Impact of pre-transplant antiaggregant and anticoagulant therapies on early hemorrhagic and cardiovascular events after kidney transplantation.

BACKGROUND: Oral anticoagulation with vitamin K antagonists (VKA) and antiaggregant therapy (AAT) are common among dialysis patients, but it is not known if they increase the risk of hemorrhagic (HE) or cardiovascular events (CVE) in the early post-transplant weeks. METHODS: We conducted a retrospective analysis on 911 consecutive kidney transplants (KTxs) in order to analyze the impact of AAT and VKA on early HE and CVE-which might be related to their withdrawal-and to identify the main risk factors for these complications. RESULTS: We observed 21/911 HE (2.3%; 1 death, 4 allograft loss); risk factors for HE at multivariate analysis were: KTx before 2004 (when anti-factor Xa activity measurement was not available; odds ratio, OR 5.835, [95% confidence interval, 1.241-27.436], p = 0.026), and VKA (OR 7.090 [2.030-24.772], p = 0.002), while AAT was not a risk factor. CVE were 32/911 (3.5%; 3 deaths, 11 allograft loss): risk factors for CVE at multivariate analysis were: previous cardiovascular events (OR 4.180 [1.615-10.948], p = 0.0032) and cinacalcet use (OR 7.930 [3.002-20.945], p < 0.0001), while neither VKA nor AAT had any impact. CONCLUSIONS: In conclusion, HE and CVE are relatively rare but can be severe, but there are no pre-KTx modifiable risk factors. If an anticoagulant therapy with low molecular weight heparins has to be started soon after surgery, monitoring of anti-Xa activity is highly recommended.

Unexpectedly high prevalence of rare genetic disorders in kidney transplant recipients with an unknown causal nephropathy.

BACKGROUND: Patients with a rare genetic disease may receive renal transplantation (KTx) without a correct diagnosis of causal nephropathy and therefore develop unexpected and even severe complications. The aim of the study was to describe the cases of rare genetic disorders diagnosed after KTx, in order to draw clinical lessons for the transplant physician. METHODS: We retrospectively assessed all patients who had received a diagnosis of a rare genetic disorder after KTx. RESULTS: In our center, more than 30% (278/911) of kidney transplant (KTx) recipients were diagnosed with a causal nephropathy: Prevalence of rare genetic disorders in this group was 4.32% (12/278), including 2,8-dihydroxyadeninuria (2,8-DHA) disease (n = 2), HNF-1B-associated nephropathy (n = 2), UMOD-related nephropathy (n = 5), Fabry disease (n = 1), INF2 focal segmental glomerulosclerosis (n = 1), and Senior-Løken syndrome (n = 1). 2,8-DHA nephropathy relapsed in both patients causing an acute renal failure and jeopardizing the graft. CONCLUSIONS: Kidney transplant recipients without a diagnosis of causal nephropathy appear to be a selected population in which rare genetic diseases might be more common than expected. As even a belated diagnosis after KTx can have a significant impact on graft and patient survival and on other family members, this possibility should be evaluated in KTx recipients without a known causal nephropathy.

Does kidney transplantation onto the external iliac artery affect the haemodynamic parameters of the cavernosal arteries?

Reduced cavernosal arterial inflow has been hypothesized to be the likely cause of erectile dysfunction after kidney transplants in recipients revascularized through end-to-end anastomosis to the internal iliac artery, suggesting that end-to-side anastomosis at the external iliac artery is preferable. The aim of this study was to prospectively evaluate the effect of the use of the external iliac artery on erectile function, hormone profiles and penile blood flow by evaluating changes in penile colour Doppler ultrasound parameters in a consecutive series of 22 recipients before and after end-to-side external iliac artery transplantation. The mean International Index of Erectile Function-Erectile Function (IIEF-EF) domain score decreased significantly 3 months after transplant (18.09±6.33 vs. 22.50±7.09, P=0.01). The reduction in peak systolic velocity (PSV) was significant for the cavernous artery homolateral to the side of transplant (42.60±18.77 vs. 52.01±19.91, P=0.01). The mean postoperative end diastolic velocity (EDV) did not differ significantly from the preoperative value (P=0.74). No statistical differences were found in the serum levels of testosterone or prolactin. Kidney grafts anastomosed at the external iliac artery produced significant (P=0.01) reductions in arterial inflow at the homolateral cavernosal artery that remained above the normal threshold. Whether these haemodynamic changes can explain the worsening of postoperative erectile function remains to be proven.

Renal outcome and monoclonal immunoglobulin deposition disease in 289 old patients with blood cell dyscrasias: a single center experience.

Monoclonal components (MC) formed by chains/fragments of intact/truncated globulin components produced in different lymphoproliferative diseases are responsible for monoclonal immunoglobulin deposition disease (MIDD) and consequent tissue damage by organized (amyloid fibrils) or non-organized (amorphous) deposits. The kidneys are the most commonly affected organs in MIDD, and renal failure represents an important adverse factor for prognosis. The renal outcome and the role of renal pathology in diagnosing MIDD was evaluated in 289 elderly patients with multiple myeloma (MM, n=115) and monoclonal gammopathy (MGUS, n=174). Renal impairment was the only significant risk factor for patient death, while significant risk factors for renal impairment were diabetes (HR 3.65, 95% CI: 2.08-6.41), light chain (LC) proteinuria (HR 2.18; 95% CI: 1.10-4.32) and type of MC (p=0.0019). Renal pathology documented MIDD in 12/30 cases (40%): six cases of AL-amyloidosis, two of LC disease, one of heavy chain disease and three of cast nephropathy, as well as four cases of glomerulonephritis, eight of arteriolosclerosis and six of normal picture. Main conclusions are that diabetes, sharing common glomerular damage with LC disease, is the strongest risk factor for progression of renal disease, and glomerular proteinuria or heavy LC proteinuria should raise a strong suspicion index of MIDD and prompt pathology assessment to reach the correct diagnosis.

Is renal living-donor transplantation indicated in adult patients with orthotopic ileal neobladder? Lessons learned from a clinical case.

Renal transplantation is the treatment of choice for patients with end-stage renal disease and it has already been described in the literature in patients with orthotopic neobladders, mostly in the paediatric population. We report the first case of a living-donor renal graft in an adult patient with a orthotopic neobladder that was performed after radical cystectomy for urinary tuberculosis and reflux nephropathy. This patient experienced urologic and metabolic complications since the early posttransplant period.

Structure-activity relationships of low molecular weight heparins expose to the risk of achieving inappropriate targets in patients with renal failure.

Heparins are used in "therapeutic doses" for systemic anticoagulation to treat patients who have confirmed venous thromboembolism, or in "prophylactic doses "for the prevention of venous thromboembolism: they are generally lower doses and are employed once a day. Structure-function relationships are strongly influenced by the chain length of the molecules. In fact, unfractionated heparin (UFH) binds to ATIII lysine site leading to a conformational change of the ATIII arginine reactive centre able to create a covalent binding to the active centre serine of thrombin in a ternary complex formation composed by heparin, ATIII and thrombin. On the other side, low molecular weight heparins (LMWHs) are too short to be able to form this ternary complex, and mainly exert their anticoagulant effect by binding the factor Xa, always via ATIII. Lastly, the short unique pentasaccharidic sequence which is crucial for heparin's activity and has been recently synthesized as Fondaparinux, only acts via the formation of the high affinity ternary complex with ATIII-factor Xa. Due to their structure-function relationships, LMWHs cannot be monitored by conventional coagulation test used for monitoring UFH and need more specific anti-factor Xa activity determinations, but monitoring has been considered unnecessary in the general population due to a predictable dose/effect ratio. However, a disturbing rise of bleeding complications in patients with renal failure treated with LMWH has been published in the last years, that is explained by the accumulation of LMWHs in this setting, due the consequences of structure-metabolisms relationships of the small members of the heparin's family. In this context, physicians are often left to a "best guess" method of empiric dose adjustment, which is at risk of achieving inappropriate targets, with a percentage of values above and below target of 51% and 34%, respectively, depending on LMWHs dosage, body mass index and renal function. Without anti-Xa activity monitoring, the quality of care delivered in the setting of renal failure is poor, as over-prophylaxis can result in potentially dangerous anticoagulation, while under-prophylaxis can result in life-threatening thrombosis.

ACE genotype, body weight changes and target organ damage in renal transplant recipients.

BACKGROUND: Carriage of the angiotensin-converting enzyme (ACE) D-allele favors weight gain in mid-life and, possibly, cardiovascular complications; we aimed to verify the relationship between these conditions and ACE polymorphisms in the renal transplant (RTx) setting. METHODS: ACE genotypes were evaluated in 169 RTx recipients (107 males, 62 females) and related to body mass index (BMI; kg/m2) changes 1 year after transplant, as well as to cardiovascular events and allograft loss. Allelic frequencies and body weights were compared with those of a control group (age- and sex-matched healthy blood donors). RESULTS: Allelic frequencies were 0.639 and 0.669 for the D-allele, and 0.361 and 0.331 for the I-allele, in recipients and controls, respectively (p=NS). In the patient population, carriage of the I/ allele was associated with a BMI >23 at the time of RTx (p<0.005). In contrast, in the control group, higher BMI values tended to occur in D/ carriers. Moreover, BMI values were higher in the control group (24.7 -/+ 3.5 vs. 23.6 -/+ 3.3, p=0.003) but, 1 year after RTx, this difference was nullified. At multivariate analysis, the factors associated with weight gain after RTx were ACE D/D (odds ratio [OR] = 2.35, 95% confidence interval [95% CI], 1.00-5.49) and age at RTx

Gadolinium-associated nephrogenic systemic fibrosis: the need for nephrologists' awareness.

Nephrogenic systemic fibrosis (NSF) / nephrogenic fibrosing dermopathy (NFD) is a recently described disease, occurring only in patients with variable degrees of renal failure (RF) previously exposed to gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging. Public advisories are consistent on some key points including that no cases of NSF/NFD have been reported in patients with normal renal function, and GBCAs may be toxic in patients with RF due to the prolongation of the half-time allowing dissociation and extravasation of highly toxic gadolinium-free ions, potentially linked to the scleroderma-like NSF/NFD, a systemic disabling disease with a mortality rate of up to 30%. The most intriguing feature remains which cofactor might be at play to explain why the disease occurs only in a minority of exposed patients. Therefore, renal dysfunction (substrate) and gadolinium chelates (trigger agent) are necessary but not sufficient. The challenge for nephrologists includes (a) evidence of transmetallation, such as gadolinium deposits in bone, increased urinary zinc excretion, iron-transferrin dissociation or "spurious hypocalcemia" in exposed people; (b) research for uremic cofactors such as increased serum calcium/phosphate, acidosis, use of phosphate-chelating agents able to act as efficient competitor ligands or other drugs; and (c) identification of at-risk patients (with moderate to severe renal dysfunction) and definition of the role of dialysis in removing gadolinium chelates, if any. Nephrologists are called to action to collect and organize information to identify cofactors for NSF/NFD, and therefore they must be aware of this new pathology, as the eye sees only what the mind knows.

Malignancy after kidney transplantation: results of 400 patients from a single center.

BACKGROUND: Post-transplant malignancies (PTM) occur in a percentage as high as 50% in patients followed 20 yr and have become a main cause of mortality and are expected to be the first cause of death within the next 20 yr in kidney transplant recipients. PATIENTS AND METHODS: We analyzed the PTM incidence in our kidney transplant recipients, and its main risk factors. The records of 400 patients (min follow up = one yr) have been retrospectively reviewed and categorized into three groups: patients without any tumor, with a non-melanoma skin cancer and with a solid or hematologic cancer. A cancer-free multivariate survival study was performed stratified by age, sex, immunosuppressive therapy, time on dialysis, body mass index (BMI), smoke, diabetes and nephropathy. RESULTS: Thirty patients developed PTM: 12 non-melanoma skin cancer, three lymphomas and 15 solid malignancies (seven genitourinary, three lung, two breast, two gastrointestinal and one sarcoma). The mean age at diagnosis was 55 yr, with a mean time from transplant of 27 months. We observed six deaths and two graft losses. Non-melanoma skin cancer-free survival and the solid/hematologic cancer-free survival was 99.5% and 98.5% at one yr, and 95.2% and 94.6% at five yr, respectively. At univariate analysis, age and induction therapy were significant risk factors for both types of PTM, while only recipient age significantly increased the risk of all PTM, and anti CD25 significantly reduced the risk of non-melanoma skin cancer at the multivariate study. CONCLUSIONS: These data confirm the role of age and induction strategies in modulating the risk of neoplasia. To look for which strategies might reduce the PTM risk, including a personalized therapy to minimize the effects of chronic immunosuppressant, will be a crucial goal.

Ciprofloxacin crystal nephropathy.

Ciprofloxacin is a widely used fluoroquinolone for the treatment of patients with complicated and uncomplicated infections. With rare exceptions, only immune-mediated interstitial nephritis was described, with direct renal damage reported only in case of overdose. Experimental studies indicated that crystalluria may be associated with the administration of this drug, but the likelihood that ciprofloxacin crystal nephropathy would occur in humans was believed to be very low on the basis of previous data showing that ciprofloxacin crystalluria depended on a urine pH greater than 6.8. However, we report 2 cases of ciprofloxacin crystal-induced nephropathy with a clinical pattern of acute reversible tubular damage and intratubular crystals identical to that previously described in elderly patients treated with ciprofloxacin dosages within therapeutic schedules. Crystals in the tubules were negative for both the von Kossa stain for phosphates and alizarin red stain for calcium.