A prediction model on incident chronic kidney disease among individuals with type 2 diabetes in the United States.

AIM: Early identification of incident chronic kidney disease (CKD) in individuals with diabetes may help improve patients' clinical outcomes. This study aimed to develop a prediction equation for incident CKD among people with type 2 diabetes (T2D). MATERIALS AND METHODS: A time-varying Cox model was applied to data from the ACCORD trial to predict the risk of incident CKD. A list of candidate variables was chosen based on literature reviews and experts' consultations, including demographic characteristics, vitals, laboratory results, medical history, drug use and health care utilization. Model performance was evaluated. Decomposition analysis was conducted, and external validation was performed. RESULTS: In total, 6006 patients with diabetes free of CKD were included, with a median follow-up of 3 years and 2257 events. The risk model included age at T2D diagnosed, smoking status, body mass index, high-density lipoprotein, very-low-density lipoprotein, alanine aminotransferase, estimated glomerular filtration rate, urine albumin-creatinine ratio, hypoglycaemia, retinopathy, congestive heart failure, coronary heart disease history, antihyperlipidaemic drug use, antihypertensive drug use and hospitalization. The urine albumin-creatinine ratio, estimated glomerular filtration rate and congestive heart failure were the top three factors that contributed most to the incident CKD prediction. The model showed acceptable discrimination [C-statistic: 0.772 (95% CI 0.767-0.805)] and calibration [Brier Score: 0.0504 (95% CI 0.0477-0.0531)] in the Harmony Outcomes Trial. CONCLUSION: Incident CKD prediction among individuals with T2D was developed and validated for use in decision support of CKD prevention.

A prediction model on incident ESKD among individuals with T2D and CKD.

BACKGROUND: Diabetes is the leading cause of end-stage kidney disease (ESKD). This study aimed to predict incident ESKD among individuals with T2D and CKD. METHOD: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial data were split into a training set and a validation set by a ratio of 7:3. A dynamic time-varying Cox model was fit to predict the development of incident ESKD. Significant predictors were identified from a list of candidate variables, including demographic characteristics, physical exam results, laboratory results, medical history, drug information, and healthcare utilization. Model performance was evaluated by Brier score and C statistics. Decomposition analysis was conducted to assess the variable importance. Patient-level data from Harmony Outcome clinical trial and CRIC study were used for external validation. RESULTS: A total of 6982 diabetes patients with CKD were used for model development, with a median follow-up of four years and 312 ESKD events. The significant predictors for the final model were female sex, race, smoking status, age at T2D diagnosis, SBP, HR, HbA1c, estimated glomerular filtration rate (eGFR), urine albumin-creatinine ratio (UACR), retinopathy event occurring in last year, antihypertensive drug use, and an interaction term between SBP and female. The model demonstrated good performance in discrimination (C-statistic 0.764 [95 % CI 0.763-0.811]) and calibration (Brier Score 0.0083 [95 % CI 0.0063-0.0108]). The top 3 most important predictors in the prediction model were eGFR, retinopathy event, and UACR. Acceptable discrimination (C-statistic: 0.701 [95 % CI 0.665-0.716]; 0.86 [95 % CI 0.847-0.872]) and calibration (Brier Score: 0.0794 [95 % CI 0.0733-0.1022]; 0.0476 [95 % CI 0.0440, 0.0506]) were demonstrated in the Harmony Outcome and CRIC data, respectively. CONCLUSION: The dynamic risk prediction of incident ESKD among individuals with T2D can be a useful tool to support better disease management to lower the risk of developing ESKD.

A prediction model of CKD progression among individuals with type 2 diabetes in the United States.

BACKGROUND: CKD progression among individuals with T2D is associated with poor health outcomes and high healthcare costs, which have not been fully studied. This study aimed to predict CKD progression among individuals with diabetes. METHOD: Using ACCORD trial data, a time-varying Cox model was developed to predict the risk of CKD progression among patients with CKD and T2D. CKD progression was defined as a 50 % decline, or 25 mL/min/1.73 m2 decline in eGFR from baseline, doubling of the serum creatinine, or onset of ESKD. A list of candidate variables included demographic characteristics, physical exam results, laboratory results, medical history, drug use, and healthcare utilization. A stepwise algorithm was used for variable selection. Model performance was evaluated by Brier score and C-statistics. Confidence intervals (CI) were calculated using a bootstrap method. Decomposition analysis was conducted to assess the predictor contribution. Generalizability was assessed on patient-level data of the Harmony Outcome trial and CRIC study. RESULTS: A total of 6982 diabetes patients with CKD were used for model development, with a median follow-up of 4 years and 3346 events. The predictors for CKD progression included female sex, age at T2D diagnosis, smoking status, SBP, DBP, HR, HbA1c, alanine aminotransferase (ALT), eGFR, UACR, retinopathy event, hospitalization. The model demonstrated good discrimination (C-statistics 0.745 [95 % CI 0.723-0.763]) and calibration (Brier Score 0.0923 [95 % CI 0.0873-0.0965]) performance in the ACCORD data. The most contributing predictors for CKD progression were eGFR, HbA1c, and SBP. The model demonstrated acceptable discrimination and calibration performance in the two external data. CONCLUSION: For high-risk patients with both diabetes and CKD, the tool as a dynamic risk prediction of CKD progression may help develop novel strategies to lower the risk of CKD progression.

Aristolochic acid I induces proximal tubule injury through ROS/HMGB1/mt DNA mediated activation of TLRs.

Aristolochic acids (AAs) are extracted from certain plants as folk remedies for centuries until their nephrotoxicity and carcinogenicity were recognized. Aristolochic acid I (AAI) is one of the main pathogenic compounds, and it has nephrotoxic, carcinogenic and mutagenic effects. Previous studies have shown that AAI acts mainly on proximal renal tubular epithelial cells; however, the mechanisms of AAI-induced proximal tubule cell damage are still not fully characterized. We exposed human kidney proximal tubule cells (PTCs; HK2 cell line) to AAI in vitro at different time/dose conditions and assessed cell proliferation, reactive oxygen species (ROS) generation, nitric oxide (NO) production, m-RNA/ protein expressions and mitochondrial dysfunction. AAI exposure decreased proliferation and increased apoptosis, ROS generation / NO production in PTCs significantly at 24 h. Gene/ protein expression studies demonstrated activation of innate immunity (TLRs 2, 3, 4 and 9, HMGB1), inflammatory (IL6, TNFA, IL1B, IL18, TGFB and NLRP3) and kidney injury (LCN2) markers. AAI also induced epithelial-mesenchymal transition (EMT) and mitochondrial dysfunction in HK2 cells. TLR9 knock-down and ROS inhibition were able to ameliorate the toxic effect of AAI. In conclusion, AAI treatment caused injury to PTCs through ROS-HMGB1/mitochondrial DNA (mt DNA)-mediated activation of TLRs and inflammatory response.

Cell spinpods are a simple inexpensive suspension culture device to deliver fluid shear stress to renal proximal tubular cells.

Rotating forms of suspension culture allow cells to aggregate into spheroids, prevent the de-differentiating influence of 2D culture, and, perhaps most importantly of all, provide physiologically relevant, in vivo levels of shear stress. Rotating suspension culture technology has not been widely implemented, in large part because the vessels are prohibitively expensive, labor-intensive to use, and are difficult to scale for industrial applications. Our solution addresses each of these challenges in a new vessel called a cell spinpod. These small 3.5 mL capacity vessels are constructed from injection-molded thermoplastic polymer components. They contain self-sealing axial silicone rubber ports, and fluoropolymer, breathable membranes. Here we report the two-fluid modeling of the flow and stresses in cell spinpods. Cell spinpods were used to demonstrate the effect of fluid shear stress on renal cell gene expression and cellular functions, particularly membrane and xenobiotic transporters, mitochondrial function, and myeloma light chain, cisplatin and doxorubicin, toxicity. During exposure to myeloma immunoglobulin light chains, rotation increased release of clinically validated nephrotoxicity cytokine markers in a toxin-specific pattern. Addition of cisplatin or doxorubicin nephrotoxins reversed the enhanced glucose and albumin uptake induced by fluid shear stress in rotating cell spinpod cultures. Cell spinpods are a simple, inexpensive, easily automated culture device that enhances cellular functions for in vitro studies of nephrotoxicity.

Accuracy of Ankle-Brachial Index, Toe-Brachial Index, and Risk Classification Score in Discriminating Peripheral Artery Disease in Patients With Chronic Kidney Disease.

The accuracy of ankle-brachial index (ABI) and toe-brachial index (TBI) in discriminating lower extremity peripheral artery disease (PAD) has not been evaluated in patients with chronic kidney disease (CKD). We measured ABI, TBI, and Doppler ultrasound in 100 predialysis patients with CKD without revascularization or amputation. Leg-specific ABI was calculated using higher systolic blood pressure (SBP) in posterior tibial or dorsalis pedis artery divided by higher brachial SBP; alternative ABI was calculated using lower SBP in posterior tibial or dorsalis pedis artery. PAD was defined as ≥50% stenosis detected by Doppler ultrasound. PAD risk classification score was calculated using cardiovascular disease risk factors. The area under the curve (AUC, 95% confidence interval [CI]) for discriminating ultrasound-diagnosed PAD was 0.78 (0.69 to 0.87) by ABI, 0.80 (0.71 to 0.89) by alternative ABI, and 0.74 (0.63 to 0.86) by TBI. Sensitivity and specificity were 25% and 97% for ABI ≤0.9, 41% and 95% for alternative ABI ≤0.9, and 45% and 93% for TBI ≤0.7, respectively. AUC (95% CI) of PAD risk classification score was 0.86 (0.78 to 0.94) with sensitivity and specificity of 95% and 60% for risk score ≥0.10, 76% and 76% for risk score ≥0.25, and 43% and 95% for risk score ≥0.55. Combining risk score with ABI, alternative ABI, and TBI increased AUC (95% CI) to 0.89 (0.82 to 0.96), 0.89 (0.80 to 0.98), and 0.87 (0.78 to 0.96), respectively. In conclusion, current ABI and TBI diagnostic criteria have high specificity but low sensitivity for classifying PAD in patients with CKD. PAD classification risk score based on cardiovascular disease risk factors improves the accuracy of PAD classification.

The Proximal Tubule Toxicity of Immunoglobulin Light Chains.

Plasma and B cells dyscrasias that overproduce monoclonal immunoglobulin free light chains (FLCs) affect the kidney frequently in various ways. The hematologic dyscrasia responsible for the production of FLCs may or may not meet the criteria for cancer, such as multiple myeloma (MM) or lymphoma, or may remain subclinical. If there is overt malignancy, the accompanying kidney disorder is called myeloma- or lymphoma-associated. If the dyscrasia is subclinical, the associated kidney disorders are grouped as monoclonal gammopathy of renal significance. Glomeruli and tubules may both be involved. The proximal tubule disorders comprise a spectrum of interesting syndromes, which range in severity. This review focuses on the recent insights gained into the patterns and the mechanisms of proximal tubule toxicity of FLCs, including subtle transport disorders, such as proximal tubule acidosis, partial or complete Fanconi syndrome, or severe acute or chronic renal failure. Histologically, there may be crystal deposition in the proximal tubule cells, acute tubule injury, interstitial inflammation, fibrosis, and tubule atrophy. Specific structural alterations in the V domain of FLCs caused by somatic hypermutations are responsible for crystal formation as well as partial or complete Fanconi syndrome. Besides crystal formation, tubulointerstitial inflammation and proximal tubulopathy can be mediated by direct activation of inflammatory pathways through cytokines and Toll-like receptors due to cell stress responses induced by excessive FLC endocytosis into the proximal tubule cells. Therapy directed against the clonal source of the toxic light chain can prevent progression to more severe lesions and may help preserve kidney function.

The Effect of Proton Pump Inhibitor Use on the Course of Kidney Function in Patients with Chronic Kidney Disease Stages G3a to G4.

BACKGROUND: Proton pump inhibitors (PPI) are widely used and implicated in the progression of chronic kidney disease (CKD). We evaluated the relation between chronic PPI use in veterans with CKD G3a to G4 and the rate of decline in renal function. METHODS: We accessed the Veteran Affairs Informatics and Computing Infrastructure national database to evaluate the relation between chronic PPI use and rate of decline in renal function in veterans with CKD (eGFR <60 ml/min1.73 m2). We applied Propensity Score Matching to match the PPI group and the no-PPI control group on age, sex, race, and Charlson Comorbidity Index. The final sample included 1406 patients (age: 62.07±7.82, 62.02% Caucasian) in the PPI cohort with a median 4.7 years follow-up and 1425 patients (age: 65.45±6.58, 71.16% Caucasian) in the control cohort with a median 3.9 years follow-up. Kaplan-Meier curve and Cox regression were performed to analyze the associations of PPI use with dialysis, all-cause mortality, metabolic acidosis, and CKD progression. RESULTS: The PPI group had a significantly increased risk of CKD progression, dialysis and all-cause mortality (aHR, 1.83; 95% CI, 1.53 to 2.19; aHR, 1.84; 95% CI, 1.26 to 2.67; and aHR, 1.34; 95% CI, 1.08 to 1.65, respectively). The PPI cohort also had a trend for development of metabolic acidosis (aHR, 1.34; 95% CI, 0.998 to 1.80), although the difference was not statistically significant. CONCLUSIONS: The data suggest that chronic PPI use accelerates progression of kidney disease and is associated with increased mortality in CKD patients.

Free light chains injure proximal tubule cells through the STAT1/HMGB1/TLR axis.

Free light chains (FLCs) induce inflammatory pathways in proximal tubule cells (PTCs). The role of TLRs in these responses is unknown. Here we present findings on the role of TLRs in FLC-induced PTC injury. We exposed human kidney PTC cultures to κ and λ FLCs and used cell supernatants and pellets for ELISA and gene expression studies. We also analyzed tissues from Stat1-/- and littermate control mice treated with daily i.p. injections of a κ FLC for 10 days. FLCs increased the expression of TLR2, TLR4, and TLR6 via HMGB1, a damage-associated molecular pattern. Countering TLR2, TLR4, and TLR6 through GIT-27 or specific TLR siRNAs reduced downstream cytokine responses. Blocking HMGB1 through siRNA or pharmacologic inhibition, or via STAT1 inhibition, reduced FLC-induced TLR2, TLR4, and TLR6 expression. Blocking endocytosis of FLCs through silencing of megalin/cubilin, with bafilomycin A1 or hypertonic sucrose, attenuated FLC-induced cytokine responses in PTCs. IHC showed decreased TLR4 and TLR6 expression in kidney sections from Stat1-/- mice compared with their littermate controls. PTCs exposed to FLCs released HMGB1, which induced expression of TLR2, TLR4, and TLR6 and downstream inflammation. Blocking FLCs' endocytosis, Stat1 knockdown, HMGB1 inhibition, and TLR knockdown each rescued PTCs from FLC-induced injury.

The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group.

The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.

Publisher Correction: The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group.

In the key to Figure 1 of this article, 'Amyloid microtubules' has been corrected to 'Microtubules'.

Fatal Hypermagnesemia Due to Laxative Use.

We report a case of fatal hypermagnesemia in a 53-year-old woman admitted for acute exacerbation of chronic obstructive pulmonary disease and with a history of chronic constipation treated regularly with magnesium-containing laxatives. On admission, her magnesium level was 2.0mg/dL, which rose to a peak of 10.8mg/dL despite hydration and diuresis in the presence of a normal kidney function. Continuous renal replacement therapy was promptly initiated, which reduced her serum magnesium levels, but her condition continued to deteriorate precipitously progressing to shock leading to oligoanuric renal failure, and she died 2 days later. A review of the literature shows that though rare and often unsuspected, severe hypermagnesemia frequently results in death even in individuals with normal renal function despite renal replacement therapy. In patients with constipation, retention of magnesium-based laxative in the gut apparently serves as a reservoir for continuous magnesium absorption and contributes to mortality.

Animal models of monoclonal immunoglobulin-related renal diseases.

The renal deposition of monoclonal immunoglobulins can cause severe renal complications in patients with B cell and plasma cell lymphoproliferative disorders. The overproduction of a structurally unique immunoglobulin can contribute to the abnormal propensity of monoclonal immunoglobulins to aggregate and deposit in specific organs. A wide range of renal diseases can occur in multiple myeloma or monoclonal gammopathy of renal significance, including tubular and glomerular disorders with organized or unorganized immunoglobulin deposits. The development of reliable experimental models is challenging owing to the inherent variability of immunoglobulins and the heterogeneity of the pathologies they produce. However, although imperfect, animal models are invaluable tools to understand the molecular pathogenesis of these diseases, and advances in creating genetically modified animals might provide novel approaches to evaluate innovative therapeutic interventions. We discuss the strategies employed to reproduce human monoclonal immunoglobulin-induced kidney lesions in animal models, and we highlight their advantages and shortcomings. We also discuss how these models have affected the management of these deposition diseases and might do so in the future. Finally, we discuss hypotheses that explain some limitations of the various models, and how these models might improve our understanding of other nephropathies without immunoglobulin involvement that have similar pathogenic mechanisms.

Paraprotein-Related Kidney Disease: Kidney Injury from Paraproteins-What Determines the Site of Injury?

Disorders of plasma and B cells leading to paraproteinemias are associated with a variety of renal diseases. Understanding the mechanisms of injury and associated nephropathies provides a framework that aids clinicians in prompt diagnosis and appropriate adjunctive treatment of these disorders. Glomerular diseases that may be associated with paraproteinemias include amyloid deposition, monoclonal Ig deposition disease, proliferative GN with monoclonal Ig deposits, C3 glomerulopathy caused by alterations in the complement pathway, immunotactoid glomerulopathy, fibrillary GN, and cryoglobulinemia. Tubular lesions include the classic Fanconi syndrome, light-chain proximal tubulopathy, interstitial fibrosis, and cast nephropathy. These paraproteinemic renal diseases are distinct in their pathogenesis as well as their urinary and kidney biopsy findings. Renal pathology is usually initiated by deposition and direct involvement of the intact monoclonal Ig or Ig fragments with resident cells of the nephron. Our review summarizes current insights into the underlying molecular pathogenesis of these interesting kidney lesions.

Anemia and risk for cognitive decline in chronic kidney disease.

BACKGROUND: Anemia is common among patients with chronic kidney disease (CKD) but its health consequences are poorly defined. The aim of this study was to determine the relationship between anemia and cognitive decline in older adults with CKD. METHODS: We studied a subgroup of 762 adults age ≥55 years with CKD participating in the Chronic Renal Insufficiency Cohort (CRIC) study. Anemia was defined according to the World Health Organization criteria (hemoglobin <13 g/dL for men and <12 g/dL for women). Cognitive function was assessed annually with a battery of six tests. We used logistic regression to determine the association between anemia and baseline cognitive impairment on each test, defined as a cognitive score more than one standard deviation from the mean, and mixed effects models to determine the relation between anemia and change in cognitive function during follow-up after adjustment for demographic and clinical characteristics. RESULTS: Of 762 participants with mean estimated glomerular filtration rate of 42.7 ± 16.4 ml/min/1.73 m(2), 349 (46 %) had anemia. Anemia was not independently associated with baseline cognitive impairment on any test after adjustment for demographic and clinical characteristics. Over a median 2.9 (IQR 2.6-3.0) years of follow-up, there was no independent association between anemia and change in cognitive function on any of the six cognitive tests. CONCLUSIONS: Among older adults with CKD, anemia was not independently associated with baseline cognitive function or decline.

Association of C-reactive protein, tumor necrosis factor-alpha, and interleukin-6 with chronic kidney disease.

BACKGROUND: We studied the association of inflammatory biomarkers including C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) with chronic kidney disease (CKD). METHODS: We conducted a case-control study among 201 CKD patients and 201 community-based controls in the greater New Orleans area. CKD was defined as estimated-glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) or albuminuria ≥30 mg/24-h. Serum CRP, TNF-α, and IL-6 were measured using standard methods. Multivariable regression models were used to examine associations between the inflammatory biomarkers and CKD adjusting for important CKD risk factors, history of cardiovascular disease, and use of antihypertensive, antidiabetic, and lipid-lowering agents and aspirin. RESULTS: The multivariable-adjusted medians (interquartile-range) were 2.91 (1.47, 5.24) mg/L in patients with CKD vs. 1.91 (0.99, 3.79) mg/L in controls without CKD (p = 0.39 for group difference) for CRP; 1.86 (1.51, 2.63) pg/mL vs. 1.26 (1.01, 1.98) pg/mL (p < 0.0001) for TNF-α; and 2.53 (1.49, 4.42) pg/mL vs. 1.39 (0.95, 2.15) pg/mL (p = 0.04) for IL-6, respectively. Compared to the lowest tertile, the highest tertile of TNF-α (OR 7.1, 95% CI 3.2 to 15.5) and IL-6 (OR 2.5, 95% CI 1.1 to 5.5) were significantly associated with higher odds of CKD in multivariable-adjusted models. Additionally, higher TNF-α and IL-6 were independently and significantly associated with lower eGFR and higher albuminuria. CONCLUSIONS: Our data suggest that TNF-α and IL-6, but not CRP, are associated with the prevalence and severity of CKD, independent from established CKD risk factors, history of cardiovascular disease, and use of antihypertensive, antidiabetic, and lipid-lowering agents and aspirin.