Nephro-oncology: clinical and biochemical aspects of kidney disease and cancer.

Onco-nephrology is a new field of medicine which combines many aspects of kidney injury in cancer patients and cancers in patients with kidney disease. This connection takes many forms and includes drug-induced nephrotoxicity, electrolyte disorders, numerous paraneoplastic syndromes and an increased rate cancers in dialysis and transplanted patients. The appropriate laboratory assessment of the kidney function allows to optimize chemotherapy and thus minimizes the risk of complications. This article focuses on acute kidney injury (AKI), chronic kidney disease (CKD), various electrolyte and acid-base disorders, the most common cancers after kidney transplantation and the kidney disorders associated with HSCT (hematopoietic stem cell transplantation). The possibility of the application of novel cancer therapy, such as cancer immunotherapy and proton therapy in transplant recipients was also discussed.

Malignancies in adult kidney transplant candidates and recipients: current status.

Posttransplant malignancies, particularly recurrent and de novo, in solid organs including kidney transplant recipients (KTRs) are a significant complication associated with substantial mortality, largely attributed to the long-term immunosuppression necessary to maintain allograft tolerance. Older age at transplantation and oncogenic virus infection along with pretransplant malignancies are among the main factors contributing to the risk of cancer in this population. As the mean age of transplant candidates rises, the rate of transplant recipients with pretransplant malignancies also increases. The eligibility criteria for transplantation in patients with prior cancer have recently changed. The overall risk of posttransplant malignancies is at least double after transplantation, including KTRs, relative to the general population, and is most pronounced for skin cancers associated with UV radiation and virally mediated tumors. The risk of renal cell carcinoma is specifically increased in the kidney transplant population. The therapy for cancer in transplant patients is associated with risk of higher toxicity, and graft rejection and/or impairment, which poses a unique challenge in its management. Reduction of immunosuppression and the use of mammalian target of rapamycin inhibitors are common after cancer diagnosis, although optimal immunosuppression for transplant recipients with cancer remains undefined. Suboptimal cancer treatment contributing to a worse prognosis has been reported for malignancies in this population. In this article, we focus on the prevalence and outcomes of posttransplant malignancies, cancer therapy including a short overview of immunotherapy, cancer screening and prevention strategies, and immunosuppression as a cancer risk factor. The 2020/2021 recommendations of the Kidney Disease: Improving Global Outcomes and the American Society of Transplantation for transplant candidates with a history of cancer are presented.

Screening for Polyomavirus Viruria Like Early Detection of Human Polyomavirus Infection and Replication: The Results of a Single-Center Observation.

BACKGROUND: Polyomavirus (PV) infection and PV-associated nephropathy (PVAN) are some of the most important problems in kidney transplantation. PURPOSE: Our objective was to determine the incidence of PV viruria and PV replication in single-center Polish kidney transplant recipients (KTR). METHODS: Urine samples from 155 cadaveric KTR were analyzed for PV viruria using quantitative real-time polymerase chain reaction and the patients were followed prospectively. The PV replication was recognized when the urine level was >107 PV DNA copies/mL of urine. RESULTS: Based on the PV DNA analysis, the patients were divided into 3 groups: Group 1 (n = 87; 56.1%) without viruria, Group 2 (n = 44; 28.4%) with viruria but without PV replication, and Group 3 (n =24; 15.5%) with PV replication. The presence of PV viruria was correlated with the type of immunosuppressive regimen, strongly associated with tacrolimus intake. There was no correlation between viruria and mycophenolate daily dose in the study population. In Group 3 there were 6 patients (3.9%) with high viruria (>1010 copies/mL), and 5 patients from this group had confirmed PVAN in allograft biopsy. CONCLUSIONS: The prevalence of BK virus infection in KTR is similar to that reported in studies from other countries. We confirmed that PV viruria can be both a good screening for PV infection and a good predictor of PVAN. Tacrolimus was the most important predictor of PV viruria and PV replication in KTR.

Short-term Effects of Losartan on Cardiovascular Risk and Allograft Injury Biomarkers in Kidney Transplant Recipients.

BACKGROUND: There is a controversy over the renoprotective and cardioprotective effects of renin-angiotensin-aldosterone system blockade in kidney transplant recipients (KTRs). The aim of the study was to evaluate the short-term effects of losartan on allograft injury, cardiovascular risk biomarkers and safety of the treatment in KTRs. METHODS: An interim analysis of a prospective, open, multicenter, controlled clinical trial CELART (Cardiovascular Effects of Losartan After Renal Transplantation) was performed. KTRs were allocated to losartan (L) 50 to 100 mg or standard hypotensive treatment (ST) group to reach target blood pressure (BP) <140/90 mm Hg. The short-term effects of the therapy were evaluated after 6 months: estimated glomerular filtration rate (eGFR), albuminuria, the intrarenal fibrosis biomarkers: urine excretion of transforming growth factor ß-1 (TGFß-1) and procollagen type III amino terminal propeptide (PIIINP), cardiac biomarker: serum concentration of N-terminal-pro-B-type natriuretic peptide (NT-proBNP), 24-hour ambulatory BP measurement, and hemoglobin and potassium concentrations. RESULTS: At baseline the groups did not differ with respect to age, primary nephropathy, comorbidity, immunosuppressive therapy, albuminuria, and graft function. A total of 61 (L group) and 73 (ST group) patients reached the target BP and completed protocol at 6 months. After 6 months of therapy there were no significant differences in changes of eGFR, albuminuria, hemoglobin and potassium concentrations, urine excretion of PIIINP, and TGFß-1 between groups. There was a trend in the L group to decrease the concentration of serum NT-proBNP. CONCLUSIONS: Losartan shows minimal adverse effects and no influence on graft function and biomarkers of graft fibrosis. It may have a positive effect on cardiovascular risk in KTRs. Further interim analyses of the CELART study will be conducted.

Gastrointestinal Pathologies in Patients After Successful Renal Transplantation.

BACKGROUND: Kidney transplantation (KT) is the most desired and cost-effective modality of renal replacement therapy for patients with chronic kidney failure. KT protects the patient from complications that may develop during chronic dialysis. Unfortunately, evidence also suggests that KT patients are more prone to developing cancer than healthy persons. Many complications after renal transplantation can be prevented if they are detected early. The aim of this study was to evaluate the prevalence of gastrointestinal pathologies in patients after KT. METHODS: Adult patients after KT who are under the care of the Outpatient Department of Nephrology at the Medical University of Gdansk, Poland, received alarm symptom questionnaires and referral for testing for the presence of fecal occult blood. Then, in 58 selected patients (36 men and 22 women), endoscopic examination was performed. Mean age was 57.34 ± 10.1 (range, 35-83) years. RESULTS: Out of 940 patients after KT, resting under supervision of the Outpatient Department, 208 patients completed the questionnaire and 118 gave a stool sample for testing: 40 results were positive. After analyzing the questionnaires and stool results, 100 patients qualified for further investigation. The endoscopic examination had been performed so far in 58 patients and revealed gastritis and/or duodenitis in 49 patients, diverticular colon disease in 26, esophagitis in 8, colon polyps in 16, stomach polyps in 4, inflammatory bowel disease in 12, and cancers in 3. CONCLUSIONS: The preliminary results indicate that patients after KT have significant risk of gastrointestinal pathologies and require detailed diagnostic endoscopy.

Pregnancy After Kidney Transplantation With Maternal and Pediatric Outcomes: A Single-Center Experience.

Outcomes of pregnancies after kidney transplantation were evaluated. Thirty-one pregnancies in 26 women were noted. The mean maternal age at pregnancy was 31 ± 5 years (range, 23-44 years). The interval between transplantation and conception was 54 ± 51 months (range, 7-213 months). The mean serum creatinine concentration before conception was 1.28 ± 0.4 mg/dL (range, 0.8-2.45 mg/dL), and mean estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration) was 62 ± 18 mL/min/1.73 m2 (range, 27-106 mL/min/1.73 m2). There were no maternal deaths. There was 1 case of suspected acute rejection after delivery. There was 1 case of graft loss during pregnancy. Maternal complications included edema (6/26), hypertension (7/26), increase of (2/26) or appearance of proteinuria (5/26), and preeclampsia (4/26). Mean creatinine increase during pregnancy was 0.02 mg/dL. Mean creatinine 1 year after pregnancy was 1.54 mg/dL (±0.8 mg/dL). There were 19 cesarean sections. Fetal outcomes included 25 live births, 4 abortions, and 2 stillbirths. Out of 25 live births, 22 children were considered healthy, 2 children had congenital defects, and there were 2 deaths at neonatal age. Mean pregnancy age was 35 ± 4 weeks (range, 24-40 weeks). The rate of premature deliveries was 15 of 25. Mean neonate birth weight was 2363 ± 1029 grams (range, 490-4100 grams). The rate of babies small for gestational age was 19%. During follow-up (range, 0.5-30 years) 5 of 26 patients lost grafts (between 3 and 15 years after pregnancy); most (20) of the children previously considered healthy had good long-term development. Our results confirm that risk of pregnancy in kidney transplant recipients can be accepted, and children considered healthy at delivery develop well.

Aliskiren reduces albuminuria after kidney transplantation.

BACKGROUND: The renoprotective effects of the direct renin inhibitor, aliskiren, in renal transplant recipients have been supposed, but not finally proven. We performed an exploratory double-blind, losartan controlled, cross-over study to evaluate the influence of aliskiren, direct renin inhibitor, on albuminuria and other surrogate markers of kidney injury in patients after renal transplantation. The safety of this therapy was also evaluated. METHOD: 16 of 18 patients (12 M, 4 F), 48.3 ± 9.0 years, 57.7 ± 9.1 months after kidney transplantation, with hypertension and stable serum creatinine 1.4 ± 0.08 mg/dl without proteinuria, completed the protocol. Each patient underwent two 8-week treatment periods (one with 150 mg of aliskiren, and one with 50 mg of losartan) in random order, allowing an 8-week placebo washout between them. RESULTS: There were no differences in albuminuria, transforming growth factor ß-1 and 15-F2t-isoprostanes urine excretion between aliskiren and losartan. Creatinine serum level, eGFR, 24 h systolic and 24 h diastolic blood pressure were stable through the study. There were no differences in haemoglobin and potassium serum concentration between studied drugs. CONCLUSION: Aliskiren decreases albuminuria in renal transplant recipients with clinically minimal side effects. The effect does not differ from that of losartan.

High serum chemerin level in CKD patients is related to kidney function, but not to its adipose tissue overproduction.

Chemerin is an adipokine modulating inflammatory response and affecting glucose and lipid metabolism. These disturbances are common in CKD. The aim of the study was: (a) to evaluate circulating chemerin level at different stages of CKD; (b) to measure subcutaneous adipose tissue chemerin gene expression; (c) to estimate the efficiency of renal replacement therapy in serum chemerin removal. 187 patients were included into the study: a) 58 patients with CKD; (b) 29 patients on hemodialysis; (c) 20 patients after kidney transplantation. 80 subjects constituted control group. Serum chemerin concentration was estimated by ELISA. The adipose tissue chemerin mRNA level was measured by RT-qPCR. The mean serum chemerin concentration in CKD patients was 70% higher than in the control group (122.9 ± 33.7 vs. 72.6 ± 20.7 ng/mL; p < 0.001) and it negatively correlated with eGFR (r = -0.71, p < 0.001). The equally high plasma chemerin level was found in HD patients and a HD session decreased it markedly (115.7 ± 17.6 vs. 101.5 ± 16.4 ng/mL; p < 0.001). Only successful kidney transplantation allowed it to get down to the values noted in controls (74.8 ± 16.0 vs. 72.6 ± 20.7 ng/mL; n.s.). The level of subcutaneous adipose tissue chemerin mRNA in CKD patients was not different than in patients of the control group. The study demonstrates that elevated serum chemerin concentration in CKD patients: (a) is related to kidney function, but not to increased chemerin production by subcutaneous adipose tissue, and (b) it can be efficiently corrected by hemodialysis treatment and normalized by kidney transplantation.

Management of renin-angiotensin system blockade in patients with chronic kidney disease under specialist care. Retrospective cross-sectional study.

BACKGROUND: Reduction of blood pressure and proteinuria by blockade of the renin-angiotensin-aldosterone system (RAAS) has been the cornerstone of renoprotective intervention for patients with chronic kidney disease (CKD) for many years. AIMS: The aims were to check the use of angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin II receptor blockers (ARBs) in CKD patients. METHODS: This was a retrospective, cross-sectional study analysing data from medical records of patients who received specialist care in 1996, 2001, 2006, 2011 in the Outpatient Unit. RESULTS: The numbers of CKD subjects included in the four independent surveys were as follows: 190, 490, 1799, 1696. The usage of RAAS blocking agents overall increased significantly in subsequent years as follows: 25, 49, 63, 74%. Patients with proteinuria and cardiovascular complications and/or diabetes were receiving RAAS blocking agents more commonly than others. The use of ACEI and/ or ARB in stage 4-5 CKD increased in subsequent years. In 2011 dual RAAS blockade was used in 10% CKD patients overall and 19% patients presented proteinuria. CONCLUSION: The use of RAAS blocking agents were increasing in CKD patients under specialist care between 1996-2011. The quality of the management was gradually improved.

Treatment of hypertension in chronic kidney disease patients under specialized care: one-center cross-sectional analyses.

AIM: The study analyzed hypertension management and control rates among non-dialysis, non-transplanted hypertensive chronic kidney disease (CKD) patients under specialized care in Gdansk nephrology center in 1996-2011. PATIENTS AND METHODS: It was a retrospective, cross-sectional study analyzing data from medical records of 190, 490, 1799 and 1696 subjects with CKD, who received outpatient care in 1996, 2001, 2006 and 2011, and were included in four independent surveys, respectively. RESULTS: The average number of antihypertensive drugs per patient increased significantly (p < 0.01) as follows 1.74 ± 0.9 (1996), 2.08 ± 1.01 (2011), 2.5 ± 1.19 (2006) and 2.65 ± 1.18 (2011). The percentage of patients receiving diuretics, beta-blockers and drugs inhibiting renin-angiotensin-aldosterone increased significantly in subsequent years, while a frequency of therapy with calcium channel blockers decreased (p < 0.001). 16%, 30%, 42% and 54% of subjects had causal BP values < 140/90 mmHg (p < 0.001). When specific thresholds for CKD patients according to JNC recommendations were used, the control rate was worse but also showed significant improvement in the second, third and final surveys, i.e. 9%, 12%, 14% and 24% (p < 0.001). The subgroup analysis revealed that a better control rate was observed in following groups: < 65 years old; I-II stage of CKD; primary glomerulonephritis; without cardiovascular complications or diabetes. CONCLUSION: The study may show an improvement in the effectiveness of antihypertensive treatment in CKD patients under specialized care in Gdansk Nephrology Centre in 1996-2011.

Elevated circulating PCSK-9 concentration in renal failure patients is corrected by renal replacement therapy.

BACKGROUND: A high level of circulating PCSK9 binds to the LDL receptor, reduces its cell's surface density and leads to hypercholesterolemia. The aim of this study was to examine the circulating PCSK9 level in patients with kidney disease. METHODS: Out of the patients treated in our Departments we selected: (a) 44 patients with CKD stage 3 and 4 (b) 29 patients with CKD stage 5 on maintenance hemodialysis treatment; and (c) 20 patients after successful renal transplantation. Thirty-four subjects, without CKD formed the control group. Serum biochemical parameters' concentrations were assayed by a certified laboratory. Serum PCSK9 concentration was estimated by a commercially available ELISA kit. RESULTS: The mean serum concentration of PCSK9 in patients with kidney disease was higher than in the control group (238.7 ± 64.5 vs. 536.7 ± 190.4; p < 0.001). A strong negative correlation between serum PCSK9 concentration and eGFR was found (r = -0.66; p < 0.001), as well as between serum concentrations of PCSK9 and total- (r = 0.482; p < 0.05) or LDL-cholesterol (r = 0.533; p < 0.05), but exclusively in patients not receiving statins. The elevated serum concentration of PCSK9 in patients before hemodialysis session declined afterwards, reaching the values observed in patients after kidney transplantation and in the control group. CONCLUSION: The circulating PCSK9 concentration is increased in patients with CKD; however, this is not accompanied by hypercholesterolemia. The positive correlations between PCSK9/TCh and PCSK9/LDL-Ch have been found only in patients not treated with statins. The elevated circulating PCSK9 level is corrected by maintenance hemodialysis treatment and normalized by a successful kidney transplantation.

Aliskiren attenuates oxidative stress and improves tubular status in non-diabetic patients with chronic kidney disease-Placebo controlled, randomized, cross-over study.

PURPOSE: Pharmacological inhibition of the renin-angiotensin-aldosteron system (RAAS) may have a beneficial impact on proteinuria and chronic kidney diseases (CKD) progression. Despite recent progress by means of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB), there is still no optimal therapy which can stop progression of the nephropathy. Recently introduced aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension. The purpose was to evaluate the extent of oxidative stress and tubular injury after the direct renin inhibitor, aliskiren compared with placebo and perindopril in patients with non-diabetic chronic kidney disease (NDCKD). MATERIAL/METHODS: A randomized, double-blind, cross-over trial was performed in 14 patients receiving 300mg aliskiren, 10mg perindopril and placebo in random order. The end point was a change in the urinary excretion of N-acetyl-ß-D-glucosaminidase (NAG) and α1-microglobulin (α1m) and 15-F(2α)-isoprostane. RESULTS: Aliskiren reduced excretion of 15-F(2α)-isoprostane (p=0.03) and α1m (p=0.01) as compared to placebo. There were no differences between aliskiren and perindopril in this regard. NAG urine excretion did not change after aliskiren and perindopril. CONCLUSIONS: Aliskiren attenuates oxidative stress and may improve functional status of tubules in patients with NDCKD.

Direct renin inhibition--a promising strategy for renal protection?

Activation of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the progression of chronic kidney disease (CKD). RAAS inhibitors, such as angiotensin converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs), decrease the rate of progression of diabetic and non-diabetic nephropathies and are first-line therapies for CKD. Although these agents are highly effective, current therapeutic strategies are unable to sufficiently suppress the RAAS and stop CKD progression. Aliskiren, the first in a new class of RAAS-inhibiting agents (direct renin inhibitors) has been approved to treat hypertension. Aliskiren exerts renoprotective, cardioprotective, and anti-atherosclerotic effects in animal models that appear to be independent of its blood pressure lowering activity. Early clinical studies using urinary protein excretion as a marker of renal involvement suggest a possibly novel role for aliskiren in treating CKD. This review discusses the antiproteinuric efficacy and safety of aliskiren and considers the evidence for its potential renoprotection.

Safety of enhanced renin-angiotensin-aldosterone system inhibition with aliskiren in nondiabetic patients with chronic kidney disease.

INTRODUCTION: Various methods of combination renin-angiotensin-aldosterone system blockade help achieve more potent antiproteinuric effects, but may be associated with higher risk of side effects. Therapies involving direct renin inhibitor, aliskiren, may promote renal fibrosis by stimulating (pro)renin receptor due to increased renin levels. OBJECTIVES: The aim of the study was to compare the effects of combination treatment with angiotensin receptor blockers, telmisartan (80 mg/d) and aliskiren (300 mg/d) with those of combination treatment with 80 mg/d telmisartan and mineralocorticoid receptor blocker (50 mg/d eplerenone) and telmisartan (160 mg/d) alone on the urinary excretion of transforming growth factor ß1 (TGF­ß1), renal function, and serum potassium levels. PATIENTS AND METHODS: A randomized open-label controlled cross-over study was performed in 18 white patients (7 women and 11 men; mean age, 42.4 ±1.9 years) with proteinuric nondiabetic chronic kidney disease and estimated glomerular filtration rate of 85.2 ±4.6 ml/min. RESULTS: The urinary excretion of TGF­ß1 was stable despite a significant increase in plasma renin levels after treatment with telmisartan and aliskiren. There were no differences in renal function and serum potassium levels between the compared treatments. Moreover, there were no episodes of hypotension or acute renal impairment. CONCLUSIONS: Combination therapy with telmisartan and aliskiren may be safe in young nondiabetic patients with normal renal function at low vascular risk. This treatment may be an alternative for a subset of patients in whom standard RAA system blockade is ineffective.

[Isoprostanes - important marker of the oxidative stress estimation in patients with chronic kidney disease]. / Izoprostany - wazny wskaznik stresu oksydacyjnego u chorych z objawami przewleklej choroby nerek.

UNLABELLED: The discovery of isoprostanes, which are products of non-enzymatic lipid peroxidation, resulted in the research on the new role of free radicals in physiology and pathophysiology. Isoprostane quantitative analysis is a great achievement in the evaluation of free radical impact on many diseases in human. Isoprostanes were also found to be elevated in end-stage renal disease, another condition associated with increased oxidative stress. The aim of the study was to evaluate the influence of nephroprotective treatments on the urinary excretion of 15-F2alpha-isoprostane in the treated patients with Chronic Kidney Disease (CKD). MATERIAL AND METHODS: 84 patients (32 females and 52 males); age 18-65 years (average 39.06 +/- 4.92), with chronic non-diabetic proteinuric nephropathy, normal or slightly impaired stable renal function expressed as estimated creatinine cleamace above 30 mi/min, were selected from the cohort that attended our renal outpatients department. Clinical evaluation and laboratory tests were performed at the randomization point and after each period of the study A commercial ELISA Kit (Cayman Chemical Co) was used to measure the urinary excretion of 15-F2alpha-isoprostane in the treated patients. RESULTS: It was found that the blockade of renin-angiotensin-aldosteron system (with aliskiren, cilazapril, perindopril, spironolakton) and the treatment with atorwastatin significantly reduced urinary levels of 15-F2alpha-isoprostane relatively to the control group. It was not observed for pentoxyfilline treatment. CONCLUSIONS: Urine levels of isoprostanes are significantly decreased in patients with Chronic Kidney Disease during nephroprotective treatments.