II-9. Causes and definition of chronic renal failure

慢性腰不全の原因と定義

Chronic Renal Failure (CRF)

Kidney becomes scarred/sclerotic (non-functioning). Result of structural/functional changes; ↑cardiovascular mortality (stroke, infarction). Often silent → needs screening.

Causes

Systemic diseases: diabetes (diabetic nephropathy), hypertension (hypertensive nephrosclerosis).
Localized kidney diseases: glomerulonephritis (ARF), tubulopathies (ATN), polycystic kidney disease (most common inherited cause).

Diabetic Nephropathy (DNP)

Most common cause of CRF. Features: sclerotic glomeruli, tubular atrophy + interstitial fibrosis, vascular sclerosis.
Two routes: glomerular (podocyte damage → albuminuria → tubulointerstitial fibrosis), tubular (ATN-like → fibrosis → tubular narrowing → occludes filtration; tubulointerstitial fibrosis → hypoxia).

Hypertensive Nephrosclerosis

Glomerular pressure (60 mmHg) autoregulated 70–180 mmHg. Persistent hypertension → afferent arteriole SM hypertrophy, inflammatory mediators, ECM → hyaline arteriosclerosis → narrowed lumen → atrophy; efferent hypoxia → tubulointerstitial fibrosis.
BP >180 mmHg → hypertensive crisis → autoregulation fails → ↑glomerular capillary pressure → podocyte loss → glomerular scarring.

Renal Fibrosis

Most common manifestation of chronic renal disease; structural damage to all compartments: arteriopathy (BM multiplication, intimal proliferation), glomerulopathy (ECM → capillary occlusion), tubulointerstitial inflammation/atrophy.
Nephron loss: GFR_total = GFR_single nephron × number of nephrons. Remaining nephrons compensate → CKD silent until GFR <50%. Causes: DNP, hypertension, glomerulonephritis, AKI, age.
Consequences: ↑volume → ↑intraglomerular pressure → hyperfiltration → TGF-α/EGFR → hypertrophy → podocyte loss → focal scarring (vicious cycle). First sign = microalbuminuria (detached podocytes).

Stages (creatinine marker, delayed by hyperfiltration)

Stage 1: GFR 90–120, reversible (creatinine-insensitive).
Stage 2: overt damage, GFR >60, creatinine normal; MDRD becomes sensitive.
Stage 3: azotemia, GFR 30–60, MDRD+, irreversible/progressive.
Stage 4: pre-uremia, GFR 15–30.
Stage 5: uremia, GFR 0–15, end-stage symptoms.

Systemic Consequences

Azotemia (lab): ↑creatinine, urea, uric acid (asymptomatic).
Uremia (clinical): toxin buildup → symptoms; GFR <15; urine-smelling breath (urea → ammonia).
Labs: anemia (↓EPO + BM suppression), acidosis (acid retention), isosthenuria (cannot concentrate/dilute → polyuria). Urea (sensitive >25% GFR drop), creatinine (>50% GFR drop), ↑K⁺ (>8 mmol/L → immediate dialysis, arrhythmia risk).

Uremic Retention Solutes & Residual Uremia

Residual uremia syndrome: dialysis can’t remove protein-bound toxins → high cardiovascular mortality; malnutrition, infections, CNS, serositis; accelerated protein aging, inflammation, calcification.
By dialysability: small molecules (<500 Da, urea filterable), medium (0.5–60 kDa, need high-flux — removes β2-microglobulin to avoid amyloidosis), albumin (68 kDa) not filterable.
By origin: endogenous (urea from guanidine; PTH → secondary hyperparathyroidism → uremic osteodystrophy + calcification; protein glycosylation), intestinal flora (phenols, indoles, amines), exogenous (oxalate).

Development of Uremic Symptoms

Oliguria: water retention → edema + hypertension + lung edema; K⁺ retention → arrhythmias.
Toxin retention: acidosis → ↓lipase → dyslipidemia/atherosclerosis; endothelial + myocardial dysfunction; BM suppression → anemia/thrombocytopenia/↓immunity; CNS (fatigue, depression, coma); GI (↓appetite, vomiting).
Albumin loss → edema; ↓EPO → anemia; ↓vitamin D + phosphate retention → secondary hyperparathyroidism → uremic osteodystrophy + soft tissue/vascular calcification.

一問一答

▶Over what range is glomerular pressure autoregulated?

Between systemic pressures of 70–180 mmHg (glomerular pressure ~60 mmHg).

▶What is the most common cause of chronic renal failure?

Diabetic nephropathy.

▶What are the histological features of diabetic nephropathy?

Sclerotic glomeruli, tubular atrophy with interstitial fibrosis, and vascular sclerosis.

▶What is the most common inherited cause of chronic renal failure?

Polycystic kidney disease.

▶What are the glomerular and tubular routes of diabetic nephropathy?

Glomerular: podocyte damage → albuminuria → tubulointerstitial fibrosis. Tubular: ATN-like injury → fibrosis → tubular narrowing occluding filtration, with fibrosis-driven hypoxia.

▶How does hypertensive nephrosclerosis damage the kidney?

Persistent hypertension causes afferent arteriole SM hypertrophy and hyaline arteriosclerosis → narrowed lumen → atrophy; efferent hypoxia drives tubulointerstitial fibrosis.

▶What happens to glomeruli when BP exceeds 180 mmHg?

Autoregulation fails → increased glomerular capillary pressure → podocyte loss → glomerular scarring (hypertensive crisis).

▶What is the relationship between total GFR and nephron number?

GFR_total = GFR_single nephron × number of nephrons; remaining nephrons compensate, so CKD stays silent until GFR <50%.

▶What is the first sign of renal fibrosis/nephron loss?

Microalbuminuria (from detached podocytes).

▶How does hyperfiltration create a vicious cycle in CKD?

Increased volume → increased intraglomerular pressure → hyperfiltration → TGF-α/EGFR → hypertrophy → podocyte loss → focal scarring, which further loads remaining nephrons.

▶Distinguish azotemia from uremia.

Azotemia is the lab finding of raised creatinine, urea, and uric acid (asymptomatic); uremia is the clinical syndrome of toxin buildup with symptoms (GFR <15), including urine-smelling breath.

▶Why does anemia develop in chronic renal failure?

Decreased EPO production plus bone marrow suppression.

▶What serum potassium level requires immediate dialysis, and why?

>8 mmol/L, because of arrhythmia risk.

▶Compare urea and creatinine as markers of GFR decline.

Urea is sensitive after a >25% GFR drop; creatinine rises only after a >50% GFR drop (delayed by hyperfiltration).

▶What is isosthenuria in CRF?

Inability to concentrate or dilute urine, leading to polyuria.

▶What is residual uremia syndrome?

Dialysis cannot remove protein-bound toxins, leading to high cardiovascular mortality, malnutrition, infections, CNS effects, serositis, accelerated protein aging, inflammation, and calcification.

▶Why is high-flux dialysis needed to remove β2-microglobulin?

It is a medium molecule (0.5–60 kDa); removing it avoids dialysis-related amyloidosis. Small molecules (<500 Da, urea) are easily filtered, but albumin (68 kDa) is not.

▶How does CRF cause secondary hyperparathyroidism and bone disease?

Decreased vitamin D plus phosphate retention drive secondary hyperparathyroidism → uremic osteodystrophy and soft tissue/vascular calcification.

▶What are the GFR ranges for CKD stages 1 through 5?

Stage 1: 90–120; Stage 2: >60; Stage 3: 30–60 (azotemia); Stage 4: 15–30 (pre-uremia); Stage 5: 0–15 (uremia).

▶How does oliguria produce uremic symptoms?

Water retention causes edema, hypertension, and lung edema, while K⁺ retention causes arrhythmias.