Pathophysiology of Chronic Kidney Disease

Pathophysiology of Chronic Kidney Disease

– Dr Shivnarayan J. Acharya
MBBS, MD Medicine from GMC,
Diplomate of National Board in Nephrology from Jaslok Hospital, Mumbai

Chronic Kidney Disease ( CKD ) is defined as a kidney damage
with a glomerular filtration rate of <60 ml/minute for more than 3 months.

Kidney damage is defined by any one of the following findings:

  1. pathologic kidney abnormalities
  2. persistent proteinuria
  3. other urine abnormalities, eg, renal hematuria
  4. imaging abnormalities
  5. eGFR <60 mL/min/1.73 m2 on two occasions separated by 90 days and that
    is not associated with a transient, reversible condition such as volume depletion.

Basic mechanisms of CKD

After a primary acute or chronic insult occurs, such as in diabetic nephropathy
or lupus nephritis, many common pathways are activated to perpetuate glomerular
and tubule-interstitial injury.

These harmful adaptations, occurring as a result of an initial injury, can be
broadly categorized into two –

  1. Hemodynamically mediated
  2. Non-hemodynamic mechanisms

Hemodynamic Injury

Glomeruli have afferent and efferent arteriole. In CKD, efferent vasoconstriction
increases intra-glomerular and filtration pressure perpetuating hyper-filtration

Following unilateral nephrectomy and 2/3 removal of the contralateral kidney
in rats, hypertension, proteinuria, and progressive decline in GFR ensue.

Micro-puncture techniques reveal an increase in renal plasma flow and hyper-filtration
of the remaining nephrons. Systemic hypertension and glomerular hypertension, from
activation of the renin-angiotensin-aldosterone system (RAAS), cause progressive
glomerular damage and proteinuria.

With nephron loss, adaptation leads to release of renin from the juxtaglomerular
apparatus due to decreased perfusion pressure and low solute delivery to the macula
densa. Renin converts angiotensinogen to angiotensin I, which, under the influence
of angiotensin converting enzyme (ACE), is converted to angiotensin II (AII). AII,
in addition to increasing aldosterone production from the adrenal gland, is the
main perpetrator of glomerular hemodynamic maladaptation.

Through an increase in sympathetic activity, AII is a potent vasoconstrictor,
especially predominant in the postglomerular arterioles. It also exhibits a role
in salt and water retention, both directly through proximal tubular sodium reabsorption
and indirectly through aldosterone dependent distal sodium reabsorption.

Non-hemodynamic Injury

Activation of the RAAS

Activation of the RAAS leads to several non-hemodynamic maladaptive pathways,
which can lead to inflammation and fibrosis. AII has been demonstrated in high concentrations
in virtually every compartment of the kidney in CKD, including the mesangial cells,
endothelial cells, podocytes, the urinary space (Bowman capsule), and the tubulointerstitium.

Activation of the RAAS eventually results in fibrosis and a progressive decline
in GFR. This fibrosis manifests with up regulation of several growth factors and
their receptors, such as connective tissue growth factor (CTGF), epidermal growth
factor (EGF), insulin-like growth factor-1 (IGF-1), platelet-derived growth factor
(PDGF), vascular endothelial growth factor (VEGF), transforming growth factor-β
(TGF-β), and monocyte chemotactic protein-1 (MCP-1).

The activation of these factors by AII and aldosterone leads to cellular proliferation
and hypertrophy of glomerular endothelial and epithelial cells, mesangial cells,
tubulointerstitial cells, and fibroblasts. AII and TGF-β also upregulate other factors
that lead to the overproduction of extracellular matrix, such as type 1 procollagen,
plasminogen activator inhibitor 1, and fibronectin. In addition, excess adhesion
molecules, such as integrins or vascular cellular adhesion molecule 1, allow the
increased extracellular matrix and hypercellularity to accumulate and persist.

This leads to cell proliferation, extracellular matrix accumulation, adhesion
of these cells, and functional changes with eventual fibrosis.

Risk Factors for Progression of CKD

Non-modifiable Risk factors for progression are

  • Male gender
  • Older age
  • Family history of DM, CKD, or ESRD
    Low birth weight

Modifiable Risk factors for progression are

  • Proteinuria
  • Hypertension
  • Episodes of acute kidney injury
  • Underlying cause of kidney disease (e.g., diabetic nephropathy)
  • Obesity
  • Hyperlipidemia
  • Smoking
  • High-protein diet
  • Metabolic acidosis
  • Hyperphosphatemia
  • Hyperuricemia


Proteinuria itself contributes to progressive nephrosclerosis. Through hyperfiltration,
the increased glomerular permeability to albumin allows reabsorption of more albuminuria
by the proximal tubular cells. When this protein becomes prevalent in the interstitium,
macrophages and inflammatory mediators, such as ET-1 and MCP-1 as well as other
chemokines, are upregulated, which eventually leads to inflammation and subsequent
tubulointerstitial and glomerular fibrosis.

Progressive skeletal disease

Abnormalities in mineral and bone metabolism occur early in the course of chronic
kidney disease (CKD) and progress as renal function declines . Traditionally, these
abnormalities have been ascribed to an early decline in 1,25(OH)2vitamin D (calcitriol)
levels, leading to increases in serum PTH and subsequent alterations in calcium
and phosphorus metabolism.

However, recent studies have revealed that circulating values of fibroblast growth
factor 23 (FGF-23), a key regulator of phosphorus and vitamin D metabolism, rise
as renal function declines and may play a key initiating role in the development
of abnormal mineral metabolism in patients with CKD.

FGF-23 and its regulators are made in osteocytes in bone, and in patients with
CKD, FGF-23 levels rise as renal function declines, likely due to decreasing capacity
of the damaged kidney to excrete dietary phosphorus loads. Rising FGF-23 levels
contribute to the development of sec- ondary hyperparathyroidism and may also be
linked to alter- ations in skeletal mineralization and to cardiovascular dis- ease
in the CKD population. Thus, through expression of various proteins crucial to mineral
metabolism, osteocytes appear to be endocrine cells with a key role in the regulation
of skeletal mineralization and vascular calcification.

Anemia in CKD

Anemia increases in prevalence and severity as renal function decreases, becoming
much more common when the glomerular filtration rate reaches 60 mL/minute or less.
It is a risk factor associated with worse prognosis.

Factors likely contributing to anemia in chronic kidney disease include blood
loss, shortened red cell life span, vitamin deficiencies, the “uremic milieu,” erythropoietin
(EPO) deficiency, iron deficiency, and inflammation.

Specialized peritubular cells that produce EPO are partially or completely depleted
or injured as renal disease progresses, so that EPO production is inappropriately
low relative to the degree of anemia.

Deficiency of erythropoietin is the primary cause of anemia in chronic renal
failure, but it is not the only cause. A minimal workup is necessary to rule out
iron deficiency and other cell-line abnormalities.

Dr Shivnarayan J. Acharya