BK Polyomavirus microRNA in Kidney Transplant Recipient.

BK polyomavirus-associated nephropathy (PyVAN) remains a serious threat for renal dysfunction and graft loss in kidney transplant recipients on immunosuppressive medication. In this study, a pilot cohort of 16 kidney transplant recipients were recruited of which eight were with significant BKPV viremia (sBKPV) and the rest were controls matched to age, gender, and time since transplant. We used next-generation sequencing to characterize the miRNA expression profile in urine samples. In total, the expression of 8 miRNAs (miR-16-5p,miR-200c-3p,bkv-miR-B1-3p,let-7b-3p,miR-1269b,bkv-miR-B1-5p,miR-193a-3p,miR-944) were upregulated whereas 21miRNAs (miR-134-5p,miR-4724-5p,miR-127-3p,miR-6500-3p,miR-507,miR-378b,miR-3911,miR-211-5p,miR-486-5p,miR-143-3p,miR-3195,miR-1307-5p,miR-29a-5p,miR-378f,miR-12136,miR-378g,miR-144-3p,miR-378a-3p,let-7i-5p,miR-204-5p,miR-146a-5p) were downregulated with fold change > 2. We found that bkv-miR-B1-5p and bkv-miR-B1-3p have 19-fold and 5-fold higher expression values in BKPV viremia patient samples, respectively. A few earlier studies have reported BKV miRNA in urine and serum samples using the RT- PCR from PyVAN patients. Our results corroborated findings from earlier studies and highlighted the need for additional evaluation of the role of sequencing approaches for monitoring BKPV specific and host miRNAs to better understand the viral reactivation and disease pathogenesis.

Is Compensation Prediction Score Valid for Contralateral Kidney After Living-Donor Nephrectomy in the United States?

BACKGROUND: Compensation after living donor nephrectomy is well known, and a compensation prediction score (CPS) was made in Japan previously. The aim of this study was to perform external validation of CPS in the United States. METHODS: We studied retrospectively 78 living donor nephrectomies in our institution. We defined a favorable compensation as a postdonation estimated glomerular filtration rate (eGFR) at 1 year of >60% of the predonation eGFR. We analyzed the living donors' clinical characteristics and outcomes and validated CPS score. RESULTS: The median (range) donor age was 43 (21-63) years, and median body mass index was 26.9 (18.3-35.9) kg/m2. Forty-four percent of donors were White. The donor predonation eGFR was 105 (61-134) mL/min/1.73 m2, and the postdonation eGFR at 1 year was 73.2 (0-115) mL/min/1.73 m2. Eighty-three percent of donors had a favorable compensation. The CPS was 9.6 (1.6-15.6) and showed strong diagnostic accuracy for predicting favorable compensation (area under the curve, 0.788; 95% confidence interval, 0.652-0.924; P = .001). The CPS showed a significant positive correlation with the postdonation eGFR at 1 year (R = 0.54; P < .001). CONCLUSIONS: In the United States, the CPS would be a valid tool with which to predict a favorable compensation of remnant kidney function.

HIV in kidney transplantation.

PURPOSE OF REVIEW: The aim of this study was to describe recent developments in renal transplantation for HIV-positive recipients, especially the HIV Organ Policy Equity (HOPE) trial results. RECENT FINDINGS: HOPE trial data show that HIV-positive D+/R+ results are excellent and similar to D-/R+ in patients controlled on antiretroviral therapy (ART). Patients coinfected with hepatitis C or B virus now have effective treatment available. As pretransplant evaluation and post-transplant management is more complex in HIV-positive individuals early referral is important and coordination of evaluation and care with an infectious disease specialist is critical. HIV coordinated care services should be involved for best outcomes. HIV-positive renal transplant recipients have an increased risk of rejection and evidence suggests that standard lymphocyte depletion induction and maintenance immunosuppression be employed. Cardiovascular risk reduction and surveillance and attention to metabolic bone disease are important for HIV-positive renal transplant recipients. SUMMARY: HIV-positive to HIV-positive renal transplantation has been established as well tolerated and successful. Further efforts are needed to expand access to transplantation in this population. VIDEO ABSTRACT: http://links.lww.com/MOT/A29.

The Case For Cadmium and Lead Heavy Metal Screening.

Exposure to cadmium and lead is widespread, and is related to environmental contamination, occupational sources, food, tobacco and other consumer products. Lower socioeconomic status increases the risk of heavy metal exposure and the diseases associated with cadmium and lead toxicity. Concurrent toxicity with both cadmium and lead is likely but has not often been assessed. There is now substantial evidence linking cadmium and lead to many diseases including hypertension, diabetes mellitus, obesity, cancer, coronary artery disease, chronic kidney disease (CKD) and lung disease. Both chronic renal failure and ischemic heart disease patients have been treated separately in recent studies with calcium disodium ethylenediaminetetraacetic acid (Ca EDTA) chelation therapy. In patients with CKD, serum creatinine 1.5-4.0 mg/dL, and increased body lead burden, weekly low dose chelation with Ca EDTA slowed the rate of decline in renal function in diabetics and non-diabetics. In patients with a history of myocardial infarction, the Trial to Assess Chelation Therapy (TACT) study showed that Ca EDTA chelation decreased the likelihood of cardiovascular events, particularly in diabetics. Ca EDTA chelation administered carefully at lower dosage (<50 mg/kg per week) is generally safe. In the past, acute renal failure associated with much higher dosage was reported. We suggest that the preponderance of the evidence favors a more activist approach towards diagnosis and possible intervention in heavy metal toxicity.

Heavy Metal Toxicity in Chronic Renal Failure and Cardiovascular Disease: Possible Role for Chelation Therapy.

Exposure to heavy metals is common. This exposure is related to environmental contamination of air, water and soil, occupational exposure, accumulation in food, tobacco, and other factors. Cadmium and lead are notable for their widespread contamination, long-lasting effects in the body, and renal as well as cardiovascular toxicity. Acute toxicity due to high-level exposure, as well as chronic low-level exposure are now well-established pathogenic entities. Both chronic renal failure and ischemic heart disease patients have been treated separately in recent studies with ethylenediaminetetraacetic acid (EDTA) chelation therapy. In patients with chronic kidney disease (serum creatinine: 1.5-4.0 mg/dL) and increased body lead burden, weekly low-dose chelation with calcium EDTA slowed the rate of decline in renal function in patients with diabetes and in non-diabetic patients. In patients with a history of myocardial infarction, the Trial to Assess Chelation Therapy study showed that EDTA chelation decreased the likelihood of cardiovascular events, particularly in patients with diabetes. However, heavy metal levels were not measured in this study. It is clear that more research is needed in this area. There is also a need to more frequently consider and test for the possibility of cadmium and lead toxicity in patients with increased risk, such as those with hypertension, diabetes mellitus, and chronic renal disease.

Obesity in Kidney Transplantation: Impact on Transplant Candidates, Recipients, and Donors.

Obesity is now common among children and adults who are kidney transplant candidates and recipients. It is associated with an increased risk of cardiovascular disease and kidney failure. This also pertains to potential living kidney donors with obesity. Obese patients with end-stage renal disease benefit from transplantation as do nonobese patients, but obesity is also associated with more risk. A complicating factor is that obesity is also associated with increased survival on maintenance dialysis in adults, but not in children. The assessment of obesity and body habitus should be individualized. Body mass index is a common but imperfect indicator of obesity. The medical management of obesity in renal failure patients is often unsuccessful. Bariatric surgery, specifically laparoscopic sleeve gastrectomy, can result in significant weight loss with reduced morbidity, but many patients do not agree to undergo this treatment. The best approach to manage obese transplant candidates and recipients is yet unresolved.

Hypertension in the Kidney Transplant Recipient: Overview of Pathogenesis, Clinical Assessment, and Treatment.

Cardiovascular disease is the leading cause of death in patients with chronic renal disease and the most common cause of death and allograft loss among kidney transplant recipients. Transplant patients often have multiple cardiovascular risk factors antedating transplantation. Among the most prominent is hypertension (HTN), which affects at least 90% of transplant patients. Uncontrolled HTN is an independent risk factor for allograft loss. The etiology of HTN in transplant recipients is complex and multifactorial, including the use of essential immunosuppressive medications. Post-transplant HTN management requires a systematic and individualized approach with nonpharmacologic and pharmacologic therapies. There is no single ideal agent or treatment algorithm. Patients should regularly monitor and record their blood pressure at home. Often, multiple antihypertensive drugs are needed to achieve a goal blood pressure of 120-140/70-90 mm Hg. As transplant recipients commonly must take 8 to 12 different medications daily, adherence must be continually encouraged and monitored. Special attention must be paid to potential drug side effects and drug interactions with immunosuppressive medications.

Drug therapy of apparent treatment-resistant hypertension: focus on mineralocorticoid receptor antagonists.

Apparent treatment-resistant hypertension (aTRH) is defined as blood pressure (BP) >140/90 mmHg despite three different antihypertensive drugs including a diuretic. aTRH is associated with an increased risk of cardiovascular events, including stroke, chronic renal failure, myocardial infarction, congestive heart failure, aortic aneurysm, atrial fibrillation, and sudden death. Preliminary studies of renal nerve ablation as a therapy to control aTRH were encouraging. However, these results were not confirmed by the Symplicity 3 trial. Therefore, attention has refocused on drug therapy. Secondary forms of hypertension and associated conditions such as obesity, sleep apnea, and primary aldosteronism are common in patients with aTRH. The pivotal role of aldosterone in the pathogenesis of aTRH in many cases is well recognized. For patients with aTRH, the Joint National Committee-8, the European Society of Hypertension, and a recent consensus conference recommend that a diuretic, ACE inhibitor, or angiotensin receptor blocker and calcium channel blocker combination be used to maximally tolerated doses before starting a 'fourth-line' drug such as a mineralocorticoid receptor (MR) antagonist. Although the best fourth-line drug for aTRH has not been extensively investigated, a number of studies summarized here show that an MR antagonist is effective in reducing BP when added to the standard multi-drug regimen.

Cardiovascular risk assessment before and after kidney transplantation.

Cardiovascular disease (CVD) is the leading cause of death in dialysis patients and the most common cause of death and allograft loss among kidney transplant recipients. End-stage renal disease (ESRD) is associated with an increased incidence and prevalence of a wide range of CVDs including coronary artery disease, stroke, congestive heart failure, atrial fibrillation, sudden cardiac death, pulmonary hypertension, and valvular heart disease. CVD risk factors are very common in patients with ESRD, and most patients have multiple risk factors. Kidney transplantation is the treatment of choice for patients with ESRD, as a successful transplant improves longevity and quality of life, primarily by decreasing the incidence and severity of CVD. Correction of the uremic state and improved glomerular filtration rate seem to be the major mechanism of this benefit. Transplant candidates should undergo cardiovascular assessment, usually echocardiography and exercise stress testing, and may require formal cardiology consultation. Higher risk candidates, including those aged >50 years, hypertension, diabetes, established coronary artery disease or peripheral vascular disease, left ventricular hypertrophy, and dialysis duration >1 year, should have repeat cardiovascular assessment every 1-2 years. Transplant candidates and recipients should have individualized treatment for CVD and risk factors such as hypertension, diabetes, hyperlipidemia, and obesity. Special consideration should be given for statin therapy, as its use is associated with decreased cardiovascular death in dialysis and transplant patients. Prospective randomized, controlled trials are needed to determine the optimal approach to diagnosis and treat CVD in the transplant candidate and recipient population.

The role of nonpharmacologic device interventions in the management of drug-resistant hypertension.

Resistant systemic hypertension in patients is defined as the inability to control blood pressure despite taking at least three antihypertensive drugs, one of which is a diuretic. Two nonpharmacologic approaches are being evaluated in resistant hypertensive patients. First, the Rheos® Baroreflex Hypertension Therapy system is an implantable device that activates the carotid baroreflex through electrical stimulation of the carotid sinus wall. Sustained and clinically lower blood pressure has been observed in patient clinical trials. The second approach is a catheter-based strategy which denervates the renal afferent and efferent autonomic nervous system. This strategy has also been shown to be effective in drug-resistant patients, and has also been shown to decrease renin production, preserve renal function, improve glucose tolerance, and reduce left ventricular hypertrophy. Both carotid sinus stimulation and renal denervation are now being evaluated in clinical trials for the long-term control of hypertension.

Pretransplant anti-HLA-Cw and anti-HLA-DP antibodies in sensitized patients.

We investigated the prevalence and the strength of anti-HLA-Cw and DP antibodies and clinical outcomes in kidney transplant recipients with isolated donor-specific anti-HLA-Cw antibodies. Patients on the waiting list were screened by Luminex single antigen beads (One Lambda). The strength of antibodies was determined by mean fluorescence intensity (MFI) values of the beads. Of the 1069 patients on the waiting list, 251 (24%) were sensitized with calculated panel reactive antibody >0%. The frequency and the median MFI values of anti-HLA antibodies to Cw (56%, 4955) and DP (35%, 2945) were lower than anti-HLA-A (79%, 10,194), B (86%, 11,235), DR (66%, 7866) and DQ (69%, 8283) (p<0.01). Among three major sensitizing events, only previous transplant was associated with development of all anti-HLA antibodies and history of pregnancy was associated only with development of anti-HLA-A antibodies. Eight patients with donor-specific anti-HLA-Cw antibodies received transplantation. During a median 6 months of follow-up (range 3-24 months), patient and graft survival was 100% without any acute rejection. In summary, the prevalence and the strength of anti-HLA-Cw and HLA-DP were lower compared to anti-HLA-A, B, DR, and DQ antibodies and previous organ transplantation was the main sensitizing event in our cohort of patients.

Lack of effect in desensitization with intravenous immunoglobulin and rituximab in highly sensitized patients.

BACKGROUND: We conducted a prospective cohort study in highly sensitized kidney transplant candidates with a calculated panel reactive antibody (cPRA) greater than 50% and on the deceased-donor waiting list for more than 5 years to investigate the effects of intravenous immunoglobulin (IVIG) and rituximab treatment. METHODS: Desensitization protocol included two doses of IVIG (2 g/kg, max 120 g each dose) and a single dose of rituximab (375 mg/m(2)). Patients were followed up monthly by Luminex single antigen beads. Whole blood gene expression profiles were studied by Affymetrix Human 1.0 ST GeneChips before and after treatment. RESULTS: Forty patients were eligible for desensitization treatment. Thirteen of these patients agreed to participate, and 11 completed the treatment. After a mean follow-up of 334 ± 82 days, two desensitized patients (18%) received a kidney transplant compared with 14 patients (52%) in the nondesensitized group. Comparing with 14 patients who received transplants without any desensitization treatment, desensitized patients showed higher class I (99% vs. 80%) and class II (98% vs. 69%) cPRA levels and more unacceptable antigens (32 vs. 8). Desensitization treatment did not lead to any significant reduction in patients' class I and II cPRA levels and any change in the mean number of unacceptable antigens or their mean fluorescence intensity values. Whole blood gene expression analysis by microarrays demonstrated down-regulation of immunoglobulin and B-cell-associated transcripts after treatment. CONCLUSION: These results suggested that pretransplant desensitization with IVIG and rituximab was not successful in highly sensitized kidney transplant candidates with cPRA levels higher than 90%.

Effect of risedronate on bone in renal transplant recipients.

Bisphosphonates may prevent or treat the bone loss promoted by the immunosuppressive regimens used in renal transplantation. Risedronate is a commonly used third-generation amino-bisphosphonate, but little is known about its effects on the bone health of renal transplant recipients. We randomly assigned 42 new living-donor kidney recipients to either 35 mg of risedronate weekly or placebo for 12 months. We obtained bone biopsies at the time of renal transplant and after 12 months of protocol treatment. Treatment with risedronate did not affect bone mineral density (BMD) in the overall cohort. In subgroup analyses, it tended to preserve BMD in female participants but did not significantly affect the BMD of male participants. Risedronate did associate with increased osteoid volume and trabecular thickness in male participants, however. There was no evidence for the development of adynamic bone disease. In summary, further study is needed before the use of prophylactic bisphosphonates to attenuate bone loss can be recommended in renal transplant recipients.

Angiotensin converting enzyme inhibitor use soon after renal transplantation: a randomized, double-blinded placebo-controlled safety study.

Activation of the renin-angiotensin system (RAS) followed by increased inflammatory cytokines may be important in the pathogenesis of chronic allograft dysfunction. As many renal transplant recipients show chronic changes on biopsy within the first year, early RAS blockade with angiotensin converting enzyme inhibitor (ACEI) could be beneficial. However, it remains unclear that early ACEI use is safe. We conducted a prospective, randomized, placebo-controlled trial to assess the safety of enalapril 5 mg during the early post-transplant period. Subjects took the study medication for six months. Primary endpoints were serum potassium (K) >5.9 mEq/L and 30% increase in baseline creatinine. A total of 53 subjects were randomized, and of them, 27 received the study drug. Twenty-nine subjects, 14 ACEI and 15 controls, completed the six-month protocol without reaching an endpoint. Patients on ACEI had higher K and higher BUN at six months. Serum creatinine, hematocrit, and urinary protein were not different. There was no difference in urinary TGF-ß1. Twenty-four subjects reached study endpoints. When the common clinical endpoints of elevated creatinine and hyperkalemia were combined, ACEI group had significantly increased endpoints vs. control (10/13, 77% vs. 5/11, 45%, p < 0.05). We conclude that ACEI use in the early post-transplant period can be safe but patients must be carefully selected and monitored for elevations in serum creatinine and potassium. Whether early ACEI is beneficial in preserving allograft function requires further study.

Successful transplantation of a donor kidney with diffuse proliferative lupus nephritis and crescents--a case report.

Pre-existing diffuse proliferative glomerulonephritis (DPGN) in a potential deceased kidney donor has been considered a contraindication for transplantation. We report a case of a patient who underwent a successful deceased donor renal transplantation from a donor with history of systemic lupus erythematosus (SLE) whose baseline biopsy revealed DPGN. Although the histology was relatively benign in the procurement kidney biopsy done by frozen section, the final light microscopy available after transplantation showed diffuse proliferative lupus nephritis, WHO class IV, with 44% crescents. The post-transplant course was complicated by delayed allograft function requiring haemodialysis for the first week. A repeat biopsy performed after 4 months of transplant showed resolution of the proliferative lesions in the glomeruli with disappearance of the crescents. At 5.5 years of follow-up, the patient's creatinine has been stable at 2.0 mg/dL (176.8 µmol/L), but he has persistent proteinuria.

Adenovirus nephritis and obstructive uropathy in a renal transplant recipient: case report and literature review.

We report an unusual case of adenoviral nephritis in a 45-year-old woman who presented with fever, gross haematuria, acute kidney injury and obstructive uropathy 17 months following renal transplantation. Adenoviral nephritis was confirmed with immunohistochemistry. We identified 10 other published cases of adenoviral nephritis proven by immunohistochemistry. Obstructive uropathy has been reported only once before in a renal transplant recipient with adenoviral nephritis. Contrary to other reports, this case series shows that renal function may not always recover to baseline following the acute adenoviral disease. Adenoviral nephritis should be considered in the renal transplant patient with fever, haematuria, acute kidney injury and hydronephrosis in both the early and late post-transplant periods.

Human and murine kidneys show gender- and species-specific gene expression differences in response to injury.

The incidence of End Stage Renal Disease (ESRD) is approximately 50% higher in men than women. In order to understand the molecular basis of this gender disparity, we examined sex specific gene expression patterns in control and diseased, human and murine kidney samples. Using the Affymetrix platform we performed comprehensive gene expression analysis on 42 microdissected human kidney samples (glomeruli and tubules). We identified 67 genes with gender biased expression in healthy human kidneys and 24 transcripts in diseased male and female human kidneys. Similar analysis performed in mice using male and female control and doxorubicin induced nephrotic syndrome kidneys identified significantly larger number of differentially expressed transcripts. The majority of genes showing gender biased expression either in diseased human and murine kidneys were different from those differentially expressed in healthy kidneys. Only 9 sexually dimorphic transcripts were common to healthy human and murine kidneys and five showed differential regulation in both human and murine diseased kidneys. In humans, sex biased genes showed statistical enrichment only to sex chromosomes while in mice they were enriched to sex chromosomes and various autosomes. Thus we present a comprehensive analysis of gender biased genes in the kidney. We show that sexually dimorphic genes in the kidney show species specific regulation. Our results also indicate that male and female kidneys respond differently to injury. These studies could provide the basis for the development of new treatment strategies for men and women with kidney disease.

The effect of sirolimus on sex hormone levels of male renal transplant recipients.

BACKGROUND: It is unclear whether sirolimus, a newer immunosuppressive agent, widely used in renal transplantation, affects male sex hormone levels or sexual function. METHODS: Sex hormone profiles in male renal transplant recipients were obtained and compared between a sirolimus-treated group and a group not on sirolimus in a cross-sectional study. Both groups also completed a sexual dysfunction questionnaire. RESULTS: Sixty-six subjects were evaluated, 32 in the sirolimus group and 34 in the control group. Total testosterone level was significantly lower in the sirolimus group than the control group (393.3 +/- 188 vs. 537.4 +/-232 pg/mL; p = 0.08) while follicle stimulating hormone and luteinizing hormone levels were significantly higher in the sirolimus group (12.8 +/- 14 vs. 6.0 +/- 5, p = 0.013; 10.9 +/- 14 vs. 4.7 +/- 4, p = 0.018, respectively). There was a significant negative correlation between 24-h sirolimus trough and total testosterone levels (p < 0.03). By multiple regression analysis, use of sirolimus was independently associated with decreased total testosterone level. There was no significant difference in subjective sexual dysfunction as assessed by questionnaire scores between the two groups. There was no correlation between questionnaire scores and total testosterone level. CONCLUSION: Sirolimus is associated with decreased total testosterone levels in male renal transplant recipients. It is unclear whether sirolimus may affect other aspects of sexual function.