11/13 Presby report: sulfonylurea toxicity, loop diuretics

Thanks to Dan Kim for giving a great talk (and to the audience of contributing lots of great learning points!) on a middle aged woman who presented with hypoglycemia after taking a dose of her sulfonylurea.

Recall that sulfonylureas work by inhibiting the ATP-sensitive potassium channel in pancreatic beta cells; this leads to increased endogenous insulin release. Long acting sulfonylureas (ie glyburide) are more likely than short-acting agents (glipizide, glimepiride) to cause hypoglycemia.

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Symptoms of hypoglycemia; remember that it can mimic virtually any neurologic condition

When thinking about hypoglycemia, it helps to think in terms of whether the patient is ill-looking or not

Ill-appearing

  • drugs (insulin or insulin secretagogue, alcohol, ?others)
  • Sepsis/critical illness
  • Hormone deficiency (cortisol, glucagon or epinephrine)

Seemingly well-appearing

  • Endogenous hyperinsulinism
    • insulinoma
    • post-gastric bypass hypoglycemia
    • antibodies to insulin or insulin receptor
  • Surreptitious/factitious hypoglycemia

Diagnosis

Sulfonylurea toxicity is generally a clinical diagnosis based on history. There are sulfonylurea assays that can be sent, but they generally take too long to result and are thus of limited use

Management of sulfonylurea toxicity

  • D50
  • D5 or D10 gtt
    • should not be used as monotherapy for sulfonylurea toxicity, as it will cause transient hyperglycemia that triggers insulin release and further episodes of hypoglycemia
  • Octreotide
    • works by decreasing insulin release from beta cells
    • Give for the first 24h, and then stop; can restart if hypoglycemia recurs
  • Glucagon
    • NB: very short acting, so should only be used as a temporizing measure while getting IV access or some other longer-acting source of glucose

Activated charcoal can be used within 2-3h of the ingestion, but hemodialysis has not been shown to be effective. Diazoxide, an older drug which also inhibits pancreatic insulin release, used to be used, but is less effective than octreotide and can cause hypotension.


 

We talked briefly about the threshold effect with loop diuretics:

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The inflection point where the blue line takes off is the ‘threshold’, and is largely determined by the rate at which the diuretic gets to its site of action. HF patients show resistance at any given diuretic dose due to Na reabsorption at other segments of the nephron. Brater 1983.

Lastly, this study compared bolus vs continuous infusion of lasix in patients with ADHF, and found that there was no real difference between the two dosing strategies. However, keep in mind that this was part of a research setting, where even bolus doses were probably timed perfectly. In real life, doses may be given late (ie beyond the point that the previous dose is effective), so continuous diuretic infusion may still have a role in clinical practice.

References

  1. Oh S et al. Loop Diuretics In Clinical Practice. Electrolyte Blood Press 2015.
  2. Felker et al. Diuretic Strategies in Patients with Acute Decompensated Heart Failure. NEJM 2011.
  3. Brater DC, Day B, Burdette A, et al. Kidney Int 1984; 26:183.
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10/17 HUP Report – Scleroderma Renal Crisis

Today we were joined by faculty expert Dr. George to discuss a case of scleroderma renal crisis. We spent some time discussing hypertensive emergency, which was this patient’s initial presentation — that has been addressed in earlier blog posts so we will focus on the diagnosis of scleroderma renal crisis (SRC) in this post.

 

There are three major diagnostic considerations for scleroderma renal crisis in a patient with signs or symptoms of scleroderma:

  • abrupt onset of moderate/severe HTN (from increased plasma renin activity)
    • NOTE: approximately 10% of patients are normotensive when presenting with SRC, so do not completely dismiss this dx from your differential in a normotensive patient! They have a worse prognosis than hypertensive patients, possibly due to delayed recognition and treatment!
  • Acute kidney injury
  • Urinalysis is usually unremarkable, though may have a few cells/casts and mild proteinuria

Scleroderma renal crisis is thought to be caused by pathology in the renal vasculature, specifically intimal proliferation and thickening that leads to narrowing and obliteration of the vascular lumen. Some people suggest conceptualizing this as a similar pathophysiologic process to bilateral renal artery stenosis.

Risk Factors

  • Almost always occurs within 5 years of onset of scleroderma
  • Diffuse systemic sclerosis (much more common than limited)
  • Glucocorticoid use (especially doses >15mg prednisone daily)
  • Rapid progression of skin involvement
  • Positive RNA polymerase III antibody
  • NOT risk factors: pre-existing HTN, elevated Cr, or abnormal UA

Monitoring

In patients diagnosed with scleroderma, it is recommended to perform frequent BP checks (daily if high risk) and further workup if sustained increase in SBP >/20 or DBP >/ 10. They should also have urine dip and Cr checked every 3 months.

 

Treatment

ACE Inhibitors are the mainstay of treatment in SRC. There have not been randomized controlled trials to support this treatment, but several observational studies noted improved outcomes. ACE Inhibitors should be initiated immediately, and usually captopril is used during inpatient treatment due to rapid effect and ability to titrate quickly.

All patients with SRC should be on lifelong ACE inhibitor therapy, even patients who present normotensive or those who go on to have improvement in renal function and HTN. Long acting formulations can be used for better adherence.

Many patients will require transient or permanent renal replacement therapy. Some will go on to get renal transplants, although other systemic manifestations of scleroderma can be contraindications. The grafts do not survive as well as in other indications for renal transplant.

 

 

10/11 Presby report: PD peritonitis

We discussed an elderly woman with ESRD who presented with progressive abdominal pain, distention and fevers and was diagnosed with PD (peritoneal dialysis-associated) peritonitis, which was ultimately found to be due to TB!

What is peritoneal dialysis?

In the simplest terms, PD involves the instillation of dialysis fluid into the peritoneum with the goal of achieving solute clearance and ultrafiltration across the peritoneal membrane.

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Dialysis fluid ‘dwells’ in the peritoneum while solute and volume move into it; it is then removed via the peritoneal catheter at the end of the dwell

There are three specific infectious complications of PD catheters: 1) PD peritonitis, 2) tunnel infection and 3) exit site infection

The microbiology of PD peritonitis differs somewhat from spontaneous bacterial peritonitis (SBP).

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Microbiology of PD peritonitis. Glickman 2017

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  • NB: unlike SBP, where >250 PMNs or a +culture is necessary for the diagnosis, about 10% of patients with PD peritonitis present without >100 WBCs, so it’s important to have a high suspicion for it
  • It’s often a difficult decision as to whether to try to preserve the catheter or to pull it. In general, fungal, mycobacterial and pseudomonal peritonitis necessitate catheter removal.
  • You can try to treat through other forms of bacterial PD peritonitis, unless it’s a recurrent or refractory infection
  • Recurrent episodes of peritonitis can make the abdomen less hospitable to PD, and can even lead to the development of peritoneal sclerosis, which may lead to small/large bowel obstruction, constipation, malnutrition and death

This patient ultimately had her peritoneal fluid tested for adenosine deaminase (ADA) given the concern for TB. A few quick notes:

  • It can be used to distinguish between tuberculous and malignant causes of lymphocytic pleural effusions/ascites, etc.
  • Test characteristics vary somewhat between different body sites, but for tuberculous ascites, ADA (particularly values >35) has a ~95% sensitivity and 96% specificity, a positive likelihood ratio of ~16 and a NLR of 0.09!

References

  1. Diagnostic accuracy of adenosine deaminase for tuberculous peritonitis: a meta-analysis. Arch Med Sci 2013.

  2. Akoh JA. Peritoneal dialysis associated infections: An update on diagnosis and management. World J Nephrol 2012.

10/9 VA Report: Chronic Kidney Disease Overview

In a delayed posting — I’d like to thank Lindsey Haddock for her excellent lecture on CKD Complete with picture-worthy whiteboard drawings!

Lindsey started off her overview highlighting the various stages of CKD and the importance of referring to nephrology when patients are stageIIIb (GFR 30-44) so that they can begin the vascular workup/preparations for dialysis.

IMG_0083 (1)

Next Lindsey tackled WHY patient’s get CKD with Hypertension and Diabetes taking the largest piece of the etiology pie at 30% and 45% respectively.

Importantly we reviewed the work up necessary and appropriate treatments/screening needed for the various sequelae of CKD including anemia, mineral bone disease and metabolic acidoses.

IMG_0084

Thanks again for a great lecture Lindsey — always proving that a picture is DEFINITELY worth a thousand words.

 

10/9 HUP Report – IgA Nephropathy

Today we discussed a case of acute kidney injury and proteinuria in a patient with well-controlled HIV, who was ultimately diagnosed with IgA nephropathy. It is important to remember that patients with well-controlled HIV have pretty much the same differential for glomerular disease as the general population.

In general, we classify glomerular diseases based on whether all glomeruli (diffuse) or only some (focal) are involved, and within each individual glomerulus whether the entire unit (global) or only part (segmental) is effected.

There are two broad syndromes of glomerular disease: nephrotic syndrome (which is characterized primarily by proteinuria >3.5 g/day) and nephritic syndrome (glomerular inflammation). Urinalysis findings of erythrocyte casts or dysmorphic red cells have a high specificity for glomerular pathology, which can also be suggested by hematuria and proteinuria.

Nephrotic Syndrome

Nephrotic syndrome can be a primary glomerular pathology, or it can be secondary to a systemic disease process (infectious, malignant, or medication-induced). Here is a basic differential for nephrotic syndrome:

  • Minimal change disease
  • Focal segmental glomerular sclerosis
  • Membranous glomerulopathy
  • Diabetic nephropathy

Nephritic Syndrome

Nephritic syndrome can be conceptualized based on mechanism of disease into three categories – pauci-immune (minimal immune cell infiltration), immune complex deposition, and anti-glomerular basement membrane antibody-mediated.

Pauci immune: seen in vasculitis (MPA, GPA, eGPA)

Anti-GBM antibodies: can have pulmonary manifestations (Goodpasture’s syndrome). Inherited collagen IV disorders can also effect renal function.

Immune complex deposition

  • IgA nephropathy
  • SLE nephritis
  • Infection-related glomerulonephritis
  • Membranoproliferative glomerulonephritis

In our patient, renal biopsy made the diagnosis of IgA nephropathy!

8/29 PPMC Report: Microscopic Hematuria

Today at PPMC we covered one of the basics — microscopic hematuria. We see it ALL the time, we make sure we’ve made the PCP aware in the discharge paperwork — but what does the PCP actually need to DO in follow up? And when should we be forcing more aggressive workup and biopsy?

These were just a few of the great questions asked and answered today. First the PPMC team developed a basic algorithm, and then we moved forward to apply this algorithm to several cases.

Microscopic hematuria

We discussed that microscopic hematuria is NEVER normal and our risk stratification really depends on a triage between glomerular sources of bleeding vs. not and then the patients individual risk factors for malignancy. If glomerular in nature, we discussed factors that require an expedited workup with nephrology for biopsy — increasing protein in urine and worsening renal function.

Our first case was a 38 yo with a PMH of recurrent UTI’s and family history of an unknown “renal disease” who was found to have persistent microscopic hematuria. First, using the above algorithm, the team wanted to confirm that she didn’t have a benign reason for microscopic hematuria including her menses or another UTI. Once that testing came back negative we wanted to “start at the top” to determine if the bleeding was glomerular in nature. Her urine demonstrated dysmorphic reds and red cell casts but importantly NO protein and a normal creatinine. Based on this information we reviewed the data behind conservative medical management without biopsy  — with the presumptive diagnosis as either thin basement membrane or IgA nephropathy.

Our second case was a 65 yo M recently started on Xarelto for a RLE DVT who was found to have microscopic hematuria after starting anticoagulation. Again, benign causes for bleeding were ruled out and an assessment of his risk factors for malignancy  was performed: Age, Smoking status, history of gross hematuria, occupational exposure, h/o cycophosphamide exposure, use of some weight loss/diet preparations with aristolochic acid. This patient was found to have a transitional cell cancer of the bladder.

References:

  1. Cohen, RA and Brown RS. Microscopic Hematuria. N Engl J Med 2003;348:2330-8.

8/24 (HUP): malignancy-induced TMA

Thanks to Amy Forrestel for presenting a crazy case today of a 48 year old man who presented with uremia and a presenting Cr of 25, and was ultimately diagnosed with a thrombotic microangiopathy (TMA) secondary to underlying multiple myeloma.

What is a TMA?

TMAs are defined by the presence of arteriolar and capillary vessel wall abnormalities that cause microvascular thrombosis. The hallmark triad of TMA is microangiopathic hemolytic anemia + thrombocytopenia + acute kidney injuryRemember, however that the presence of all three of those features is not specific for TMA, and can be representative of other conditions (see chart below) that manifest similarly. Also keep in mind that many of these disease entities share common pathophysiologic features, and as we were reminded by Dr. Hogan, the biology of TMAs is evolving and far from fully understood. 

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See this excellent NEJM review about primary TMA syndromes.

  1. When someone presents with the TMA triad (MAHA+thrombocytopenia+AKI), the first priority is to rule out TTP (caused by ADAMTS13 deficiency), as that requires emergent plasma exchange.
  2. Send off an ADAMTS13 level; less than ~10% activity suggests TTP (although some malignancies can decrease levels)– but don’t hesitate to empirically start plasma exchange (PEX/PLEX) and adjunctive steroids if you have a high suspicion for TTP and are waiting for ADAMTS13 to result.

In trying to differentiate clinically amongst the primary TMAs, a few pearls:

  • Have a high suspicion for Shiga-toxin mediated TMA in patients that present with diarrhea (although other TMAs can present with nonspecific GI sx as well)
  • Drug-induced TMA has been linked to quinine (found in tonic water, bitter lemon, antimalarials) most commonly, as well as quetiapine, gemcitabine, and in those that intravenously abuse oxymorphone. Classically, patients who become symptomatic from quinine-induced DITMA will remember the exact moment when they started to feel crummy (see this excellent NEJM case challenge on it which gives a great explanation). See picture below for suspected mechanism.

    Screen Shot 2017-08-25 at 10.55.09 AM.png

    NEJM 2017

  • TTP tends to have less severe AKI compared to the other TMAs, maybe because it’s a problem with ADAMTS13, and not an intrinsic immune-mediated problem with the renal vascular endothelium
    • The risk of post-TMA CKD varies between different causes of TMA (ex: high in quinine-induced TMA, low in Shiga-toxin TMA)
  • Complement-mediated TMA (aka atypical HUS) is very rare, and is sort of a diagnosis of exclusion (unless you’re able to send off testing for genetic complement mutations, which only a few places do); once you’ve excluded TTP (using a normal ADAMTS13 level) and the other TMAs by history, you can settle on complement mediated TMA (aka ‘atypical HUS’)
    • If complement-mediated TMA is suspected, eculizumab (a monoclonal antibody to C5 which blocks membrane attack complex formation) should be started ASAP.
    • Eculizumab caveats: very expensive (~$400K/year), and puts patients at high risk for invasive meningococcal infections (as well as Strep pneumo and H. flu B)
  • Random pearl: vasculitis causes glomerulonephritis most commonly; the absence of proteinuria does not rule out vasculitis, and in fact microscopic hematuria on UA is more sensitive for renal vasculitis than the presence of protein

Finally, see the algorithm below for an approach to TMAs

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UpToDate 2017

 

 

References

  1. Legendre et al. Terminal Complement Inhibitor Eculizumab in Atypical Hemolytic-Uremic Syndrome. 2013 NEJM. 368 (23) 2169-81.
  2. Syndromes of TMA. NEJM.
  3. CDC MMWR. High Risk for Invasive Meningococcal Disease Among Patients Receiving Eculizumab (Soliris) Despite Receipt of Meningococcal Vaccine. 
  4. Approach to the patient with suspected TMA. UpToDate.