Consult Rounds: Low Urinary Na

Urinary Na concentration is a very useful urinary test that we use in clinical practice to decide the volume status of the patient. It is also very useful in helping decide pre renal vs intrinsic renal disease. 

There are several causes of AKI where urine Na concentration and fractional excretion of Na may be initially low, only to increase later. They are listed below

1.       Radiocontrast agent induced AKI- due to AngII increase and ischemic damage

2.       Sepsis- activation of AngII leads to initial vasoconstriction and low levels of urinary Na

3.       NSAIDs- unopposed vasoconstriction from Ang II

4.       Rhabdomyolysis- mechanism unclear

5.       Acute obstruction( initial phase)- again activation of AngII

6.       Acute GN- cytokines that lead to decrease GFR causing lowering of filtered Na load

7.       Acute rejection- similar to GN

A recent article in CJASN reviews the use of urinary studies in diagnosis of kidney diseases.

HATs off to Nephrology: The various HATs of a nephrologist

As I finished my 2 weeks on consults, I just realized why I love nephrology because it let's me wear various types of HATs

Day 1:- Consult 1: - Minimal Change Disease on kidney biopsy- starting steroids, no secondary cause. Nice GN to start the day ( putting on the GN hat)

Day 2: Consult 3: AKI on CKD in someone with CHF, getting diuresis but serum creatinine rising. Intern says, we stopped diuresis as AKI ensued.  On exam, +JVP, + B lines on our portal lung US exam, Ascites and + LE edema. Dear Intern, please don’t be nephrocentric but continue diuresis as this is renal venous congestion and bingo- 2 days later serum creatinine downtrends. Pre renal success shall we say( putting on the critical care or cardioneph hat)

Day 2: Consult 5: Na of 167, Diabetes Insipidus, bring on the ddavp please!( putting on my electrolyte hat)

Day 3: Consult 3: AKI in someone getting vanco-zosyn combination, rising vancomycin levels and creatinine going from 1mg/dl to 5mg/dl in 3 days. Kidney biopsy confirms ATN/AIN.  That vanco-zosyn combo is becoming lethal to the kidneys. How many drugs can we stop? – NSAIDS, PPIs, Vanco-zosyn. I feel like the medication police!( putting on my AKI hat)

Day 4: Consult 4: Hypomagnesemia severe enough to be admitted 3 times. PPI still on board and FeMg<2%.  Sorry but those PPIs are causing Ulcers for us the Nephrologists!( putting on my electrolyte hat)

Day 5: Consult 5: AKI in a 85 year old with MODs, septic shock and overall poor prognosis. Surprise question asked and dialysis not offered. Palliative care nephrology is important as well. Not every patient is an ideal dialysis candidate( putting on our palliative care nephrology hat)

Day7: Consult 6: Hypercalcemia and an elevated 1,25 vitamin D level- lymphoma, TB or Sarcoid and the only hypercalcemia that responds to steroids!!( putting on the onconephrology hat)

Day 8: Consult 2: AKI with someone with severe AS. Diuresis begins but guiding volume management is a tough decision. Severe AS scares me. Point of care lung US daily assessing for B lines guides management proves to be a great addition to our physical exam.( putting on the ICU nephrology hat)

Day 9: Consult 1: AKI, low platelets, low hemoglobin, rising LDH, down-trending haptoglobin and worsening HTN—bring on the TMA team. From what- virus, systemic disease, complement deficiency, not sure—but oh well onconephrology rocks! ( putting on the onconephrology hat)

Day 10: Consult 1: HTN HTN, HTN severe HTN—adrenal mass, and record high metanephrine levesl- pheochromocytoma in the house!, get the surgeons and endocrine on board( putting on the HTN specialist hat)

Day 11: Consult 2: Hyponatremia 127 but serum osmolality is 290. Hmmmm!! Paraproteins made an appearance and masquerading myeloma- more onconephrology! ( ofcourse this hat comes twice)

Day 12: Consult 3: Acute ESRD, doesn’t want HD--- but would consider acute PD –so urgent start PD done.. The new wave in PD care. Not every patient needs HD, you can in the right environment get urgent start PD and get PD arranged as outpatient- we need to make this mainstream. ( putting on the ESRD hat)

Day 12: Consult 4: AKI and proteinuria in someone with history of SLE. Kidney biopsy shows nodular sclerosis and diabetic nephropathy. No active lupus. Not all kidney biopsies in SLE are lupus nephritis.( putting on the Rheum-Renal hat)

Day 13: Consult 1: AKI, proteinuria - biopsy confirms Post infectious GN, ongoing infection treatment needed. ( putting on the GN hat)

 

Now with the above case listing- wouldn’t you feel so excited. This is why Nephrology is so much fun!! Which other field in medicine allows for so much variety!

Concept Map: Hypomagnesemia and it's effect on other electrolytes

Topic Disciussion: Bold and BRASH

Bold and BRASH

As we all know, one of the cornerstones of nephrology is the intimate relationship between the ever-present and masterfully made kidneys and that other thing less important thing a little higher up that pumps blood (remember this is a nephrology blog.) In all seriousness though, we can never forget that renal disease inevitably begets cardiac disease and vice versa and must always be vigilant about that relationship. And of course, there are many ways that this phenomenon called cardiorenal syndrome comes to exist. I want to touch upon a special phenomenon called BRASH syndrome.

BRASH syndrome which stands for Bradycardia, Renal Failure, AV-nodal blocking agents, Shock, Hyperkalemia is a phenomenon that usually occurs (but not necessarily required) in the setting of AV-nodal blockers that cause bradycardia which leads to poor renal perfusion which progresses to renal failure which causes hyperkalemia which in turn leads to worsening bradycardia and the cycle continues. It is an incredibly interesting scenario in that seemingly unrelated or previously thought unrelated components are very closely related.

Looking back, people have described a phenomenon whereby people who have bradycardia end up in renal failure.  Physiologically this makes perfect sense when thinking about cardiac output as seen below:

 Cardiac Output = Heart Rate X Stroke Volume

As heart rate drops stroke volume is not always enough to keep up with cardiac output especially if a patient has pre-existing cardiac disease and cannot mount a good volume response to drop in HR. Patient’s with kidney disease are also susceptible to this. Eventually, patients will go into shock from this perpetual cycle.

Treatment for this disease really hinges on two things: restoring sinus rhythm at appropriate which should in turn start to relieve acute kidney injury by restoring renal perfusion and temporizing patients with hyperkalemia. In most cases invasive measures like transvenous pacing are NOT necessary unless advanced heart blocks are present however medications such as dopamine or isoproterenol or even epinephrine can be used to try and restore perfusion to the kidney. If patient’s have suspected AV-nodal blocking agent toxicity even conventional methods like glucagon or insulin drip are not usually necessary. Next, IV calcium should be used to help stabilize cardiac membrane to prevent further bradycardia. Then, kaluresis is important as well to help stop bradycardia. If a patient is hypovolemic fluid resuscitation is very important and Lactated Ringers or Bicarbonate infusion can be used based on the patient’s acid-base status. Also, if patient is anuric, diuretics can be tried to help open up kidneys to eliminate potassium however if patient’s do not respond, dialysis may be required to intervene in this cycle to prevent further bradyarrhythmia and/or arrest.

Overall, BRASH syndrome is a sometimes-overlooked entity which can be resolved quickly if caught early and usually can prevent worsening renal and cardiac disease.

Major Take Away Points:

1)      BRASH Syndrome - Bradycardia, Renal Failure, AV-nodal blocking agents, Shock, Hyperkalemia

2)      Vicious cycle where one entity (sometimes started by AV-nodal blockers) usually leads to another

3)      Occurs due to drop in cardiac output from bradycardia without appropriate response of stroke volume to compensate

4)      AKI occurs in low flow state causing renal hypoperfusion leading to pre-renal state and possible ATN causing build-up of potassium

5)      Treatment relies on managing bradycardia to restore renal perfusion, and cardiac membrane stabilization along with kaluresis

For more information, there is a great review here:

http://emcrit.org/pulmcrit/brash-syndrome-bradycardia-renal-failure-av-blocker-shock-hyperkalemia/

 image courtesy: https://spongebob.fandom.com/wiki/Bold_and_Brash

Post by
Rushang Parikh, MD

Topic Discussion: Icodextrin and it's important pseudo-lab effects

Icodextrin is a glucose polymer used in peritoneal dialysis to help in improved clearance and ultrafiltration. Laboratory and metabolic effects of icodextin is important to know( especially the effect on glucose, Na and serum osmolarity)

There are a few that are important to remember

1.      The predominant circulating metabolites of icodextrin are maltose , maltotriose , and maltotetraose, with little glucose released in the systemic circulation due to the absence of circulating maltase. The release of glucose from the metabolized polymers occurs predominantly during the intra-cellular metabolism of maltose or other polymers by way of cellular enzymes involved in carbohydrate metabolism.

2.       The “glucose load” arising from the use of icodextrin is “functionally invisible” to the peritoneal cavity and systemic circulation, and its predominant systemic exposure is intracellular.

3.      In contrast to the acute hyperglycemia and hyperinsulinemia associated with glucose-based solutions, icodextrin does not lead to hyperglycemia or hyperinsulinemia following its intraperitoneal administration. 

4.      Point of care glucose testing might not be accurate when using icodextrin and serum glucose values should be used for insulin management.  Maltose interferes with glucose assays that utilize glucose dehydrogenase enzymes of the pyrroloquinolinequinone class (GDH PQQ), causing falsely elevated readings. The overestimation of glycemia is likely due to the presence of maltose and other oligosaccharide metabolites of icodextrin in the systemic circulation and the reaction of GDH-PQQ with the free reducing group of the glucose molecule located at the end of each saccharide chain.

5.      The decline in serum sodium and chloride associated with icodextrin therapy is caused mainly by a dilutional effect resulting from blood levels of icodextrin metabolites, particularly maltose and maltotriose. The presence of osmotically active particles in the vascular compartment is sufficient to cause a slight shift in water from the interstitial and cellular compartments to the vascular compartment, resulting in the dilutional hyponatremia (sometimes called hypertonic hyponatremia). It is like having hyperglycemia or mannitol induced hyponatremia.  

6.      Use of icodextrin has been associated with a slight increase in plasma osmolality in some studies. It can last up to 2 weeks after discontinuing icodextrin

7.      A small increase in mean serum alkaline phosphatase  has been reported in some studies of icodextrin Increases in alkaline phosphatase are not associated with true liver or billiary disease.

8.      Icodextrin interferes with amylase activity measurements by acting as a competitive inhibitor in the amylase activity assay.

Topic Discussion: Krüppel-Like Factors and the Kidney

Krüppel-Like Factors are now creeping their ways in to the Nephrology world. What are they and why is this important for kidney disease- and specifically glomerular diseases? The Krüppel-like factor (KLF) family of transcription factors regulates diverse biological processes that include proliferation, differentiation, growth, development, survival, and responses to external stress. Seventeen mammalian KLFs have been identified, and numerous studies have been published that describe their basic biology and contribution to human diseases. KLFs are critical regulators of physiological systems that include the cardiovascular, digestive, respiratory, hematological, and immune systems and are involved in disorders such as obesity, cardiovascular disease, cancer, and inflammatory conditions.

When I pubmed this, you get over 4000 citations.  

Several studies have looked at these factors and their role in kidney disease and specifically podocytes. 

Few deserve some mention.

Several studies showed that treatment with glucocorticoids restores podocyte differentiation markers and normal ultrastructure and improves cell survival in murine podocytes. A series of papers have looked at KLF15 and it is required for restoring podocyte differentiation markers in mice and human podocytes under cell stress. In one study in JASN  2016, the investigators showed that in vitro treatment with dexamethasone induced a rapid increase of KLF15 expression in human and murine podocytes and enhanced the affinity of glucocorticoid receptor binding to the promoter region of KLF15 In three independent proteinuric murine models, podocyte-specific loss of Klf15 abrogated dexamethasone-induced podocyte recovery. Furthermore, knockdown of KLF15 reduced cell survival and destabilized the actin cytoskeleton in differentiated human podocytes. Conversely, overexpression of KLF15 stabilized the actin cytoskeleton under cell stress in human podocytes. Finally, the level of KLF15 expression in the podocytes and glomeruli from human biopsy specimens correlated with glucocorticoid responsiveness in 35 patients with minimal change disease or primary FSGS.  In a more recent JASN article, Tg26 mice model, inducing podocyte-specific KLF15 attenuated podocyte injury, glomerulosclerosis, tubulointerstitial fibrosis, and inflammation, while improving renal function and overall survival; it also attenuated podocyte injury in ADR-treated mice.So it is possible that KLF15 might be important in podocyte protection and overexpression of this factor might help response of steroids. Both steroids and retinoic acid induces increase expression of this factor in certain patients.

In addition, KLF2 might have a similar protective effect but in endothelial cells and endothelial injury. KLF2 is down-regulated in glomerular endothelial cells of patients with diabetic kidney disease and that endothelial cell-specific reduction in KLF2 expression in experimental model of diabetic kidney disease exacerbates glomerular endothelial cell injury and accelerates the disease progression.   

KLF6 might be involved in mitochondrial injury protection in diabetic disease.

Another study showed human kidney biopsy specimens of RPGN showing reduced KLF4 expression with a concomitant increase in phos-STAT3 expression. This loss of KLF4 results in STAT3 activation and cell-cycle reentry, leading to mitotic catastrophe. Conversely, either restoration of KLF4 expression or inhibition of STAT3 signaling improved survival in KLF4-knockdown podocytes. 

With the advent  of KLFs in the kidney world, perhaps we might have a potential way to help enhance our therapy in glomerular diseases.

Topic Discussion: Secondary Oxalate Nephropathy

Oxalate deposition in the kidney is rare but recently several case reports have highlighted this finding.

A recent KI reports paper summarized and did a systematic review of all published cases showing biopsy proven oxalate nephropathy.

In their systematic review, the most common presentation of oxalate nephropathy was acute kidney injury (35%), followed by acute on CKD (29%). Twenty-six percent of patients presented with kidney disease and stones, and 10% with CKD. In contrast, 20%–50% of patients with primary hyperoxaluria present with recurrent nephrolithiasis, and CKD or kidney failure. Proteinuria was the most common urinary finding (69%), followed by hematuria (32%). Urinary oxalate crystals were identified in only 26% of cases. 

What did the pathology show in most cases?  Kidney biopsy findings of acute tubular injury and interstitial infiltration were reported in 71% and 72% of patients, respectively, which suggested a cause role for the oxalate crystals. Majority of the patients had chronicity. Interestingly, glomerular changes were found in 59% of the biopsy specimens, which were mostly mesangial cellular proliferation; this might explain the high prevalence of proteinuria. There were no cases of crystal deposition in the glomeruli.
 

Renal replacement therapy is required in >50% of patients and most patients remain dialysis-dependent.  Monitoring the 24-hour urinary oxalate excretion rate might be a useful tool for prevention of oxalate nephropathy in high-risk patients.

Some of the causes the authors noted that could lead to secondary oxalate nephropathy were:

Pancreatic adenocarcinoma
Systemic sclerosis
Roux-en-Y bypass surgeries of various types
Hemicolectomy
Gastric bypass
Jejunoileal bypass
Bariatric surgery of various types
Cystic fibrosis
Orlistat( weight loss drug)
Octreotide
Mycophenolate mofetil ( rare)
Clostridium difficile colitis
Averrhoa carambola
Vitamin C
Peanuts
Tea
Rhubarb
Chaga mushroom
Piridoxylate

Crohn’s disease
Celiac disease
Absence of Oxalobacter formigenes colonization
Chronic pancreatitis
Small bowel resection
Diabetic gastroenteropathy

On twitter, I asked a question "
What determines why someone can develop oxalate nephropathy while someone else develops nephrolithiasis?"

7:54 AM - 8 Jan 2019

#askrenal @askrenal What determines why someone can develop oxalate nephropathy while someone else develops nephrolithiasis?

— Kenar Jhaveri (@kdjhaveri) January 8, 2019