Chronic Kidney Insufficiency: Causes

Pathogenesis (disease development)

Progressive (progressive) impairment of renal function results in the need to build up increased pressure in the glomeruli (renal corpuscles; part of the blood-urine barrier) to maintain residual function. To do this, an increase in angiotensin II (tissue hormone that occupies a key position in the renin-angiotensin-aldosterone system (RAAS), which is responsible for maintaining blood pressure and water balance) induces hypertrophy (increase in size) of the glomeruli. However, angiotensin II simultaneously causes increased glomerular permeability (permeability), which in turn leads to proteinuria (increased excretion of protein in the urine). Proteinuria leads to further glomerulosclerosis (chronic disease of the kidney associated with scarring (sclerosis) of the capillary loops of the renal corpuscle (glomerulus)). Note: The 500-50-50 rule describes the risk of drug-induced kidney damage (nephrotoxic drugs; see below) as follows: Approximately 500 essential drugs are 50 percent renally eliminated and 50 percent of people over 70 years of age are renally insufficient.

Etiology (Causes)

Biographic causes

  • Genetic burden from parents, grandparents
    • Genetic diseases/misformations
      • Alport syndrome (also called progressive hereditary nephritis) – genetic disorder with both autosomal dominant and autosomal recessive inheritance with malformed collagen fibers that can lead to nephritis (inflammation of the kidneys) with progressive renal failure (kidney weakness), sensorineural hearing loss, and various eye diseases such as a cataract (cataract)
      • Dysplastic kidneys (maldevelopment of the kidneys) (mode of inheritance: mostly sporadic).
      • Fabry disease (synonyms: Fabry disease or Fabry-Anderson disease) – X-linked lysosomal storage disease due to a defect in the gene encoding the enzyme alpha-galactosidase A, resulting in progressive accumulation of the sphingolipid globotriaosylceramide in cells; mean age of manifestation: 3-10 years; early symptoms: Intermittent burning pain, decreased or absent sweat production, and gastrointestinal problems; if left untreated, progressive nephropathy (kidney disease) with proteinuria (increased excretion of protein in urine) and progressive renal failure (kidney weakness) and hypertrophic cardiomyopathy (HCM; disease of the heart muscle characterized by thickening of the heart muscle walls).
      • Urinary tract malformations
      • Polycystic kidney disease – kidney disease due to multiple cysts (fluid-filled cavities) in the kidneys.
        • Partly with autosomal dominant as well as autosomal recessive inheritance (see below Cystic Kidney Disease).
      • Sickle cell anemia (med.: Drepanocytosis; also sickle cell anemia, sickle cell anemia) – genetic disease with autosomal recessive inheritance, which affects the erythrocytes (red blood cells); it belongs to the group of hemoglobinopathies (disorders of hemoglobin; formation of an irregular hemoglobin, the so-called sickle cell hemoglobin, HbS).
  • Age – esp. due to persistent inflammation and cellular senescence (cell aging).

Behavioral causes

  • Consumption of stimulants
    • Tobacco (smoking) – promotes the progression of renal insufficiency
  • Overweight (BMI ≥ 25; obesity) – HDL levels and glomerular filtration rate decreased with increasing BMI; chronic kidney disease (defined as estimated glomerular filtration rate below 60 ml/min/1.73 m2) was diagnosed 2.6 years later in underweight than in normal weight individuals, whereas it was diagnosed 1.1 years earlier in overweight and 2.0 years earlier in obese individuals

Disease-related causes

  • Abacterial chronic interstitial nephritis – chronic inflammation of the connective tissue (tissue between glomeruli (renal corpuscles) and tubules) of the kidney (immunological).
  • Acute kidney injury (AKI). [independent risk factor]
  • Analgesic nephropathy (tubulointerstitial nephropathy; see drugs below).
  • ANCA-associated vasculitides (AAV) – ANCA stands for anti-neutrophil cytoplasmic antibodies.ANCA-associated vasculitides are systemic diseases, meaning they can affect approximately all organ systems
  • Amyloidosis – extracellular (“outside the cell”) deposits of amyloids (degradation-resistant proteins) that can lead to cardiomyopathy (heart muscle disease), neuropathy (peripheral nervous system disease), and hepatomegaly (liver enlargement), among other conditions.
  • Anorexia nervosa (anorexia).
  • Chronic tubulointerstitial kidney disease (TIN).
  • Diabetic nephropathy (synonym: diabetes-associated nephropathy (DNP)) – secondary disease of diabetes mellitus (diabetes), in which the kidneys are damaged by microangiopathy (vascular changes affecting the small vessels) (about 30-40% of diabetics have nephropathy).
  • Glomerulonephritides – kidney diseases with inflammation of the glomeruli (renal corpuscles) (diffuse, focal or rapid progressive glomerulonephritis, focal-segmental glomerulosclerosis, membranous glomerulonephritis, minimal-change glomerulonephritis).
  • Hemolytic uremic syndrome (HUS) – triad of microangiopathic hemolytic anemia (MAHA; form of anemia in which erythrocytes (red blood cells) are destroyed), thrombocytopenia (abnormal decrease in platelets/platelets), and acute kidney injury (AKI); Mostly occurring in children in the context of infections; most common cause of acute renal failure requiring dialysis in childhood.
  • HIV nephropathy – kidney disease caused by HIV infection.
  • Hypertension (high blood pressure) or hypertensive nephropathy (hypertension-related kidney disease) – nephrology professional associations estimate that chronic kidney failure in Germany is 24 percent due to hypertension
  • Hyperuricemia (gout)
  • Collagenoses (group of connective tissue diseases caused by autoimmune processes) – systemic lupus erythematosus (SLE), polymyositis (PM) or dermatomyositis (DM), Sjögren’s syndrome (Sj), scleroderma (SSc) and Sharp syndrome (“mixed connective tissue disease”, MCTD).
  • Leukemia (blood cancer)
  • Nephrolithiasis (kidney stone disease), recurrent.
  • Obstructive nephropathies – kidney diseases due to narrowing or occlusion of the urinary tract.
  • Paraproteinemia – proteins from uncontrolled proliferation of cells occur in increased amounts in the blood in various diseases such as plasmocytoma (malignant systemic disease)
  • Polycystic kidney disease – kidney disease characterized by the presence of many cysts (fluid-filled cavities).
  • Polycythemia – abnormal multiplication of blood cells (especially affected are erythrocytes, to a lesser extent platelets and leukocytes); prickly itching after contact with water (aquagenic pruritus).
  • Pyelonephritis (inflammation of the renal pelvis).
  • Systemic lupus erythematosus (SLE) – systemic disease that affects the skin and connective tissue of the vessels, leading to vasculitides (vascular inflammation) of numerous organs such as the heart, kidneys, or brain
  • Vascular nephropathy – kidney disease due to changes in the renal vessels, usually atherosclerosis (arteriosclerosis, hardening of the arteries).

Laboratory diagnoses – laboratory parameters that are considered independent risk factors.

Drugs (nephrotoxic – drugs that damage the kidneys/nephrotoxic drugs).

  • ACE inhibitors (benazepril, captopril, cilazapril, enalapril, fosinopril, lisinopril, moexipril, peridopril, quinapril, ramipril, spirapril) and AT1 receptor antagonists (candesartan, eprosartan, irbesartan, losartan, olmesartan, valsartan, telmisartan) (acute: Decrease in glomerular filtration rate (GFR) associated with creatinine increase: ACE inhibitors as well as AT1 receptor antagonists abolish vasoconstriction (vasoconstriction) in the vas efferens, and a decrease in GFR and increase in serum creatinine result. Up to 0.1 to 0.3 mg/dl, this is usually tolerable. However, in the presence of hemodynamically relevant renal artery stenosis (not uncommon in patients with atherosclerosis/arteriosclerosis), GFR becomes markedly angiotensin II-dependent impaired, and administration of an ACE inhibitor or AT1 receptor antagonist may result in acute renal failure (ANV))!
  • Angiotensin receptor neprilysin antagonists (ARNI) – dual drug combination: sacubitril/valsartan.
  • Allopurinol
  • Antiphlogistic and antipyretic analgesics (non-steroidal anti-inflammatory drugs (NSAID), non-steroidal anti-inflammatory drugs) and non-steroidal anti-inflammatory drugs (NSAID), respectively.
    • Adverse effects on renal function especially in the elderly and patients with pre-damaged kidneys or associated risk factors.Younger, physically active adults also have an increased risk of acute and chronic renal injury with frequent NSAID use (> 7 defined daily doses of NSAIDs per month).NSAID-related risk of renal injury was even higher in: BMI ≥ 30, hypertension or diabetes mellitus, or male sex.
    • Note: The combination of a diuretic, an RAS blocker, and an NSAID is associated with a significant risk of acute kidney injury:
      • Acetylsalicylic acid (ASA).
      • Diclofenac
      • Ibuprofen/naproxen
      • Indometacin
      • Metamizole (novaminsulfone) is a pyrazolone derivative and analgesic from the group of non-acidic non-opioid analgesics (highest analgesic and antipyretic activity. Side effects: Circulatory fluctuations, hypersensitivity reactions, and very rarely agranulocytosis.
      • Paracetamol / acetaminophen
      • Phenacetin (phenacetin nephritis)
      • Selective COX-2 inhibitors such as rofecoxib, celecoxib (side effects: decreased sodium and water excretion, blood pressure increase and peripheral edema. This is usually accompanied by hyperkalemia (excess potassium)!)
  • Antibiotics
  • Antifungals
    • Polyenes (amphotericin B, natamycin)
  • Chloral hydrate
  • Diuretics
  • Colchicine
  • D-Penicillamine
  • Gold – sodium aurothiomalate, auranofin
  • Immunosuppressants – ciclosporin (cyclosporin A) – esp. ciprofloxacin plus ciclosporin A.
  • Interferon
  • Colloidal solution with hydroxyl starch
  • Contrast media – Of particular importance here are magnetic resonance imaging (MRI) contrast media containing gadolinium, which can lead to nephrogenic systemic fibrosis (NSF). Particularly affected by NSF are patients with a glomerular filtration rate (GFR) of less than 30 ml/min. [CKD stage 4]; iodine-containing radiographic contrast agents; [require prophylactic irrigation in renal insufficiency]EMA (European Medicines Agency): categorization of GBCAs (gadolinium-based contrast agents) in terms of NSF (nephrogenic systemic fibrosis) risk, based on thermodynamic and kinetic properties:
    • High risk: gadoversetamide, gadodiamide (linear/non-ionic chelates) gadopentetate dimeglum (linear/ionic chelate).
    • Medium risk: gadofosveset, gadoxetic acid disodium, gadobenate dimeglumine (linear/ionic chelates).
    • Low risk: gadoterate meglumine, gadoteridol, gadobutrol (macrocyclic chelates).
  • Lithium – not nephrotoxic in therapeutic doses, but in acute intoxication.
  • Oncological therapy
  • Proton pump inhibitors (proton pump inhibitors, PPI; acid blockers).
    • “Atherosclerosis Risk in Communities” (ARIC): 10-year PPI use: rate of chronic renal failure in patients on PPI 11.8%, without 8.5%; rate of renal damage: 64%; two pills a day resulted in significantly more frequent damage: 62%
    • Geisinger Health System: observation period 6.2 years; rate of chronic renal failure disease: 17%; rate of renal damage: 31%; two pills a day resulted in significantly more frequent damage: 28%
    • Significantly more likely to develop chronic renal failure in the five years following PPI use than patients prescribed H2 blockers
    • Analysis of the FAERS database, where the U.S. Food and Drug Administration (FDA) collects adverse drug event (ADE) reports:
      • Chronic kidney disease: 28.4-fold; acute kidney injury: 4.2-fold; end-stage renal disease (dialysis): 35.5-fold; nonspecific renal dysfunction: 8-fold more common
      • Electrolyte disorders (disorders of salt balance): hypomagnesemia (magnesium deficiency): 78.5-fold more common, hypocalcemia (calcium deficiency): 26-fold, hypokalemia (potassium deficiency): 6.3-fold, hyponatremia (sodium deficiency): 2.2-fold more common
  • Rast blockers: the combination of a diuretic, an RAS blocker, and an NSAID is associated with a significant risk of acute kidney injury.
  • Tacrolism (macrolide derived from the gram-positive bacterium Streptomyces tsukubaensis. Tacrolimus is used as a drug in the group of immunomodulators or calcineurin inhibitors).
  • TNF-α antibodies – adalimumab → IgA nephropathy (the most common form of idiopathic glomerulonephritis in adults, accounting for 30%).
  • Antivirals

Environmental pollution – intoxications (poisonings).

  • Metals (cadmium, lead, mercury, nickel, chromium, uranium).
  • Halogenated hydrocarbons (HFCs; trichloroethene, tetrachloroethene, hexachlorobutadiene, chloroform).
  • Herbicides (paraquat, diquat, chlorinated phenoxyacetic acids).
  • Mycotoxins (ochratoxin A, citrinin, aflatoxin B1).
  • Aliphatic hydrocarbons (2,2,4-trimethylpentane, decalin, unleaded gasoline, mitomycin C).
  • Melamine

Other factors

  • Kidney donor
    • Increased risk compared with nondonors for end-stage renal disease/highest risk among African American donors; however, lifetime risk is lower than that of the general population
    • After nephrectomy (removal of a kidney), the glomerular filtration rate (GFR; volume filtered per unit time by the glomeruli of the kidneys) is about one-third lower than before. In every third donor it was thus below 60 ml/min/1.73 m2.
  • Magnesium levels – Patients with serum magnesium below 1.8 mg/dl (0.79 mmol/l) had a 61% higher mortality risk (risk of death) than patients with levels above 2.2 mg/dl (0.90 mmol/l)