Timing of Onset of CKD-Related Metabolic Complications

Chronic kidney disease (CKD) guidelines recommend evaluating patients with GFR <60 ml/min per 1.73 m² for complications, but little evidence supports the use of a single GFR threshold for all metabolic disorders. We used data from the NephroTest cohort, including 1038 adult patients who had stages 2 through 5 CKD and were not on dialysis, to study the occurrence of metabolic complications. GFR was measured using renal clearance of ⁵¹Cr-EDTA (mGFR) and estimated using two equations derived from the Modification of Diet in Renal Disease study. As mGFR decreased from 60 to 90 to <20 ml/min per 1.73 m², the prevalence of hyperparathyroidism increased from 17 to 85%, anemia from 8 to 41%, hyperphosphatemia from 1 to 30%, metabolic acidosis from 2 to 39%, and hyperkalemia from 2 to 42%. Factors most strongly associated with metabolic complications, independent of mGFR, were younger age for acidosis and hyperphosphatemia, presence of diabetes for acidosis, diabetic kidney disease for anemia, and both male gender and the use of inhibitors of the renin-angiotensin system for hyperkalemia. mGFR thresholds for detecting complications with 90% sensitivity were 50, 44, 40, 39, and 37 ml/min per 1.73 m² for hyperparathyroidism, anemia, acidosis, hyperkalemia, and hyperphosphatemia, respectively. Analysis using estimated GFR produced similar results. In summary, this study describes the onset of CKD-related complications at different levels of GFR; anemia and hyperparathyroidism occur earlier than acidosis, hyperkalemia, and hyperphosphatemia.Since the National Kidney Foundation published its definition and classification of chronic kidney disease (CKD),¹ evidence has accumulated showing that it is a common disease,^2,3 associated with morbidity and mortality risks far broader and higher than those of simple progression to kidney failure.^4–6 Early detection of CKD and its metabolic complications is now a priority for delaying disease progression and for primary prevention of many CKD-associated chronic diseases, including cardiovascular, mineral, and bone diseases^5,7–9; however, data on the natural history of these complications according to reference methods are sparse, and there is little evidence about the most appropriate timing for their detection.CKD metabolic complications, which include anemia, metabolic acidosis, and mineral and electrolyte disorders, may be asymptomatic for a long time.^10–21 According to Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines,¹ all patients at stage 3 CKD or above (i.e., those with a GFR <60 ml/min per 1.73 m²), should be evaluated for all complications. This threshold, however, was defined from clinical and population-based studies, all of which used equation-estimated GFR (eGFR),¹ a method sensitive to both the choice of equation and serum creatinine (Scr) calibration, particularly for the highest GFR values.^22,23 Population-based studies, with one exception,²⁴ have also lacked the power to search for complication-specific GFR thresholds below 60 ml/min per 1.73 m². Moreover, although a few studies showed the influence of some patient characteristics, such as ethnic origin and diabetes, on the prevalence of various complications,^24–29 neither their potential impact nor the effect of clinical factors on metabolic disorders has been investigated systematically.Our primary purpose, therefore, was to define GFR thresholds, measured with a reference method (mGFR: ⁵¹Cr-EDTA renal clearance), and factors associated with CKD-related metabolic complications in a clinical cohort of 1038 patients with stages 2 through 5 CKD. Because mGFR is rarely performed in clinical practice, we also estimated these thresholds with eGFR and studied how the results differed according to method.