TY  - JOUR
AB  - RATIONALE & OBJECTIVE: Stratification of chronic kidney disease (CKD) patients at risk for progressing to end-stage kidney disease (ESKD) requiring kidney replacement therapy (KRT) is important for clinical decision-making and trial enrollment. STUDY DESIGN: Four independent prospective observational cohort studies. SETTING & PARTICIPANTS: The development cohort was comprised of 4,915 CKD patients and three independent validation cohorts were comprised of a total of 3,063. Patients were followed-up for approximately five years. NEW PREDICTORS & ESTABLISHED PREDICTORS: 22 demographic, anthropometric and laboratory variables commonly assessed in CKD patients. OUTCOMES: Progression to ESKD requiring KRT. ANALYTICAL APPROACH: A Least Absolute Shrinkage and Selection Operator (LASSO) Cox proportional hazards model was fit to select laboratory variables that best identified patients at high risk for ESKD. Model discrimination and calibration were assessed and compared against the 4-variable Tangri (T4) risk equation. Both used a resampling approach within the development cohort and in the validation cohorts using cause-specific concordance (C) statistics, net reclassification improvement, and calibration graphs. RESULTS: The newly derived 6-variable (Z6) risk score included serum creatinine, albumin, cystatin C and urea, as well as hemoglobin and the urine albumin-to-creatinine ratio. Based on the resampling approach, Z6 achieved a median C value of 0.909 (95% CI, 0.868-0.937) at two years after the baseline visit, whereas the T4 achieved a median C value of 0.855 (95% CI, 0.799-0.915). In the three independent validation cohorts, Z6 C values were 0.894, 0.921, and 0.891, whereas the T4 C values were 0.882, 0.913, and 0.862. LIMITATIONS: The Z6 was both derived and tested only in White European cohorts. CONCLUSIONS: A new risk equation, based on six routinely available laboratory tests facilitates identification of patients with CKD who are at high risk of progressing to ESKD.
AU  - Zacharias, H.U.*
AU  - Altenbuchinger, M.*
AU  - Schultheiss, U.T.*
AU  - Raffler, J.
AU  - Kotsis, F.*
AU  - Ghasemi, S.*
AU  - Ali, I.*
AU  - Kollerits, B.*
AU  - Metzger, M.*
AU  - Steinbrenner, I.*
AU  - Sekula, P.*
AU  - Massy, Z.A.*
AU  - Combe, C.*
AU  - Kalra, P.A.*
AU  - Kronenberg, F.*
AU  - Stengel, B.*
AU  - Eckardt, K.U.*
AU  - Köttgen, A.*
AU  - Schmid, M.*
AU  - Gronwald, W.*
AU  - Oefner, P.J.*
C1  - 62639
C2  - 51015
CY  - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa
SP  - 217-230.e1
TI  - A predictive model for progression of CKD to kidney failure based on routine laboratory tests.
JO  - Am. J. Kidney Dis.
VL  - 79
IS  - 2
PB  - W B Saunders Co-elsevier Inc
PY  - 2022
SN  - 0272-6386
ER  - 

TY  - JOUR
AB  - Rationale & Objective: Hereditary nephropathies are clinically and genetically heterogeneous disorders. For some patients, the clinical phenotype corresponds to a specific hereditary disease but genetic testing reveals that the expected genotype is not present (phenocopy). The aim of this study was to evaluate the spectrum and frequency of phenocopies identified by using exome sequencing in a cohort of patients who were clinically suspected to have hereditary kidney disorders.Study Design: Cross-sectional cohort study.Setting & Participants: 174 unrelated patients were recruited for exome sequencing and categorized into 7 disease groups according to their clinical presentation. They included autosomal dominant tubulointerstitial kidney disease, Alport syndrome, congenital anomalies of the kidney and urinary tract, ciliopathy, focal segmental glomerulosclerosis/steroid-resistant nephrotic syndrome, VACTERL association, and "other."Results: A genetic diagnosis (either likely pathogenic or pathogenic variant according to the guidelines of the American College of Medical Genetics) was established using exome sequencing in 52 of 174 (30%) cases. A phenocopy was identified for 10 of the 52 exome sequencing-solved cases (19%), representing 6% of the total cohort. The most frequent phenocopies (n = 5) were associated with genetic Alport syndrome presenting clinically as focal segmental glomerulosclerosis/steroidresistant nephrotic syndrome. Strictly targeted gene panels (<25 kilobases) did not identify any of the phenocopy cases.Limitations: The spectrum of described phenocopies is small. Selection bias may have altered the diagnostic yield within disease groups in our study population. The study cohort was predominantly of non-Finnish European descent, limiting generalizability. Certain hereditary kidney diseases cannot be diagnosed by using exome sequencing (eg, MUC1-autosomal dominant tubulointerstitial kidney disease).Conclusions: Phenocopies led to the recategorization of disease and altered clinical management. This study highlights that exome sequencing can detect otherwise occult genetic heterogeneity of kidney diseases.
AU  - Riedhammer, K.M.*
AU  - Braunisch, M.C.*
AU  - Günthner, R.*
AU  - Wagner, M.
AU  - Hemmer, C.*
AU  - Strom, T.M.
AU  - Schmaderer, C.*
AU  - Renders, L.*
AU  - Tasic, V.*
AU  - Gucev, Z.*
AU  - Nushi-Stavileci, V.*
AU  - Putnik, J.*
AU  - Stajić, N.*
AU  - Weidenbusch, M.*
AU  - Uetz, B.*
AU  - Montoya, C.*
AU  - Strotmann, P.*
AU  - Ponsel, S.*
AU  - Lange-Sperandio, B.*
AU  - Hoefele, J.*
C1  - 59003
C2  - 48655
CY  - 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa
SP  - 460-470
TI  - Exome sequencing and identification of phenocopies in patients with clinically presumed hereditary nephropathies.
JO  - Am. J. Kidney Dis.
VL  - 76
IS  - 4
PB  - W B Saunders Co-elsevier Inc
PY  - 2020
SN  - 0272-6386
ER  - 

TY  - JOUR
AB  - Background: Metabolites such as creatinine and urea are established kidney function markers. High-throughput metabolomic studies have not been reported in large general population samples spanning normal kidney function and chronic kidney disease (CKD). Study Design: Cross-sectional observational studies of the general population. Setting & Participants: 2 independent samples: KORA F4 (discovery sample, n = 3,011) and TwinsUK (validation sample, n = 984). Exposure Factors: 151 serum metabolites, quantified by targeted mass spectrometry. Outcomes & Measurements: Metabolites and their 22,650 ratios were analyzed by multivariable-adjusted linear regression for their association with glomerular filtration rate (eGFR), estimated separately from creatinine and cystatin C levels by CKD-EPI (CKD Epidemiology Collaboration) equations. After correction for multiple testing, significant metabolites (P < 3.3 x 10(-4) for single metabolites; P < 2.2 x 10(-6) for ratios) were meta-analyzed with independent data from the TwinsUK Study. Results: Replicated associations with eGFR were observed for 22 metabolites and 516 metabolite ratios. Pooled P values ranged from 7.1 x 10(-7) to 1.8 x 10(-69) for the replicated single metabolites. Acylcarnitines such as glutarylcarnitine were associated inversely with eGFR (-3.73 mL/min/1.73 m(2) per standard deviation [SD] increase, pooled P = 1.8 x 10(-69)). The replicated ratio with the strongest association was the ratio of serine to glutarylcarnitine (P = 3.6 x 10(-81)). Almost all replicated phenotypes associated with decreased eGFR (<60 mL/min/1.73 m(2); n = 172 cases) in KORA F4: per 1-SD increment, ORs ranged from 0.29-2.06. Across categories of a metabolic score consisting of 3 uncorrelated metabolites, the prevalence of decreased eGFR increased from 3% to 53%. Limitations: Cross-sectional study design, GFR was estimated, limited number of metabolites. Conclusions: Distinct metabolic phenotypes were reproducibly associated with eGFR in 2 separate population studies. They may provide novel insights into renal metabolite handling, improve understanding of pathophysiology, or aid in the diagnosis of kidney disease. Longitudinal studies are needed to clarify whether changes in metabolic phenotypes precede or result from kidney function impairment.
AU  - Goek, O.N.*
AU  - Döring, A.
AU  - Gieger, C.
AU  - Heier, M.
AU  - Koenig, W.*
AU  - Prehn, C.
AU  - Römisch-Margl, W.
AU  - Wang-Sattler, R.
AU  - Illig, T.
AU  - Suhre, K.
AU  - Sekula, P.*
AU  - Zhai, G.J.*
AU  - Adamski, J.
AU  - Köttgen, A.*
AU  - Meisinger, C.
C1  - 8569
C2  - 30275
SP  - 197-206
TI  - Serum metabolite concentrations and decreased GFR in the general population.
JO  - Am. J. Kidney Dis.
VL  - 60
IS  - 2
PB  - Elsevier
PY  - 2012
SN  - 0272-6386
ER  - 

TY  - JOUR
AU  - Schwaiger, J.P.*
AU  - Lamina, C.
AU  - Neyer, U.*
AU  - König, P.*
AU  - Kathrein, H.*
AU  - Sturm, W.*
AU  - Lhotta, K.*
AU  - Gröchenig, E.*
AU  - Dieplinger, H.*
AU  - Kronenberg, F.*
C1  - 5698
C2  - 23836
SP  - 888-897
TI  - Carotid plaques and their predictive value for cardiovascular disease and all-cause mortality in hemodialysis patients considering renal transplantation: A decade follow-up.
JO  - Am. J. Kidney Dis.
VL  - 47
PY  - 2006
SN  - 0272-6386
ER  -