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.

In the News: Urine Na as a marker for diuresis success

A recent editorial in JAHA discusses the use of urinary sodium (UNa) as a biomarker for monitoring and guiding diuretic therapy in patients with acute heart failure (AHF). Activation of the renin-angiotensin system in heart failure leads to sodium retention, hyperaldosteronism, and increased sympathetic activity, contributing to fluid overload. The authors highlight that assessing diuretic response through traditional methods, such as weight loss and urine volume output, can be inaccurate and logistically challenging. Instead, they propose using UNa measurements from spot urine samples taken 2 hours after diuretic administration as a more dynamic and early indicator of diuretic response.

The European Society of Cardiology (ESC) guidelines recommend using spot UNa analysis to evaluate diuretic treatment response in AHF patients. A low UNa (<50-70 mEq/L) at 2 hours post-diuretic administration is associated with inadequate diuretic response and suggests the need for more intensive diuretic therapy. The paper discusses observational studies and expert opinions that support this approach. However, it also points out limitations, such as the influence of kidney function, concurrent conditions like chronic kidney disease (CKD) and cirrhosis, and the potential loss of UNa's predictive strength after the first day of treatment due to changes in sodium excretion patterns.

The authors present data from studies that endorse the feasibility and efficacy of UNa-guided diuretic therapy in AHF. They discuss the ENACT HF trial, which showed improved natriuresis, diuresis, and shorter hospitalization duration with UNa-guided diuretic treatment. Another ongoing study, PUSH-AHF, aims to provide more definitive results on natriuresis-guided therapy using a stepwise diuretic approach.

The authors acknowledge that UNa assessment alone may not fully capture diuretic response and recommend combining UNa measurements with other indicators of decongestion, such as urine output. They also emphasize the importance of accounting for different patient factors like fluid overload status, kidney function, and the type of diuretics used.

In conclusion, while UNa-guided diuretic therapy appears promising for AHF management.. interesting and simple to do.

Love this figure from the paper

Topic Discussion: Chloride in Cardio-Renal Syndrome

At recent ASN Kidney Week 2020, Dr. Amir Kazory really gave a great lecture highlighting the importance of an important ion that often is ignored in CHF and Cardio-renal syndrome.

We should perhaps move away from the Na centric view of CHF.

Some interesting points made in his talk and overall what we know.

1. Hyponatremia is a predictor of CHF outcomes. But when we correct the Na, mortality doesn't improve. - classic V2R antagonist EVEREST trial showed no benefit

2. When we give 3% saline as shown by the Yale group recently in JACC, there is significant weight loss in diuretic resistant patients. 

3. The Na restriction in diet has limited evidence that it works

Some interesting data on Cl in CHF.

One of the first studies done looking at Cl in CHF found that for every 4.1meq/L of drop in Cl, there is 25-30% increase in 5 year-mortality. 

Contemporary advanced CHF cohort suggest that serum chloride levels at admission are independently and inversely associated with mortality in this one study. The prognostic value of serum sodium in CHF was diminished compared with chloride.

Why does this matter? 
Two physiological reasons:

1. Low Chloride can stimulate renin release in macula densa

2. Low intracellular chloride can increase TAL NKCC activity and DCT NCC activity

Interestingly, low chloride patients are also diuretic resistant. 

It would be fascinating to see if increasing Cl, without Na really has a good effect on diuresis. Azetazolamide trials are ongoing as a potential way to do this. Could SLGT2i be potentially working via this mechanism? It is very possible that Cl is a more important player than Na in CHF and Cardio-renal syndrome. Fascinating!!

Check out this excellent review. ( also for figure source)

Topic Discussion: Amyloidosis and Renal Infarction

Usually when we think of amyloidosis in the kidney- we think of paraprotein mediated amyloidosis (AL or AH) leading to nephrotic syndrome and in some rare cases- vascular amyloid presenting as AKI.

A recent study published in Mayo Clinic Proceedings suggests that renal infarction might be a common finding in patients with cardiac amyloidosis. Three groups of patients were identified according to the underlying amyloidosis disorder: AL amyloidosis in 24 patients, mutated-transthyretin amyloidosis in 24 patients, and wild-type transthyretin amyloidosis in 39 patients. Patients with AL amyloidosis had significantly higher N-terminal pro-B-type natriuretic peptide levels (P=.02) and were more likely to have nephrotic syndrome (P<.001). Renal infarction was detected in 18 patients (20.7%), at similar frequencies in the various groups. The likelihood of RI diagnosis was 47.1% (8 of 17) in the presence of AKI and 14.5% (10 of 69) in its absence (P=.003).  Renal infarction (defined by defect(s) on the DSMA scan) was reported in 20.7% of patients with and 25% without evidence of cardiac amyloidosis. Prior studies have not really shown any association like this before of amyloidosis and infarction. Renal infarcts were described in an autopsy study in 3 kidneys that had either cast nephropathy, plasma cell nodules, or autolysis but not with amyloid deposits. Dang et al interesting are reporting is a high percentage of abnormal DSMA scans in patients with wild-type transthyretin amyloidosis (wtATTR) and mutant transthyretin amyloidosis (mATTR) amyloidosis.

These findings are intriguing. The 20% to 25% prevalence reported by Dang and colleagues was therefore unexpected. Renal involvement in ATTR is thought to be rare, especially in patients with wtATTR amyloidosis. Recent drugs used to treat this form of amyloidosis might lead to a glomerulonephritis( my recent post). The finding from the current study suggests that we may be vastly underestimating the prevalence of kidney involvement in ATTR amyloidosis. These patients usually don’t present with nephrotic range proteinuria but more with AKI and subacute AKI. Perhaps, instead of labeling all of these as cardio-renal syndrome, we should consider looking for renal infarction in these patients. And as I have always thought about ruling out amyloidosis in young males who present with renal infarction, I usually stop at AL-AH amyloidosis testing. Given the above findings, perhaps an amyloid scan to look for wtATTR and mATTR might be important as perhaps renal infarction could be a potential relationship here. 

Quite an interesting association!!

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.