In the NEWs: Hydralazine and the Kidney

Hydralazine- you can love or hate as a nephrologist. Hydralazine is used a lot for both inpatient and outpatient setting my several internists, cardiologists and nephrologists for management of blood pressure. In clinical practice, many times we have noticed vasculitis from hydralazine : both of the lupus or the ANCA kind. Drug induced kidney diseases are important to keep in mind when the clinical picture doesn't make any sense. 

See this exhaustive table from Izzedine and Ng in the recent Kidney News issue on drug induced glomerular diseases. 

A recent study in KI just focused on hydralazine induced ANCA vasculitis and looked at 80 patients.
As suspected, the clinical clues are: many have low complements, +ANCA( both p and c in some cases- 40%), ANA and anti histone positive and even dsDNA positive. When you see several auto antibodies come back positive- think drug induced. Treatment is cessation of the agent and treat like regular vasculitis. 

Check out an old detective nephron from 2013 on this topic.

Topic Discussion: Electrolytes Disorders with COVID19

AKI has been reported with COVID19 ,electrolyte disorders have been less well described. A recent paper in CKJ describe the full spectrum of electrolyte disorders seen with COVID19.

The most common presentation was hyponatremia and hypochloremia together (second vertical bar) in 1289 (12.4%), followed by hyponatremia alone (third vertical bar) in 1150 (11.1%).

What about patients with eGFR<60 but >15? 30.3% had hyponatremia, 11.1% had hyperkalemia, and 19.7% had hypochloremia. Hypocalcemia was seen in 19.2% of patients. Hyperphosphatemia (13.9%) and hypermagnesemia (12.2%) were seen in fewer patients.

What about ESKD patients?

In these patients the most common disorders were hypochloremia (62%), hyponatremia (40.9%), and hyperkalemia (23.4%). Hyperphosphatemia was seen in 45.7% of patients but we had some missing phosphorus data.

What about kidney transplant recipients? The most commonly seen were hyponatremia (42.4%), hyperkalemia (16.7%), and hypochloremia (19%).

Limitations: Purely descriptive.

But highlights for the first time and the largest to date on the various electrolyte disorders in hospitalized COVID-19 patients. Further studies are needed to look at mortality outcomes related specifically to each electrolyte disorder.

Prevalence of Hyponatremia related to COVID19 has been described in the NY region. Looking at the spectrum of both hyponatremia and hypernatremia and it's relation to patient outcomes has not been well studied.

To take this further, Na disorders were evaluated in detail with outcome of mortality. This is published in NDT. Among 9946 patients included in the study ,4808 (48.3%) had normonatremia, 3532 (35.5%) had mild hyponatremia, 904 (9.1%) had moderate/severe hyponatremia, 319 (3.2%) had mild hypernatremia, and 383 (3.8%) had moderate/severe hypernatremia. When examined by decile of age, dysnatremia occurred in 46-54% of patients in each group, with hyponatremia the predominant disorder across all age groups. The proportion of patients who experienced in-hospital death was highest for those with moderate/severe hypernatremia (232/383 [60.6%]), followed by mild hypernatremia (163/319 [51.1%]), moderate/severe hyponatremia (261/904 [28.9%]), mild hyponatremia (818/3532 [23.2%]) and normonatremia (1089/4808 [22.6%]), a trend seen across all age groups. 

U-shaped pattern was seen in the relationship between admission serum sodium level and the odds of in-hospital death, with hyponatremia and hypernatremia both significantly associated with mortality, even after full adjustment for demographics, comorbid conditions and illness severity. Compared to hyponatremia, hypernatremia carried a strong association with in-hospital death, in both mild and moderate/severe categories, and across all ages, a relationship that persisted even following correction for serum glucose. While hypernatremia has  been shown to be  a strong predictor of mortality in prior studies, this finding is novel for COVID-19. 

Both hyponatremia and hypernatremia were also associated with a prolonged hospital length of stay. The magnitude of the odds ratio was substantial, especially for moderate/severe hypo- and hypernatremia, and was not substantively changed after multivariable adjustment. This suggests that at least a portion of the prolonged hospitalization may be directly related to electrolyte disorder management. 

This is the largest study to describe prevalence and outcomes of both hyponatremia and hypernatremia in a diverse population of almost 10,000 patients hospitalized with COVID-19. Other similar studies just published in the endocrine literature as well.

Concept Map: Anorexia Nervosa and the Kidney

 

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)

IN the News: Pediatric AKI related with COVID19 and MISC- tale of two NY centers

 

A recent study published in Kidney International looked at a single health system 4 hospital admissions of AKI with COVID19 and MISC in children in NY. It was during the first wave in 2020.  

Over 150 patients met inclusion criteria; 97 (63.8%) with acute-COVID-19 and 55 (36.2%) with MIS-C, AKI occurred in 11.8% of the cohort; 8 with acute-COVID-19 and 10 with MIS-C.  All but one patient with AKI were admitted to a pediatric intensive care unit (PICU). There was no significant difference in age, or ethnicity in those with and without AKI. Those who identified as black had 2.86 times higher odds of AKI (p=0.042; 95%CI 1.04-7.93). 

Majority of AKI occurred early in the course of hospitalization, 72% (N=13) within 24 hours of admission. MIS-C patients with AKI had greater rates of systolic dysfunction, compared to those without AKI (80% vs 49%, p= 0.038).  AKI, in unadjusted models, was associated with a lower serum albumin level (OR 0.17)and higher white blood cell counts (OR 1.11). In addition, patients with AKI had 8.4 day greater length of stay. Major Limitations: 1. Small sample size precluded adjustment for confounders 2. As this was an observational study, we are unable to determine causal associations. 3. Single health system/region of the country
Strengths of this study: One of the largest, detailed cohorts of pediatric patients at the epicenter of the COVID-19 outbreak and represents a diverse racial, ethnic and socioeconomic population.

Similar to reports in other PICU patients, pediatric COVID-19-related AKI was associated with longer lengths of stay published in Kidney360 also from NY area. In that study, 57 children who met inclusion criteria, 46% (26/57) were found to have AKI.  All patients had resolution of AKI at discharge, with 61% achieving recovery by day 2. One patient required dialysis. When compared to those without renal injury, the AKI cohort was older (p < 0.001) and with higher median peak values of CRP (p <0.001), IL-6 (p <0.05), ferritin (p < 0.001), and procalcitonin (p <0.05). More patients with AKI had left ventricular systolic dysfunction (p < 0.001) and lymphopenia (p <0.01), when compared to those without AKI. No differences in Body Mass Index or sex were found. 

These findings may reflect the inflammatory cascade’s complex role in development and perpetuation of COVID-19 related AKI. In addition, decreased intravascular volume and distributive/cardiogenic shock may have contributed to AKI in the MIS-C cohort. 

Check out the tweetorial by Abby Baselely 

Warp Speed Drugs for Kidney diseases 2021

 In ASN Kidney News 2021, Feb issue, I created this figure that gives a sense of the amazing rapid development for kidney disease therapeutics. The figure appears in the Feb issue of kidney news. Created using biorender.com 

Topic Discussion: ACEI/ARB ( hold em or keep them going)

 The COVID19 pandemic has ignited an ongoing saga of holding ACEi/ARB when someone is hospitalized. Normally a consult note in nephrology would include holding of these agents before a cardiac cath, CABG, or major procedure ( with little data on doing it).

A recent study in JASN done using a novel methodology showed no real benefit in stopping these agents in late stage CKD patients in the Swedish Renal Registry for the last 10 years.  Advanced CKD ( GFR<30) on these agents were evaluated. A target trial emulsion technique was used on risk of stopping these agents for 6 months and their outcomes on 5 year mortality, and MACE and KRT. So while KRT risk increased, the MACE and mortality decreased. MACE was mainly driven by mortality. In this nationwide observational study of people with advanced CKD, stopping RAS inhibition was associated with higher absolute risks of mortality and major adverse cardiovascular events, but also with a lower absolute risk of initiating KRT.

Meanwhile, in the COVID19 world,  REPLACE COVID published in Lancet was published. This trial began on March 31, 2020, within a few months of COVID-19 hitting North America and in the thick of the first wave. All COVID19 patients hospitalized , already on chronic ACEi or ARB  were randomized to either continue or stop their ACEi or ARB. In terms of the results, there was absolutely no difference in any of the outcomes, all cause death and length of stay. There was also no difference in the exploratory outcomes of ICU admission, ventilation, or hypotension requiring hemodynamics support. These findings are also bolstered by the similar findings from the BRACE CORONA trial published in JAMA in a slightly less sick cohort of 659 patients showing similar results. The primary outcome was the number of days alive and out of the hospital through 30 days. Secondary outcomes included death, cardiovascular death, and COVID-19 progression.  The study found that in patients hospitalized with mild to moderate COVID-19 and who were taking ACEIs or ARBs before hospital admission, there was no significant difference in the mean number of days alive and out of the hospital for those assigned to discontinue vs continue these medications. These two trial (RCTs done in pandemic)  findings do not support routinely discontinuing ACEIs or ARBs among patients hospitalized with COVID19.  Check out this nice editorial on this in ASN kidney news 2021

There is an ongoing trial called STOP-ACEi. Do we really need that trial? Given we were able to do an RCT in a middle of a pandemic with sick patients with COVID19 and that showed no real difference in terms of outcomes of holding ACEi or ARBs, my guess is that STOP-ACEi will show the same. Unless there is hyperkalemia, or hypotension, no real strong indication to hold or stop these life saving cardiac medications.

Culture change will take time:  It is hard to convince nephrologists to start ACEi/ARB in late stage CKD, let alone convincing hospitalists or internists. It is hard to NOT to hold ACEi/ARB when creatinine is rising during an acute cardio-renal syndrome- convincing will take time. Hope these trials will help us continue these life saving agents in hospitalized patients( and ok to even stop them) but sometimes- nobody restarts them on discharge...