Chronic renal failure pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]Feham Tariq, MD [3]Leena Josephin Jetty, M.B.B.S[4]

Overview

The pathophysiologic mechanisms leading to chronic kidney disease stem from the underlying etiologies responsible for the primary renal damage. Maladaptive systemic and renal responses arise that maintain and perpetuate the existing renal disease. Broadly, 3 main mechanisms exist that are related in part to the activation of the RAAS: hyperfiltration, inflammation, and accelerated fibrosis. As loss of kidney function progresses, nitrogen waste products are no longer cleared by the kidneys, and patients develop uremia as these uremic solutes accumulate over time.

Pathophysiology

• The pathophysiologic mechanisms that lead to chronic kidney disease (CKD) stem from the underlying etiologies responsible for the primary renal damage.
• The initial insult is responsible for a decrease in the number of functional nephrons.
• However, beyond that initial insult, a form of maladaptive systemic and renal response arise that maintains and perpetuates the existing renal disease.
• With the activation of the renin-angiotensin-aldosterone system (RAAS), a combination of mechanisms herald a progressive loss of nephrons.
• Broadly, 3 main mechanisms exist related in part to the activation of the RAAS which are as follows:
  • Hyperfiltration
  • Inflammation
  • Accelerated fibrosis

Hyperfiltration

• The landmark works of Brenner et al were the first to propose the maladaptive changes that occur after renal injury.
• The team showed that after significant loss of nephron mass, major alterations in glomerular hemodynamics occur.
• The changes lead to glomerular hypertension with an increase in single nephron glomerular filtration rate termed hyperfiltration.
• Hyperfiltration is a direct result of the increase in glomerular plasma flow and hydrostatic pressure in response to a decrease in preglomerular arteriolar resistance more than the decrease in postglomerular resistance with a net vasocontrictive effect on the efferent arteriole.
• The observed alterations occur due to the activation of the RAAS system.
• Initially, the juxtaglomerular apparatus increases the release of renin in response to the decreased perfusion pressure and solute delivery to the macula densa. Renin converts angiotensinogen to angiotensin I which is then converted to angiotensin II is then produced by angiotensin converting enzyme (ACE).
• Angiotensin II has been shown to be the main perpetrator in the maladaptation of the kidney to significant damage.

• Most animal models exploring glomerular hypertension and hyperfiltration show progressive glomerular sclerosis and eventual proteinuria that usually occurs at a linear rate compared to the extent of nephron loss.
• Furthermore, studies examining the prevention or reduction of glomerular hypertension and single nephron GFR have almost invariably shown a reduction in the rate of progression of renal disease.
• Among the proposed interventions include dietary protein restriction, ACE inhibitors, and angiotensin receptor blockers (ARBs).

Inflammation

• Angiotensin II has also been linked to and increase in inflammation after renal injury.
• It has been shown to activate the transcription factor NF-κB, an important player in the inflammatory response mediating transcription of several cytokines and chemokines.
• ATII has also been shown to stimulate endothelin-1 leading to the recruitment of T-cells and macrophages.
• Beyond that, it upregulates the expression of adhesion molecules notably integrins, intracellular adhesion molecule-1, and vascular cellular adhesion molecule-1 all of which lead to and increase in leukocyte concentration in the area.
• This creates a vicious cycle as lymphocytes can be a source of angiotensin II themselves amplifying its maladaptive effects.

Accelerated Fibrosis

• The increase in angiotensin II has also been directly associated with accelerated fibrosis in the remaining nephrons independently of the hemodynamic changes.
• Angiotensin II is thought to exert direct effects in the glomerular micromilieu leading to extracellular matrix (ECM) expansion.
• Angiotensin II has been shown to increase mRNA encoding type I procollagen and fibronectin in cultured mesangial cells.
• This effect is multiplied by the increase in expression of TGF-β further activating ECM protein production.
• In normal renal tissue, the balance between ECM synthesis and degradation is essential to prevent fibrotic glomerular changes.
• Beyond the increase in ECM production, angiotensin II also disrupts this balance.
• Via ATI receptors, it activates tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) both of which shift the balance towards ECM accumulation.
• Another method of accelerated fibrosis is a process called epithelial-to-mesenchymal transition (EMT) where tissue epithelial cells transform into active fibroblasts.
• Although previously recognized as a physiologic mechanism during embryologic development, it has come to light as a process that provides fibroblasts during organ fibrosis after injury.
• Experimentally, more than one third of fibroblast at the site of renal injury were shown to originate from the renal tubular epithelial cells.
• The prototypical factor linked to EMT is TGF-β which is usually elevated after renal injury; however, other local factors also induce EMT including epidermal growth factor (EGF), Insulin growth factor II (IGF-II), and fibroblast growth factor (FGF-2).

Genetics

• The CKD poses a major public health challenge that affects roughly 800 million people globally.But many a times the cause for CKD is difficult to identify just based on clinical diagnosis. With the emerging idea that genetics play a significant role in the causation of CKD the KIDGO  The (Kidney Disease: Improving Global Outcomes organization  is advising physicians to consider genetic testing for patients with CKD to pinpoint the diagnosis and to tailor their management accordingly.

• The first gene connected with kidney disease was the locus for APCKD. Since then hundreds of genes have been identified.Several factors like the pattern in which the CKD cluster in certain racial and ethnic groups suggests genetic contributions.
• Even when a clinical phenotype based diagnosis supports a genetic cause ,it is suggested to get a variant-based diagnosis because it establishes precise cause which further can help personalised monitoring and treatment and for effective genetic family counselling.
• The genetic risk of CKD can be viewed as a spectrum of low penetrance to high penetrance variants.
• The diseases at the high end of the spectrum, the Mendelian diseases have tight genotype-phenotype correlations.
• In contrast the low penetrance variants are influenced by environmental factors.

Nephropathies with single genetic cause:

Cystic Kidney Disease:

Cystic kidney diseases are mostly due to ciliopathies, caused by alterations in the cilium-centrosome complex.Clinical phenotypes include

• • Multiple renal cysts as in ADPKD
  • Normal size or small echogenic kidneys as in Nephronophthisis.

ADPKD:

• Genotype-phenotype correlation studies show that truncated PKD1 variants are associated with more severe disease when compared to PKD1 missense and PKD2 variants.
• Recently several genes have been implicated in rare cases of ADPKD.These include  IFT140, GANAB, NEK8, and DNAJB11 .

Nephronopthisis:

• Nephronophthisis is a group of genetically heterogeneous autosomal recessive diseases characterized by nonspecific, progressive deterioration in kidney function. 
• It can occur at any age like in childhood, adolescence or adulthood with symptoms like polyuria, growth retardation kids, and anemia. But the urine is generally bland.
• Homozygous variants in NPHP1 account upto 50% of cases ,remaining cases are caused by variants in 90 different genes involved in molecular pathways regulating cell polarity, sonic hedgehog signaling, the DNA damage response, or cyclic AMP signaling.
• Genotype-phenotype studies show that null variants are associated with younger age at presentation and more severe disease phenotypes.

1. Genetic Glomerular Diseases:

• Genetic glomerular diseases often involve mutant gene products that normally maintain podocyte function or pathogenic variants of proteins that make up the glomerular basement membrane (e.g., collagen type IV)
• Clinical presentations include the steroid-resistant nephrotic syndrome (SRNS) with focal segmental glomerulosclerosis (FSGS) on kidney biopsy or chronic proteinuria with or without hematuria.
• FSGS is a nonspecific lesion that represents a pattern of podocyte injury rather than a defined disease entity. Genetic forms of FSGS may be familial or sporadic. Extrarenal features may be present, depending on the involved gene.

CKD Related to Type IV Collagen

• Variants in the genes encoding the α3, α4, and α5 chains of type IV collagen (COL4A3, COL4A4, and COL4A5, respectively) are the second most common genetic cause of CKD after ADPKD accounting for 2-3% of adults with advanced CKD.
• Over 30 years ago changes in type  IV collagen a major component of GBM (glomerular basement membrane) was found to be seen in patients with Alport syndrome a.k.a Familial nephritis.
• Further studies showed that the phenotypic variations are associated with difference in the modes of variation and the location and types of variant within the genes encoding type IV collagen.
• In. Cases of CKD due to aport syndrome without its classical features studies shows that under-appreciated variants in genes encoding type IV collagen are responsible for it.
• X-linked disease is caused by pathogenic variants in COL4A5 .
• Autosomal recessive or autosomal dominant inheritance of pathogenic variants in COL4A3 or COL4A4.
• Highest risk of renal failure is associated with X-linked and Autosomal Resistive inheritance.
• Disease resulting from pathogenic variants in two different genes encoding type IV collagen (digenic inheritance) may have worse clinical outcomes than disease due to a single-gene heterozygous variant.
• Truncated variants have worse outcome when compared to missense variants.

Missense variants affect glycine residues there by altering the assembly of collagen heterotrimer structure.

Monogenic Forms of SRNS and FSGS:

Identification of variants in the podocyte-associated genes encoding nephrin (NPHS1)and podocin (NPHS2) established podocyte disease as a cause of chronic proteinuria and progressive kidney failure.

• Autosomal dominant and recessive inherited alterations in more than 50 different gene products that maintain podocyte ultrastructure, mediate signal transduction, or control podocyte cytoskeletal rearrangements have been reported as genetic causes of nephrotic syndrome or chronic proteinuria.
• These variants often seen in children can sometime result in adult disease like FSGS.

R229Q is associated with increased risk of adult-onset FSGS.

• Single-gene causes of adult-onset proteinuria and FSGS include autosomal dominant variants in the cytoskeletal genes ACTN4 and INF2 and the cation channel protein encoded by TRPC6.

TUBULOINTERSTITIAL DISEASES

• Genetic conditions affecting renal tubular function (tubulopathies) involve ion channels or transporters.
• Autosomal dominant disease due to gain-of-function variants in UMOD is one of the most prevalent monogenic causes of adult CKD worldwide.
• Uromodulin (also known as Tamm–Horsfall protein) is a kidney-specific protein that is synthesized by the thick ascending limb of the loop of Henle and autosomal dominant disease due to gain-of-function variants in UMOD is one of the most prevalent monogenic causes of adult CKD worldwide.
• UMOD variants cause a spectrum of disorders that have been termed UMOD-related autosomal dominant tubulointerstitial kidney disease (ADTKD).
• ADTKD is characterized by insidious kidney failure between the third and sixth decades of life. Patients may also have hyperuricemia and gout related to reduced fractional excretion of urate, despite a normal GFR.
•  Most disease-causing genetic variants are missense variants, often located in exons 3 and 4; 60% involve a cysteine residue.
• Pathogenic UMOD variants cause protein misfolding, with subsequent retention of protein in the endoplasmic reticulum and mistargeting of uromodulin in the thick ascending limb of the loop of Henle.
•  Variants in MUC1 are the second most common genetic cause of ADTKD and should always be considered in UMOD-negative cases.

KIDNEY STONE DISEASE

It is a multifactorial disease with a genetic component.

• Metabolic imbalances lead to urine crystallization and defective genes that normally encode proteins that maintain metabolic balance causes heritable forms of nephrolithiasis, sometimes leading to CKD.
• Genetic forms of kidney stone disease include adenine phosphoribosyltransferase deficiency, Dent’s disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, and primary hyperoxaluria, frequently lead to CKD and progress to kidney failure.
• These patients have the risk of recurrence after a transplantation as it doesnot address the underlying metabolic imbalance.

Syndromes like monogenic diabetes, monogenic hyperlipidemia or hypertension, and monogenic systemic lupus erythematosus are known to cause secondary kidney damage.

NEPHROPATHIES WITH A COMPLEX GENETIC BASIS

APOL1-Related CKD

APOL1 is a protein that provides protection against Trypanosomc mediated African sleeping sickness.

• Two variants of APOL1 a linked pair of missense variants, S342G and I384M, and two consecutive amino acid deletions, N388 and Y389are suspected to be major contributors for several subtypes of progressive CKD.
• They are designated as G1 and G2 ,confer protection against an extended spectrum of Trypanosoma species compared with its ancestral G0 allele.
• Although they offer protection they also contribute to an increased frequency of CKD among the Sub Saharan African ancestry.
• APOL1 is associated with broad spectrum of Nephropathies like FSGS<Hypertensive Nephropathies,HIV associated nephropathies and lupus-associated nephropathies.They define a new spectrum of APOL1 related CKD.
• Success with inaxaplin in FSGS suggests glomerular podocyte as the target of cell injury more specifically  luminal endoplasmic reticulum trafficking of the aberrant gene product is thought to result in abnormal cell-membrane cation channel activity.

Uremia

Definition

• Uremia (urine constituents in blood) is a clinical syndrome caused by progressive accumulation of nitrogen waste products among patients with kidney failure who with unable to clear these waste products by the kidneys.
• It is thought to account for the clinical features of chronic kidney failure that cannot be explained by other classical abnormalities of chronic kidney failure (abnormalities of ion concentrations or extracellular volume overload).

Progression to Uremia

• Uremia is a progressive clinical syndrome that is not typically characterized by a specific onset.
• Progressive build-up of nitrogen waste products is usually detected among patients with eGFR below 50% of normal rate (normal GFR for a young healthy man approximately 100 to 120 mL/min/1.73m²).
• Clinical features of uremia are more evident with lower GFR values, and uremic features are often prominent as GFR drops below 10 ml/min/1.73m² (loss of approximately 90% of kidney function), signaling the need for renal replacement modalities (either dialysis or transplantation).

Solutes of Uremia

• The majority of uremic solutes are unidentified.
• A few solutes that are present in high concentrations are identified. The toxic effects of these solutes have been studied.
• Examples of uremic solutes that have been studied include:
  • Beta-2-microglobulin
  • Guanidines
  • Nucleosides
  • Phenols
  • Indoles
  • Furans
  • Polyols
  • Carbonyls
  • Other advanced glycosylation end (AGE) products

• Protein intake is thought to increase the concentration of certain uremic solutes.
• Chemical characteristics of individual solutes may determine the capacity of dialysis to appropriately filter these solutes. Large solutes, solutes bound to albumin, and sequestered solutes are generally poorly filtered by conventional dialysis techniques. The use of ultrafiltration methods and improvement in dialysis membrane sizes are active areas of research that aim to increase filtration capacity of toxic solutes.
• The association between high concentrations of uremic solutes and adverse clinical outcomes is still controversial and is currently under investigation.
• Although uremia is classically associated with chronic kidney failure, experimental studies have recently demonstrated a role of uremic solutes in acute kidney injury (acute uremia), but the pathophysiological significance of these solutes in the context of acute kidney injury is yet to be identified.