Does erythrocyte sedimentation rate (ESR) have diagnostic utility in my patient with chronic renal failure?

Short answer: No! This is because most studies have shown frequently high ESR’s in stable “uninflamed” patients with chronic renal failure (CRF) (including those on dialysis) at levels often associated with infection, connective tissue disease, or malignancy in normal renal function. 1-4  

In fact, in a study involving patients with CRF, 57% of patients had markedly elevation of ESR (greater than 60 mm/h), with 20% having ESR greater than 100 mm/h; type or duration of dialysis had no significant effect on ESR levels.1 Another study reported a specificity for abnormal ESR of only 35% for commonly considered inflammatory conditions (eg, infections or malignancy) among patients with CRF. 2

But is it the chronic inflammation in diseased kidneys or the uremic environment that elevates ESR? A cool study compared ESR in CRF in patients who had undergone bilateral nephrectomies with those with retained kidneys and found no significant difference in the ESR between the 2 groups. 4  So it looks like it’s the uremic environment, not diseased kidneys themselves that result in elevated ESR in these patients.

The mechanism behind these observations seem to reside entirely within the patients’ plasma, not the erythrocytes. Within the plasma, fibrinogen (not gammaglobulins) seem to be the most likely factor explaining elevated ESR among patients with CRF. 1,2

Bonus pearl:  Did you know that ESR is nearly 100 years old, first described in 1921? 5

References

  1. Barthon J, Graves J, Jens P, et al. The erythrocyte sedimentation rate in end-stage renal failure. Am J Kidney Dis 1987;10: 34-40. https://www.ncbi.nlm.nih.gov/pubmed/3605082
  2. Shusterman N, Morrison G, Singer I. The erythrocyte sedimentation rate and chronic renal failure. Ann Intern Med 1986;105:801. http://annals.org/aim/fullarticle/700910
  3. Arik N, Bedir A, Gunaydin M, et al. Do erythrocyte sedimentation rate and C-reactive protein levels have diagnostic usefulness in patients with renal failure? Nephron 2000;86:224. https://www.ncbi.nlm.nih.gov/pubmed/11015011
  4. Warner DM, George CRP. Erythrocyte sedimentation rate and related factors in end-stage renal failure. Nephron 1991;57:248. https://www.karger.com/Article/PDF/186266
  5. Fahraeus R. The suspension stability of the blood. Acta Med Scan 1921;55:70-92. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.0954-6820.1921.tb15200.x

 

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Does erythrocyte sedimentation rate (ESR) have diagnostic utility in my patient with chronic renal failure?

My patient with cirrhosis has hypohonia and cogwheel rigidity. Is there a connection between cirrhosis and Parkinson’s disease?

There is a high prevalence of extra-pyramidal or Parkinson-like (PL) clinical findings in patients with cirrhosis. In fact, over 75% of patients with cirrhosis may exhibit PL signs, such as tremor, rigidity, and akinesia, with 88% also showing hyperintensity in the globus pallidus of basal ganglia on T1-weighted brain MRI.1

What’s even more interesting is the similarity between PL clinical and MRI findings among patients with cirrhosis and those with Manganese (Mn) toxicity.2,3 More specifically, similar MRI findings involving the globus pallidus have been reported in Mn-exposed workers, patients with cirrhosis, and those undergoing total parenteral nutrition with excessive Mn replacement. 4 These observations seem more than coincidental as 67% of patients with cirrhosis have been reported to have elevated blood Mn concentrations, with significantly higher levels in patients with previous portacaval anastomoses or transjugular intrahepatic portosystemic shunt (TIPS).1

Mn-induced parkinsonism is distinguishable from classic Parkinson’s disease in several ways, including the absence of Lewy bodies, more frequent dystonia, and less resting tremor.5 Also, remember that Mn-induced PL disease does NOT respond to L-dopa, a drug used to treat early stages of PD. 5 This finding can be explained by the fact that, in contrast to Parkinson’s disease where many of the dopamine-producing cells in the substantia nigra of the brain degenerate resulting in dopamine deficiency, in Mn-induced PL disease the problem is release of dopamine into synapses not its production.5

Bonus Pearl: Did you know that due to its paramagnetic properties, manganese can be effectively seen by MRI!

References

  1. Spahr L, Butterworth RF, Fontaine S, et al. Increased blood manganese in cirrhotic patients: relationship to pallidal m agnetic resonance signal hyperintensity and neurological symptoms. Hepatology 1996;24:1116-1120. https://www.ncbi.nlm.nih.gov/pubmed/8903385
  2. Hauser RA, Zesiewicz TA, Rosemurgy AS, et al. Manganese intoxication and chronic liver failure. Ann Neurol 1994;36:871-75. https://www.ncbi.nlm.nih.gov/pubmed/7998773
  3. Krieger S, Jaub M, Jansen O, et al. Neuropsychiatric profile and hyperintense globus pallidus on T1-weighted magnetic resonance images in liver cirrhosis. Gastroenterol 1996;111:147-55. https://www.ncbi.nlm.nih.gov/pubmed/8698193
  4. Lucchini R, Albini E, Placidi D, et al. Brain magnetic resonance imaging and manganese exposure. Neurotoxicity 2000;21:769-75. https://www.ncbi.nlm.nih.gov/pubmed/11130281
  5. Kwakye GF, Paoliello MMB, Mukhopadhyay S, et al. Manganese-induced parkinsonism and Parkinson’s disease: Shared and distinguishable features. Int J Environ Res Public Health 2015;12;7519-40. https://www.ncbi.nlm.nih.gov/pubmed/26154659

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My patient with cirrhosis has hypohonia and cogwheel rigidity. Is there a connection between cirrhosis and Parkinson’s disease?

Why is latent tuberculosis usually treated with one antibiotic while active tuberculosis is treated with 2 or more drugs?

Conventional wisdom has been that in active tuberculosis (TB) patients harbor large numbers of replicating Mycobacterium tuberculosis (Mtb), requiring multiple antibiotics to prevent the emergence of resistant mutants. In contrast, Mtb under latent or “inactive” conditions is presumed to have little capacity for mutation due to reduced bacterial replication, thus generally requiring only one antibiotic for preventive therapy.1

However, the assumption that Mtb has a low capacity for mutation in latent TB due to slow bacterial replication has been challenged in recent years. An experimental study in macaque monkeys with latent Mtb infection using whole genome sequencing demonstrated that despite reduced replication, Mtb acquires a similar number of chromosomal mutations during latency as it does during active infection.1

This finding supports the more current and evolving concept of latent TB which assumes diverse mycobacterial growth states, ranging from complete absence of organisms to actively replicating bacterial populations.2 It also explains why, although effective, isoniazid monotherapy may be a risk factor for the emergence of INH resistance in latent TB. 1,3

 Bonus Pearl: Did you know that INH treatment of latent TB in adults is 60-80% protective when given for 6 months, and 90% protective when given for 9 months? 4

References

  1. Ford CB, Lin PL, Chase M, et al . Use of whole genome sequencing to estimate the mutation rate of Mycobacterium tuberculosis during latent infection. Nat Genet. 2011;43:482-86. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101871/
  2. Gideon HP, Flynn JL. Latent tuberculosis: what the host “sees”? Immunol Res 2011;50:202-12. https://www.ncbi.nlm.nih.gov/pubmed/21717066
  3. Balcells ME, Thomas SL, Faussett PG, et al. Isoniazid preventive therapy and risk for resistant tuberculosis. Emerg Infect Dis 2006;12:744-51. https://www.ncbi.nlm.nih.gov/pubmed/16704830
  4. Piccini P, Chiappini E, Tortoli E, et al. Clinical peculiarities of tuberculosis. BMC Infect Dis 2014; 14 (Suppl 1):S4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015485/

 

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Why is latent tuberculosis usually treated with one antibiotic while active tuberculosis is treated with 2 or more drugs?

How is prealbumin related to albumin?

Aside from being synthesized in the liver and serving as a transport protein in the blood, prealbumin (PA) doesn’t really have much in common with albumin. More specifically, PA is not derived from albumin and, in fact, the two proteins are structurally distinct from each other!

So where does PA get its name? PA is the original name for transthyretin (TTR), a transport protein that primarily carries thyroxine (T4) and a protein bound to retinol (vitamin A). The name arose because TTR migrated faster than albumin on gel electrophoresis of human serum.1

Because of its much shorter serum half-life compared to that of albumin ( ~2 days vs ~20 days),2 PA is more sensitive to recent changes in protein synthesis and more accurately reflects recent dietary intake (not necessarily overall nutritional status) than albumin. 3

But, just like albumin, PA may represent a negative acute phase reactant, as its synthesis drops during inflammatory states in favor of acute phase reactants such as C-reactive protein. 4 So be cautious about interpreting low PA levels in patients with active infection, inflammation or trauma.

 

Reference

  1. Socolow EL, Woeber KA, Purdy RH, et al. Preparation of I-131-labeled human serum prealbumin and its metabolism in normal and sick patients. J. Clin Invest 1965; 44: 1600-1609. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC292644/
  2. Oppenheimer JH, Surks MI, Bernstein G, and Smith JC. Metabolism of Iodine-131-labeled Thyroxine-Binding Prealbumin in Man. Science 1965; 149: 748-750. https://www.ncbi.nlm.nih.gov/pubmed/14330531
  3. Ingenbleek Y, Young VR. Significance of prealbumin in protein metabolism. Clin Chem Lab Med 2002; 40: 1281-1291. https://www.ncbi.nlm.nih.gov/pubmed/12553432
  4. Shenkin A. Serum prealbumin: is it a marker of nutritional status or of risk of malnutrition? Clin Chem 2006;52:2177 – 2179. http://clinchem.aaccjnls.org/content/52/12/2177

 

Contributed by Colin Fadzen, Medical Student, Harvard Medical School, Boston, MA.

 

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How is prealbumin related to albumin?

Could constipation contribute to hyperkalemia in my patient with chronic kidney disease?

Yes! Constipation may be an important contributor to hyperkalemia in some patients with chronic kidney disease (CKD).

 Under normal conditions, 80-90% of excess dietary potassium (K+) is excreted by the kidneys, with the remainder excreted through the GI tract.1 However, in advanced CKD, particularly in the setting of end-stage kidney disease (ESKD), the GI tract assumes a much more important role in maintaining K+ balance. 

As early as 1960’s, the daily fecal excretion of K+ was found to be directly related to the wet stool weight, irrespective of creatinine clearance. Furthermore, K+ excretion in stool was as high as ~80% of dietary intake (average 37%) in some hemodialysis (HD) patients compared to normal controls (average 12%). 2

Such increase in K+ excretion in the GI tract of patients with CKD was later found to be primarily the result of K+ secretion into the colon/rectum rather than reduced dietary K+ absorption in the small intestine 1,3, was inversely related to residual kidney function, and as a consequence could serve as the main route of K+ excretion in patients with ESKD. 4

Collectively, these findings suggest that in addition to non-dietary factors such as medications, we may need to routinely consider constipation as a potential cause of hyperkalemia in patients with advanced CKD or ESKD. 1

Bonus Pearl: Did you know that secretion of K+ by the apical surface of colonic epithelial is mediated in part by aldosterone-dependent mechanisms? 5

References

  1. St-Jules DE, Goldfarb DS, Sevick MA. Nutrient non-equivalence: does restricting high-potassium plant foods help to prevent hyperkalemia in hemodialysis patients? J Ren. Nutr 2016;26: 282-87. https://www.ncbi.nlm.nih.gov/pubmed/26975777
  2. Hayes CP, McLeod ME, Robinson RR. An extrarenal mechanism for the maintenance of potassium balance in severe chronic renal failure. Trans Assoc Am Physicians 1967;80:207-16.
  3. Martin RS, Panese S, Virginillo M, et al. Increased secretion of potassium in the rectum of humans with chronic renal failure. Am J Kidney Dis 1986;8:105-10. https://www.ncbi.nlm.nih.gov/pubmed/3740056
  4. Cupisti A, Kovesdy CP, D’Alessandro C, et al. Dietary approach to recurrent or chronic hyperkalemia in patients with decreased kidney function. Nutrients 2018, 10, 261;doi:10.3390/nu10030261. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872679/
  5. Battle D, Boobes K, Manjee KG. The colon as the potassium target: entering the colonic age of hyperkalemia treatment. EBioMedicine 2015;2: 1562-1563. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740340/pdf/main.pdf

 

Contributed in part by Alex Blair, MD, Mass General Hospital, Boston, MA.

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Could constipation contribute to hyperkalemia in my patient with chronic kidney disease?

Should I routinely screen my patients with heart failure for iron deficiency?

Even in the absence of anemia, screening for iron deficiency (ID) has been recommended in patients with heart failure (HF) with reduced ejection fraction (HFrEF) by some European and Australia-New Zealand cardiology societies. 1

In contrast, the 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines do not mention routine screening for ID in such patients but instead state (under “Anemia”) that in patients with NYHA class II and III HF and ID (ferritin < 100 ng/mL or 100 to 300 ng/mL plus transferrin saturation <20%), IV iron replacement “might be reasonable” to improve functional status and quality of life (IIb-weak recommendation).2

As these guidelines are primarily based on data derived from patients with HFrEF, whether patients with HF with preserved (eg, >45%) ejection fraction (HFpEF) should undergo routine screening for ID is even less clear due to conflicting data based on limited small studies 3,4

What is known is that up to 50% or more of patients with HF with or without anemia may have ID. 5 Although most studies involving ID and HF have involved patients with HFrEF, similarly high prevalence of ID in HFpEF has been reported. 6,7

A 2016 meta-analysis involving patients with HFrEF and ID found that IV iron therapy alleviates HF symptoms and improves outcomes, exercise capacity and quality of life irrespective of concomitant anemia; all-cause and cardiovascular mortality rates were not significantly impacted, however.8  

Fortunately, larger trials in the setting of acute and chronic systolic HF are underway (Affirm-AHF, 9 IRONMAN 10).  Stay tuned!

Bonus Pearl: Did you know that iron deficiency directly affects human cardiomyocyte function by impairing mitochondrial respiration  and reducing its contractility and relaxation?11

References

  1. Silverberg DS, Wexler D, Schwartz D. Is correction of iron deficiency a new addition to the treatment of the heart failure? Int J Mol Sci 2015;16:14056-74. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490538/
  2. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure. Circulation 2017;136:e137-e161. https://www.ahajournals.org/doi/pdf/10.1161/CIR.0000000000000509
  3. Kasner M, Aleksandrov AS, Westermann D, et al. Functional iron deficiency and diastolic function in heart failure with preserved ejection fraction. International J of Cardiol 2013;168:12:4652-57. https://www.ncbi.nlm.nih.gov/pubmed/23968714
  4. Enjuanes C, Klip IT, Bruguera J, et al. Iron deficiency and health-related quality of life in chronic heart failure: results from a multicenter European study. Int J Cardiol 2014;174:268-275. https://www.ncbi.nlm.nih.gov/pubmed/24768464
  5. Drodz M, Jankowska EA, Banasiak W, et al. Iron therapy in patients with heart failure and iron deficiency: review of iron preparations for practitioners. Am J Cardiovasc Drugs 2017;17:183-201. https://www.ncbi.nlm.nih.gov/pubmed/28039585
  6. Bekfani T, Pellicori P, Morris D, et al. Iron deficiency in patients with heart failure with preserved ejection fraction and its association with reduced exercise capacity, muscle strength and quality of life. Clin Res Cardiol 2018, July 26. Doi: 10. 1007/s00392-018-1344-x. https://www.ncbi.nlm.nih.gov/pubmed/30051186
  7. Nunez J, Dominguez E, Ramon JM, et al. Iron deficiency and functional capacity in patients with advanced heart failure with preserved ejection fraction. International J Cardiol 2016;207:365-67. https://www.internationaljournalofcardiology.com/article/S0167-5273(16)30185-1/abstract
  8. Jankowska EA, Tkaczynszyn M, Suchocki T, et al. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Failure 2016;18:786-95. https://www.ncbi.nlm.nih.gov/pubmed/26821594
  9. https://clinicaltrials.gov/ct2/show/NCT02937454
  10. https://clinicaltrials.gov/ct2/show/NCT02642562
  11. Hoes MF, Beverborg NG, Kijlstra JD, et al. Iron deficiency impairs contractility of human cardiomyoctyes through decreased mitochondrial function. Eur J Heart Failure 2018;20:910-19. https://www.ncbi.nlm.nih.gov/pubmed/29484788  

 

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Should I routinely screen my patients with heart failure for iron deficiency?