Concept Map: Cholesterol Embolic Renal Disease

 

Based on a recent study published by Jain et al. 

Topic Discussion: Hyponatremia with Spironolactone

Hyponatremia from MRAs is a rare phenomenon but we have encountered it clinically. There are times, when we check labs after starting spironolactone for HTN, 3-4 weeks later, the Potassium is slightly up and the Na comes back 130 or 131 mmol/L.  What is the data and the mechanism for hyponatremia following spironolactone use? Is this even related.

In an abstract presented at AHA few years ago, small amount of patients were noted in an EHR to have hyponatremia following starting of spironolactone but most were following on after being started on a thiazide.

In another paper, high doses of furosemide and spironolactone, or concomitant use of these diuretics, seem to be an important cause of hyponatremia in HF patients, particularly in combination with advanced age, diabetes, and alcohol consumption. Diuretic dose reduction may help avoid hyponatremia and improve clinical status and prognosis in such patients.

Is it possible that a combination of a thiazide and a K⁺-sparing diuretic such as amiloride and spironolactone can increase the risk of hyponatremia because of the enhanced urinary loss of sodium in the cortical distal tubule? Perhaps not the main mechanism.

What about the concept of vasopressin escape? During hyponatremia, the body limits the degree to which serum sodium concentration falls through a mechanism called "vasopressin escape". Vasopressin escape is a process that prevents the continuous decrease in serum sodium concentration even under conditions of sustained high plasma vasopressin levels. In a recent basic science study, the abilities of aldosterone synthase (Cyp11b2) knockout and wild-type mice to escape from vasopressin were compared. Wild-type mice escaped while the aldosterone synthase knockout mice did not. Both the water channel aquaporin 2 (AQP2) and the urea transporter UT-A1 protein abundances were higher in aldosterone synthase knockout than in wild-type mice at the end of the escape period. Vasopressin escape was also blunted in rats given spironolactone, a mineralocorticoid receptor blocker. The authors results indicate that aldosterone regulates vasopressin escape through calcineurin-mediated protein changes in UT-A1 and AQP2.

    So is it possible that we are blunting the natural vasopressin escape when we combine thiazides with MRAs? Do all MRAs do this?- this is still unclear. Hyponatremia related to MRAs is an understudied area worth exploring.

Concept Map: Onco-HTN( cancer therapy related HTN)

 

Based on a recent AHA scientific statement, a concept map on onco-HTN

In the NEWS: Cardio-renal syndrome scientific statement by AHA

A scientific statement was just issued on cardio-renal syndrome by the AHA. This is one of the first and comprehensive summary on cardio-nephrology. The mission of this scientific statement is to describe the epidemiology and pathogenesis of cardiorenal syndrome in the context of the continuously evolving nature of its clinicopathological description over the past decade. It also describes diagnostic and therapeutic strategies applicable to cardiorenal syndrome, summarizes cardiac-kidney interactions in special populations such as patients with diabetes mellitus and kidney transplant recipients, and emphasizes the role of palliative care in patients with cardiorenal syndrome. Some of the key summaries in the large statement are summarized in table 8 of the freely available statement. The important ones are: Distinguishing true AKI from functional causes of fluctuations in serum creatinine in the context of diuresis for acute decompensated heart failure is critical in ensuring delivery of goal-directed medical therapies; Identifying the factors contributing to diuretic resistance is a key step in optimizing decongestion in cardio-renal syndrome(CRS); Biomarkers of cardiac and kidney injury represent a new dimension in the diagnostic algorithm in evaluating HF with impaired kidney function and offer prognostic value in acute and chronic CRS; High-quality data for goal-directed medical therapy in chronic CRS with moderate to severe decline in kidney function are lacking. In addition, a multidisciplinary approach is required for cardiac device therapies to reduce arrhythmia burden in patients with CHF and CKD. Palliative care is an underused strategy in patients with the dual burden of CHF and advanced CKD. A cardio-nephrology multidisciplinary approach is essential in the joint management of patients with CRS with an emphasis on core outcome measures based on patient and physician priorities. Cross specialty educational programs are extremely important to promote the data on this important topic and also to increase awareness of newer technology. In addition, cross talk within two specialties could breed important decisions to improve patient related outcomes.

Topic Discussion: ECMO and the Kidney

Extracorporeal membrane oxygenation (ECMO) is an effective therapy for patients with reversible cardiac and/or respiratory failure. AKI  often occurs in patients supported with ECMO; it frequently evolves into chronic kidney damage or end-stage renal disease and is associated with a reported 4-fold increase in mortality rate. What are the mechanisms of injury of AKI with ECMO?

This table below summarizes what might be the potential causes.

Here is a nice reference

Patient-related variables
Pretreatment factors	Hypoperfusion, loss of autoregulation Hypoxia
	Nephrotoxic drugs Systemic inflammation
ECMO-related variables
Hemodynamic factors	Blood flow alterations
Hormonal factors	Renin-angiotensin-aldosterone dysregulation ANP downregulation
ECMO-related	Blood shear stress
Systemic inflammation	Exposure to a non-self membrane Blood/air interface
Organ crosstalk	Cardio-renal syndrome
Circuit-related factors	Hypermyoglobinemia
	Embolism
	Hemolysis

Hemolysis is an interesting cause. This is an image of a patient getting CRRT on ECMO.  CRRT was on a zero K bath and high clearance rates. Within hours of starting CRRT, effluent bags of the CRRT turn red. Despite being on max CRRT,  patient’s potassium rose to 9mmol/L. This is hemolysis and can be reported in 18% of cases with ECMO.  Rhabdomyolysis can also be noted in some cases. Checking a free Hgb and effluent myoglobin can aid diagnosis for both entities. In addition, classic markers for hemolysis such as LDH, haptoglobin, anemia and so forth should be checked regularly. 

 https://www.ncbi.nlm.nih.gov/pubmed/26606144

 https://www.ncbi.nlm.nih.gov/pubmed/28470926

Topic Discussion: Pre-Renal Success

Pre renal success is an interesting way to think about increases in serum creatinine when overall the patient is improving due to a therapy. Classically, this has been utilized when one uses ACEI/ARBs. Too often the internists ( and even nephrologists) diagnose initial decline in GFR following ACEI/ARB as “pre renal” AKI and reverse the beneficial effects of these amazing therapies.  Many times I have seen such meds taken off due to an increase in creatinine. Long term effects on mortality and CKD are more important than short term hardships of elevated creatinine.  In an article many years ago in Kidney International, a term pre renal success was suggested rather than renal failure for such cases to allow for non nephrologists to feel that it’s a success from a patient stand point even though the serum creatinine increased mild to moderately.  We see this a lot in HTN control as well.  A patient bp runs in 170/100 range and after few months of good therapy, you have got it good control to 130-140 SBP range but serum creatinine increased from 1 to 1.3mg/dl—big deal! – This is PRE RENAL SUCCESS as long term- this bp control is benefiting the patient from cardio vascular benefits.

A recent article in AJN, this term is being re introduced.

Similarly, in CHF patients, aggressive diuresis also leads to the rise in creatining that scares the cardiologists and nephrologist to further diuresis the patients. A recent  publication in Circulation confirms the assertion with use of tubular markers such as NGAL and KIM-1 that aggressive diuresis associated increases in creatinine are not bad. This is also pre renal success as overall, the patient benefits from being “less short of breath” and decreased hospitalizations.  Levels of NAG and KIM-1 did not change with aggressive diuresis. Worsening renal function occurred in 21.2% of the population and was not associated with an increase in any marker of renal tubular injury: Interesting, these increases in NGAL, NAG, and KIM-1 were paradoxically associated with improved survival (adjusted HR: 0.80 per 10 percentile increase, 95% CI: 0.69-0.91; P=0.001)—again suggesting this concept of Pre renal success

These findings reinforce the notion that the small to moderate deteriorations in renal function commonly encountered with aggressive diuresis are dissimilar from traditional causes of acute kidney injury.

It’s about time we called the following situations Pre Renal Success( this is personal opinion and there is room for debate)

1.    Increases in creatinine 25-30% after initiation of ACEI/ARB and perhaps we can add SGLT-2 inhibitors here as well

2.    Increase in creatinine 25-30% after aggressive 2-4 months of blood pressure control in a patient with severe HTN

3.    Increases in creatinine 25-30% after aggressive diuresis and a patient with severe CHF

In the NEWS: LVADs and ESRD

Should patients on dialysis or kidney transplant be offered LVADS for severe CHF?
A new study just published in JAMA internal Medicine showed that patients with ESRD at the time of LVAD placement had an extremely poor prognosis, with most surviving for less than 3 weeks.

This was a observational analysis of the USRDS data of all patients on ESRD that received an LVAD.  155 Medicare beneficiaries with ESRD (median and interquartile range [IQR] days from ESRD onset to LVAD placement were 1655 days [453-3050 days]) and 261 beneficiaries without ESRD in the Medicare 5% sample received an LVAD. During a median follow-up of 762 days, 127 patients (81.9%) with and 95 (36.4%) without ESRD died. More than half of patients with ESRD (80 [51.6%]) compared with 11 (4%) of those without ESRD died during the index hospitalization. The median time to death was 16 days for patients with ESRD compared with 2125 days for those without ESRD. Most of these patients were hemodialysis with a small minority being PD and transplantation. So, unclear what the data is for PD vs transplantation.

In addition, what would have happened if the patients continued conservative management and not offered LVAD- would their outcomes have been similar or better? This really brings the question on whether LVADS should be offered to ESRD patients on dialysis.

Two recent reviews in AJKD and CJASN discuss the role of the Nephrologist and the Kidney in patients with LVADs.

TOPIC DISCUSSION: Diuresis in CHF

An amazing article this month in NEJM discusses Diuretic use in CHF- a must read for Cardiologist and Nephrologists.

Some interesting take home points:

1. Diuretic resistance causes: Non adherence, gut edema, impaired diuretic secretion due to CKD or aging, hypoproteinemia, hypotension, nephrotic syndrome, use of NSAIDS, low renal blood flow, nephron remodeling and neurohormonal activation.

2. Bumetanide and torsemide have higher and more consistent oral bioavailability over furosemide and make oral and IV doses kinetics similar( often under utilized by many)

3. Torsemide has the longest half life of all loop diuretics-- 6 hours.

4. Two forms of adaptations: a) A dose of loop diuretic increases urinary Na loss for few hours but then is followed by a period of very low sodium excretion often called " post diuretic Na retention". When dietary Na intake is high, the post diuretic Na retention effect will offset the initial natriuresis. 
The second is braking phenomenon.  When diuresis happens and fluid volume declines, this activates the SNS and RAS leading to nephron remodeling( distal nephron hypertrophy). This is a helpful thing to put brakes on the severe contraction of the ECF. But when this occurs in a patient that is volume overloaded, it's causing harm.

5. Treatment should aim for daily urine volume of 3-5L till euvolemia.  A stepped wise approach is suggested in bolus of furosemide followed by drip if needed. Metolazone or HCTZ( high dose) can be used as additional agents.

6. Tolvaptan: Data is mixed and can be used in some especially if Na issues are also a concern
7. Dopamine and Nesirtide - no data to support use
8. Aldactone didn't improve outcomes in acute CHF patients that require aggressive diuresis
9. Diuretic Resistance: Failure of diuretics to achieve decongestion, so with max doses you still get a a urine Na<10.
10. Use of amiloride and carbonic anhydrase inhibitors may be beneficial in diuretic resistant patients.
11. UF in CHF appears to be indicated primarily when dialytic therapy is also indicated for worsening cardiorenal syndrome.
12. Hypertonic saline with diuresis might be an interesting option -- robust trials still pending.
13. Skillful use of diuretics is the bottom line on how to succeed in treating CHF with renal dysfunction.

I had hoped the authors had commented on use of lung US in this disease. Diuretic use guided by Lung US findings might be more useful in many cases than later exam findings of edema( personal observation). 

AMACING trial: Fluids vs No fluids for Contrast Nephropathy prevention: A visualabstract

An animated #visualabstract for the recent AMACING study published in Lancet 2017 that was a randomized controlled trial for prevention of CIN with IV fluids vs placebo.

Below is a non animated version of the abstract

In the NEWS: Death of Contrast induced Nephropathy

If you were a twitter follower: I am sure you saw this post by Dr Topf on

Call it...Time of death?

6:29 AM.

It had a long full life. RIP contrast nephropathy. https://t.co/wNZNnGA1Hh

— Joel Topf, MD FACP (@kidney_boy) February 21, 2017

The article just published in Lancet proves in a RCT that fluids don't help in high risk patients in preventing contrast nephropathy (CIN).

http://www.sciencedirect.com/science/article/pii/S0140673617300570

This comes after many recent papers that have questioned the very existence of this entity. While it exists, perhaps the incidence has been over sized.  This was nicely shown by Chertow's team in 2016
https://www.ncbi.nlm.nih.gov/pubmed/27688297

Bigger questions will arise as we move forward in the era of Cardiac-Nephrology. Discussions with cardiologists are going to be essential. While the Lancet paper will get it's share of supporters and opposers, the debate will continue as now the question has arisen- does CIN even exist? Is this the death of CIN?



1. Does intra-arterial vs intra-venous contrast make the kidneys worse?
2. Does giving NAC matter?
3. Does giving IV fluids matter?- pre and post and or based on wedge pressure
4. Does holding ACEi/ARB matter?
5. Does holding diuretics matter?- Might so if they are planning to do a TAVR.

Tough road ahead as - what can the Nephrologist do then for these patients? I guess - Nothing! and perhaps doing nothing might be beneficial to the patient. We shall see!

Topic Discussion: Novel anticoagulants in CKD and ESRD

New Oral Anticoagulants(NOACs)	Renal clearance of parent drug	Dosage in ESRD	GFR 15-29ml/min	GFR 30-40ml/min	GFR >-50ml/min	Dialyzable (yes/no)	Reversal agent
Dabigatran( Direct thrombin inhibitor)	80%	Avoid	75mg BID	150mg BID	150mg BID	Yes with 10% rebound rate	Idarucizumab Dialysis
Rivaroxaban(Factor Xa inhibitor)	36%	15mg QD	15mg QD	15mg QD	20mg QD	No	4-factor prothrombin complex concentrate Andexanet Alfa
Apixaban( Factor Xa inhibitor)	27%	5mg BID	2.5mg BID	5mg BID	5mg BID	No	4-factor prothrombin complex concentrate Andexanet Alfa
Edoxaban (Factor Xa inhibitor)	50%	30mg QD	30mg QD	30mg QD	60mg QD	No	4-factor prothrombin complex concentrate Andexanet Alfa

Patients with atrial fibrillations are being treated with NOACs as they are simple to use, no monitoring and excellent safety profile. They are higher in costs and experience still limited. NOAC use in patients with advanced CKD and on dialysis is substantial and increasing, despite AHA, ACC, and HRS and European Heart Rhythm Association guidelines that endorse warfarin as the anticoagulant of choice when CrCl is <30 ml/min. There are few randomized trial data on NOACs among patients with advanced CKD or on dialysis. Most NOACS are dependent on the kidney for elimination. Since most patients with advanced CKD were excluded in clinical trials, this topic is important. 

The above table summarizes what the current data exists on this topic for use of NOACs in CKD patients with Atrial Fibrillation for prevention of stroke.  Bleeding risk is important in patients with CKD and ESRD due to uremic dysfunction of platelets and use of heparin in HD.  Unfortunately, no patients with CKD Stage V or ESRD were not allowed in any of the NOAC trials. Apixaban was the most commonly used NOAC in a recent analysis in advanced CKD patients. Apixaban and Rivaroxaban have renal eliminations around 30% hence most safe in late stage CKD with lower dosing. Dabigatran and Edoxaban ar 80% and 50% renal elimination respectively and should technically avoided in late CKD patients.  Dabigatran is the only NOAC removed by dialysis based on studies thus far.

This review in JACC summarizes the latest uptodate information on use of these agents in CKD and ESRD patients. – A must read!