Lithium and Nephrogenic Diabetes Insipidus: Mechanism

Within the collecting duct of the kidney, Aquaporin water channels (AQP2) under the regulation of anti diuretic hormone (ADH) control the movement of water into principal cells.

Principal cells: Manage the Na+/K+ exchange in the collecting duct.

Long term lithium ingestion can manifest with polyuria/ polydipisa due to ADH resistance.

HOW?

The proposed thought is principal cells uptake Lithium (cation) via the epithelial sodium channels (ENac) located on the luminal side of the principal cells.

The lithium accumulates in the principal cells, interfering with the ability of ADH to increase water permeability.

REFERENCES

  1. M.J. Godinich, D.C. BatlleRenal tubular effects of lithium. Kidney Int, 37 (Suppl 28) (1990), pp. S52-S57.
  2. J.N.J. Forrest, A.D. Cohen, J. Torretti, M. Himmelhoch, F.H. Epstein. On the mechanism of lithium-induced diabetes insipidus in man and the rat. J Clin Invest, 53 (1974), pp. 1115-1123.
  3. Trepiccione F., Christensen BM. Lithium-induced nephrogenic diabetes insipidus: new clinical and experimental findings. J Nephrol. 2010 Nov-Dec;23 Suppl 16:S43-8.
  4. Ecelbarger CA. Lithium treatment and remodeling of the collecting duct. Am J Physiol Renal Physiol. 2006 Jul;291(1):F37-8. Epub 2006 Mar 28.

Trimethoprim/sulfamethoxazole and increased Creatinine: Mechanism

Img Cred: http://cjasn.asnjournals.org

The serum creatinine concentration (Cr) is typically used as a surrogate for renal function. Hence, when increased it is often a sign of acute kidney injury. However, there are circumstances in which an increase in serum creatinine may not reflect true renal pathology. Such is the case with Trimethoprim/sulfamethoxazole (Bactrim/ Septra).

In normal, healthy subjects, about 15% of the urinary creatinine is from proximal tubule secretion. 

Creatinine is an organic positively charged molecule (cation) and hence is secreted by the organic cation secretory transporters (OCTs) that can be inhibited/ occupied by other organic cations.

Trimethoprim/sulfamethoxazole (organic cation) can cause a self-limited and reversible increase in serum creatinine (30 to 50 micromol/L) without affecting true renal function by occupying those transporters and preventing proximal tubular secretion.  

NOTE: Trimethoprim/sulfamethoxazole contains sulfa moieties and can also acute interstitial nephritis (AIN).

REFERENCES

  1. Berg KJ et al. Renal effects of trimethoprim in ciclosporin- and azathioprine-treated kidney-allografted patients. Nephron. 1989;53(3):218-22.
  2. Berglund F, Killander J, Pompeius R. Effect of trimethoprim-sulfamethoxazole on the renal excretion of creatinine in man. J Urol. 1975 Dec;114(6):802-8.
  3. Andreev E, Koopman M, Arisz L. A rise in plasma creatinine that is not a sign of renal failure: which drugs can be responsible?. J Intern Med. 1999 Sep;246(3):247-52.

 

Urea: Ineffective Osmole

Plasma Osmolality: The total solute concentration within a given fluid compartment (Mosm/kg).

Hence it is NOT dependent on temperature and pressure like OsmolaRity. See image.

An effective osmole is one that is UNABLE to cross from the Extracellular fluid (ECF) to the Intracellular fluid (ICF). Therefore it will generate an oncotic force that draws fluid across a membrane.
Effective osmoles include: Na+ and Glucose.
An ineffective osmole will contribute to total plasma osmolality but because it can freely move from the ECF to ICF, it generates no oncotic pressure. A classic example of an ineffective osmole is Urea.
NOTE: Osmolality may be increased in the setting of increased Urea (BUN); but the tonicity will not change because the increased Urea will freely equilibrate between the ICF and ECF.  
REFERENCES:
  1. Bhave G, Neilson EG. Body Fluid Dynamics: Back to the Future. Journal of the American Society of Nephrology : JASN. 2011;22(12):2166-2181. doi:10.1681/ASN.2011080865.

How does CHF cause AKI?

It is quite common to see accompanying acute kidney injury during a congestive heart failure exacerbation. 

WHY?

  1. Renal hypo-perfusion secondary to poor cardiac output.
  2. Renal venous congestion. Increased central venous pressure (CVP) is transmitted into the efferent arteriole, reducing the pressure gradient and subsequently the GFR.  
  3. Neurohumoral mechanisms (i.e RAAS, ADH) which help acutely but are maladaptive in the long term on the kidneys’ GFR.
Pathophysiological mechanisms of worsening renal function in acute heart failure. Img Cred KCJ.

REFERENCES

  1.  Marlies Ostermann, Heleen M. Oudemans-van Straaten and Lui G. Forni. Fluid overload and acute kidney injury: cause or consequence?. Critical Care 201519:443https://doi.org/10.1186/s13054-015-1163-7 
  2. Han SW, Ryu KH. Renal Dysfunction in Acute Heart Failure. Korean Circulation Journal. 2011;41(10):565-574. doi:10.4070/kcj.2011.41.10.565.

Hypokalemia Treatment and Dextrose

A common treatment modality for hypokalemia is intravenous potassium replacement; especially in the setting of critically low values (<2.5).

When replacing with intravenous fluid mixtures; dextrose should be avoided as a base solution.

WHY? The use of dextrose, will increase blood glucose levels and drive up endogenous insulin production; thereby further lowering K+ levels as insulin increases intra-cellular uptake. 

REFERENCES

  1. Li T, Vijayan A. Insulin for the treatment of hyperkalemia: a double-edged sword? Clinical Kidney Journal. 2014;7(3):239-241. doi:10.1093/ckj/sfu049. 

Post-hypercapnic Alkalosis: Mechanism

Post hypercapnic alkalosis (PHA) is frequently overlooked as a complication of acutely intubated & mechanically ventilated patients with COPD exacerbations.

HOW DOES IT WORK?

Post hypercapnic alkalosis refers to patients who are hypercapnic (chronic CO2 retainers) and develop a compensatory metabolic alkalosis due to renal bicarbonate (HCO3) retention. After they are intubated, their Pco2 is corrected rapidly, however their chronically elevated bicarbonate remains. This generates a metabolic alkalosis that is typically slow to fall.

REFERENCES

  1. B F Palmer and R J Alpern. Metabolic alkalosis. JASN. September 1, 1997 vol. 8 no. 9 1462-1469
  2. Banga A., Khilnani GC. Post-hypercapnic alkalosis is associated with ventilator dependence and increased ICU stay. COPD. 2009 Dec;6(6):437-40.

11β-Hydroxysteroid dehydrogenase and Licorice: Mechanism

Cortisol, the primary glucocorticoid in the body binds to glucocorticoid receptors. However, given its molecular similarity to Aldosterone (mineralcorticoid) it can also bind to mineralcorticoid receptors.

Both Aldosterone and Cortisol bind the mineralocorticoid receptors with similar affinities; however, given the vastly more abundant levels of Cortisol in the systemic circulation this could lead to over stimulating of mineralocorticoid receptors.

In order to prevent this, an enzyme, 11β-Hydroxysteroid dehydrogenase (HSD-11β or 11β-HSD) coverts cortisol to its biologically inactive metabolite cortisone (which is no longer able to bind to mineralocorticoid receptors).

However, Licorice contains glycyrrhetinic acid which inhibits 11β-Hydroxysteroid dehydrogenase (HSD-11β or 11β-HSD) and allows cortisol to over stimulate mineralcorticoid receptors resulting in mineralocorticoid excess syndrome.

REFERENCES

  1. Whorwood CB, Sheppard MC, Stewart PM. Licorice inhibits 11 beta-hydroxysteroid dehydrogenase messenger ribonucleic acid levels and potentiates glucocorticoid hormone action. Endocrinology. 1993 Jun;132(6):2287-92.
  2. van Uum SH, Hermus AR, Smits P, Thien T, Lenders JW. The role of 11 beta-hydroxysteroid dehydrogenase in the pathogenesis of hypertension. Cardiovasc Res. 1998 Apr;38(1):16-24.

Nephrogenic systemic fibrosis

Multi system disorder seen only in patients with CKD (GFR <15; rarely with a GFR of 15–29, but FDA currently warns against using gadolinium-based contrast agents in patients with a GFR <30), acute kidney injury, and after kidney transplantation.

Nephrogenic systemic fibrosis was first recognized in hemodialysis patients during the 1990s and there is a strong link to use of contrast agents containing gadolinium. Incidence is estimated around 1–4% in the highest risk (ESRD) population that has received gadolinium, and lower in patients with less severe kidney dysfunction.

Clinical Findings

Nephrogenic systemic fibrosis affects several organ systems, including: the skin, muscles, lungs, and cardiovascular system.

Img Cred: researchgate.net

The most common manifestation is a debilitating fibrosing skin disorder that can range from skin-colored to erythematous papules, which coalesce to brawny patches. The skin can be thick and woody in areas and is painful out-of-proportion to findings on examination.

Treatment

Several case reports and series have described benefit for patients after treatment with corticosteroids, photopheresis, plasmapheresis, and sodium thiosulfate. The true effectiveness of these interventions is still unclear.

REFERENCES

  • Daftari Besheli L et al. Current status of nephrogenic systemic fibrosis. Clin Radiol. 2014 Jul;69(7):661–8.
  • Current Medical Diagnosis & Treatment 2017. Chapter 22: Kidney Disease. Suzanne Watnick; Tonja C. Dirkx.
  • Schlaudecker JD, Bernheisel CR. Gadolinium-associated nephrogenic systemic fibrosis. Am Fam Physician. 2009 Oct 1;80(7):711-4.

Hydrochlorothiazide (HyperGLUC) Mnemonic

Hydrochlorothiazide (HCTZ) is a thiazide diuretic that acts in the distal convoluted tubule of the kidney on the Na/Cl- symporter to reduce blood pressure/ volume. However, like any medication it comes with side effects. A common mnemonic used to remember these effects is HyperGLUC

HYPERglycemia (It occurs at higher doses of HCTZ (> 50 mg/d); Thiazides have a weak, dose-dependent, effect to stimulate ATP-sensitive K+ channels and cause hyperpolarization of beta cells, thereby inhibiting insulin release)

HYPERlipidemia (cause a 5–15% increase in total serum cholesterol and low-density lipoproteins (LDLs))

HYPERuricemia (may precipitate acute gouty arthritis)

HYPERcalcemia (increased renal calcium resorption and decrease calcium in urine)

NOTE: It can have HYPO effects in serum: including HYPOkalemia, HYPOnatremia and HYPOtension (decreases blood volume and peripheral vascular resistance)

REFERENCES

  1. CHAPTER 15: Diuretic Agents. Ramin Sam; David Pearce; Harlan E. Ives. Basic & Clinical Pharmacology, 13e

Piperacillin-tazobactam induced hypokalemia: Mechanism

Piperacillin/tazobactam is a commonly used antibiotic with tolerable side effects and broad antimicrobial activity in general practice.

Rare side-effects can include hypokalemia.
WHY? Two theories exist:

  1. Piperacillin-sodium is a negatively charged molecule (anion) and nonabsorbable. This increases transepithelial electronegativity in the distal nephron, increasing  potassium (cation) excretion. (-) draws out the (+)
  2. The large volume of sodium administered with Piperacillin-tazobactam can result in solute diuresis.

REFERENCES

  1. Hussain S, Syed S, Baloch K. Electrolytes imbalance: a rare side effect of piperacillin/ tazobactam therapy. J Coll Physicians Surg Pak. 2010;20(6):419-420.
  2. Zaki SA, Lad V. Piperacillin-tazobactam-induced hypokalemia and metabolic alkalosis. Indian Journal of Pharmacology. 2011;43(5):609-610. doi:10.4103/0253-7613.84986.
  3. Polderman KH, Girbes AR. Piperacillin-induced magnesium and potassium loss in intensive care unit patients. Intensive Care Med. 2002;28(4):520-522.c