Among the dozens of kidney diseases that can be identified through kidney biopsy, all eventually lead to the same two final pathways: glomerular sclerosis and tubular fibrosis.
While we’ve discussed fibrosis extensively before, today we’ll focus on glomerular sclerosis, specifically examining:
- What exactly is sclerosis?
- Can sclerosis be reversed?
What Is Sclerosis?
The discovery of “sclerosis” dates back 500 years to 16th century Egypt, when a physician made a bold decision to perform an autopsy on his father to understand the cause of death.
He found yellow, porridge-like substances on his father’s arterial walls that felt as hard as bone. He called this “ossification” and termed the condition “arterial porridge-like ossification.”
Later, researchers discovered these hard substances were completely different from bone composition, so the term was changed to “sclerosis.” This name was then applied to similar debris accumulation in blood vessels of other organs, including the kidneys. These deposits aren’t necessarily cholesterol—they can include fats, collagen, fibrin, enzymes, and cellular debris.
What Accumulates in Kidney Glomerular Capillaries?
The culprit is called “extracellular matrix”—and it’s bad news.
Kidney function depends entirely on cells, specifically the cells lining glomerular capillary walls. The kidney is essentially a vascular network—each glomerulus is blood vessels wound into a ball shape.
Think of the kidney as one long blood vessel that’s twisted and coiled into kidney shape, similar to how the heart is one blood vessel coiled into a heart shape. Kidneys and hearts are essentially two segments of the same vascular system.
The blood vessel wall cells (like podocytes) are the kidney’s most critical cells. These cells have gaps and filter pores that allow toxins to be filtered out of the body while retaining essential nutrients.
Extracellular materials serve a supportive role but shouldn’t dominate. However, when kidney cells become inflamed, they secrete excessive waste products, causing extracellular matrix to grow dramatically while the cells themselves die off.
When podocytes decrease by just 10-20%, extracellular matrix explodes in growth, forming sclerosis. The living space originally occupied by cells gradually becomes overtaken by extracellular matrix.
Eventually, the blood vessels constructed by glomerular cells become clogged, collapsed, or even disappear entirely. Blood cannot flow through, so toxins like creatinine and blood urea nitrogen cannot be filtered, leading to toxin accumulation and kidney failure.
In essence, sclerosis is blood vessel blockage. In advanced stages, blood vessels disappear entirely, and the entire glomerulus becomes occupied by metabolic waste—a “dead ball.”
Can Glomerular Sclerosis Be Reversed?
Initially, medical experts had little confidence in reversing glomerular sclerosis. Managing inflammation was challenging enough—rebuilding blood vessels seemed impossible.
However, cardiologists showed that atherosclerotic plaques could be reduced when patients achieved target blood pressure and cholesterol levels. This gave kidney specialists hope.
Kidney researchers made a remarkable discovery: when kidneys from diabetic patients were transplanted into non-diabetic recipients, the sclerosis in these “diseased” kidneys reversed in their new hosts. Similarly, when diabetic kidney patients received pancreas transplants that eliminated their diabetes, their glomerular blood vessels gradually recovered.
Could simply eliminating the underlying cause trigger kidney self-repair?
To investigate, researchers conducted animal studies using puromycin aminonucleoside to induce disease, then stopped the toxic agent. Results showed glomerular capillaries extended and developed new branches.
Encouraging animal results led to human studies.
In 2004, Ma Jilin and colleagues published results in the Chinese Journal of Integrated Traditional and Western Nephrology:
After an average of 36 months, repeat kidney biopsies showed: segmental sclerosis in the kidneys had decreased.
However, global sclerosis showed no difference. Since early-stage patients with normal creatinine were studied, no changes in kidney function were detected (average creatinine remained 89-88 μmol/L).
How Does Glomerular Sclerosis Recover?
The recovery process follows this pattern:
Normal glomeruli ⇌ Segmental sclerosis glomeruli → Global sclerosis glomeruli → Absorption → New capillary growth
In other words:
- Normal glomeruli and segmental sclerosis glomeruli can convert back and forth. Some segmental sclerosis returns to normal, while other cases progress to global sclerosis. Result: more normal glomeruli, fewer segmental sclerosis cases.
- Global sclerosis showed no reversal—it forms and gets absorbed simultaneously, showing no overall difference (no statistical significance).
- Kidneys grow new capillaries (new glomeruli).
Where Do New Capillaries Come From?
Recent research has identified several sources.
Professor Charles Alpers at University of Washington Medical Center discovered that parietal epithelial cells on the glomerular capsule function as podocyte progenitor cells.
When podocytes on blood vessel walls die, these capsular epithelial cells proliferate and differentiate into podocytes, compensating for podocyte loss and rebuilding blood vessel walls and lumens.
For this discovery and related therapeutic developments, Professor Alpers received the 2023 Roscoe R. Robinson Award.
Conclusion
From the discovery of arterial sclerosis and glomerular capillary sclerosis, to understanding the process of glomerular sclerosis reversal and remodeling, to identifying blood vessel remodeling mechanisms—this journey has taken 500 years.
Today we know that sclerosis and reversal occur simultaneously: kidney self-repair mechanisms constantly work to reverse sclerosis, while nephritis, proteinuria, diabetes, and hypertension constantly create new sclerosis.
Many patients haven’t achieved target control of underlying causes and key indicators, making sclerosis outpace reversal.
If kidneys had better regenerative capacity, broken blood vessels would regenerate quickly like skin cells. However, kidneys sacrificed much of their regenerative ability to develop the sophisticated capability to precisely distinguish and filter various toxins and nutrients throughout the body.
Skin cells regenerate powerfully but lack the kidney’s extreme functional precision. Gaining one capability requires sacrificing another—it’s like the difference between quickly making a simple paper airplane versus slowly building a complex Boeing 747. Growing substantial new kidney blood vessels takes years, not weeks.
Since reversal is slow, we must maximize treatment efforts to reach targets and prevent sclerosis formation! Slow down the enemy, and you become relatively faster.
Sclerosis vs. reversal is a race of speed:
- As long as kidney blood vessel death slows down, new blood vessels will multiply
- As long as glomerular sclerosis slows down, clinical outcomes will show accelerated reversal
Here’s to every kidney patient: may your sclerotic glomeruli decrease and your distance from end-stage kidney disease increase!
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