P. Przybylowski

Serum Renalase Depends on Kidney Function But Not on Blood Pressure in Heart Transplant Recipients

INTRODUCTION Renalase, an enzyme that breaks down catecholamines like adrenaline and noradrenaline in the blood circulation, was discovered in 2005. The human kidney releases this protein into the bloodstream to regulate blood pressure. Heart transplant recipient show a high prevalence of hypertension. The aim of this study was to assess possible correlations between renalase, blood pressure, and kidney function among 130 prevalent heart transplant recipients. To obtain normal ranges we also studied renalase levels in 27 healthy volunteers. METHODS Complete blood counts, urea, serum lipids, fasting glucose, and creatinine were measured using standard laboratory methods in the hospital central laboratory. Renalase was assessed using commercially available kits. RESULTS In heart transplant recipients renalase levels correlated with age (r=0.25; P<.05); time after transplantation (r=0.22; P<.05); serum creatinine (r=0.85; P<.001); estimated glomerular filtration rate (chronic kidney disease-epidemiological study formula; r=0.59; P<.0001; Modification of Diet of Kidney Disease (r=-0.58; P<.001); Cockcroft-Gault (r=-0.59; P<.001); 24-hour creatinine clearance (r=-0.52; P<.001); NT-proBNP (r=0.41; P<.001); erythrocyte count (r=-0.42; P<.001); hemoglobin (r=0.44; P<.001); cystatin C (r=0.82; P<.001); ejection fraction (r=-0.26; P<.01; and New York Heart Association class (r=0.31; P<.001). Multiple regression analysis showed renalase concentration to be predicted in 75% by serum creatinine (beta value, 0.79; P=.0000000; SE 3.00; F statistics 15.96; P<.0000001). Serum renalase was higher among heart transplant recipients than healthy volunteers. CONCLUSION Renalase, highly elevated in heart transplant recipients, is predominantly dependent on kidney function, which deteriorates with time after heart transplantation and age. Further studies are needed to establish its putative role in the pathogenesis of hypertension after transplantation and possible novel targeted therapies. However, is seems that among heart transplant recipients renalase was not related to blood pressure.

Hypertension in solid organ transplant recipients

Hypertension (HT) is one of the most frequent complications of solid organ transplantation; about 70-90% of this population have high blood pressure or require antihypertensive therapy. Abnormal blood pressure is a potent non-immunological risk factor directly related to patient and graft survival. The etiology of hypertension after orthotopic heart transplantation is multifactorial and varies depending on the time following transplantation. In the early period after transplantation, hypertension is generally related to intravascular volume expansion and persistently increased systemic vascular resistance. Other factors predominant in kidney allograft recipients include: donor age, donor familial history of hypertension, transplant renal artery stenosis, graft function, the recurrence or de novo appearance of glomerulonephritis in transplanted kidney, and post-biopsy arteriovenous fistula. In liver and heart transplantation, hypertension is mainly due to impaired kidney function, with all its consequences. Another contributing factor is immunosuppressive regimen based on calcineurin inhibitors and steroids. The management of post-transplant hypertension usually requests non-pharmacological and pharmacological treatment. In this review, the pathogenesis and treatment of post-transplant hypertension in solid organ transplantation is presented.

Renalase and endothelial dysfunction in heart transplant recipients.

INTRODUCTION Renalase, an enzyme that cetabolyzes catecholamines, such as circulating adrenaline and noradrenaline, is released by the human kidney to regulate blood pressure. In solid organ transplant recipients endothelial dysfunction is often present. The aim of our study was to assess correlations among renalase, blood pressure, endothelial injury markers, and kidney function in 130 prevalent heart allograft recipients (OHT). METHODS Complete blood counts, urea, serum lipids, fasting glucose and creatinine were measured using standard laboratory methods in the hospital central laboratory. We assessed markers of endothelial function/injury: vWF (von Willebrand factor), inflammation: hsCRP, interleukin (IL)-6, TRAIL (tumor necrosis factor related apoptosis-inducing ligand), TWEAK (tumor necrosis factor-like weak inducer of apoptosis) and midkine renalase using commercially available kits. RESULTS The mean serum renalase among OHT was significantly higher compared with a control group (P < .001). Among heart transplant recipients renalase correlated weakly (P < .05) with time after transplantation and TRAIL; moderately (P < .01), with ejection fraction and age; and strongly, with kidney function, IL-6, vWF, midkine, and New York Heart Association class (P < .05). Multiple regression analysis revealed renalase values to be 70% predicted by serum creatinine measurements. CONCLUSION Impaired kidney function was strongly associated with endothelial damage and inflammation. Renalase, which was highly elevated among heart transplant recipients, was predominantly dependent on renal function, which deteriorated with time after transplantation and in correlation with age.

Blood Pressure Control in Orthotopic Heart Transplant and Kidney Allograft Recipients Is Far From Satisfactory

Hypertension is widely accepted as a risk factor for coronary artery disease, heart failure, stroke, or chronic kidney disease. According to ESH/ESC and JNC guidelines, the target blood pressure should be low 140/90 mm Hg in the general population, and 130/80 mm Hg among patients with chronic kidney disease or diabetes. The aim of this study was to assess the prevalence of achieved target blood pressure among 164 prevalent heart transplant recipients as well as 172 prevalent, kidney transplant, 100 hemodialyzed, and 50 peritoneally dialyzed patients on renal replacement therapy. We assessed kidney function in transplanted patients using the simplified MDRD formula. In the heart transplant (OHT) population, 10% had diabetes and 65% chronic kidney disease; in the kidney transplant population 18% had diabetes. Hypertension was treated in 70% of OHT, 92% of kidney 90% of hemodialyzed and 70% of peritoneally dialyzed patients. In the OHT population, only 43% of subjects achieved the target blood pressure, while 42% among kidney transplant, 50% of hemodialzyed, and only 20% of peritoneally dialyzed patients did so. Hypertensive OHT as well as kidney transplant subjects were older, displayed higher serum creatinine values and lower estimated glomerular filtration rates. Hypertensive patients after OHT were treated with ACE inhibitors (50%), calcium channel blockers (55%), diuretics (34%), β-blockers (34%), and/or spironolactone (5%). Among hypertensive kidney allograft recipients, the most commonly used drugs were calcium channel blockers (80%), β-blockers (60%), diuretics (55%) ACE inhibitors (40%), and α-blockers (12%). The kidney transplant population required three and more hypotensives in 63% of cases. Despite polytherapy optimal blood pressure control was not achieved in the majority of patients. OHT and kidney graft recipients displayed a high prevalence of hypertension, which should be treated adequately. More efforts must be dedicated to optimize blood pressure control, particularly in the presence of other comorbidities.

Prevalence of Iron Deficiency in Heart and Kidney Allograft Recipients

BACKGROUND Functional iron deficiency is characterized by the presence of adequate iron stores as defined by conventional criteria, but insufficient iron mobilization to adequately support erythropoiesis. The aim of this study was to assess the prevalence of functional iron deficiency in heart and kidney transplant recipients based on data from recent medical records. METHODS Using standard laboratory methods obtained during routine checkups, we assessed iron status by determinations of serum iron, total iron-binding capacity, ferritin and total saturation of transferrin (TSAT), as well as complete blood count and creatinine. RESULTS Iron parameters were available for 62% of heart transplant recipients, but only for 26% of kidney transplant recipients. Absolute iron deficiency was observed in 35% of the heart and 8% of the kidney transplant recipients (P<.001). Functional iron deficiency was present in 4% of the heart and 6% of the kidney transplant recipients. Functional iron deficiency was associated with significantly higher serum ferritin and lower TSAT. In addition, although their hemoglobin values did not differ significantly, heart transplant recipients with absolute iron deficiency showed lower erythrocyte blood counts, were younger, and had a shorter time after transplantation. CONCLUSIONS Iron parameters are assessed infrequently, particularly among kidney transplant recipients. Iron deficiency was present in a considerable group of heart transplant recipients. This population should be carefully screened for possible reversible causes of iron deficiency to slow or to minimize anemia development.

Prevalence of chronic kidney disease in orthotopic heart transplant recipients and kidney allograft recipients using the new Chronic Kidney Disease Epidemiology Collaboration formula.

Chronic kidney disease (CKD) is an important long-term complication of all forms of nonrenal organ transplantation. The aim of this study was to assess the prevalence of kidney dysfunction among heart (n = 163) and kidney allograft recipients (n = 169) using the new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, which includes age, gender, and comorbidities. The mean serum creatinine values in these populations were 1.58 ± 0.75 mg/dL and 1.36 ± 0.56 mg/dL, respectively. In heart allograft recipients mean estimated glomerular filtration rate (eGFR) by (MDRD) was 57.14 ± 26.17 mL/min, and by CKD-EPI formula was 57.44 ± 26.76 mL/min whereas in kidney allograft recipients it was 63.91 ± 25.43 mL/min and 65.20 ± 25.60 mL/min, respectively. According to the MDRD formula, stage 2 CKD was noted in 35 patients; stage 3 CKD in 79 patients, and stage 4 in 23 patients. According to the CKD-EPI formula stage 2 CKD was displayed by 35 patients; stage 3 CKD in 78 patients, and stage 4 in 23 patients. Clinically significant CKD (GFR < 60 mL/min) was observed in 62% of patients. According to the MDRD normal kidney function was present in 22 and according to the CKD-EPI formula in 27 patients. According to the MDRD formula stage 2 CKD was found in 59 kidney allograft recipients; stage 3 in 58 patients; and stage 4 in 16 patients. According to the CKD-EPI formula, stage 2 CKD was noted in 63 patients; stage 3 in 58 patients; and stage 4 in 15 patients. Clinically significant CKD was observed in 44% of patients. Using MDRD or CKD-EPI normal kidney function was found in 36 and 33 patient, respectively. CKD prevalence is extremely high among heart and kidney transplant recipients. Evaluation of renal function is important to select the appropriate strategy to reduce the cardiovascular risk.

Absolute and Functional Iron Deficiency Is a Common Finding in Patients With Heart Failure and After Heart Transplantation

BACKGROUND Anemia is relatively common in patients with heart failure and heart transplant recipients. Both absolute and functional iron deficiency may contribute to the anemia in these populations. Functional iron deficiency (defined as ferritin greater than 200 ng/mL with TSAT (Transferrin saturation) less than 20%) is characterized by the presence of adequate iron stores as defined by conventional criteria, but with insufficient iron mobilization to adequately support. The aim of this study was to determine prevalence of absolute and functional iron deficiency in patients with heart failure (n = 269) and after heart transplantation (n = 130) and their relation to parameters of iron status and inflammation. METHODS Iron status, complete blood count, and creatinine levels were assessed using standard laboratory methods. C-reactive protein, hepcidin and hemojuvelin were measured using commercially available kits. RESULTS Absolute iron deficiency was present in 15% of patients with heart failure and 30% in heart transplant recipients, whereas functional iron deficiency was present in 18% of patients with heart failure and 17% in heart transplant recipients. Functional iron deficiency was associated with significantly higher C-reactive protein and hepcidin levels in heart failure patients, and higher hepcidin and lower estimate glomerular filtration rates in heart transplant recipients. Prevalence of anemia (according to the World Health Organization) was significantly higher in heart transplant recipients (40% vs 22%, P < .001), they were also younger, but with worse kidney function than patients with heart failure. CONCLUSIONS Both absolute and functional iron deficiency were present in a considerable group of patients. This population should be carefully screened for possible reversible causes of inflammation.

Iron Metabolism, Hepcidin, and Anemia in Orthotopic Heart Transplantation Recipients Treated with Mammalian Target of Rapamycin

PURPOSE Functional iron deficiency is characterized by the presence of adequate stores as defined by conventional criteria, but with the inability to sufficiently mobilize iron for erythropoiesis. Hepcidin, produced by hepatocytes in response to anemia, hypoxia, or inflammation, is a key regulator of iron homeostasis. Anemia is relatively common among patients treated with mammalian target of rapamycin (mTOR) antagonists. We tested hypothesis that hepcidin was related to the functional iron deficiency, defined as a ferritin value above 200 ng/mL with transform saturation (TSAT) below 20% among orthotopic heart transplant recipients (OHT) treated (n = 35) versus not treated (n = 134) with mTOR. METHODS AND MATERIALS Using standard laboratory methods we assessed iron status: serum iron, total iron binding capacity, ferritin, TSAT, complete blood count and creatinine. Soluble transferrin receptor (sTFR), high sensitivity C-reactive protein (hSCRP), interleukin-6 (IL-6) hepcidin, and cystatin C were measured using commercially available kits. RESULTS According to the World Health Organization definition, the prevalence of anemia was 51% among mTOR treated whereas in the rest of the OHT the prevalence of anemia 30% among the other OHT patients. Functional iron deficiency was present in 80% of mTOR-treated patients. Serum hepcidin, IL-6, hsCRP, serum creatinine, cystatin C, NT-proBNP were significantly higher among mTOR treated patients; whereas sTFR, estimated glomerular filtration rate, hemoglobin, and erythrocyte count were significantly lower. CONCLUSIONS Functional iron deficiency which is common among OHT patients treated with mTOR, was associated with high hepcidin levels and inflammatory markers. This form of anemia in mTOR-treated OHT resembles the disorder of chronic disease, suggesting that OHT patients show low-grade inflammation, which should be investigated for underlying, potentially reversible causes. Iron treatment should also be considered.

Liver fatty-acid-binding protein in heart and kidney allograft recipients in relation to kidney function.

Mammalian intracellular fatty-acid-binding proteins (FABPs), a large multigene family, encode 14-kD proteins that are members of a superfamily of lipid-binding proteins. FABPs are tissue specific. Liver-type FABP (L-FABP) can be filtered through the glomerulus owing to its small molecular size, similar to cystatin C, but it is reabsorbed by proximal tubule epithelial cells like other small proteins. In the human kidney, L-FABP is expressed predominantly in proximal tubules. It had been suggested that the presence of L-FABP in urine reflects hypoxic conditions resulting from decreased peritubular capillary flow, serving as a marker of acute kidney injury. The aim of this study was to assess urinary L-FABP in 111 heart and 76 kidney transplant recipients in relation to kidney function. Complete blood count, urea, fasting glucose, creatinine, and the N-terminal fragment of brain natriuretic protein were studied by standard laboratory methods; L-FABP and cystatin C, by ELISA using commercially available kits. Kidney transplant recipients displayed significantly higher L-FABP than heart recipients. Upon univariate analysis, urinary L-FABP correlated, with serum creatinine, cystatin C and estimated glomerular filtration ratio (eGFR) in kidney allograft recipients. However, in heart transplant recipients it was not related to kidney function, as reflected by creatinine or eGFR; was strongly related to cystatin C (r=0.34; P<.001) and urinary creatinine (r=-0.29; P<.01), and NGAL (r=0.29; P<.01). Upon multiple regression analysis, the best predictor of urinary L-FABP in kidney allograft recipients, was eGFR whereas in heart recipients, no parameter independently predicted L-FABP. Successful heart transplantation is associated with kidney injury as reflected by a reduced eGFR; however, in this population, L-FABP did not serve as a marker of kidney function. In contrast, in kidney allograft recipients, L-FABP may be a potential early marker for impaired kidney function/injury.

Tumor necrosis factor-related apoptosis-inducing ligand is a marker of kidney function and inflammation in heart and kidney transplant recipients.

BACKGROUND Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was originally identified as the third member of the TNF superfamily to induce apoptosis. TRAIL is normally expressed in many human tissues including kidney. Circulating soluble TRAIL is a negative marker for inflammation and is inversely associated with the mortality risk in chronic kidney disease patients. One increasingly prevalent complication in heart transplant recipients appears to be chronic kidney disease. MATERIALS AND METHODS The aim of the study was to assess TRAIL concentration in 136 heart transplant recipients and 80 prevalent kidney allograft recipients in relation to kidney function. Complete blood count, urea, serum lipids, fasting glucose, creatinine, NT-proBNP were studied. Soluble TRAIL, hsCR P, interleukin-6 (IL-6), von willebrand factor (vWF) were assayed using commercially available kits. RESULTS Heart transplant recipients had significantly higher serum creatinine, urea, cholesterol, triglycerides, fasting glucose, white blood cell count, serum TRAIL and lower estimated glomerular filtration rate than the control group. Similar results were obtained for kidney allograft recipients. Serum TRAIL levels fell, together with decline in glomerular filtration rate in heart transplant patients. Serum TRAIL was related to age, kidney function, erythrocyte count, hemoglobin, NT-proBNP, New York Heart Association class, presence of diabetes, high-density lipoprotein (HDL), IL-6, and ejection fraction. Age and HDL turn out to be predictors of TRAIL in heart transplant recipients. In kidney transplant recipients, TRAIL was related, in univariate analysis, to age, NT-proBNP, time after transplantation, kidney function, and vWF. In multiple regression analysis, predictors of TRAIL were vWF and time after transplantation. CONCLUSION TRAIL may represent a surrogate marker of endothelial dysfunction and atherosclerosis as these processes are accelerated in heart and kidney dysfunction.