Association of Increasing GFR with Change in Albuminuria in the General Population.
Hyperfiltration at the single-nephron level has been proposed as an early stage of kidney dysfunction of different origins. Evidence supporting this hypothesis in humans is lacking, because there is no method of measuring single-nephron GFR in humans. However, increased whole-kidney GFR in the same individual implies an increased single-nephron GFR, because the number of nephrons does not increase with age. We hypothesized that an increase in GFR would be associated with an increased albumin-to-creatinine ratio in a cohort of the general population.



We measured GFR by iohexol clearance at baseline in 2007-2009 and follow-up after 5.6 years in a representative sample of 1246 persons (aged 50-62 years) who were nondiabetic from the general population of Tromso, northern Norway. Participants were without cardiovascular disease, kidney disease, or diabetes at baseline. We investigated the association between change in GFR and change in albumin-to-creatinine ratio. Increased GFR was defined as a positive change in GFR (change in GFR>0 ml/min) from baseline to follow-up. An albumin-to-creatinine ratio >30 mg/g was classified as albuminuria.



Change in GFR was positively associated with a change in albumin-to-creatinine ratio in the entire cohort in the multiple linear regression. The albumin-to-creatinine ratiofollow-up-to-albumin-to-creatinine ratiobaselineratio increased by 8.0% (95% confidence interval, 1.4 to 15.0) per SD increase in change in GFR. When participants with increased GFR (n=343) were compared with those with a reduced GFR (n=903), the ratio increased by 16.3% (95% confidence interval, 1.1 to 33.7). The multivariable adjusted odds ratio for incident albuminuria (n=14) was 4.98 (95% confidence interval, 1.49 to 16.13) for those with an increased GFR (yes/no).



Increasing GFR is associated with an increase in albumin-to-creatinine ratio and incident albuminuria in the general nondiabetic population. These findings support single-nephron hyperfiltration as a risk factor for albuminuria in the general population.
Metabolic and Renal Research Group and.|Section of Nephrology, University Hospital of North Norway, Tromso, Norway; and.
Toralf
T
Melsom
Metabolic and Renal Research Group and.
Vidar
V
Stefansson
Metabolic and Renal Research Group and.|Section of Nephrology, University Hospital of North Norway, Tromso, Norway; and.
Jørgen
J
Schei
Metabolic and Renal Research Group and.|Section of Nephrology, University Hospital of North Norway, Tromso, Norway; and.
Marit
M
Solbu
Metabolic and Renal Research Group and.|Section of Nephrology, Department of Organ Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
Trond
T
Jenssen
Department of Community Medicine, UiT The Arctic University of Norway, Tromso, Norway.
Tom
T
Wilsgaard
Metabolic and Renal Research Group and.|Section of Nephrology, University Hospital of North Norway, Tromso, Norway; and.
Bjørn O
BO
Eriksen
D000419:Albuminuria / Q000503:physiopathology* / Q000652:urine; D003404:Creatinine / Q000652:urine*; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D009399:Nephrons / Q000503:physiopathology*; D012307:Risk Factors
D003404:Creatinine
ACR; Albumins; Iohexol; Kidney Diseases; Kidney Function Tests; Linear Models; Nephrons; Norway; Odds Ratio; albumin creatinine ratio; albuminuria; cardiovascular disease; clinical epidemiology; creatinine; diabetes mellitus; follow-up studies; general population; glomerular filtration rate; glomerular filtration rate OR GFR or “incident CKD”; glomerular hyperfiltration; humans; hyperfiltration; iohexol clearance; risk factors
Naghavi M, Wang H; GBD 2013 Mortality and Causes of Death Collaborators: Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: A systematic analysis for the Global Burden of Disease Study 2013. Lancet 385: 117–171, 201525530442
Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, Coresh J, Gansevoort RT; Chronic Kidney Disease Prognosis Consortium: Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: A collaborative meta-analysis. Lancet 375: 2073–2081, 201020483451
Turin TC, Coresh J, Tonelli M, Stevens PE, de Jong PE, Farmer CK, Matsushita K, Hemmelgarn BR: Change in the estimated glomerular filtration rate over time and risk of all-cause mortality. Kidney Int 83: 684–691, 201323344477
Coresh J, Turin TC, Matsushita K, Sang Y, Ballew SH, Appel LJ, Arima H, Chadban SJ, Cirillo M, Djurdjev O, Green JA, Heine GH, Inker LA, Irie F, Ishani A, Ix JH, Kovesdy CP, Marks A, Ohkubo T, Shalev V, Shankar A, Wen CP, de Jong PE, Iseki K, Stengel B, Gansevoort RT, Levey AS; CKD Prognosis Consortium: Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. JAMA 311: 2518–2531, 201424892770
Brenner BM, Lawler EV, Mackenzie HS: The hyperfiltration theory: A paradigm shift in nephrology. Kidney Int 49: 1774–1777, 19968743495
Ruggenenti P, Remuzzi G: Time to abandon microalbuminuria? Kidney Int 70: 1214–1222, 200616871239
Nelson RG, Bennett PH, Beck GJ, Tan M, Knowler WC, Mitch WE, Hirschman GH, Myers BD; Diabetic Renal Disease Study Group: Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. N Engl J Med 335: 1636–1642, 19968929360
Jerums G, Premaratne E, Panagiotopoulos S, MacIsaac RJ: The clinical significance of hyperfiltration in diabetes. Diabetologia 53: 2093–2104, 201020496053
Melsom T, Schei J, Stefansson VT, Solbu MD, Jenssen TG, Mathisen UD, Wilsgaard T, Eriksen BO: Prediabetes and risk of glomerular hyperfiltration and albuminuria in the general nondiabetic population: A prospective cohort study. Am J Kidney Dis 67: 841–850, 201626744126
Melsom T, Mathisen UD, Ingebretsen OC, Jenssen TG, Njølstad I, Solbu MD, Toft I, Eriksen BO: Impaired fasting glucose is associated with renal hyperfiltration in the general population. Diabetes Care 34: 1546–1551, 201121593291
Okada R, Yasuda Y, Tsushita K, Wakai K, Hamajima N, Matsuo S: Glomerular hyperfiltration in prediabetes and prehypertension. Nephrol Dial Transplant 27: 1821–1825, 201222140135
Mathisen UD, Melsom T, Ingebretsen OC, Jenssen TG, Njølstad I, Solbu MD, Toft I, Eriksen BO: Ambulatory blood pressure is associated with measured glomerular filtration rate in the general middle-aged population. J Hypertens 30: 497–504, 201222278141
Wuerzner G, Pruijm M, Maillard M, Bovet P, Renaud C, Burnier M, Bochud M: Marked association between obesity and glomerular hyperfiltration: A cross-sectional study in an African population. Am J Kidney Dis 56: 303–312, 201020538392
Pinto-Sietsma SJ, Mulder J, Janssen WM, Hillege HL, de Zeeuw D, de Jong PE: Smoking is related to albuminuria and abnormal renal function in nondiabetic persons. Ann Intern Med 133: 585–591, 200011033585
Mathisen UD, Melsom T, Ingebretsen OC, Jenssen T, Njølstad I, Solbu MD, Toft I, Eriksen BO: Estimated GFR associates with cardiovascular risk factors independently of measured GFR. J Am Soc Nephrol 22: 927–937, 201121454717
Hoy WE, Douglas-Denton RN, Hughson MD, Cass A, Johnson K, Bertram JF: A stereological study of glomerular number and volume: Preliminary findings in a multiracial study of kidneys at autopsy. Kidney Int Suppl 83: S31–S37, 200312864872
Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, Kusek JW, Manzi J, Van Lente F, Zhang YL, Coresh J, Levey AS; CKD-EPI Investigators: Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 367: 20–29, 201222762315
Rule AD, Bailey KR, Lieske JC, Peyser PA, Turner ST: Estimating the glomerular filtration rate from serum creatinine is better than from cystatin C for evaluating risk factors associated with chronic kidney disease. Kidney Int 83: 1169–1176, 201323423253
Melsom T, Fuskevåg OM, Mathisen UD, Strand H, Schei J, Jenssen T, Solbu M, Eriksen BO: Estimated GFR is biased by non-traditional cardiovascular risk factors. Am J Nephrol 41: 7–15, 201525612475
Eriksen BO, Mathisen UD, Melsom T, Ingebretsen OC, Jenssen TG, Njølstad I, Solbu MD, Toft I: Cystatin C is not a better estimator of GFR than plasma creatinine in the general population. Kidney Int 78: 1305–1311, 201020844470
Nilsson-Ehle P: Iohexol clearance for the determination of glomerular filtration rate: 15 years' experience in clinical practice. EJIFCC 13: 1–5, 2002
Jacobsson L: A method for the calculation of renal clearance based on a single plasma sample. Clin Physiol 3: 297–305, 19836684515
Eriksen BO, Stefansson VT, Jenssen TG, Mathisen UD, Schei J, Solbu MD, Wilsgaard T, Melsom T: Elevated blood pressure is not associated with accelerated glomerular filtration rate decline in the general non-diabetic middle-aged population. Kidney Int 90: 404–410, 201627188503
Solbu MD, Kronborg J, Eriksen BO, Jenssen TG, Toft I: Cardiovascular risk-factors predict progression of urinary albumin-excretion in a general, non-diabetic population: A gender-specific follow-up study. Atherosclerosis 201: 398–406, 200818405901
Levey AS, de Jong PE, Coresh J, El Nahas M, Astor BC, Matsushita K, Gansevoort RT, Kasiske BL, Eckardt KU: The definition, classification, and prognosis of chronic kidney disease: A KDIGO Controversies Conference report. Kidney Int 80: 17–28, 201121150873
Melsom T, Mathisen UD, Eilertsen BAW, Ingebretsen OC, Jenssen T, Njølstad I, Solbu MD, Toft I, Eriksen BO: Physical exercise, fasting glucose, and renal hyperfiltration in the general population: The Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6). Clin J Am Soc Nephrol 7: 1801–1810, 201222917703
Hirji KF, Mehta CR, Patel NR: Computing distributions for exact logistic regression. J Am Stat Assoc 82: 1110–1117, 1987
Royston P, Ambler G, Sauerbrei W: The use of fractional polynomials to model continuous risk variables in epidemiology. Int J Epidemiol 28: 964–974, 199910597998
Cachat F, Combescure C, Cauderay M, Girardin E, Chehade H: A systematic review of glomerular hyperfiltration assessment and definition in the medical literature. Clin J Am Soc Nephrol 10: 382–389, 2015
Kremers WK, Denic A, Lieske JC, Alexander MP, Kaushik V, Elsherbiny HE, Chakkera HA, Poggio ED, Rule AD: Distinguishing age-related from disease-related glomerulosclerosis on kidney biopsy: The Aging Kidney Anatomy study. Nephrol Dial Transplant 30: 2034–2039, 201525888387
Kasiske BL: Relationship between vascular disease and age-associated changes in the human kidney. Kidney Int 31: 1153–1159, 19873599655
Pinto-Sietsma SJ, Janssen WM, Hillege HL, Navis G, De Zeeuw D, De Jong PE: Urinary albumin excretion is associated with renal functional abnormalities in a nondiabetic population. J Am Soc Nephrol 11: 1882–1888, 200011004219
Palatini P, Mos L, Ballerini P, Mazzer A, Saladini F, Bortolazzi A, Cozzio S, Casiglia E; HARVEST Investigators: Relationship between GFR and albuminuria in stage 1 hypertension. Clin J Am Soc Nephrol 8: 59–66, 2013
Thomas MC, Moran JL, Harjutsalo V, Thorn L, Wadén J, Saraheimo M, Tolonen N, Leiviskä J, Jula A, Forsblom C, Groop PH; FinnDiane Study Group: Hyperfiltration in type 1 diabetes: Does it exist and does it matter for nephropathy? Diabetologia 55: 1505–1513, 201222322918
Ruggenenti P, Porrini EL, Gaspari F, Motterlini N, Cannata A, Carrara F, Cella C, Ferrari S, Stucchi N, Parvanova A, Iliev I, Dodesini AR, Trevisan R, Bossi A, Zaletel J, Remuzzi G; GFR Study Investigators: Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Diabetes Care 35: 2061–2068, 201222773704
Ribstein J, du Cailar G, Mimran A: Combined renal effects of overweight and hypertension. Hypertension 26: 610–615, 19957558220
Tomaszewski M, Charchar FJ, Maric C, McClure J, Crawford L, Grzeszczak W, Sattar N, Zukowska-Szczechowska E, Dominiczak AF: Glomerular hyperfiltration: A new marker of metabolic risk. Kidney Int 71: 816–821, 200717332732
Palatini P, Dorigatti F, Saladini F, Benetti E, Mos L, Mazzer A, Zanata G, Garavelli G, Casiglia E: Factors associated with glomerular hyperfiltration in the early stage of hypertension. Am J Hypertens 25: 1011–1016, 201222673015
Srivastava T, Celsi GE, Sharma M, Dai H, McCarthy ET, Ruiz M, Cudmore PA, Alon US, Sharma R, Savin VA: Fluid flow shear stress over podocytes is increased in the solitary kidney. Nephrol Dial Transplant 29: 65–72, 201424166460
Kriz W, Lemley KV: A potential role for mechanical forces in the detachment of podocytes and the progression of CKD. J Am Soc Nephrol 26: 258–269, 201525060060
Glassock RJ, Rule AD: The implications of anatomical and functional changes of the aging kidney: With an emphasis on the glomeruli. Kidney Int 82: 270–277, 201222437416
Elsherbiny HE, Alexander MP, Kremers WK, Park WD, Poggio ED, Prieto M, Lieske JC, Rule AD: Nephron hypertrophy and glomerulosclerosis and their association with kidney function and risk factors among living kidney donors. Clin J Am Soc Nephrol 9: 1892–1902, 2014
Hodgin JB, Bitzer M, Wickman L, Afshinnia F, Wang SQ, O’Connor C, Yang Y, Meadowbrooke C, Chowdhury M, Kikuchi M, Wiggins JE, Wiggins RC: Glomerular aging and focal global glomerulosclerosis: A podometric perspective. J Am Soc Nephrol 26: 3162–3178, 201526038526
Luyckx VA, Bertram JF, Brenner BM, Fall C, Hoy WE, Ozanne SE, Vikse BE: Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease. Lancet 382: 273–283, 201323727166
Chagnac A, Weinstein T, Herman M, Hirsh J, Gafter U, Ori Y: The effects of weight loss on renal function in patients with severe obesity. J Am Soc Nephrol 14: 1480–1486, 200312761248
Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, Fagan NM, Woerle HJ, Johansen OE, Broedl UC, von Eynatten M: Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129: 587–597, 201424334175
Holtkamp FA, de Zeeuw D, Thomas MC, Cooper ME, de Graeff PA, Hillege HJ, Parving HH, Brenner BM, Shahinfar S, Lambers Heerspink HJ: An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int 80: 282–287, 201121451458
Górriz JL, Nieto J, Navarro-González JF, Molina P, Martínez-Castelao A, Pallardó LM: Nephroprotection by hypoglycemic agents: Do we have supporting data? J Clin Med 4: 1866–1889, 201526512703
Bolignano D, Zoccali C: Effects of weight loss on renal function in obese CKD patients: A systematic review. Nephrol Dial Transplant 28[Suppl 4]: iv82–iv98, 201324092846
Eriksen BO, Løchen ML, Arntzen KA, Bertelsen G, Eilertsen BA, von Hanno T, Herder M, Jenssen TG, Mathisen UD, Melsom T, Njølstad I, Solbu MD, Toft I, Mathiesen EB: Subclinical cardiovascular disease is associated with a high glomerular filtration rate in the nondiabetic general population. Kidney Int 86: 146–153, 201424304885
Stevens LA, Levey AS: Measured GFR as a confirmatory test for estimated GFR. J Am Soc Nephrol 20: 2305–2313, 200919833901