Nephrosclerosis is a morphological and clinical term describing progressive renal damage characterized by vascular, glomerular, and interstitial sclerosis, resulting from chronic processes such as arterial hypertension, as well as hereditary and metabolic diseases. It is one of the most common causes of chronic kidney disease (CKD) and progression to end-stage renal disease (ESRD).

Nephrosclerosis arises as a result of:

• Chronic renal ischemia due to damage to arterioles (hyaline or hyperplastic arteriolosclerosis).
• Secondary glomerular sclerosis from perfusion loss and increased intraglomerular pressure.
• Interstitial fibrosis and tubular atrophy contribute to the loss of functional renal mass.

• Intimal thickening and arteriolar hyalinization.
• Global glomerulosclerosis (focal or diffuse).
• Interstitial fibrosis with mild chronic inflammatory infiltrate.

• Associated with mild to moderate essential hypertension and aging.
• Slowly progressive course.
• Clinically silent for years.
• Findings: mild proteinuria, initially preserved renal function, small and symmetrical kidneys on imaging.

• Associated with malignant hypertension (BP >180/120 mmHg with acute target organ damage).
• Rapidly progressive vascular damage with fibrinoid necrosis, retinal hemorrhages, and hypertensive encephalopathy.
• Leads to acute or rapidly progressive renal failure.

• Essential hypertension is the most common cause of nephrosclerosis, particularly when long-standing and poorly controlled.
• In many cases, hypertension has a significant genetic component. Studies have documented:
  • Increased risk in individuals with a family history of hypertension.
  • Genetic polymorphisms such as ACE, AGT, AGTR1, and CYP11B2 affect blood pressure regulation and increase renal damage susceptibility.
  • APOL1 mutations (G1 and G2), especially in individuals of African descent, are associated with aggressive forms of hypertensive nephropathy and collapsing glomerulosclerosis.

Certain genetic disorders lead to primary or secondary nephrosclerosis:

• Alport Syndrome (COL4A3/COL4A4/COL4A5 mutations): type IV collagen defect leading to progressive glomerulosclerosis.
• Fabry Nephropathy (GLA mutation): lysosomal storage disease with globotriaosylceramide deposits in podocytes and tubules.
• APOL1-associated nephropathy: G1/G2 variants lead to collapsing focal segmental glomerulosclerosis (FSGS).
• Autosomal dominant polycystic kidney disease (PKD1/2): although cystic in pattern, it progresses to fibrosis and pericystic sclerosis.

Nephrosclerosis progression depends on the control of risk factors, particularly:

• The main predictor of progression to ESRD.
• Higher systemic pressure causes more severe damage to renal microvasculature.

• Proteinuria >300 mg/day indicates glomerular barrier dysfunction and activates inflammatory and profibrotic pathways (TGF-β, angiotensin II).
• A major driver of renal function decline.

• Progressive GFR decline reflects cumulative structural damage.
• Increases the risk of ESRD and cardiovascular events.

• Interstitial infiltrates activate fibroblasts, leading to loss of functional nephrons.

• History of chronic hypertension, persistent proteinuria, and reduced GFR.
• Fundoscopy with signs of advanced hypertensive retinopathy.

• Renal ultrasound: small kidneys, increased cortical echogenicity.
• MRI or Doppler: useful to rule out stenosis or secondary vascular causes.

• Indicated when disease progression is rapid, unexplained by hypertension, or when hereditary/metabolic causes are suspected.

• Asymptomatic in most cases.
• Incidental findings:
  • Mild proteinuria (microalbuminuria or <1 g/day).
  • Difficult-to-control hypertension.
  • Mild elevation in serum creatinine.

• Nonspecific symptoms:
  • Fatigue, weakness.
  • Nocturnal muscle cramps.
  • Polyuria/nocturia.
  • Resistant hypertension.
  • Mild peripheral edema.

• Early uremic symptoms:
  • Anorexia, nausea, metallic taste.
  • Pruritus, skin changes.
  • Edema, exertional dyspnea.

              Full uremic syndrome:

              Vomiting, confusion, somnolence.

• Uremic pericarditis and pleuritis.
• Severe anemia, renal osteodystrophy.

• Target <130/80 mmHg (KDIGO 2021).
• ACE inhibitors or ARBs are first-line therapies.

• Target <300 mg/day.
• Use of RAAS blockers and SGLT2 inhibitors in selected patients.

• Fabry: enzyme replacement therapy (agalsidase beta) or migalastat.
• Alport: early use of ACE inhibitors.
• APOL1: experimental gene therapy under investigation.

• Hemodialysis (HD): commonly performed in specialized centers.
• Peritoneal Dialysis (PD): home-based, either continuous or automated.

• Indicated in patients with good general condition and no immunological contraindications.
• Careful evaluation of related donors in genetic conditions.

Prognosis depends on:

• Blood pressure control.
• Degree of proteinuria.
• Rate of GFR decline.

Patients with uncontrolled hypertension and proteinuria >1 g/day may reach ESRD in under 5 years. Early and aggressive management significantly improves outcomes.

Nephrosclerosis represents a final common pathway of chronic renal damage. Its etiology is multifactorial, involving both acquired and hereditary causes. It requires early diagnosis, individualized treatment, and integration of modern strategies, including precision medicine and renal replacement therapy when necessary.

As I always teach, prevention and early diagnosis can change or slow the course of the disease. If you have relatives with early-onset hypertension, you may have a genetic predisposition. Do not smoke, keep your blood pressure well controlled, and reduce salt intake in your diet.

Raúl Ayala, MD