21.6% vs 10.1%; AD, 11.5%; 95% CI, 6.8%-16.9%; P < .001), but not cardiovascular autonomic neuropathy (15.7% vs 14.4%; AD, 1.2%; 95% CI, -3.1% to 6.5; P = .62). After adjustment for established risk factors measured over time, participants with type 2 diabetes vs those with type 1 had significantly higher odds of diabetic kidney disease (odds ratio [OR], 2.58; 95% CI, 1.39-4.81; P=.003), retinopathy (OR, 2.24; 95% CI, 1.11-4.50; P = .02), and peripheral neuropathy (OR, 2.52; 95% CI, 1.43-4.43; P = .001), but no significant difference in the odds of arterial stiffness (OR, 1.07; 95% CI, 0.63-1.84; P = .80) and hypertension (OR, 0.85; 95% CI, 0.50-1.45; P = .55). Conclusions and Relevance: Among teenagers and young adults who had been diagnosed with diabetes during childhood or adolescence, the prevalence of complications and comorbidities was higher among those with type 2 diabetes compared with type 1, but frequent in both groups. These findings support early monitoring of youth with diabetes for development of complications.

The dose-response effect of insulin sensitivity on albuminuria in children according to diabetes type.

BACKGROUND: Insulin resistance is associated with microalbuminuria among youth with diabetes mellitus. We sought to determine the dose-response effect of insulin sensitivity (IS) on the magnitude of albuminuria and whether there is a threshold below which urine albumin excretion increases. METHODS: These analyses included participants from the SEARCH for Diabetes in Youth Study with incident diabetes who completed a baseline study visit (n = 2988). We estimated IS using a validated equation incorporating waist circumference, HbA1C, and fasting serum triglycerides. Multivariate regression analyses were performed to assess the effect of IS on urine albumin creatinine ratio (UACR), stratified by diabetes type. The IS threshold was then determined using segmented regressions within each diabetes type and incorporated into the multivariate model. RESULTS: There was an association between IS and UACR in type 2 diabetes only (beta = -0.39; p < 0.001). There was strong statistical evidence for a threshold effect of IS score on UACR in the group of youth with type 2 (beta = 0.40; p < 0.001) but not type 1 diabetes (p = 0.3). CONCLUSIONS: In cross-sectional analyses, there is a negative association between IS and UACR in youth with type 2 but not type 1 diabetes, and this association likely includes a threshold effect of IS on UACR.

Chronic kidney disease and intensive glycemic control increase cardiovascular risk in patients with type 2 diabetes.

Results of the main Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial indicate that intensive glucose lowering increases cardiovascular and all-cause mortality. As the contribution of mild-to-moderate chronic kidney disease (CKD) to these risks is not known, we assessed the impact on cardiovascular outcomes in this population. Renal function data were available on 10,136 patients of the original ACCORD cohort. Of those, 6,506 were free of CKD at baseline and 3,636 met the criteria for CKD. Participants were randomly assigned to a treatment strategy of either intensive or standard glycemic goal. The primary outcome, all-cause and cardiovascular mortality, and prespecified secondary outcomes were evaluated. Risk for the primary outcome was 87% higher in patients with than in those without CKD (hazard ratio of 1.866; 95% CI: 1.651-2.110). All prespecified secondary outcomes were 1.5 to 3 times more frequent in patients with than in those without CKD. In patients with CKD, compared with standard therapy, intensive glucose lowering was significantly associated with both 31% higher all-cause mortality (1.306: 1.065-1.600) and 41% higher cardiovascular mortality (1.412: 1.052-1.892). No significant effects were found in patients without CKD. Thus, in high-risk patients with type II diabetes, mild and moderate CKD is associated with increased cardiovascular risk. Intensive glycemic control significantly increases the risk of cardiovascular and all-cause mortality in this population.

Phenotypic heterogeneity in females with X-linked Alport syndrome.

AIMS: X-linked Alport syndrome (AS) is a monogenic inherited disorder of type IV collagen, a structural protein in the kidney and cochlea. Males typically exhibit a severe phenotype with end-stage renal disease (ESRD) and/or deafness by early adulthood. Because of the presence of two X chromosomes, females often have a less severe phenotype and hence the diagnosis of AS is often not considered. Herein, we present a case of an adolescent girl with proteinuria and hematuria in the setting of a strong family history of AL. CASE REPORT: The mother and maternal aunt of the proband had both presented with dipstick positive hematuria and proteinuria at age 8 years. These girls were not evaluated by nephrology until mid-adolescence when they had worsening creatinine levels. Kidney biopsy in the younger sister demonstrated segmental glomerulosclerosis with segmental thinning and lamination of the glomerular basement membrane, consistent with AS. Kidney biopsy in the older sister was performed just prior to the need for renal replacement therapy and showed only global glomerulosclerosis. Both sisters were transplanted by the age of 20 years. Their mother subsequently developed ESRD at age 53 years. With the advent of genetic testing, the proband and her family were brought in for evaluation. It had been assumed this family of AS had autosomal dominant transmission, however, genetic testing of the proband was positive for a splice site mutation of COL4A5 located on the X-chromosome. Sequencing of genes COL4A3, COL4A4, and COL4A6 were negative for mutation. CONCLUSIONS: The current case report demonstrates the importance of considering skewed X-inactivation in females who exhibit signs or symptoms of Xlinked disorders.