Supramaximal elevation in B-type natriuretic peptide and its N-terminal fragment levels in anephric patients with heart failure: a case series

Introduction Little is known about the responses of natriuretic peptides to developing congestive heart failure in ‘anephric’ end-stage kidney disease. Case presentation We present three consecutive cases of surgically-induced anephric patients in a critical care environment: a 28-year-old Caucasian woman (with congestive heart failure), a 42-year-old Caucasian woman (without congestive heart failure), and a 23-year-old Caucasian woman (without congestive heart failure). Our limited study data indicate that cut-off values advocated for B-type natriuretic peptide and its N-terminal fragment to ‘rule out’ congestive heart failure in two of our end-stage kidney disease patients (without congestive heart failure) are largely appropriate for anephric patients. However, our index (first) patient developed congestive heart failure accompanied by the phenomenon of massive and persistent elevation of these natriuretic levels. Conclusion Our findings suggest that patients from the anephric subclass suffering from congestive heart failure will develop supramaximal elevation of B-type natriuretic peptide and its N-terminal fragment, implying the need for dramatically higher cut-off values with respective magnitudes of the order of 50-fold (B-type natriuretic peptide ~5780pmol/L; 20,000ng/L) to 100-fold (N-terminal fragment ~11,800pmol/L; 100,000ng/L) higher than current values used to ‘rule in’ congestive heart failure. Further research will be required to delineate those cut-off values. The role of our devised ‘Blood Volume – B-type natriuretic peptide feedback control system’ on ‘anatomical’ and ‘functional’ anephric patients led to significant mathematically-enriched arguments supporting our proposal that this model provides plausible explanations for the study findings, and the model lends support to the important hypothesis that these two groups of anephric patients inflicted with congestive heart failure should effectively have similar natriuretic response behavior.

Similarly, the 'control of BV' variable (mediated by natriuretic peptides such as BNP in conjunction with RAAS) is affected to a varying degree by the 'control of TBW' and 'control of BP' variables. The '↑/↓ BV → ↑/↓ myocardial stretch or tension → ↑/↓ BNP release' homeostatic mechanism leads to the end-target organ effects of: (a) ↓/↑ BV (via (natriuresis and diuresis) / (sodium and water conservation) by kidneys) and (b) ↓/↑ peripheral vascular resistance (via (vasodilatation) / (vasoconstriction) on blood vessels). This signifies that our proposed homeostasis (with integrator = hypothalamus likely connected via autonomic neural pathway) acting through its compensatory pathways is invoked to help restore the disturbance in BV ('hypervolemic' / 'hypovolemic') to its 'euvolemic' set point resulting in improved diastolic relaxation (lusitropy) and decreased myocardial fibrosis. Measurements on BV status are largely carried out by the low-pressure volume receptors in the atrium (which essentially equates to central venous pressure clinical measurements). Likewise, detailed analysis for a 2 U hypothalamic-pituitary axis for prolactin hormone or a 3 U hypothalamic-pituitary-thyroid axis for thyroid hormones could also be carried out.
For a given €, the magnitude of its size and complexity would increase exponentially if a linear increase in the number of U were to occur due to the associated power-law increase in the number of 'controlled variables' along with their 'mini-components' (input, output, effect and compensatory pathway). The total number of possibilities arising from n mini-components when considering the '(↑ or +)' or '(↓ or -)' state (i.e. r = 2) for each mini-component is given by the permutations with repetition formula: n r = n 2 from combinatorics. Let the symbol Σ denote 'the sum of'; and xi and yi denote 'n individual factors or causes of endocrine disorder' for i = 1, 2, 3,…, n that tend to have elevating or lowering properties, respectively, on the relevant hormone. The overall magnitudes of rises or falls in the particular hormonal output (O) (which is a controlled variable), such as BNP, NT-proBNP and prolactin hormonal concentrations, are governed by the net difference between the resultant effect from Σ (effects from xi that tend to increase O) and Σ (effects from yi that tend to decrease O). This overall resultant effect stemming from the absolute difference between the n value for xi (nx) and the n value for yi (ny), namely |nx -ny|, that tends to increase or decrease O respectively would be some nonlinear function of this absolute difference of a synergistic nature. Then this overall resultant effect will be of ever greater cumulative rises or falls (of an exponential nature) in O when |nx -ny| is numerically >1 and constitutes an ever larger integer number.
The '↑/↓ BV causing ↑/↓ myocardial stretch or tension, resulting in ↑/↓ BNP release' is the main mechanism for BNP (and NT-proBNP) pulsatile co-secretion. Other mechanisms such as heart muscle cell damage from myocardial infarct will also lead to BNP and NT-proBNP release. There are two major cardiac and non-cardiac causes of BNP and NT-proBNP elevations as follows: First, moderate increases in BNP (100-500ng/L) or NT-proBNP (250-1000ng/L): ventricular dysfunction, ischemic heart disease, pulmonary HT, acute pulmonary embolism, cor pulmonale, septic shock, renal insufficiency, liver cirrhosis, subarachnoid hemorrhage and hyperthyroidism.
In addition to glomerular filtration, BNP is eliminated from plasma mainly through natriuretic peptide receptors and degraded by neutral endopeptidases. By contrast, it is possible that NT-proBNP is largely eliminated by glomerular filtration. Levels of both BNP and NT-proBNP are: elevated with ageing, higher in women than in men, higher in RF and CHF of greater severity, and higher in LV systolic HF than LV diastolic HF. Stage of HF (early versus late) and genetic polymorphisms may result in inter-individual variation of BNP and NT-proBNP. Obesity with and without CHF is associated with lower levels of both molecules; obesity with and without CHF is presumably attributed to non-hemodynamic factors such as BMI-related defect in natriuretic peptide secretion (from either ↓myocardial hormone release or ↓synthesis), and ↑BNP metabolism in adipose tissue either via peptide degradation or regulation of clearance receptors.
The end target-organs for BNP are the kidneys and blood vessels. These are associated with the 'kidney compensatory pathway' and 'blood vessel compensatory pathway' respectively. The SIA state corresponds to the loss of the kidney as (a) an end target-organ and (b) a compensatory pathway, although the contribution of the collective blood vessels as an end target-organ and compensatory pathway is still intact. The primary endpoint of our study was to demonstrate the supramaximal elevation of BNP and NT-proBNP in Patient 1. Computing from Figure 2 (together with the 'major cardiac and non-cardiac causes of BNP and NT-proBNP elevations'), this can be seen to be due to multiple xi (with no identifiable yi); namely: (i) CHF itself, (ii) decreased MCR for BNP and NT-proBNP, and (iii) total loss of kidney tissue acting as an endtarget organ (but intact collective blood vessels acting as an end-target organ) with total disruption of 'kidney compensatory pathway' loop.
The secondary endpoint of our study was to demonstrate the supramaximal elevation of prolactin in Patient 1 as suggested by the persistently high prolactin values obtained between Event X (development of acute CHF) and Event Y (death of the patient). This was due to multiple xi (with no identifiable yi); namely, the systemic disorders of: (i) chronic RF, (ii) emotional stress, (iii) epileptic seizures, (iv) pharmacologic factors (anti-HT dopamine synthesis inhibitors methyldopa), and (v) decreased MCR for prolactin. Both the mildly elevated prolactin levels in Patients 2 and 3 mainly reflect the decreased MCR of prolactin due to CKD Stage 3 and anephric status (needing intermittent HD) for each respective patient.
The nx = 3 in Patient 1 for Σ (effects from xi that tend to increase the 'outputs' of BNP and NT-proBNP) with resultant massive and persistent elevation of these two natriuretic peptides. Applying the nx = 3 minus ny = 0 calculation giving a 'relatively large' |nx -ny| value of 3 predicts the overall magnitude of rises to be consistent with the supramaximal elevation of these hormones as seen in our study. Similar calculation of a 'relatively large' |nx -ny| value of 5 for prolactin xi and yi in Patient 1 also showed that they act in concert to greatly increase and maintain the high prolactin 'output' in a synergistic manner to explain its supramaximal elevation.
'Functional' anephric states should occur in adult ESKD patients when their in-situ remnant kidney tissues have totally lost all their functions or have atrophied completely. One could extrapolate that these patients should behave physiologically in a similar manner to SIA patients. A corollary to this argument would result in the hypothesis that when ESKD patients develop CHF with supramaximal elevations of BNP and NT-proBNP, they are likely to be functionally anephric. The full significances of this hypothesis in adults are yet to be fully realized. Supramaximal hormonal elevations when observed in neonates, infants and children will undoubtedly be due to mechanisms similar to that of their adult counterpart; and with the full impact of this hypothesis lying in uncharted territories. These are exciting areas for future medical research.
Let us mathematically analyze the following statement in a logical manner: The defined parameters nx, ny, and |nx -ny| are applicable to both 'anatomical' and 'functional' anephric patients. Because one can safely assume that all supporting criteria for the statement to hold true are present in both sets of patients, then this 'common denominator' statement per se can provide intuitive non-contradictory explanations for the supramaximal elevation phenomenon in all anephric patients inflicted with CHF. This 'common denominator' statement thus lends support to our proposed hypothesis that 'anatomical' and 'functional' anephric patients inflicted with CHF should have similar natriuretic response behavior.

Footnote on 'An infant in temporary anephric and congestive heart failure state manifesting supramaximal elevations of natriuretic peptides'
In October 2010, we encountered the case of a 5-month-old male baby (weight 7kg) with out-ofhospital cardiac arrest (due to commotio cordis) requiring 30 minutes of cardiopulmonary resuscitation before return of spontaneous circulation. He developed multiple organ dysfunction syndrome (MODS) requiring full ICU supportive care. The ICU supportive care included therapeutic hypothermia between 33°C and 34°C for the first 48 hours, full invasive ventilation for 12 days for acute CHF with fractional shortening (FS) 31% on echocardiogram (normal >30%) while on multiple inotropic and vasopressor agents, and CVVHDF for 5 days from Day 3 to 7 for (anuric) acute kidney injury with peak creatinine 93µmol/L (20-50) on Day 8: this probably equates to the baby being a temporary 'functional' anephric patient. Blood tests on Day