Could this be Refeeding Syndrome?

A young patient who was engaging in heavy weightlifting presented to the ED with proximal muscle weakness. The night before he had one hour of acute onset bilateral leg and hip flexor cramps with stiffness and "hardened" muscles and marked weakness that prevented him from standing or walking. This resolved spontaneously. After an intense workout the next morning he noted cramping and weakness in his legs and was unable to walk, therefore he presented to the ED. 

He had been taking a thyroid supplement for several months but had stopped about three weeks prior. He was also taking lisinopril for hypertension. He was currently using a steroid supplement containing designer steroids (10 mg androstenone and 10 mg androstan-one-azine) for several months. He also took vitamin B5 and niacin. He was eating a high protein diet mainly consisting of chicken and sauce (some sort of Teriyaki sauce) and some rice and very few vegetables for several months averaging 4000 to 8000 calories on most of the days of the week.

Two days before presentation he started eating "normally" again with high amounts of carbohydrates as a treat (cake and sweets).

In the ED: K 2.0 mmol/L, PO4 1.0 mg/dl, glucose 197 mg/dl, Mg 2.0 meq/L, CK 5070 U/L, TSH 0.01, low normal total T3, low total T4 and low free T4 but normal free T3. Urine electrolytes at the time of presentation were notable for a potassium of < 10 and an undetectable phosphorus level (Fractional excretion Phos < 5%). His ECG showed slight abnormalities but troponins were negative x 3.

Phosphate was repleted with 12 mmol NaPhosphate and normalized. Potassium was repleted with 40 meq KCl IV and 120 meq po until normal. His leg weakness resolved and the CK started to trend down.

The question is: what caused his profound electrolyte abnormalities? 

One possibility is refeeding syndrome as described in a previous post. The sudden surge of carbohydrates following a long period of high protein, low carb diet might have caused an increase in insulin driving potassium and phosphate into the cells. Hypomagnesemia was, however, not present in this patient. The time frame (within 4 days) would be consistent with refeeding syndrome. The rhabdomyolysis occurred as a consequence of hypokalemia and hypophosphatemia with a contribution from heavy exercise. He responded quite fast to potassium and phosphate supplementation and improved clinically within a day.

Patients with the following conditions have traditionally been at risk for refeeding syndrome: anorexia, chronic malnutrition (e.g. in patients with cancer), alcoholism, prolonged fasting, after a duodenal switch operation for obesity, hunger strikers and postoperative states. In these times of extreme dieting one should think outside the box and ask about special diets such as high protein diets. The kidney on the other side has been doing it's duty and preserved whatever electrolytes were still in the circulation by absolutely minimizing excretion of potassium and  and phosphate.
Posted by Florian Toegel

Kidney Biopsy Case: AKI

A 54 year old man was referred to the Nephrology service due to AKI after presenting with lethargy and severe thirst. He had a long history of pulmonary and hepatic sarcoidosis which had been quiescent for some time. He likely had some baseline mild CKD with a serum creatinine of 1.3 mg/dl and 0.5 g/day proteinuria. His medications were unremarkable except for a calcium and vitamin D preparation which he had been taking for several months. His creatinine was 4.0 mg/dL and calcium was 13.5 mg/dl on presentation. He was volume resuscitated, treated for his hypercalcemia and proceeded to renal biopsy. Low power light microscopy is below which reveals an interstitial infiltrate with moderate fibrosis and some sclerosed glomeruli.

Higher power demonstrates multiple non-caseating granulomas. The granulomas consist of amorphous reddish material as well as multi-nucleated giant cells (below; top left and right of center).

Another example below of a granuloma (on the left of the panel) in a sick looking tubulo-interstitium.

The diagnosis was sarcoidosis-related granulomatous interstitial nephritis. He was commenced on high dose oral steroids and his renal function settled back down to normal over several weeks. Sarcoidosis does uncommonly affect the kidneys and is a major differential for granulomatous interstitial nephritis (see previous post). A teaching point for this case is not to presume the hypercalcemia is all iatrogenic. The high calcium points to sarcoid activity which was demonstrated nicely on the biopsy.

Genetic Defects of the Glomerular Basement Membrane

The glomerular basement membrane is a thin layer of extracellular membrane proteins that is an important part of the filtration barrier, particularly glomerular permselectivity, by preventing proteins from crossing into the filtrate. The major proteins in the GBM are laminin, type IV collagen, nidogen and the heparan sulphate proteoglycan agrin. Interestingly, in the past, I was taught that the highly negative charge on agrin played the major role in mediating charge selectivity. However, recent studies have shown that mutations in the gene encoding agrin, leading to a reduction in charge along the GBM, have no effect of glomerular function in mice. Similarly, deletion of agrin has little effect on permselectivity further suggesting that the role of the proteoglycans in selective filtration is minor at best.

There are two conditions associated with genetic defects in glomerular basement membrane proteins:

Syndrome	Gene(s) affected	Protein	Phenotype
Alports Syndrome	COL4A3 COL4A4 COL4A5	Type IV Collagen, α3, α4, α5 subunits	Initial normal formation of GBM but eventually hematuria, proteinuria and eventual ESRD with characteristic splitting of the GBM. COL4A5 mutations are commonest and are X-linked. Other forms are autosomal.
Pierson Syndrome	LAMB2	Laminin β2	Autosomal recessive disorder with variable phenotype depending on the particular mutation. However, ocular abnormalities (microcoria) are present at birth and the majority of affected individuals progress to ESRD within the first few weeks/months of life. Extrarenal manifestations including hypotonia and neurodevelopmental defects have been reported.

Please see this excellent review in Nature Reviews Nephrology for further information.

Diabetes and CKD: Pitfalls - Monitoring response to therapy

There are two important issues to remember when assessing glucose control in patients ESRD, one relating to immediate blood sugar measurement, and another relating to longer term diabetes control.

The first has previously been mentioned on this blog. The use of icodextrin in PD solutions is increasingly common as a means of increasing fluid removal with less absorption of the solute. Icodextrin is not generally metabolized in the peritoneum but small quantities can cross into the systemic circulation where it is metabolized to maltose. Some commercial blood sugar test strips are unable to differentiate between glucose and maltose in the serum. This is not normally an issue because there is very little sugar apart from glucose in the blood. However, in patients on PD, the presence of maltose can lead to falsely elevated blood sugar readings with certain analyzers. This has lead to at least one death in a patient who was inappropriately treated with insulin in this setting. Of course, icodextrin is not the only potential source of maltose - certain IG preparations can also contain maltose resulting in similar presentations.

Traditionally, long-term monitoring of glucose control is done by regularly measuring HbA1c levels. However there are some concerns regarding the use of HbA1c in dialysis patients. RBCs in patients with ESRD tend to have shorter half-lives while the use of EPO appears to affect Hb glycation in unpredictable ways also. The relationship between HbA1c and mortality in dialysis patients is complex and contradictory results have been noted in various studies. A recently published study using data from the DOPPS study found that HbA1c was associated with mortality but only at substantially higher levels that would typically be considered normal.

One possibility is to use alternative measures of glycemic control such as glycated albumin or fructosamine. These have the advantage of not being affected by the Hb concentration. However, in contrast to HbA1c, they measure short-term glucose control only - for example, glycated albumin is a marker of glucose control over a period of about 17 days. One recent study found a significant association between glycated albumin and mortality while HbA1c was not as useful. It's possible that the reduced association between HbA1c and glucose control in diabetics with ESRD may be a contributing factor in recurrent episodes of hypoglycemia in some patients.

Thromboembolic Prophylaxis in Patients with AFib and CKD: Caught between the Devil and the Deep Blue Sea

I often get curb-sided by cardiologists and internists for my opinion on using warfarin or other anticoagulants for thromboembolic risk prophylaxis in CKD +/- Afib patients. A similar conundrum of using anticoagulation for stroke prophylaxis in dialysis patients was discussed about three years ago on this blog by Conall. Like many other issues in patients with CKD, things are not always black-and-white, and a lot could depend on patient and physician preference.  This often makes the “right answer” a confusing exercise, since CKD patients are also at a higher bleeding risk. Most randomized trials addressing this issue have excluded patients with a GFR below 30. Furthermore, newer direct thrombin inhibitors (dabigatran), or Factor Xa inhibitors (apixaban, rivaroxaban) are available, which might be better than warfarin, at least in the early-CKD patient (although the lack of a reversing antidote is a potential pitfall). Finally, warfarin has a well-established link with vascular calcification (a mortality risk) in dialysis patients. As nephrologists, it is imperative that we are knowledgeable about the best-available data that can help us make an evidence-based recommendation, and so I put together a concise decision-table with links to primary literature sources.

In addition to the “traditional” risk factors for stroke in patients with AFib (as exemplified by the acronym CHADS), it is known that CKD itself is an independent risk factor for stroke. Thus CKD patients, both with, and without AFib, are at an increased risk of stroke. This has been demonstrated in CKD as well as dialysis patients, and the risk worsens with decline in GFR. 

Thus, with the above background in mind, the two main variables that determine what, if any, anticoagulation is to be used in this setting, are (1) the stage of CKD, and (2) the CHADS2 score:

CHADS2 Score	CKD STAGE
	Stage 3, eGFR 30-59	Stage 4, eGFR 15-29	Stage 5, eGFR less than 15, or dialysis
0	Either ASA or AC (weak recommendation)	ASA vs. AC (warfarin) vs. no antithrombotic treatment given bleeding risk??	ASA vs. AC (warfarin) vs. no antithrombotic treatment given bleeding risk??
>1	AC (Direct thrombin inhibitors (dabigatran), and Factor Xa inhibitors (rivaroxaban, apixaban) potentially superior to warfarin	AC (warfarin preferred since no data on direct thrombin or factor Xa inhibitors)	AC (warfarin preferred since no data on direct thrombin or factor Xa inhibitors)

 

ASA = Aspirin

AC = Anticoagulation

?? = Expert opinion only, no strong evidence available - weight risks vs. benefits

Remember that no antithrombotic therapy is warranted if bleeding is a concern

Posted by Veeraish Chuahan

(Apologies for any formatting issues)