HTN and TMA- Topic Discussion

Malignant hypertension with AKI or AKD is a life-threatening emergency that demands rapid blood-pressure control and carries a high risk of permanent kidney damage. When thrombotic microangiopathy (TMA) is present, diagnostic challenges intensify. Although complement-mediated TMA frequently presents with severe hypertension, malignant hypertension itself can cause TMA-like vascular injury. This has been a point of debate for many years. Does the TMA cause HTN or is HTN a cause of TMA as well? 

Early evaluation must therefore exclude secondary hypertension and secondary TMAs, which require etiology-specific treatment. Because a definitive distinction between essential hypertension and complement-mediated TMA relies on genetic testing that takes weeks, clinicians must use clinical and histologic clues to guide early complement-blocker therapy. Significant gaps remain in understanding pathogenesis, diagnosis, and treatment. A recent paper in KI really takes this to a better understanding. 

Some key messages from the review article

1. Malignant hypertension can directly cause a true TMA.
Severely elevated blood pressure can injure small vessels, leading to endothelial damage, platelet consumption, hemolysis, and classic TMA findings. This is not simply “secondary hemolysis”—it is a bona fide microangiopathic process.
2. Distinguishing hypertensive TMA from other TMAs is critical.
Hypertensive TMA can mimic HUS/TTP and complement-mediated TMA. Misdiagnosis can delay the correct therapy. The clinical context (markedly high BP, long-standing HTN, LVH, retinal changes) is key.
3. Treatment hinges on rapid but careful blood-pressure control.
The cornerstone is controlled BP reduction—typically in the ICU—with parenteral antihypertensives. This alone often reverses hematologic abnormalities and improves renal function.
4. ADAMTS13 and complement studies help guide management but should not slow treatment.
Work-up is important, especially when features are atypical or improvement is slower than expected. But initial management should start immediately based on clinical suspicion.
5. Kidney recovery varies widely—follow-up matters.
Some patients experience near-complete recovery; others progress to CKD or ESRD, especially when treatment is delayed. Long-term blood-pressure control is essential to prevent recurrence and preserve renal function.

     An important component is the heme component of TMA and it's presence in the systemic form of TMA. The figure( similar to the paper in KI) suggests that the complement-mediated TMA had most likely to have heme parameters of TMA as well followed by drug induced TMA and systemic diseases.  HTN is not that common. 

 

Concept Map: Hypertension in Hemodialysis

 

This is a schematic of the treatment of resistant HTN in the hemodialysis patient. Based on a review published in JASN

Figure made using biorender.com 

Concept Map: Endothelin-1 and the Kidney

Emerging concept of use of endothelin antagonists in the field of Nephrology. This concept figure is on data up to May 2023

Figure created using biorender.com and adapted from this review. 

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

 

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

Concept Map: Hypokalemia and HTN workup

 

Created using biorender.com 
Content edited: Dr Rondon and Dr Sharma

Topic Discussion: As needed anti HTN meds in the hospital- can we stop the madness?

 

We often see in the hospital, BP is treated as needed. Often, as nephrologists we have suggested to NOT do this. Outpatient problem that exists for years cannot be corrected in 2 hours by hydralazine or beta blockers so that the "vitals" look good and " numbers" are good for rounds. A recent study published in Hypertension nicely showcases this via a retrospective propensity matched protocol. When compared to scheduled BP meds patients to Scheduled meds and PRN patients ( over 4000 each), risk of AKI, stroke and mortality was higher in the as needed group. In addition, length of stay was higher as well. 

This comes following another recent article in JAMA looking at a similar concept. Among 22,000+ patients studied in hospitals with non cardiac diagnosis, hypertension was treated as needed in several patients.  In a propensity-matched sample controlling for patient and BP characteristics, treated patients had higher rates of subsequent acute kidney injury (466 of 4520 [10.3%] vs 357 of 4520 [7.9%]; P < .001) and myocardial injury (53 of 4520 [1.2%] vs 26 of 4520 [0.6%]; P = .003). There was no BP interval in which treated patients had better outcomes than untreated patients. A total of 1645 of 17 821 patients (9%) with hypertension were discharged with an intensified antihypertensive regimen. Treating with intensification of anti HTN meds without signs of end organ damage lead to worse outcomes.

Finally, another study in 2019 in JAMA found that among older adults hospitalized for noncardiac conditions, prescription of intensified anti-hypertensives at discharge was not associated with reduced cardiac events or improved BP control within 1 year but was associated with an increased risk of readmission and serious adverse events within 30 days.

So basically, let's not try to treat a number but the patient and let's not make a chronic problem a priority in the admission that doesn't warrant too many changes. That may be doing some harm!

Topic Discussion: Primary aldosteronism: You can’t find it if you don’t look for it

Here is a guest post straight from the author of a recent study in Annals of Internal Medicine. 

Visual abstract from Annals of IM website.

As a group of clinical hypertension specialists and researchers, my co-authors and I performed this study out of concern of under-recognition of primary aldosteronism as a common cause of secondary hypertension. Treatment-resistant hypertension occurs in about 20% of adults with hypertension and primary aldosteronism is a common cause of treatment-resistant hypertension. Identification and appropriate management of primary aldosteronism can reduce the risk of development and progression of heart disease and chronic kidney disease. Although guidelines recommend testing for primary aldosteronism in all patients with treatment-resistant hypertension, prior evidence in small, local health systems suggested extremely low rates of screening with plasma renin and aldosterone levels.

In a nationally representative cohort of over 250,000 Veterans with treatment resistant hypertension we found that rates of guideline-based testing for primary aldosteronism from 2000 to 2017 occurred in less than 2% of patients in whom it’s recommended. We identified several patient-, provider-, and center-level factors associated with better screening practices (such as being seen by an endocrinologist or nephrologist, or being cared for at a non-rural medical center). We were surprised to observe that patient adherence, which was identified by medication fills from the pharmacy, was not associated with screening practices. We found that patients who were screened were 4-times more likely to be managed with evidence-based antihypertensive therapy with mineralocorticoid antagonists (regardless of the screening results) compared with patients who were not screened. We also found that patients who were screened had much better blood pressure control over time, also regardless of the results of the screening.

Overall, we observed widespread and concerning missed opportunities for primary aldosteronism screening and for appropriate treatment of patients with treatment-resistant hypertension. The fact that screening practices are strongly associated with evidence-based treatment of apparent treatment-resistant hypertension and blood pressure control over time suggests that good provider behaviors beget other good behaviors, that there are major gaps in provider knowledge of the importance of screening these patients, and that there are likely barriers to implementing appropriate management for these patients. 

These findings suggest a need to improve education of providers and to leverage innovative tools to increase screening and appropriate management of patients with treatment resistant hypertension.

Tweetorial: https://twitter.com/jordy_bc/status/1343678945393315840?s=20

 

Post by:  Jordana Cohen, MD, MSCE

Assistant Professor of Medicine and Epidemiology

Perelman School of Medicine, University of Pennsylvania

Concept Map: Secondary causes of Hypertension

Based on Article by Hirsch et al. https://link.springer.com/article/10.1007%2Fs11936-019-0790-8

Topic Discussion: Zytiga (Abiraterone) induced hypernatremia, and HTN

Zytiga (Abiraterone) is a hormonal chemotherapy agent used to treat prostate cancer. It selectively and irreversibly inhibits CYP17 (17 alpha-hydroxylase/C17,20-lyase), an enzyme required for androgen biosynthesis which is expressed in testicular, adrenal, and prostatic tumor tissues. Inhibits the formation of the testosterone precursors dehydroepiandrosterone (DHEA) and androstenedione.

Interestingly. it has a high rate of hypernatremia as a known renal complication. In several studies, hypernatremia (33%), hypokalemia (17% to 30%) were reported as known complications. Why? It is postulated that it can increase mineralocorticoids due to CYP17 inhibition may result in hypertension, hypokalemia, and fluid retention (including grade 3 and 4 events) and perhaps some component of hypernatremia as well- almost like a Cushing's state. Per package insert, concomitant administration with corticosteroids reduces the incidence and severity of these adverse events.

In the LATITUDE trial, which used prednisone 5 mg daily in combination with 1000 mg abiraterone acetate daily, grades 3-4 hypokalemia were detected in 10% of patients on the zytiga arm and 1% of patients on the placebo arm, grades 3-4 hypertension were observed in 20% of patients on the zytiga arm and 10% of patients on the placebo arm. Grades 3-4 fluid retention occurred in 1% of patients each arm.

It is recommended that patients get monitored for hypertension, hypokalemia, and fluid retention at least once a month. Treatment of hypertension is recommended, choice of drug is not defined.

This is an interesting toxicity that as nephrologist seeing prostate cancer with CKD and perhaps new onset hypertension, hypokalemia or hypernatremia should consider in the differential diagnosis.

Topic Discussion: Diagnosis of Pheochromocytoma in a Dialysis patient

Dialysis patients have ups and downs of blood pressure and a diagnosis of pheochromocytoma(PH) is always challenging. Screening for PH is always a tough challenge in non CKD/ESRD patients. It is even more challenging in ESRD patients. Many medications can interfere with measurements of catecholamine levels. Tricyclic antidepressants interfere most frequently with the interpretation of plasma fractionated metanephrines and 24-hour urinary catecholamines and metabolites.  Most of these should be tapered and discontinued at least two weeks before any hormonal assessments. 

In general, the approach to diagnosis is initial biochemical testing based upon the index of suspicion that the patient has a PH. If there is a low index of suspicion, a 24-hour urinary fractionated catecholamines and metanephrines; if there is a high index of suspicion, a plasma metanephrine level should be done. The endocrine society clinical practice guideline suggests initial biochemical testing using 24-hour urinary fractionated metanephrines or plasma fractionated metanephrines (drawn supine with an indwelling cannula for 30 minutes). However, many times the measurement of plasma fractionated metanephrines is not done under these conditions, and the test is associated with a high false-positive rate.

Biochemical tests in renal disease might not be valid. In patients without PH who are receiving dialysis, plasma norepinephrine and dopamine concentrations are increased threefold and twofold above the upper limit of normal, respectively. When patients with CKD have plasma norepinephrine concentrations more than threefold above the upper normal limit or epinephrine concentrations greater than the upper normal limit, PH should be suspected. It is hard to distinguish PH just with plasma metanephrines in ESRD and CKD patients. Studies done have shown mixed results. Most ESRD patients are anuric and hence urinary studies are not available. A new biomarker has been recently discovered in the world of PH- Plasma methoxytyramine. This is still not used in routine practice and data on ESRD-CKD is not available to my knowledge. 

What about the imaging studies?

CT dedicated to the adrenals or MRI of the abdomen and pelvis is usually performed first. Either test is a reasonable first test as both detect almost all sporadic symptomatic tumors because most are 3 cm or larger in diameter. If abdominal and pelvic CT or MRI is negative in the presence of clinical and biochemical evidence of PH, think of a perhaps a different diagnosis. If it is still considered likely, then iodine-123 (123-I) iobenguane (also known as metaiodobenzylguanidine [MIBG]) scintigraphy may be done. MIBG is a compound resembling norepinephrine that is taken up by adrenergic tissue. Normal adrenal glands take up MIBG, and the uptake may be asymmetric. One prior paper showed perhaps a false positive scan in ESRD. No newer studies have shown this. No specific studies have looked at MIBG scans in ESRD patients except one case series from Japan.

Finally, FDG-PET scan is more sensitive than 123-I MIBG and CT/MRI for detection of metastatic disease. A scan called 68-Ga DOTATATE PET — Gallium 68 (68-Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE)-positron emission tomography (68-Ga DOTATATE PET) is proving to be more sensitive in some patients than 123-I MIBG, CT/MRI, or FDG-PET for detection of metastatic disease. 

So what does one do finally for a CKD-ESRD patient?

If the plasma metanephrines are threefold the upper limit of normal and there is an abnormal CT scan or MRI localizing a lesion in one of the adrenals( depending on contrast load), a MIBG scan is reasonable. If that is positive, there is a good chance that it is a PH. Surgery decision should not be based solely on MIBG scan alone. A PET scan or a TATE scan might be required to confirm the diagnosis in the grey zone of CKD-ESRD and diagnosis of a PH.

The curse of wisdom—making sense of the ever-changing blood pressure targets Part 2

The curse of wisdom—making sense of the ever-changing blood pressure targets

Part 2

BP targets according to comorbidities and CV risk calculators- too much of a good thing?

Given the scope and thoroughness of trials in the field of hypertension, why has the post-SPRINT landscape been littered with such controversy?

1)      A uniform protocol for measuring blood pressure remains unresolved. Many physicians have become disenfranchising citing their frustration with not only having to keep up with the guidelines but now qualifying BP readings according to how they were ascertained (i.e. via the auscultatory or oscillometric method). However, the clinician should not assume that the methodology for measuring BP has been an overlooked technicality within the specialty. Whether it be the debate as to the width of the BP cuff or the validation protocols for ensuring BP machine accuracy (the AAMI validation protocol is 125 pages), researchers continue to dedicate their lives to answering these questions and have created journals (e.g. Blood Pressure Monitoring) to disseminate their findings

2)      The rapid succession of discordant guideline statements. In 2004, JNC 7  recommended a universal BP goal of ≤ 140/90 mm Hg. Because JNC 8 was not published for another decade (2014), the JNC 7 guidelines were widely circulated and institutionalized. As such, when JNC 8 recommended a BP of ≤ 150/90 mmHg for those older than 60, many felt a law of nature had been violated (In defense of the JNC 8 authors, the panel was charged with generating recommendations based exclusively on “definitive evidence.” It was therefore limited with respect to the trials and publications it could cite). Just 12 months later, SPRINT  furthered this sense of tumult. It not only showed the benefit of treating to previously unheard-of levels (120/80 mm Hg) but stood in sharp contrast to the BP targets found in the JNC 8 guidelines published 1 year earlier. Just 2 years after SPRINT, the ACC/AHA guidelines appeared (2017), incorporating treatment to ≤130/80 mm Hg in high risk populations, an affirmation that lower targets were to be immediately implemented. 

3)      The demise of a universal blood pressure target. Further serving to agitate matters, the determination of BP goals now requires the prescriber to quantify a patient’s cardiovascular risk level (yet an additional calculation) and consider which medical condition one should tailor BP therapy to (the optimal BP for secondary prevention of stroke is different from that for preventing kidney disease progression). This latter, treat-by-comorbid approach quickly loses its intuitive appeal when patients suffer from multiple comorbids, each with a distinct BP target (i.e. a kidney disease patient with a prior stroke).

 Given the frustration and confusion generated, should we resign ourselves to the “more questions than answers” doctrine emblematic of modern medicine? Should we wax nostalgic for days gone by?  For our patient’s sake and the survival of our specialty, we should not. These variations in treatment goals represent the ongoing maturation of the field of hypertension and the source of perpetually declining CV event rates. Just as Part 1 of this piece highlighted the early challenges of accepting that hypertension was a pathologic process, the challenge of our times is to relinquish some of our clinical autonomy in order to integrate (complex) treatment algorithms. The oncology community has been at the vanguard of leveraging these developments. With distinct chemotherapeutic regimens based on the hormonal and genetic profiles of phenotypically similar cancers, they have come to appreciate that this “complexity” is the foundation of precision medicine. 

Guest Post by

Hillel Sternlicht, MD
Author, Concepts in Hypertension Newsletter

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The curse of wisdom—making sense of the ever-changing blood pressure targets Part 1

The curse of wisdom—making sense of the ever-changing blood pressure targets

Part 1

“All things will be ambiguous, for this is the curse of wisdom.” -Greg Bear (1951-present)

            Our initial understanding of hypertension, like others disease states, evolved fitfully.  While the circulatory system was first identified by Harvey in the early 1600s, a full century would pass before Stephen Hales cannulated the carotid artery of a horse (Circa 1730) and observed the bobbing of its blood in a glass tube. Incremental advances over the subsequent 125 years allowed for measurement of blood pressure in the 1860s through radial artery pulsation analysis both invasively (Etienne Marey) and ultimately non-invasively (Samuel Siegfried Karl Ritter von Basch). These efforts culminated in Nikolai Korotkov’s description (1905) of the sounds generated by the turbulent blood flow created upon relief of an upstream arterial occlusion. Of course, the ability to externally compress a vessel would not have been possible without the introduction of a brachial artery cuff by Scipione Riva-Rocci’s (1900).         

            In the decades that followed, an approximate sense of readings consistent with “normal” and elevated blood pressures emerged. Perhaps even before the 1930’s, “hypertension” was an accepted medical term. However, at that time, it was purely descriptive (i.e. blood pressure higher than the normal) and did not connote a pathologic process. Eminent physicians of that era such as Paul Dudley White felt elevated blood pressure was an adaptive response necessary to ensure satisfactory perfusion; therefore, hypertension was not only benign but also essential. 

Concerned with offering policies to only the healthiest of individuals, it was life insurance actuaries that unequivocally noted the pathologic significance of elevations in blood pressure. As noted by the New York Life statistician Louis Dublin in 1949, “It is clear from the table that mortality rises steadily and markedly with increasing elevation of both the systolic and diastolic pressure.” (Dublin Length of Life 1949). So it began, the journey of blood pressure control as defined by the actuarial scientist. 

           

 From Dublin, L et al. Length of Life: A study of the life table. 1949.

          

             In light of this multi-century journey from discovering and measuring blood pressure to identifying harmful elevations in the same, the number and scope of therapeutic trials in the last 50 years is dizzying. From the first randomized controlled trial (VACoop1 in 1967)

seeking to establish whether diastolic blood pressures between 115-129mm Hg merit treatment, double-blind randomized trials, each with thousands and often tens of thousands of patients have been realized. For example, as early as 1979, the Hypertension Detection and Follow up trial enrolled 11,000 individuals and in 1985 the Medical Research Council study recruited 17,000.  Research has not only focused on the effects of an achieved blood pressure on broad outcomes such as all-cause mortality, but whose primary outcome is geared towards a specific disease state such as preeclampsia (CHIPS NEJM 2015), secondary stroke prevention (SPS3 Lancet 2013), kidney and disease progression (MDRD NEJM 1994).  Other trials have focused on optimal agents for various clinical scenarios such as resistant hypertension (PATHWAY-2 Lancet 2015), the elderly (SystEur Lancet 1997), or establishing the preferred second agent when monotherapy is insufficient (ACCOMPLISH NEJM 2008). Moreover, there are dozens of trials comparing anti-hypertensive classes through the application of similar achieved blood pressures in each arm. These range from the very broad to specialized populations such as AA with CKD (AASK JAMA 2001) or normotensives with coronary artery disease (CAMELOT JAMA 2004).

 

From Booth, J et al. Proceedings of the Royal Society of Medicine. 1977.   

https://www.ncbi.nlm.nih.gov/pubmed/341169

 

Guest Post by

Hillel Sternlicht, MD
Author, Concepts in Hypertension Newsletter

Subscribe for free