Acid/Base Pathophys
The lungs compensate for metabolic alkalosis by ____.
Decreasing minute ventilation (MV).
MV = [Tidal Volume (TV)] x [Respiratory Rate (RR)]
In Type 1 RTA, Alpha Intercalated Cells are unable to secrete ____ into the lumen.
Hydrogen Ions (H+)
Impairment of this portion of the nephron results in Type 2 RTA.
Proximal Convoluted Tubule
Receptor resistance to this hormone in the Principle Cells and Alpha Intercalated Cells can lead to the Type 4 RTA.
Aldosterone
Roughly how much of the body's plasma calcium exists in an ionized state?
Generally more than 50%.
40% exists bound to proteins such as albumin or specific globulins (ie. calmodulin, calsequestrin).
Remaining plasma Ca2+ is complexed to to anions such as bicarbonate, phosphate, citrate, lactate, or sulfate.
Breakdown of this amino acid results in ammoniagenesis.
Glutamine -> Glutamate -> alpha-ketoglutarate -> 2HCO3- + NH4+.
This renal finding is more commonly found in Type 1 RTA when compared to other tubular acidoses.
Kidney stone formation. Urine will be CONSISTENTLY alkaline which allows for solute deposition and stone formation.
Failure of the PCT to reabsorb bicarbonate, glucose, phosphorus, and amino acids is called ______
Fanconi Syndrome: Generalized dysfunction of the proximal renal tubule characterized by impaired reabsorption leading to urinary losses of glucose, phosphate, amino acids, bicarbonate, and low-molecular-weight proteins. This results in metabolic acidosis, hypophosphatemia, hypokalemia, and often dehydration.
____ is an aldosterone analogue that is used to treat Type 4 RTA in patients with Adrenal Insufficiency
Fludrocortisone
Produced by osteocytes, this signaling molecule downregulates sodium-phosphorus cotransporters, decreasing phosphorus reabsorption.
Fibroblast Growth Factor 23. Key regulator of phosphorus homeostasis.
Synthesized in response to PTH and 1,25-OH vitamin D.
There is resistance to FGF-23 in advanced CKD, subsequently blood levels of phosphorous increase (hyperphosphatemia).
The most abundant TITRATABLE Acid in the urine is _____.
Phosphate (HPO42-). Can accept another H+ that is secreted into the luminal space (forming H2PO4-). This mainly occurs in the DCT (though it can occur in the PCT).
Other titratable acids in the urine include: uric acid and citrate.
The most common treatment for Type 1 RTA is _____.
Sodium bicarbonate.
Corrects chronic metabolic acidosis that results from the kidney's inability to excrete acid normally. Maintains plasma bicarbonate in the normal range.
Sometimes referred to as "alkali therapy"
This malignancy can cause Type 2 RTA due to monoclonal light chain-induced proximal tubular cell dysfunction.
Multiple Myeloma
What lifestyle change may be implemented to help mitigate symptoms of Type 4 RTA?
Low potassium diet. This will help reduce the effects of hyperkalemia. Dietary potassium is incredibly abundant.
- butternut squash, avocados, tomatoes, bananas, dried fruits, leafy greens, fatty fish, lentils, dairy products, etc. (Its in Everything!!)
Activation of the VDR/RXR heterodimer increases transcription of ______ which increases Ca2+ transport in the brush border epithelium.
Calbindin. Calbindin facilitates calcium diffusion from the apical (luminal) entry side to the basolateral membrane where calcium is extruded.
It buffers cytosolic calcium concentration to maintain low, non-toxic levels during high calcium influx, while simultaneously shuttling calcium-bound complexes across the cell.
These three renal mechanisms explain the relationship between potassium depletion (hypokalemia) and metabolic alkalosis.
1. Upregulation of acid (H+) secreting transporters, decreasing H+ in the blood.
2. Enhancement of ammoniagenesis and ammonium excretion.
3. Downregulation of NaCl reabsorption in the DCT and LoH.
Amphotericin B is a common iatrogenic cause of Type 1 RTA. Used to treat fungal infections it binds strongly to what component of the fungal cell wall?
Ergosterol.
Binds to ergosterol -> creates transmembrane pores -> cytoplasm leakage and cell lysis
The main enzyme responsible for reclaiming bicarbonate at the epithelial brush boarder is ____. The intracellular counterpart of this enzyme, anchored within the proximal tubule cell is ____.
Carbonic Anhydrase IV; Carbonic Anhydrase II.
____ is the most common cause of Type IV RTA.
Diabetic nephropathy; which causes hyporeninemic hypoaldosteronism.
What treatment for osteoporosis inhibits bone matrix resorption?
Bisphosphonates (Alendronate, Risedronate). Decreases osteoclast activity and enhances osteocyte survival.
What type of acid/base imbalance would be most likely in a patient who has had severe gastroenteritis (+vomitting/+diarrhea) for the past 4 days?
Mixed metabolic acidosis and metabolic alkalosis.
- Metabolic acidosis from the loss of base (HCO3-) in diarrhea.
- Metabolic alkalosis from the loss of acid (H+) in vomitus.
This autoimmune syndrome can cause Type 1 RTA through autoimmune-mediated dysfunction of the H⁺-ATPase pump in the collecting duct.
Sjogren's Syndrome (most common); Lupus also an acceptable answer.
Far less common is rheumatoid arthritis.
Defects in the ____ and ____ ion transporters are responsible for impaired bicarbonate (HCO3-) reasorption in the PCT.
Na+/H+ Exchanger (NHE3) on the Apical Membrane; Na+/3HCO3- Cotransporter (NBCe1-a) on the Basolateral Membrane
Why will proximal tubule production of ammonia be inhibited in Type 4 RTA?
Hyperkalemia suppresses enzymes that help generate ammonia such as phosphate-dependent glutaminase and simultaneously increase the activity of ammonia recycling enzymes like glutamine synthetase. Both of these factors decrease ammonia levels and inhibit formation of new ammonia molecules.
These three interconnected factors explain why Chronic Kidney Disease can lead to development of Secondary Parathyroidism.
1. Hyperphosphatemia due to reduced phosphorus excretion directly stimulates PTH production through post-transcriptional mechanisms.Elevated phosphate also increases fibroblast growth factor 23 (FGF23) production by osteocytes.
2.Reduced renal production of 1a-hydroxylase -> reduced activation of 25,OH-VitD3 into calcitriol -> hypocalcemia
3. Hypocalcemia due to poor reabsorption (due to low calcitriol production). Reduces activation of calcium-sensing receptors (CaSR) on parathyroid cells, which allows secretion of PTH.