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.

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.

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.

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.

Increased urinary excretion of angiotensinogen is associated with risk of chronic kidney disease.

BACKGROUND: The effect of intrarenal renin-angiotensin system (RAS) activity on risk of chronic kidney disease (CKD) has not been well studied in human subjects. METHODS: We investigated the association between urinary angiotensinogen, a reliable biomarker of intrarenal RAS activity, and risk of CKD in 201 patients and 201 controls. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) or presence of albuminuria ( ≥ 30 mg/24 h). RESULTS: Compared to controls, median urinary angiotensinogen excretion (45.4 versus 7.4 µg/24 h, P < 0.0001) and angiotensinogen-to-creatinine ratio (26.3 versus 4.4 µg/g, P < 0.0001) were significantly higher in patients with CKD. Log-transformed urinary angiotensinogen excretion and angiotensinogen-to-creatinine ratio were inversely correlated with eGFR (r = -0.59 and -0.57, both P < 0.0001) and positively correlated with log-transformed urinary albumin excretion (r = 0.89 and 0.87, both P < 0.0001). After adjusting for multiple covariables, including the use of angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers, diuretics and statins, the odds ratios (95% confidence interval) for CKD comparing the highest tertile to the lowest two tertiles of urinary angiotensinogen excretion and angiotensinogen-to-creatinine ratio were 6.70 (3.43, 13.1; P < 0.0001) and 6.45 (3.34, 12.4; P < 0.0001), respectively. CONCLUSIONS: These data indicate the intrarenal RAS may play an important role in the etiology of CKD, and urinary angiotensinogen may be a useful clinical biomarker for the identification of patients at a high risk for CKD.

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.

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 effect of PACAP38 on MyD88-mediated signal transduction in ischemia-/hypoxia-induced acute kidney injury.

BACKGROUND/AIMS: toll-like receptor 4 (TLR4) and its adaptor protein MyD88 play an important role in ischemia/reperfusion (I/R) injury in the kidney, and pituitary adenylate cyclase-activating polypeptide (PACAP) could ameliorate renal I/R injury. METHODS: primary cultures of proximal tubule epithelial cells (PTEC) were prepared from wild-type and MyD88(-/-) mice, and subjected to hypoxia in vitro. Acute kidney injury (AKI) was induced by I/R in vivo in wild-type mice only. RESULTS: hypoxia resulted in significant increases in cytokine production and apoptosis/necrosis in wild-type PTEC, but these responses were markedly blunted in MyD88(-/-) PTEC. Treatment with PACAP38 before or after hypoxia further suppressed the hypoxia-induced cytokine responses and apoptosis in both MyD88(+/+) and MyD88(-/-) PTEC cultures. PACAP38 significantly inhibited TLR4/MyD88/TRAF6 as well as TRIF and IRF3 expression in mouse kidney and PTEC, and inhibited the secretion and mRNA expression of cytokines in kidneys from mice after I/R, paralleling the cytokine responses in vitro. Moreover, treatment with PACAP38 protected mice from renal failure, histological damage, neutrophil influx and tubule cell apoptosis after I/R. CONCLUSION: our data reveal that the TLR4-mediated cytokine responses to hypoxia are primarily dependent on MyD88 signaling and highlight the pivotal role of MyD88-dependent mechanisms in the coordination of the innate immune responses to ischemic/hypoxic acute renal tubular injury. The renoprotective effect of PACAP in AKI involves both MyD88-dependent and -independent pathways.

Myeloma light chain-induced renal injury in mice.

We investigated the effects of human light chain (LC) protein-overload in mice kidney to gain further insights into the molecular mechanisms involved in the pathogenesis of myeloma kidney. Intact male C57BL/6, 10- to 12-week-old mice were given daily intraperitoneal (i.p.) injections of 1 ml of human κ-LCs (1.5 mg/ml, low dose), or (100 mg/ml, high dose) to uninephrectomized mice for 2 weeks. Intact, sham-operated or uninephrectomized control animals were given the same volume (1 ml/day) of saline, human serum albumin (10 mg/ml) or bovine serum albumin (100 mg/ml) i.p. for 2 weeks in place of LCs. The low-dose LC-treated mice had human LCs in their urine and a significant increase in monocyte chemoattractant protein-1 (MCP-1) mRNA in the kidneys. Uninephrectomized mice treated with high-dose κ-LCs showed tubule casts, and foci of intracytoplasmic rhomboid crystals within the proximal tubules, along with cytoskeletal disruptions and alterations in the brush-border membrane, and high concentrations of human κ-LC were present in their sera. High-dose LC treatment also led to increases in serum creatinine and tumor necrosis factor-α levels, and marked increases in interleukin-6 and MCP-1 expression as well as cellular apoptosis in the kidneys. These studies demonstrate that myeloma LC overload over a range of LC concentrations in mice causes significant functional and morphological kidney injury. The model should be helpful in investigating pathophysiologic mechanisms and exploring therapeutic interventions for myeloma kidney and other LC-associated renal disorders.

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.

Vitamin D: a new hope for chronic kidney disease?

Vitamin D analogs may slow the progression of chronic kidney disease. Tan et al. report that paricalcitol has additive effects with an angiotensin-converting enzyme inhibitor (ACEI) in suppressing extracellular matrix expression, interstitial inflammation, and myofibroblast activation in obstructive nephropathy. Paricalcitol inhibited renin transcription, countering the compensatory ACEI-induced rise in renin, thus achieving a more complete blockade of the renin-angiotensin system (RAS). Vitamin D analogs may enhance the renoprotective effects of RAS inhibitors.

Myeloma kidney: toward its prevention--with new insights from in vitro and in vivo models of renal injury.

Renal involvement in patients with multiple myeloma complicates their treatment and shortens their life span. The main renal lesion is predominantly a tubulointerstitial disease characterized by fibrosis, frequently associated with light chain-containing casts. At present there is no effective treatment for kidney disease associated with multiple myeloma. Recent research highlights the importance of interactions between myeloma light chains and proximal tubule epithelial cells in the pathogenesis of myeloma kidney. Dissecting the cellular and molecular events has identified novel avenues for potential treatment. Among these, pituitary adenylate cyclase-activating polypeptide-38 (PACAP38), a pituitary immune-modulating peptide, has emerged as a promising novel therapy. PACAP38 prevented light chain-induced renal injury patterns in vitro, and in experimental animals in vivo. Further clinical studies are necessary to establish the usefulness of these novel therapies in preserving the kidney function in patients with multiple myeloma.

Offspring of parents with Balkan Endemic Nephropathy have higher C-reactive protein levels suggestive of inflammatory processes: a longitudinal study.

BACKGROUND: Despite the characteristic extensive tubulointerstitial fibrosis, Balkan Endemic Nephropathy (BEN) is usually considered a non-inflammatory disease. METHODS: We examined a marker of inflammation, C-reactive protein (CRP), in the offspring of patients with BEN, a population at risk for BEN, prior to development of established disease to determine if an inflammatory process could be identified in the early stages of the disease. In 2003/04, 102 adult offspring whose parents had BEN and a control group of 99 adult offspring of non-BEN patients were enrolled in this prospective study. This cohort was re-examined yearly for four consecutive years. Levels of serum CRP were measured in years 3 and 4 and compared between groups. The data were analyzed with mixed models. RESULTS: Compared to controls, offspring of BEN parents had statistically higher CRP levels in two consecutive years, suggestive of early inflammatory reactivity. Whenever the mother was affected by BEN (both parents, or mother only), serum CRP was significantly increased, but not if only the father had BEN. CRP was inversely related to kidney cortex width but not to markers or renal function. CONCLUSION: Early stages of BEN may involve inflammatory processes. The observation of a maternal involvement supports the concept of fetal programming, which has been implicated in the pathogenesis of other chronic kidney diseases.

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.