Kidney disease;

Why doesn’t my patient with lactic acidosis have hyperkalemia?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , Leave a comment

Although hyperkalemia may be observed in a variety of conditions associated with metabolic acidosis, it is less likely to be seen in conditions associated with excess organic acids (eg, in lactic acidosis or diabetic ketoacidosis). A likely explanation for this finding revolves around the amazing organic anion transporter (OAT) and its attendant role in counteracting hyperkalemia by bringing potassium (K+) back into the cells.1-5 See details of impact of extracellular and intracellular pH on K+ homeostasis in Figure.1 

Recall that in metabolic acidosis the increased concentration of hydrogen ion (H+) outside the cell reduces sodium (Na+) influx into cells through the Na+-H+ exchange channel resulting in a drop in the intracellular Na+.  Since the Na+K+ATPase ion channel depends on the intracellular Na+ for bringing K+ into the cells, the end-result is higher K+ concentrations in the extracellular space, potentially resulting in hyperkalemia.  This is what is often seen in conditions of mineral (non-organic) acid excess (eg, in respiratory acidosis or poor renal function).

In the case of organic acidosis, however, the OAT also plays an important factor in K+ homeostasis (Figure)1.  As the name suggests, this transporter allows  organic acids such as lactic acid or ketones to enter the cell. As the H+ concentration increases intracellularly, there is more Na+-H+ exchange and more influx of Na+ into the cell.  More available Na+ intracellularly means more Na+ is pumped out by Na+K+ATPase, and more K+ is brought into the cell,1-5 mitigating the impact of metabolic acidosis on K+ efflux into the  extracellular space and potentially even causing hypokalemia! 

Concurrent hyperkalemia and lactic acidosis or diabetic ketoacidosis may of course still occur.  However, in such cases, hyperkalemia is often due to an epiphenomenon related to complicating factors.  In the case of lactic acidosis, this may be related to concurrent renal dysfunction,3 while in diabetic ketoacidosis it may be related to hyperosmolarity or insulin deficiency.1

So next time you see a patient who has hyperkalemia and lactic acidosis, ask yourself  “What else am I missing that can explain the hyperkalemia?“.

Bonus Pearl

Did you know that lactic acid in human blood was first discovered by the German physician–chemist, Johann Joseph Sherer, who sampled post-mortem blood from 2 women who died of puerperal fever in 1843? 6

Contributed by Nabi Chaudhri-Martinez MD, Mercy Hospital-St. Louis, St. Louis, Missouri

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References:

  1. Aronson PS, Giebisch G. Effects of pH on potassium: new explanations for old observations. J Am Soc Nephrol. 2011 Nov;22(11):1981-9. doi: 10.1681/ASN.2011040414. Epub 2011 Oct 6. PMID: 21980112; PMCID: PMC3231780. https://jasn.asnjournals.org/content/22/11/1981.long
  2. Orringer CE, Eustace JC, Wunsch CD, Gardner LB. Natural history of lactic acidosis after grand-mal seizures. A model for the study of an anion-gap acidosis not associated with hyperkalemia. N Engl J Med. 1977 Oct 13;297(15):796-9. doi: 10.1056/NEJM197710132971502. PMID: 19702. https://www.nejm.org/doi/10.1056/NEJM197710132971502?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
  3. Fulop M. Serum potassium in lactic acidosis and ketoacidosis. N Engl J Med. 1979 May 10;300(19):1087-9. doi: 10.1056/NEJM197905103001905. PMID: 34793. https://www.nejm.org/doi/10.1056/NEJM197905103001905?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub 0pubmed
  4. Adrogué HJ, Madias NE. Changes in plasma potassium concentration during acute acid-base disturbances. Am J Med. 1981 Sep;71(3):456-67. doi: 10.1016/0002-9343(81)90182-0. PMID: 7025622. https://www.amjmed.com/article/0002-9343(81)90182-0/pdf
  5. Nigam SK, Bush KT, Martovetsky G, et al. The organic anion transporter (OAT) family: A systems biology perspective. Physiol Rev 2015;95:83:123. The Organic Anion Transporter (OAT) Family: A Systems Biology Perspective (physiology.org)
  6. Kompanje EJ, Jansen TC, van der Hoven B, Bakker J. The first demonstration of lactic acid in human blood in shock by Johann Joseph Scherer (1814-1869) in January 1843. Intensive Care Med. 2007;33(11):1967-1971. doi:10.1007/s00134-007-0788-7 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2040486/

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University, their affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

Why doesn’t my patient with lactic acidosis have hyperkalemia?

Is there a connection between urinary tract infections (UTIs) and hypokalemia?

FA Manian MD, MPH, , , , , , Leave a comment

Although we don’t usually think of UTIs being associated with electrolyte abnormalities, there seems to be a connection between UTI—particularly pyelonephritis—and hypokalemia in adults, possibly related to the impairment of renal potassium resorption due to tubular injury.1

A 2020 study of over 80,000 hospitalized patient found a significantly higher rate of hypokalemia (10%) in patients with UTI (identified based on ICD9 codes) vs non-UTI patients (4%, O.R. 2.3, 95% C.I. 2.2-2.4). This association was independent of patients’ comorbidities and medications. Among patients with UTI, recurrent UTI was associated with hypokalemia (O.R. 1.1, 95% C.I. 1.1-1.2). Unfortunately, no attempt was made to distinguish cystitis from pyelonephritis. The authors reported that in “several patients”, the urinary potassium secretion was increased.  

The association between pyelonephritis and hypokalemia was first reported back in the 1950s and was initially referred to as “potassium losing nephropathy”. 2 It turns out that some of these cases might have had underlying primary hyperaldosteronism (Conn’s) and perhaps pyelonephritis unmasked this condition.  Later, cases of urinary potassium wasting with probable pyelonephritis in the absence of excessive aldosterone excretion were also reported, with resolution of potassium wasting with treatment of the infection in some instances.3,4  

So it looks like the association between pyelonephritis and hypokalemia may be real! Next time you see hypokalemia in a patient with pyelonephritis, don’t be surprised! The corollary: watch for hypokalemia in your patient with pyelonephritis!

Bonus Pearl: Did you know that prevention of potassium loss with spironolactone treatment in pyelonephritis has been reported, suggesting a possible role for aldosterone despite lack of hyperaldosteronism.3

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References

  1. Shen AL, Lin HL, Lin HC, et al. Urinary tract infection is associated with hypokalemia: a case control study. BMC Urology 2020;20:108. Urinary tract infection is associated with hypokalemia: a case control study | BMC Urology | Full Text (biomedcentral.com)
  2. Eastham RD, McElligott M. Potassium-losing pyelonephritis. BMJ 1956; :898-89. Potassium-losing pyelonephritis. – Abstract – Europe PMC
  3. Gerstein AR, Franklin SS, Kleeman CR, et al. Potassium losing pyelonephritis:response to spironolactone. Arch Intern Med 1969;123:55-57. Potassium Losing Pyelonephritis: Response to Spironolactone | JAMA Internal Medicine | JAMA Network
  4. Jones NF, Cantab MB, Mills IH, et al. Reversible renal potassium loss with urinary tract infection. Am J Med 1964;37:305-310. REVERSIBLE RENAL POTASSIUM LOSS WITH URINARY TRACT INFECTION – PubMed (nih.gov)

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy-St. Louis, Massachusetts General Hospital, Harvard Catalyst, Harvard University,their affiliate healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

Is there a connection between urinary tract infections (UTIs) and hypokalemia?

What’s the connection between dialysis and cognitive impairment in patients with chronic kidney disease (CKD)?

FA Manian MD, MPH, , , , , , , , , , , , Leave a comment

Cognitive impairment (CI) is extremely common among dialysis patients affecting  up to ~70% or more  of patients (1-3).   Pre-existing conditions, dialysis process itself and uremic, metabolic and vascular disturbances associated with end stage renal failure may all contribute to the CI in patients on dialysis (1-5).

Among pre-existing conditions, vascular disease is considered the major contributing factor to the risk of CI in dialysis patients (3). The prevalence of stroke is very high among hemodialysis (HD) ( ~15%) and CKD patients (~10%) compared to non-CKD patients (~2%).  History of stroke also doubles the risk of dementia in both the non-CKD and HD patients. Subclinical cerebrovascular disease due to silent strokes and white matter disease —common in CKD and dialysis patients—are also associated with increased risk of cognitive and physical decline and incident dementia.  White matter disease is thought to be related to microvascular disease and chronic hypoperfusion (1).

Dialysis itself may be associated with acute confusional state due to cerebral edema caused by  acute fluid, urea, and electrolyte shifts during dialysis (particularly among newly initiated HD patients).  Some have suggested that the optimal cognitive function in HD patients is around 24 h after HD (1).

Chronic rapid fluctuations in blood pressure, removal of large fluid volumes and hemoconcentrations can further increase the risk of cerebral hypoperfusion, potentially accelerating vascular cognitive impairment in HD patients (1).

 Bonus Pearl: Did you know that while cerebral ischemia (measured by PET-CT or other non-invasive means) is common during HD, it may occur in the absence of intra-dialysis hypotension (6,7)?

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References

  1. Murray AM. Cognitive impairment in the aging dialysis and chronic kidney disease populations: an occult burden. Adv Chronic Kidney Dis 2008;15:123-32. https://www.ackdjournal.org/article/S1548-5595(08)00011-6/pdf
  2. Murray AM, Tupper DE, Knopman DS, et al. Cognitive impairment in hemodialysis patients is common. Neurology 2006;67:216-223. https://experts.umn.edu/en/publications/cognitive-impairment-in-hemodialysis-patients-is-common
  3. Van Zwieten A, Wong G, Ruospo M, et al. Prevalence and patterns of cognitive impairment in adult hemodialysis patients: the COGNITIVE-HD study. Nephrol Dial Transplant 208;33:1197-1206. https://pubmed.ncbi.nlm.nih.gov/29186522/
  4. Seliger SL, Weiner DE. Cognitive impairment in dialysis patients: focus on the blood vessels? Am J Kidney Dis 2013;61:187-90. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433757/
  5. Findlay MD, Dawaon J, Dickie DA, et al. Investigating the relationship between cerebral blood flow and cognitive function in hemodialysis patients. J Am Soc Nephrol 30:147-58. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317612/
  6. Polinder-Bos HA, Garcia DV, Kuipers J, et al. Hemodiaysis induces an acute decline in cerebral blood flow in elderly patients. J Am Soc Nephrol 208;29:1317-25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875962/
  7. MacEwen C, Sutherland S, Daly J, et al. Relationship between hypotension and cerebral ischemia during hemodialysis. J Am Soc Nephrol 2017;38:2511-20. https://www.researchgate.net/publication/314298128_Relationship_between_Hypotension_and_Cerebral_Ischemia_during_Hemodialysis

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

What’s the connection between dialysis and cognitive impairment in patients with chronic kidney disease (CKD)?

How common are acute kidney abnormalities in patients with Covid-19?

FA Manian MD, MPH, , , , , , , , , Leave a comment

Although early reports suggested a low incidence (3-9%) of AKI among Covid-19 patients, more recent studies have shown higher frequencies of renal abnormalities, including albuminuria and hematuria (1).

 
A study of 59 patients with Covid-19 reported that 34% had “massive albuminuria” on the first day of admission, and 63% developed proteinuria during their hospitalization (2 [unpublished]). BUN was elevated in 27% of patients and in two-thirds of those who died. In another study involving 710 patients with Covid-19, nearly one-half had proteinuria and hematuria and a quarter had hematuria on admission. Overall, around 15% of patients had an elevated serum creatinine and BUN (3).

 
Possible explanations for renal manifestations of Covid-19 include sepsis, cytokine storm, secondary infections, and direct cellular injury due to the virus itself (1, 4). Interestingly, SARS-CoV-2 has been reportedly isolated from the urine sample of a Covid-19 patient (1). This should not be surprising given the presence of ACE2 receptors in the proximal tubules and, at lower concentrations, in the glomeruli (5).

 
An autopsy study of patients with Covid-19 found evidence of diffuse proximal tubule injury with the loss of brush border, vascular degeneration but no vasculitis, interstitial inflammation or hemorrhage. Coronavirus particles were found in the tubular epithelium and podocytes (6).

 
Bonus Pearl: Did you know that proteinuria (2-3+) and hematuria are independent risk factors for in-hospital mortality (3)?

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References
1. Naicker S, Yang CW, Hwang SJ. The novel coronavirus 2019 epidemic and kidneys. Kidney International 2020, May. DOI: https://doi.org/10.1016/j.kint.2020.03.001
2. Li Z, Wu M, Guo J, et al. Caution on kidney dysfunctions of 2019-nCoV patients . medRxiv 2020.02.08.20021212
3. Cheng Y, Luo R, Wang K, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney International 2020;97:829-38.
4. Su H, Yang M, Wan C, et al. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney International 2020, April 9. https://www.sciencedirect.com/science/article/pii/S0085253820303690  
5. Mizuiri S, Ohashi Y. ACE and ACE2 in kidney disease. World J Nephrol 2015;4:74-82. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317630/
6. Cheng N, Zhou M, Dong X, et al. Kidney impairment is associated with in-hospital death of COVID-19 patients. medRxive 2020 .0218.20023242. https://doi.org/10.1101/2020.02.18.20023242.

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 
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How common are acute kidney abnormalities in patients with Covid-19?

Why is my relatively healthy elderly patient so prone to hyperkalemia?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , Leave a comment

Hyporeninemic hypoaldosteronism (HH)—without impairment of cortisol synthesis— is associated with hyperkalemic (type IV) renal tubular acidosis (RTA) and is not uncommon among older patients despite glomerular filtration rates (GFRs) >20 ml/min, and absence of diabetes mellitus or chronic tubulointerstitial disease (1-7).  

Hyperkalemia due to HH in the elderly should come as no surprise because the renin-angiotensin-aldosterone system (RAAS) function declines with age, reaching its lowest level by age 60. 1-4   In fact, older people have comparatively lower mean levels of plasma renin and aldosterone at baseline and have an impaired ability to mount appropriate responses to RAAS stimuli, such as upright posture, volume depletion, catecholamines, or potassium administration (3-5).

The impaired RAAS capacity in the elderly often becomes more obvious when they are prescribed medications that further suppress RAAS (3). These include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium-channel blockers, nonsteroidal anti-inflammatory agents and heparin (3,7). 

Drugs that increase aldosterone resistance, including potassium-sparing diuretics (eg, spironolactone, amiloride, triamterene, eplerenone) and certain antibiotics (eg, trimethoprim, pentamidine) may also aggravate hyperkalemia associated with HH (7). 

A variety of mechanisms leading to HH with aging have been proposed. These include impaired conversion of prorenin to renin, prostaglandin deficiency, sympathetic nervous system dysfunction and increased plasma levels of atrial natriuretic factors as found in congestive heart failure (1,7). 

Bonus pearl: Did you know that the first case of “pure hypoaldosteronism” was described in 1957 in a 71 year old non-diabetic patient with hyperkalemia in the setting of congestive heart failure? (8)

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References

  1. Bauer JH. Age-related changes in the renin-aldosterone system. Physiological effects and clinical implications. Drugs & Aging 1993;3:238-45. https://www.ncbi.nlm.nih.gov/pubmed/8324299
  2. Musso CG, Jauregui JR. Renin-angiotensin-aldosterone system and the aging kidney. Expert Rev Endocrinol Metab 2014;9:543-46. https://www.tandfonline.com/doi/full/10.1586/17446651.2014.956723
  3. Yoon HE, Choi BS. The renin-angiotensin system and aging in the kidney. Korean J Intern Med 2014;29:291-95. https://www.researchgate.net/publication/262530577_The_renin-angiotensin_system_and_aging_in_the_kidney
  4. Nadler JL, Lee FO, Hsueh W, et al. Evidence of prostacyclin deficiency in the syndrome of hyporeninemic hypoaldosteronism. N Engl J Med 1986;314:1015-20. https://www.ncbi.nlm.nih.gov/pubmed/3515183
  5. Williams GH. Hyporeninemic hypoaldosteronism. N Engl J Med 1986;314:1041-42. https://www.ncbi.nlm.nih.gov/pubmed/3515186
  6.  Block BL, Bernard S, Schwartzstein RM. Hypo-hypo: a complex metabolic disorder. Ann Am Thorac Soc 2016;13:127-133. https://www.ncbi.nlm.nih.gov/pubmed/26730868
  7. Michelis MF. Hyperkalemia in the elderly. Am J Kid Dis 1990;16:296-99.https://www.ajkd.org/article/S0272-6386(12)80005-9/pdf
  8. Hudson JB, Chobanian AV, Relman AS. Hypoaldosteronism. A clinical study of a patient with an isolated adrenal mineralocorticoid deficiency, resulting in hyperkaliemia and Stokes-Adams attack. N Engl J Med 1957;257:529-36. https://www.ncbi.nlm.nih.gov/pubmed/13464977

 

Why is my relatively healthy elderly patient so prone to hyperkalemia?

Is my patient with gout at higher risk of cancer?

FA Manian MD, MPH, , , , , , , , , , , , , , , , Leave a comment

Although the association of gout with cardiovascular disease, chronic kidney disease, hypertension, diabetes mellitus or obesity is well known, increasingly number of epidemiologic studies support the association of gout with higher risk of malignancy. 1,2

A 2015 meta-analysis of 3 studies involving over 50,000 persons concluded that gout was an independent risk factor for cancer, particularly urological, gastrointestinal and lung cancers. 1

A population-based study of comorbidities in over 2 million persons in Sweden found that in addition to an increased risk of diabetes mellitus, hypertension, chronic heart failure, chronic kidney disease and alcohol abuse, gout was associated with increased risk of malignancy: odds ratio 1.3 (1.2-1.5) in men and 1.1 (1.1-1.2) in women. 2

Although serum uric acid has been considered to have anti-oxidant properties, a prospective study of over 28,000 women followed over a median of 15.2 years did not find high serum acid levels to be protective of cancer.3 In fact, uric acid levels > 5.4 mg/dL at the time of subject enrollment was independently associated with increased risk of total cancer mortality and deaths from a variety of malignant neoplasms, including those of breast, female genital organs, and nervous systems. 3 In a similar prospective study involving men, high uric acid levels (>6.7 mg/dL) were associated with increased risk of mortality from gastrointestinal, respiratory and intrathoracic organ malignancies. 4

Whether the observed association between gout and higher risk of malignancy is causal or due to the company that gout often keeps (eg, lifestyle) is unclear.

Fun fact: Did you know that among mammals, only humans, great apes and certain breeds of dogs (eg, Dalmation) produce elevated levels of uric acid in the urine and blood? 5

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References

  1. Wang W, Xu D, Wang B, et al. Increased risk of cancer in relation to gout: a review of three prospective cohort studies with 50,358 subjects. Mediators of Inflammation 2015, Article ID 680853, 6 pages. https://www.ncbi.nlm.nih.gov/pubmed/26504360
  2. Wandell P. Gout and its comorbidities in the total population of Stockholm. Preventive Medicine 2015; 81:387-91. ISSN 0091-7435. https://www.ncbi.nlm.nih.gov/pubmed/26500085
  3. Strasak AM, Rapp K, Hilbe W, et al. The role of serum uric acid as an antioxidant protecting against cancer: prospective study in more than 28000 older Austrian women. Ann Onc 2007;18:1893-97. https://www.ncbi.nlm.nih.gov/pubmed/17785768
  4. Strasak Am, Hilbe RK, Oberaingner W, et al. Serum uric acid and risk of cancer mortality in a large prospective male cohort. Cancer Causes Control 2007;18:1021-9. https://www.ncbi.nlm.nih.gov/pubmed/17665312
  5. Bannasch D, Safra N, Young A, et al. Mutations in the SLC2A9 gene cause hyperuriosuria and hyperuricemia in the dog. PLOS Genet 2008;4:e1000246. https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1000246&type=printable
Is my patient with gout at higher risk of cancer?

Why is my diabetic patient complaining of arm pain and localized edema for couple of weeks without an obvious cause?

FA Manian MD, MPH, , , , , , , , , , , , , , Leave a comment

Aside from the usual suspects associated with a painful extremity (eg, trauma, deep venous thrombosis and soft tissue infections), think of spontaneous diabetic myonecrosis (DMN), also known as diabetic muscle infarction (1-3).

DMN is characterized by abrupt onset of painful swelling of the affected muscle, most often of the lower extremities, but also occasionally upper extremities. DMN occurs in patients with longstanding DM whose blood glucose control has deteriorated over time, often with nephropathy, retinopathy and/or neuropathy (1-3).

Couple of things to remember when considering DMN in your differential of a painful extremity. First, except for localized edema and tenderness over the involved muscle, the exam may be unremarkable. Specifically, there is no erythema or signs of compartment syndrome and fever is absent in the great majority of patients (~90%) (2). Even white blood cell count and creatine kinase (CK) are usually normal. The reason for normal CK at presentation is not clear but CK might have already peaked by the time of patient presentation (3). In contrast, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are usually elevated (>80%) (1).

MRI (without contrast in patients with renal insufficiency) is the imaging of choice with muscle enlargement and edema with hyperintense signal on T2-weighted images and other changes, including perifascial, perimuscular and or subcutaneous edema (1-3). Muscle biopsy is not currently recommended because of its adverse impact on time to symptomatic improvement. Non-surgical therapy, with rest, analgesia and glycemic control is usually recommended (1-3).

 
Though its exact cause is still unclear, atherosclerosis, diabetic microangiopathy, vasculitis with thrombosis and ischemia-reperfusion injury have been posited as potential precipitants for DMN. The role of anti-phospholipid syndrome, particularly in patients with type I DM, is unclear (1,2).

 
Bonus pearl: Did you know that symptoms of DMN may last for weeks with at least one-third of patients having a recurrence in the same muscle or elsewhere (1)?

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Reference
1. Horton WB, Taylor JS, Ragland TJ, et al. Diabetic muscle infarction: a systematic review. BMJ Open Diabetes Research and Care 2015;3:e000082.
2. Trujillo-Santos AJ. Diabetic muscle infarction. An underdiagnosed complication of long-standing diabetes. Diabetes Care 2003;26:211-15.
3. Diabetes muscle infarction in end-stage renal disease:A scoping review on epidemiology, diagnosis and treatment. World J Nephrol 2018;7:58-64.

Why is my diabetic patient complaining of arm pain and localized edema for couple of weeks without an obvious cause?

Could measurement of urinary albumin-protein ratio be useful in my patient with renal insufficiency and proteinuria?

FA Manian MD, MPH, , , , , , , , , Leave a comment

A spot urine test for determination of albumin-protein ratio (uAPR) may be useful in distinguishing glomerular vs tubulointerstitial source of proteinuria. A low (<0.4) uAPR, defined as urinary albumin to creatinine ratio(uACR)/urinary protein to creatinine ratio (uAPR) is more suggestive of a tubulointerstitial renal disease and less suggestive of glomerular pathology.1-3  

A 2012 study involving simultaneous measurements of urinary albumin and total protein in over 1000 proteinuric patients found a relatively high (0.84) area under curve (AUC) in a receiver operating characteristic curve analysis for uAPR (vs 0.74 for uACR and 0.54 for uPCR) in discriminating between tubular and non-tubular proteinuria pattern on urine protein electrophoresis and immunofixation. An uAPR cut-off of <0.4 was found to be 88% sensitive and 99% specific for the diagnosis of primary tubulointerstitial disorders on renal biopsy.1  

Due to the limitations of this study (including a relatively small subset of patient who had renal biopsy), a related editorial concluded that a low uAPR gives a “reasonable prediction of a tubular electrophoretic proteinuria”, but that it warrants further validation. Nevertheless, uAPR could potentially be useful in patients with moderate proteinuria (>300 mg/day to <3 g/day) who have not had renal biopsy and  where assessment of likelihood of tubulointerstitial vs glomerular source of proteinuria is desired.3 Interestingly, the utility of uAPR in predicting non-glomerular source of hematuria has also been reported.4

Bonus pearl: Did you know that the negatively-charged glomerular capillary wall repels negatively charged albumin thus preventing its filtration (charge-barrier) (5)?  

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References

  1. Smith ER, Cai MMX, McMahon LP, et al. The value of simultaneous measurement of urinary albumin and total protein in proteinuric patients. Nephrol Dial Transplant 2012;27:1534-41. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035283/
  2. Fraser SDS, Roderick PJ, McIntyre NJ, et al. Assessment of proteinuria in patients with chronic kidney disease stage 3: albuminuria and non-albumin proteinuria. PLOS ONE 2014;9:e98261. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035283/pdf/pone.0098261.pdf
  3. Ellam T, Nahas ME. Urinary albumin to protein ratio: more of the same or making a difference. Nephrol Dial Transplant 2012;27:1293-96. https://www.ncbi.nlm.nih.gov/pubmed/22362784
  4. Ohisa N, Yoshida K, Matsuki R, et al. A comparison of urinary albumin-total protein ratio to phase-contrast microscopic examination of urine sediment for differentiating glomerular and nonglomerular bleeding. Am J Kidney Dis 2008;52:235-41. https://www.ajkd.org/article/S0272-6386(08)00828-7/pdf
  5. Venkat KK. Proteinuria and microalbuminuria in adults: significance, evaluation, and treatment. S Med J 2004;97:969-79. https://internal.medicine.ufl.edu/files/2012/07/5.18.05.04.-Proteinuria-review.pdf
Could measurement of urinary albumin-protein ratio be useful in my patient with renal insufficiency and proteinuria?

My patient with no known liver disease appears to have bilateral asterixis. What other causes should I consider?

FA Manian MD, MPH, , , , , , , , , , , , Leave a comment

Although originally described in 1949 in patients with liver disease and labelled as “liver flap”, numerous other causes of asterixis exist aside from severe liver disease (1,2). As early as 1950s, asterixis was observed among some patients with heart failure and pulmonary insufficiency but without known significant liver disease (3). Azotemia has also been associated with asterixis.

Don’t forget about medication-associated asterixis . Commonly used drugs such as gabapentin, pregabalin, phenytoin, and metoclopramide have been associated with asterixis (1,4) . Even antibiotics such as ceftazidime and high dose trimethoprim-sulfamethoxazole may be culprits (1,5). There are many psychiatric drugs including lithium, carbamazepine, clozapine, and valproic acid that have been implicated (1,6) as well. Some reviews have also included hypomagnesemia and hypokalemia on the list of causes of asterixis (1).

Although asterixis is essentially a negative myoclonus with episodic loss of electrical activity of muscle and its tone, its exact pathophysiology remains unclear (7). 

 

Bonus Pearl: Did you know that the origin of the word asterixis is An (negative)-iso (equal)-sterixis (solidity) which was shortened by Foley and Adams, its original discoverers, to what we now refer to as “asterixis” (1).

 

References
1. Agarwal R, Baid R. Asterixis. J Postgrad Med 2016;62:115-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944342/

2. Pal G, Lin MM, Laureno R. Asterixis: a study of 103 patients. Metab Brain Dis; 2014:29:813-24. https://link.springer.com/article/10.1007%2Fs11011-014-9514-7
3. Conn HO. Aterixis—Its occurrence in chronic pulmonary disease, with a commentary on its general mechanism. N Engl J Med 1958;259:564-569. https://www.nejm.org/doi/full/10.1056/NEJM195809182591203
4. Kim JB, Jung JM, Park MH. Negative myoclonus induced by gabapentin and pregabalin: a case series and systemic literature review. J Neurol Sci 2017;382:36-9. https://www.sciencedirect.com/science/article/pii/S096758681830225X
5. Gray DA, Foo D. Reversible myoclonus, asterixis, and tremor associated with high dose trimethoprim-sulfamethoxazole: a case report. J Spinal Cord Med 2016; Vol. 39 (1), pp. 115-7. https://www.ncbi.nlm.nih.gov/pubmed/26111222
6. Nayak R, Pandurangi A, Bhogale G, et al. Aterixis (flapping tremors) as an outcome of complex psychotropic drug interaction. J Neuropsychiatry Clin Neurosci 2012;24: E26-7. https://neuro.psychiatryonline.org/doi/pdf/10.1176/appi.neuropsych.101102667.

7.Ugawa Y, Shimpo T, Mannen T. Physiological analysis of asterixis: silent period locked averaging. J Neurol Neurosurg Psych 1989;52:89-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1032663/pdf/jnnpsyc00523-0104.pdf

 

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My patient with no known liver disease appears to have bilateral asterixis. What other causes should I consider?

My patient with cocaine and alcohol addiction is admitted with repeated convulsions during which he seems totally conscious. What could I be missing?

FA Manian MD, MPH, , , , , , , , , Leave a comment

Consider strychnine poisoning as a cause of recurrent generalized tonic clonic seizures and muscle spasm with clear sensorium either during or following the episode. 1-4 In contrast to the cortical source of most seizures, convulsions due to strychnine poisoning are due to the blocking of the action of spinal and brain-stem inhibitory neurons resulting in overwhelming muscle rigidity, not unlike that seen in tetanus.

Although strychnine was found in various tonics and cathartic agents and was a common cause of accidental death in children under 5 years of age in early 20th century, it is still used in various rodenticides and pesticides.3  Today, it may be used intentionally in suicide attempts as well as an adulterant in street drugs, such as amphetamines, heroin and especially cocaine. 1,3,5

The initial symptoms of strychnine poisoning include nervousness, a hyperalert state, and confusion. These symptoms may be followed by severe muscle rigidity throughout the body often in response to minimal stimuli, such as physical contact, bright lights, noise and medical procedures.3, 6,7  Interestingly, strychnine also has an excitatory action on the medulla and enhances the sensation of touch, smell, hearing and sight.6  The cause of death is usually respiratory arrest due to prolonged muscle spasms, often complicated by rhabdomyolysis and associated renal failure.1

So among the numerous causes of seizures, think of strychnine as another potential cause when there is no concurrent loss of consciousness or the expected postictal state.

Bonus Pearl: Did you know that strychnine may be present in street drugs with a variety of names such as “back breakers”, “homicide”, “red rock opium”, “red stuff” and “spike”? 7

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References

  1. Wood DM, Webser E, Martinez D, et al. Case report: survival after deliberate strychnine self-poisoning, with toxicokinetic data. Critical Care 2002;6:456-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC130147/
  2. Santhosh GJ, Joseph W, Thomas M. Strychnine poisoning. J Assoc Physicians India 2003;51:736. https://www.ncbi.nlm.nih.gov/pubmed/14621058
  3. Libenson MH, Young JM. Case records of Massachusetts General Hospital. A 16 years boy with an altered mental status and muscle rigidity. N Engl J Med 2001;344:1232-9. https://www.nejm.org/doi/full/10.1056/NEJM200104193441608
  4. Smith BA. Strychnine poisoning. J Emerg Med 1990;8: 321-25. https://www.ncbi.nlm.nih.gov/pubmed/2197324
  5. O’Callaghan WG, Ward M, Lavelle P, et al. Unusual strychnine poisoning and its treatment: report of eight cases. B Med J 1982;285:478. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1499293/
  6. Burn DJ, Tomson CRV, Seviour J, et al. Strychnine poisoning as an unusual cause of convulsions. Postgrad Med J 1989;65:563-64. https://www.ncbi.nlm.nih.gov/pubmed/2602253
  7. Radosavljevic J, Jeffries WS, Peter JV. Intentional strychnine use and overdose—an entity of the past? Crit Care Resusc 2006;8: 260-61. https://www.ncbi.nlm.nih.gov/pubmed/16930120

 

My patient with cocaine and alcohol addiction is admitted with repeated convulsions during which he seems totally conscious. What could I be missing?