Potential Relationship Between eGFR_{cystatin C}/eGFR_creatinine-ratio and Glomerular Basement Membrane Thickness in Diabetic Kidney Disease

Abstract

BackgroundDiabetic nephropathy (DN) is a leading cause of end stage renal disease and renal replacement therapy worldwide. A pathophysiological hallmark of DN is glomerular basal membrane (GBM) thickening, whereas this feature is absent in minimal change disease. Theoretically, a thicker GBM will impede the diffusion of middle-molecules such as cystatin C, potentially leading to a lower estimated GFR (eGFR) from cystatin C compared to that of creatinine. Here we test the hypothesis that thickening of the glomerular filter leads to an increased diffusion length, and lower clearance, of cystatin C.MethodsTwenty-nine patients with a kidney biopsy diagnosis of either DN (n=17) or minimal change disease (MCD) (n=12) were retrospectively included in the study. GBM thickness was measured at 20 separate locations in the biopsy specimen and plasma levels of cystatin C and creatinine were retrieved from health records. A modified two-pore model was used to simulate the effects of a thicker GBM on glomerular water and solute transport.ResultsThe mean age of the patients was 52 years, and 38% were women. The mean eGFRcystatin C/eGFRcreatinine-ratio was 74% in DKD compared to 98% in MCD (P < 0.001). Average GBM thickness was strongly inversely correlated to the eGFRcystatin C/eGFRcreatinine-ratio (Pearson’s r=-0.61, P < 0.01). Two-pore modeling predicted a eGFRcystatin C/eGFRcreatinine-ratio of 78% in DN.ConclusionsWe provide clinical and theoretical evidence suggesting that thickening of the glomerular filter, increasing the diffusion length of cystatin C, lowers the eGFRcystatin C/eGFRcreatinine-ratio in DN.Significance statementIncreased thickness of the glomerular basement membrane (GBM) is an early structural abnormality in diabetes, and has been identified as an independent risk factor for progression to diabetic nephropathy (DN). Increased GBM thickness will increase the diffusion length of mid-sized molecules like cystatin C across the renal filter, potentially leading to increased plasma concentrations and lower estimated GFR from cystatin C. The authors show theoretically that estimated GFR from cystatin C (eGFRcystatin C) is lower than that of creatinine (eGFRcreatinine) in DN to a degree directly depending on GBM thickness. In line with theory, they provide clinical data showing a lower eGFRcystatin C in diabetic patients with the eGFRcystatin C/eGFRcreatinine-ratio being inversely correlated to GBM thickness assessed from electron micrographs.

Glomerular filtration and shrunken pore syndrome in children and adults

“…Some experimentally verified such proteins are interleukins 6 and 18 (IL‐6, IL‐18) and C‐X‐C motif chemokine 10 (CXCL 10). Recent data suggest that a thickening of the glomerular basement membrane results in SPS 45 …”

Impaired selective renal filtration captured by eGFRcysC/eGFRcrea ratio is associated with mortality in a population based cohort of older women

“…At present, no generally accepted pathophysiological explanation for SPS exists, although shrinking of the pore size and thickening of the glomerular basement membrane (GBM) are the main hypotheses 1 , 5 . In diabetic glomerulosclerosis, thickening of the GBM may be reversible, at least in its early stages 18 and it is possible that this is also the case in SPS, with data from pregnant women suggesting plasma levels of middle sized molecules returned to normal after delivery 3 .…”

“…1 ). A thickening of the GBM would lead to an increased diffusion length of cysC, thus affecting the plasma concentration 1 , 5 . While the syndrome has been associated with mortality, both in individuals with normal kidney function and those with reduced GFR 4 , 6 – 8 , to date only one study has follow-up above five years 6 , hence, the association to long-term mortality is unknown.…”

Reduced renal elimination of larger molecules is a strong predictor for mortality

“…4). The pathologic mechanism of SPS and its relation to diabetic glomerulopathy is unclear, but it is possible that the thickening of the glomerular basement membrane in diabetes is related to the development of SPS 18 . This could explain why SPS occurs more frequently in diabetic patients and be a possible shared pathway for both SPS and diabetes for mortality.…”

“…We hypothesised that this finding is explained by the kidneys having a reduced clearance for large molecules compared to small molecules, as the molecular weight for creatinine is 113 Da compared to 13,300 Da for cystatin C. Other groups have also reported that this pattern yields a higher mortality in otherwise healthy seniors 14 , a higher incidence of right ventricular failure 15 and a higher mortality in a mixed patient population with a normal GFR measured by iohexol clearance 16,17 (Table 1). This pattern where the clearance of cystatin C is reduced compared to that of creatinine has been associated with thickening of the basal membrane in the glomerulus (submitted, available at medRxiv) 18 and is referred to as Shrunken Pore Syndrome (SPS) [19][20][21] . We have previously determined that a cut-off of 60% (eGFR Cystatin C ≤ 60% of eGFR creatinine, ) yields high specificity for premature death 13 .…”