Abstract
The proximate genetic cause of both Thin GBM and Alport Syndrome (AS) is abnormal α3, 4 and 5 collagen IV chains resulting in abnormal glomerular basement membrane (GBM) structure/function. We previously reported that podocyte detachment rate measured in urine is increased in AS, suggesting that podocyte depletion could play a role in causing progressive loss of kidney function. To test this hypothesis podometric parameters were measured in 26 kidney biopsies from 21 patients aged 2–17 years with a clinic-pathologic diagnosis including both classic Alport Syndrome with thin and thick GBM segments and lamellated lamina densa [n = 15] and Thin GBM cases [n = 6]. Protocol biopsies from deceased donor kidneys were used as age-matched controls. Podocyte depletion was present in AS biopsies prior to detectable histologic abnormalities. No abnormality was detected by light microscopy at <30% podocyte depletion, minor pathologic changes (mesangial expansion and adhesions to Bowman’s capsule) were present at 30–50% podocyte depletion, and FSGS was progressively present above 50% podocyte depletion. eGFR did not change measurably until >70% podocyte depletion. Low level proteinuria was an early event at about 25% podocyte depletion and increased in proportion to podocyte depletion. These quantitative data parallel those from model systems where podocyte depletion is the causative event. This result supports a hypothesis that in AS podocyte adherence to the GBM is defective resulting in accelerated podocyte detachment causing progressive podocyte depletion leading to FSGS-like pathologic changes and eventual End Stage Kidney Disease. Early intervention to reduce podocyte depletion is projected to prolong kidney survival in AS.
Highlights
Genetic variants of the COL4A3, COL4A4, and COL4A5 genes encoding α3, α4 and α5 type IV collagen polypeptide chains cause structural alterations of the glomerular basement membrane (GBM) that comprise both Alport Syndrome and Thin GBM Disease [1,2]
The focus on podocyte depletion in Alport Syndrome Complex (ASC) was precipitated by our finding that the rate of podocyte detachment as measured by urine podocyte mRNA markers was increased in Alport Syndrome urine [31]
We show that podocyte depletion as measured by podocyte number per glomerulus, % podocyte depletion compared to an age-matched control group, or Glepp1 positive % of tuft area [podocyte cellular density], all demonstrate that podocyte depletion occurs in association with ASC
Summary
Genetic variants of the COL4A3, COL4A4, and COL4A5 genes encoding α3, α4 and α5 type IV collagen polypeptide chains cause structural alterations of the glomerular basement membrane (GBM) that comprise both Alport Syndrome and Thin GBM Disease [1,2]. Since the COL4A5 gene is resident on the X chromosome, classical AS affects males severely while females with random X inactivation in their podocyte population have a somewhat milder phenotype recognized to cause end stage kidney disease (ESKD) in older age (15% by 60 years) [2,6]. All progressive glomerular diseases in man, including Alport Syndrome, are associated with an increased rate of podocyte detachment as identified by the urine podocin mRNA:creatinine ratio [31]. This result raised the question as to whether progression in ASC could be the result of progressive podocyte depletion from glomeruli.
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