Renal hypoxia can lead to acute kidney injury and chronic kidney disease.
The kidneys weigh less than 0.5% of body weight and receive 20%–25% of our cardiac output at rest. The kidneys are the most highly perfused organs in the body if we calculate blood per gram of the tissue.
Despite having an ample supply of blood, the kidney especially, the renal medulla is highly vulnerable to hypoxia and subsequent ischemia. Hypoxia and ischemia are the significant pathophysiological features of acute kidney injury and chronic kidney disease.
The S3 segment (straight segment) of the proximal tubule and the medullary thick ascending limb of the loop of Henle (mTAL) are most prone to ischemic injury. Both these tubular areas exist in relatively lower oxygen conditions. It is a trade-off to be able to get a high osmotic gradient and concentrated urine.
1.Renal tubules have high metabolic demands due to active reabsorption of sodium -Metabolic demands of renal tubules keep them hungry for oxygen, especially proximal convoluted tubules of the renal medulla are always on the verge of getting hypoxia.
The proximal convoluted tubules reabsorb most of sodium and water from tubular filtrate. Sodium reabsorption is an active process that requires energy in the form of ATP. The production of ATP is dependent upon oxygen supply. PCT cells are always in demand of oxygen, and anything which compromises the oxygen delivery to these cells causes PCT cell injury and death.
Capillary Leak Syndrome is associated with an increased capillary permeability to proteins. It leads to the loss of protein-rich fluid from the intravascular space to the interstitial space.
Capillary leak syndrome is characterized by
• diffuse pitting edema,
• exudative serous cavity effusions,
• noncardiogenic pulmonary edema,
• hypotension
• hypovolemic shock with multiple-organ failure (in severe cases)
Following conditions can lead to increased capillary permeability and CLS-
• Sepsis (most associated) Idiopathic systemic capillary leak syndrome (SCLS) or Clarkson’s disease
• Engraftment syndrome
• Differentiation syndrome
• Ovarian hyperstimulation syndrome (OHSS)
• Hemophagocytic lymphohistiocytosis (HLH)
• Viral hemorrhagic fevers (VHFs)
• Autoimmune diseases
• Snakebite envenomation
• Ricin poisoning
• Drugs (monoclonal antibodies e.g. rituximab)
Pathophysiology
Most diseases causing capillary leak syndrome have a similar underlying pathophysiologic abnormality—an increased capillary permeability to proteins.
Hypercytokinemia → Adherens junction and tight junction disruption → capillary endothelial damage and disruption → capillary become permeable for proteins→ loss of protein-rich fluid→ reduced intravascular volume and increased interstitial fluid → sign and symptoms of capillary leak syndrome.
Clinical Presentation
Hemodynamic manifestations
Capillary leak → Loss of protein-rich fluid from the intravascular space→ intravascular volume depletion → secondary activation of the renin, angiotensin, and aldosterone system →sodium and water retention → systemic edema and exudative serous cavity effusions and ascites.
Loss of intravascular volume can cause hemoconcentration in severe cases. And abrupt and significant fluid loss through the intravascular compartment. The hemoconcentration can be used as an indicator of capillary leak severity.
The capillary leak syndrome can lead to hypovolemic shock and acute kidney injury in severe cases.
Carbon monoxide (CO) is an odorless, tasteless, and colorless gas that can cause sudden illness and death if inhaled.
CO is generated in the incomplete combustion of carbon compounds. And the common sources include fire, engine exhaust, and faulty furnaces.
Risk factors
• Wood burning heaters
• Poorly ventilated buildings
• Use of charcoal, gas, or petroleum
• Faulty furnaces
• Motor vehicle exhaust
• Inhalation of methylene chloride from paint thinners
Pathogenesis
Absorption of inhaled carbon monoxide occurs in the gas exchange region (alveoli) of the respiratory tract following inhalation.
It displaces oxygen from hemoglobin and causes tissue hypoxia.
Most carbon monoxide binds reversibly to hemoglobin (Hb) in red blood cells and other heme proteins. Carbon monoxide’s affinity for hemoglobin is 200–250 times greater than that of oxygen.
After binding to Hb to displace oxygen and form carboxyhemoglobin, carbon monoxide is transferred rapidly throughout the body, where it causes cellular hypoxia and asphyxia.
Dissociation and excretion of carbon monoxide occur rapidly after cessation of exposure.
Binds to cytochrome oxidase and impairs electron transport chain leading to cellular hypoxia and reduced ATP generation, cell injury, and cell death.
Cardiovascular injury can result from carboxymyoglobin formation and vasodilation from the cellular effects of carbon monoxide.
Clinical neurological effects and any delayed neurological complications are due to cellular hypoxia. The cellular lipid peroxidation also increases neuronal injury, brain edema, and neurological dysfunction.
How much is too much?
According to the World Health Organization, levels greater than six ppm are potentially toxic over a longer period of time.
The COHb levels of 2% or more in nonsmokers and 10% or greater in smokers are considered potentially harmful and likely to produce symptoms.
Clinical Signs and Symptoms
Headache
Dizziness and confusion
Nausea and vomiting
Shortness of breath
Altered mental status
Cherry-red skin (late finding)
Coma, Loss of consciousness, Death
Cardiovascular complications
• Myocardial injury
• Myocarditis
• Arrhythmia
Neurological complications
• Impaired memory
• cognitive dysfunction
• depression
• anxiety
• vestibular and motor deficits
Calciphylaxis or calcific uremic arteriolopathy (CUA) in chronic kidney disease is a rare but fatal complication seen in patients in the late stage of chronic kidney disease.
The calcification of small vessels, especially arterioles, is a characteristic feature. And it eventually leads to the obstruction of the blood flow.
The blood flow obstruction causes ischemia, necrosis, severe pain, and color changes at the site of obstruction.
Pathophysiology
Calcific uremic arteriolopathy (CUA) has a multifactorial pathogenesis.
• The imbalance between inducers and inhibitors of calcification
• Increased use of oral calcium as a phosphate binder
• Secondary hyperparathyroidism
• Hyperphosphatemia – elevated serum phosphate induces a change in gene expression and switches vascular cells into osteoblast-like cells. These cells cause vascular calcification.
• Uremia in end-stage renal failure causes inflammation and suppression of calcification inhibitors. Suppression of calcification inhibitors leads to more calcification and obstruction.
• Warfarin in dialysis patients – Warfarin used in hemodialysis decreases the vitamin K–dependent regeneration of matrix GLA protein. The matrix GLA protein is crucial in preventing vascular calcification. That’s why warfarin treatment is considered a risk factor for calciphylaxis. If the patient develops calciphylaxis, discontinue warfarin and replace it with another anticoagulant.
The sequence of events in calciphylaxis
vascular calcification→ luminal narrowing→ ischemia →skin necrosis and ulceration. If left untreated, it can cause secondary bacterial infection. Which can lead to sepsis, septic shock, and death.
Clinical presentation
In the early stage of the disease, the patient presents with pruritus and cutaneous laminar erythema or a violaceous rash. It may resemble livedo reticularis.
In the late stage of disease, cases have painful eschars and painful non-healing ulceration and necrosis.
In every menstrual cycle, the ovaries select and induce the growth of a single dominant follicle that participates in single ovulation. The selection of the dominant follicle is under the control of the hormones FSH and LH.
Any interference directly or indirectly with the normal action of the gonadotropins can lead to apoptosis of follicles and may cause infertility.
Morphometric analysis of healthy ovaries showed that the dominant follicle which ovulates in the subsequent cycle is selected from healthy follicles measuring 4.7 ± 0.7 mm in diameter at the end of the luteal phase of the menstrual cycle. The selection of the dominant follicle occurs at the late luteal phase of the menstrual cycle.
The dominant follicle has a high rate of mitosis in the granulosa cells, it is the characteristic feature of the dominant follicle.
When one follicle is selected, the granulosa cells in the chosen follicle continue dividing at a relatively fast rate. And proliferation slows in the granulosa cells of the other follicles. These follicles will become atretic follicles eventually (dies via apoptosis).
How the dominant follicle is selected
The secondary rise in plasma FSH is a must to find/select dominant follicles.
The secondary FSH rise in women begins a few days before the progesterone levels fall to basal levels at the end of the luteal phase. And the FSH levels remain elevated during the first week of the follicular phase of the cycle.
FGF-23 in chronic kidney disease
FGF-23 (fibroblast growth factor-23) is a part of a family of phosphatonins that promotes renal phosphate excretion. It is a hormone secreted by osteocytes, and it regulates phosphorus and vitamin D metabolism. FGF23 promotes phosphaturia and decreases the production of calcitriol.
Its levels increase in early CKD as a physiological adaptation to maintain normal serum phosphate levels.
FGF-23 maintains normal serum phosphorus levels by three mechanisms:
(1) Phosphaturia- Increased renal phosphate excretion (by reducing tubular reabsorption of phosphorus)
(2) Secondary Hyperparathyroidism- stimulation of PTH, which also increases renal phosphate excretion
(3) Suppresses calcitriol formation– suppression of the formation of 1,25(OH)2 D3, leading to diminished phosphorus absorption from the GI tract.
It becomes maladaptive by causing a progressive decline in 1,25(OH)(2)D levels. It leads to secondary hyperparathyroidism and related complications of bone metabolism.
Hypothalamic-pituitary-ovarian (HPO) axis has three components –
Hypothalamus – It is located at the base of the brain, above the brainstem. It secretes gonadotropin-releasing hormone (GnRH).
Pituitary – it is located in the base of the skull just below the hypothalamus, and pulsatile release of GnRH from the hypothalamus stimulates the secretion of Follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
Ovaries- FSH and LH from the pituitary stimulates granulosa cells and theca cells of the ovaries to secrete estrogen and progesterone. Excess in estrogen causes negative feedback and causes inhibition of GnRH release from the hypothalamus.
FSH stimulates primordial follicles to mature by acting on granulosa cells, the fall in FSH causes the selection of dominant follicles. The follicles which have the highest number of FSH receptors get more concentrated FSH micro-environment and thus they grow faster and become dominant follicle one of these dominant follicles releases ova every month. Only one of the maturing follicles can dominate over the others. It is called the Graafian follicle.
The Granulosa cells of these follicles produce estrogen which stimulates the hypothalamus to secrete GnRH. There is LH and FSH surge 24 hours before ovulation, this surge causes Graafian follicle to release ova. This phase of the reproductive cycle, from FHS release until ovulation, is called the follicular phase.
After ovulation, the ruptured follicle becomes the corpus luteum. In addition to producing estrogen, it also produces progesterone. Progesterone stimulates the uterine endometrium’s secretory functions and signals the hypothalamus to stop producing GnRH. This, in turn, deactivates FSH and LH production.
Congenital Solitary Kidney introduction slide
Congenital Solitary Kidney is a congenital anomaly where the affected person has only one functioning kidney. It can be due to the absence or anomaly of the contralateral kidney.
Causes
Anatomical – in these cases, the person has only a single kidney since birth. Unilateral Renal agenesis
Functional- in these cases, the person has two kidneys, but only one kidney is functional. Renal aplasia, hypoplasia, or dysplasia can lead to such situations.
Compensatory renal hypertrophy develops in solitary kidneys. In most cases, it remains asymptomatic. They are diagnosed during prenatal ultrasound screening or routine examination in younger children. Recent research says that there is Hyperplasia in the solitary kidney as it has double the number of nephrons in comparison to the normal kidney.
Associated complications
The compensatory hypertrophy causes hyperfiltration →increased podocytes and, basement injury →Loss of functional renal parenchyma →Chronic kidney disease and renal insufficiency →End-stage renal disease (ESRD)
Vesicoureteral reflux
Increased risk of hypertension
Neuropathic arthropathy: Charcot arthropathy
Neuropathic arthropathy (Charcot arthropathy) is a complication of peripheral neuropathy that results in fractures, dislocations, subluxations. It has an increased risk of progressive deformity of the affected joint. Sometimes, the resulting joint deformity increases the risk of amputation.
Charcot arthropathy is a specific manifestation of peripheral neuropathy, also known as Neuropathic Joint Disease. It is named after Jean-Martin Charcot, who recognized that peripheral neuropathy could lead to neuropathic joints. Any condition resulting in decreased peripheral sensation, proprioception, and fine motor control can cause Charcot arthropathy. There is a progressive degeneration of a weight-bearing joint. The affected joint has bony destruction, bone resorption, and eventual deformity.
Most common locations
• Foot and ankle (most commonly affected joint)
• Shoulder
• Elbows
Conditions causing neuropathy and Charcot arthropathy
• Diabetes mellitus- foot and ankle are most affected
• Tertiary syphilis (tabes dorsalis) – the knee is the most affected joint
• Syringomyelia – shoulder is the most affected joint
• Trauma
• Leprosy
• Spinal cord tumor
• Subacute combined degeneration (Vit B12 deficiency)
Pathophysiology (underlying mechanisms responsible for the neuropathic joint)
Mechanisms are responsible for joint destruction in these cases are-
Neurotrauma
Peripheral neuropathy → loss of sensation, proprioception, and deep tendon reflexes → imbalanced and clumsy joints with poor fine motor control → repetitive trauma → no pain since joint is insensate → patient remains unaware of injury and doesn’t fix it → prolonged inflammation, destruction and Injury continues → swollen, red and nontender joint in beginning → deformed joint later in course of the disease → may lead to amputation
Neurovascular
Repetitive injury → Joint inflammation → increased blood flow towards the joint by dilating vessels → Autonomic Neuropathy → reduced ability to vasoconstrict → vessels fails to constrict → hyperemia in injured and inflamed joint → stimulates osteoclasts → increased osteoclast-mediated bone resorption→ decreased bone mineral density→ osteopenia→ increased risk of fractures and the deformity
Clinical presentation
Acute arthropathy – patient presents with swollen, erythematous but nontender joint. Physical examination shows loss of sensation and absent deep tendon reflexes (DTR)
Chronic arthropathy- patient presents with deformed joint, bony prominences, and foot ulcers. The most common deformity is a collapse of the tarsometatarsal joint, with valgus angulation.
Analgesic nephropathy is chronic tubulointerstitial nephritis. It is caused by long-term use of high doses (>1-2 Kgs) of certain analgesics, especially if taken in combinations.
The combinations of the following analgesics are most commonly associated with AN-
• phenacetin, aspirin, and caffeine
• phenacetin-acetaminophen
• NSAIDs and acetaminophen
most analgesics (including NSAIDs) reduce pain by inhibiting prostaglandin (PG) synthesis. Prostaglandins have a vasodilatory effect which helps in the maintenance of renal blood flow. In patients with normal renal function and normal volume state, the renal synthesis of PG is low, and it does not play a significant role in the maintenance of renal blood flow.
But in decreased renal perfusion, the local synthesis of vasodilator prostaglandins is increased. And renal perfusion is maintained. This autoregulatory mechanism is crucial for adequate renal blood flow: in cases with volume contracted states (congestive heart failure, ascites, hepatic failure, and chronic kidney disease, diuretic users, and the elderly with vascular damage/atherosclerosis).
Mechanism of renal injury, prostaglandin is blocked by analgesics –
Analgesics in high doses → inhibition of prostaglandin synthesis → less prostaglandin for renal vasodilation→ reduced renal blood flow → increased chances of ischemic and hypoxic injury to tubules and interstitial tissue→ acute kidney injury
