Kidneys Inc.

medicine and nephrology updates and interesting cases by a practicing nephrologist in USA

Archive for the category “Drugs”

Vitamin C and kidney disease

61 y old man who had hyperaldosteronism requiring adrenalectomy 4 y prior, bariatric surgery for morbid obesity 1.5 y ago, was off medications for both HTN & DM after the surgery, had contrast nephropathy after cardiac cath done during pre op evaluation for adrenalectomy (no CAD found). Baseline creatinine around 2.

Had transferred care to our facility about 2 mths ago. Had been found to be anemic started on iron therapy. worked as a hydraulic engineer and looks very organized with a neatly maintained folder for all his healthcare issues.


BP high in clinic. But states it has been good at home.

Creatinine has trended up from 2.2 in oct 2010 to 2.4 on aug 5 2011, 2.6 on aug 26 2011. 2.9 on sep 16 2011. HgbA1C 5.8

No obvious cause. No NSAID use. No evidence of volume depletion. No reports of hypotension. On enquiry has been drinking some supplement that his wife give him- supposed to be a multivitamin.

Also UA – no proteinuria. HCO3 decreasing to ~ 18. anion gap is 7.8 alb 3.7 protein 7.4

Scratched my head- (if only it worked) I discussed it with colleagues. No luck.  Omeprazole started on his first visit to pcp at our facility (replacement for nexium) was discontinued, even though there was no other evidence for AIN (like rash, fever, Wbc in urine). suddenly one of my colleagues who was talking with a pathologist who mentioned oxalises suddenly remembered this pt who was on vitamin C. The primary care provider had prescribed it in order to enhance iron absorption

I immediately called the patient asked him to stop taking his vit C

I am bringing him back next week. will try to spin his urine and look for oxalate crystals

Thanks to my colleague who kept this case in the back of her mind..

Vit C in CKD

Can cause oxalosis. Many patients tend to take it as they see advertisements for Vit C for its anti-oxidant properties, to increase iron absorption to treat iron def anemia  etc. however, in CKD this may be detrimental since it acts as a precursor for oxalate and can cause oxalate nephropathy.

Could his bariatric surgery contribute to increased absorption of vit C. I do not know the type of bariatric surgery he had done. If he had the most common type (Roux en Y) then it is likely that the Calcium chelated with the unabsorbed fatty acids allowing for increased absorption of the Vit C causing hyperoxalosis and AKI.

This is still the suspected diagnosis. will know more when he gets his herbal OTC vitamin supplement with his next visit.

will update this soon

BARD for Diabetic nephropathy

This week in NEJM, there is a major article with results from a new study BEAM, showing efficacy of a medication, Bardoxolone methyl (BARD) an oral antioxidant, in chronic kidney disease due to diabetes. We have always known of medications that decrease renal function. This would be the first medication that improves renal function. It works by inhibiting renal injury by oxidative stress and inflammation in diabetic kidney disease. However, Its role in other conditions with the same pathophysiology has not been tested, yet. Type 2 Diabetes being the most common cause of CKD (chronic Kidney disease) this new drug (if tested safe and effective in long term studies), might give the much needed major turn in management of diabetic kidney disease.

Summary from the NEJM article:

Sponsored by Reata pharmaceuticals, an employee of the sponsor wrote the first draft of the manuscript. study design by first author and representatives of the sponsor.

Glomerular Filtration Rate GFR estimated using the four variable (Modification of diet in Renal disease) MDRD equation

Patient characteristics: similar in all four groups. mean age 67 y, well controlled blood sugars, 98% were receiving ACE, ARB or both. Mean GFR was about 32 +/- 7 ml/min/1.73m2. Albumin to creatinine ratio (ACR) was distributed almost in thirds.

Exclusion criteria: type 1 diabetes, nondiabetic kidney disease, a glycated hemoglobin level of more than 10%, hepatic dysfunction, or a cardiovascular event within the previous 3 months.


Primary outcome: Change from baseline of estimated GFR Bardoxolone methyl vs placebo at 24 wks –> upto 12ml/min/1.73 m2 difference in eGFR between placebo and the BARD group

Secondary outcome: change in eGFR at 52 weeks–> upto 10 ml/min/1.73 m2 difference in eGFR between placebo and BARD group

Exploratory outcomes:

a) Cumulative changes in estimated GFR from baseline to 52 wks –>54% in placebo group. ~ 20 % in 25 mg group and 75 mg groups, 27% in 150 mg group

b) Time to and percentage of patients with > 25% reduction in eGFR 13% in placebo vs 2% in BARD group

c) Slight but significant increase in ACR in 75 & 150 mg BARD group at 24 & 52 wks.

d) Significant decreases in levels of blood urea nitrogen, serum phosphorus, uric acid, and magnesium, as compared with placebo at 24 wks

Adverse events: more in bardoxolone group 18% vs > 50%

1. muscle spasm most common in first 12 wks, resolved spontaneously with continuation of drug

2. Hypomagnesemia (not related temporally to 1.)

3. Alanine amino transferase elevation, mild and transient

4. GI side effects (nausea, vomiting, decreased appetite)

5. Last but not least : The BARD group had slight but significant increases in ACR. Authors explain it by attributing it to increased GFR but decreased tubular reabsorption.

Discussion: Oxidative stress and inflammation is the final common pathway for chronic kidney disease in diabetic nephropathy. Bardoxolone activates the Keap1-nrf 2 (kelch like ECH associated protein1nuclear factor E2 related factor) pathway thus ameliorating damage, hence preventing deterioration the pathogenic agents. It interacts with cysteine residues in keap1, causing translocation of Nrf2 to nucleus and upregulation of several cytoprotective genes. Bardoxolone activates nrf2 expression in glomerular endothelial cells and peritubular capillaries, increased hemoxygenase 1 in tubules and interstitial leucocytes. BARD also exerts inhibitory effect on nuclear factor kB pathway. This leads to decreased inflammation, BUN, and amelioration of both glomerular and tubular injury

Side note: Nrf2 deletion causes inflammation/oxidative stress.


Treatment with BARD lead to sustained and significant improvement in GFR in patients with CKD due to diabetes. The effect was sustained after 4 weeks after discontinuation of the drug.

Increases in the estimated GFR was independent of changes in albumin excretion

The absence of a significant decline in the estimated GFR among patients receiving placebo may reflect the fact that most patients did not have macroalbuminuria at baseline and their important risk factors (e.g., blood pressure and glycated hemoglobin levels) were well controlled with standard medical care

However, bringing skepticism to the table: we know that proteinuria is a not only a major marker for renal function but also mediates injury. If the glomerulus is in some way protected by BARD, it has to be reflected by decrease in albuminuria. or there might be a possibility that the protection conferred by BARD might be negated by increased proteinuria.

Important questions that pop up:

The GFR was estimated by creatinine based equations. Does BARD have any effect on serum creatinine itself outside of its reported protective effect, either in laboratory measurements or in its production or secretion. In any of such situations, it can lead to a falsely higher GFR on calculations. There is reference (Number 28) that says no.

By excluding patients with poorly controlled diabetes, with higher glycated hemoglobin levels is there a selection bias where only patients with better predicted outcomes were studied. Note that the placebo group

But being optimistic, if it works out, this medication could potentially play a major role in many disease processes that are mediated by the Keap1-Nrf2 pathway.

Lactic acidosis in metformin overdose

Lactic acidosis associated due to metformin is rare and especially so in normal renal function. I had the opportunity to see this. 45 y old woman with major depression who had been prescribed metformin but had not been taking it, ingested about 90 tablets as a suicidal attempt. Seen in the ER within 2-3 hours after ingestion, given charcoal, started on gentle IV hydration, admitted for monitoring. Lactate was elevated to 5.1. Renal function was completely normal with Creatinine of 0.9. Lactate decreased to 0.9 within 24 hours.

Metformin decreases lactate metabolism by suppressing pyruvate carboxylase in the Kreb’s cycle. Glucose utilisation is decreased and lactate production by the hepatocytes is increased.

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