The temporal and long-term impact of donor body mass index on recipient outcomes after kidney transplantation - a retrospective study.

The impact of increasing body mass index (BMI) on development and progression of chronic kidney disease is established. Even implantation kidney biopsies from obese living donors demonstrate subtle histologic changes despite normal function. We hypothesized that kidneys from obese living (LD) and deceased donors (DD) would have inferior long-term allograft outcomes. In a study utilizing US transplant registry, we studied adult kidney transplant recipients from 2000 to 2014. Donors were categorized as BMI <20 (underweight), 20-25 (normal), 25-30 (overweight), 30-35 (mildly obese), and >35 kg/m2 (very obese). Our outcome of interest was death censored graft failure (DCGF). Cox proportional hazards model were fitted separately for recipients of DD and LD kidneys, and adjusted for donor, recipient, and transplant characteristics, including donor and recipient size mismatch ratio. Among 118 734 DD and 84 377 LD transplants recipients, we observed a significant and graded increase in DCGF risk among the overweight (LD:HR = 1.06, DD:HR = 1.04), mildly obese (LD:HR = 1.16, DD:HR = 1.10), and very obese (LD:HR = 1.22, DD:HR = 1.22) compared to normal BMI (P < 0.05). The graded effect of donor BMI on outcomes begins early and persists throughout the post-transplant period. Donor obesity status is an independent risk factor for inferior long-term renal allograft outcome despite adjusting for donor and recipient size mismatch and other donor, recipient, and transplant factors.

Trends in utilization of deceased donor kidneys based on hepatitis C virus status and impact of public health service labeling on discard.

BACKGROUND: Kidneys from deceased donors infected with hepatitis C virus (HCV) are underutilized. Most HCV virus-infected donors are designated as Public Health Service increased donors (PHS-IR). Impact of PHS and HCV designations on discard is not well studied. METHODS: We queried the UNOS data set for all deceased donor kidneys between January 2015 and December 2018. The final study cohort donors (n = 38 702) were stratified into three groups based on HCV antibody (Ab) and NAT status: (a) Ab-/NAT- (n = 35 861); (b) Ab+/NAT- (n = 973); and (c) Ab±/NAT+ (n = 1868). We analyzed utilization/discard rates of these organs, the impact of PHS-IR and HCV designations on discard using multivariable two-level hierarchical logistic regression models, forecasted number of HCV viremic donors/kidneys by 2023. RESULTS: During the study period, (a) the number of viremic donor kidneys increased 2 folds; (b) the multilevel mixed-effects logistic regression models showed that, overall, the PHS labeling (OR 1.20, CI 95% CI 1.15-1.29) and HCV designation (OR 2.29; 95% CI 2.15-2.43) were independently associated with increased risk of discard; (c) contrary to the general perception, PHS-IR kidneys across all HCV groups, compared to PHS-IR kidneys were more likely to be discarded; (d) we forecasted that the number of kidneys from HCV viremic donor kidneys might increase from 1376 in 2019 to 2092 in 2023. CONCLUSION: Hepatitis C virus viremic kidneys might represent 10%-15% of deceased donor organ pool soon with the current rate of the opioid epidemic. PHS labeling effect on discard requires further discussion of the utility of this classification.

Contribution of polyclonal free light chain deposition to tubular injury.

INTRODUCTION: Excretion of monoclonal free light chains (MFLC) beyond the renal threshold can cause kidney injury, but evidence for polyclonal free light chains (PFLC)-mediated injury is limited. We aimed to study the degree of PFLC deposition in the proximal tubules of chronic kidney disease (CKD) and hypothesized that excess deposition may contribute to tubular injury. METHODS: In this retrospective study, immunohistochemical staining to assess the degree of FLC deposition, periodic acid-Schiff staining for the degree of tubular brush border injury and trichrome staining for interstitial fibrosis were evaluated. Normal renal parenchyma from tumor nephrectomy specimens (control group I, n = 39), minimal change disease controls (group II, n = 13), renal biopsies from CKD and proteinuria (polyclonal study group III, n = 33) and monoclonal light chain nephropathy (group IV, n = 37) were studied. The results of the study including serum creatinine were compared between groups. RESULTS: Both polyclonal and monoclonal groups (groups III and IV) had significantly higher light chain deposition and brush border injury by periodic acid-Schiff scores compared to control groups (groups I and II). When the first three polyclonal groups (groups I-III) were analyzed together, polyclonal light chain deposition was significantly correlated with serum creatinine levels, brush border injury and interstitial fibrosis. CONCLUSION: The results of our study suggest that in CKD patients with proteinuria, excess PFLC deposition in the proximal tubules may cause acute tubular injury akin to monoclonal gammopathy and lead to renal chronicity.

Primary cilia metaplasia in renal transplant biopsies with acute tubular injury.

Primary cilia are hair-like organelles singly distributed along the apical surface of proximal and distal nephron tubules as mechanosensors. The goal of this study was to use electron microscopy to systemically evaluate cilia changes in acute tubular injury (ATI) from both transplant and native renal biopsies. Three groups of cases were included: control group 1-native biopsies without major changes in renal tubules; study group 2-native biopsies with prominent ATI; and study group 3-renal transplant biopsies with prominent ATI (delayed renal function group). Extensive search for ciliary structures along renal tubules was conducted in each case, focused on proximal tubular areas with injured (diminished) apical microvilli. Singly located cilia were found in 3/19 specimens in control group 1, 4/18 in group 2 (native ATI), and 6/24 in group 3 (transplant ATI). Importantly, there were clusters of cilia in proximal tubules with markedly diminished apical microvilli in 3/24 biopsies from 2 patients in group 3, but none from groups 1 and 2. The clusters of cilia ranged from 6 to 15 individual cilia along the apical surface with diminished apical microvilli. Under high magnifications, the cilia demonstrated 9 pairs of peripheral microtubules without a central pair of microtubules, consistent with primary cilia (9 + 0) rather than motile cilia (9 + 2). In summary, the authors found clusters of cilia in proximal tubules with remarkable apical microvillar injury in 3 renal transplant biopsies with ATI, implying a reactive, or repairing, process following tubular injury, thus they name this finding "cilia metaplasia".

Proposed relationship between intravenous immunoglobulin and thrombosis in renal transplant recipients.

OBJECTIVE: To report 2 cases of intravenous human immunoglobulin (IVIG)-associated thrombosis in kidney transplant patients. CASE SUMMARY: Both cases involved female patients presenting to Henry Ford Hospital in Detroit for renal transplantation. Patient 1 presented with systemic lupus erythematosus, positive for both anticardiolipin and anti-DNA antibody. Patient 2, postnephrectomy, was found to have moderate hyperhomocysteinemia, with a total plasma homocysteine level of 3.9 mg/L. Both patients were considered highly sensitized and at high risk for rejection due to the presence of either high panel reactive antibody or a positive B cell flow cytometry crossmatch, in addition to other risk factors. Therefore, IVIG was considered a viable treatment option to be included in induction therapy. IVIG was administered both peri- and postoperatively, and both patients experienced immediate graft function with good urine output. Within 24 hours following transplantation, elevations in serum creatinine and decreases in urine output were seen. Subsequently, kidney exploration was performed and palpable thrombi in renal arteries and veins were detected. Immediate nephrectomy was performed in both cases. DISCUSSION: Currently, evidence derived from case reports highlights numerous risk factors for IVIG-associated thrombosis, one of which appears to be a hypercoagulable state. It has also been reported that some IVIG products contain amounts of anticardiolipin antibodies; these antibodies may potentiate thrombosis in the presence of hypercoagulable states, such as hyperhomocysteinemia or antiphospholipid syndrome. In these 2 patients, the Naranjo probability scale indicated that there was a possible association between the thrombotic events and the use of IVIG. CONCLUSIONS: Prospective trials evaluating the safety of IVIG in highly sensitized transplant patients are scarce. Therefore, it is imperative that the benefits and risks be weighed when considering the use of IVIG in highly sensitized transplant patients.

Infectious complications in renal transplant recipients.

Post-kidney transplant infection is the most common life-threatening complication of long-term immunosuppressive therapy. Optimal immunosuppression, in which a balance is maintained between prevention of rejection and avoidance of infection, is the most challenging aspect of posttransplantation care. The study of infectious complications in immunologically compromised recipients is changing rapidly, particularly in the fields of prophylactic and preemptive strategies, molecular diagnostic methods, and antimicrobial agents. In addition, emerging pathogens such as BK polyomavirus and West Nile flavivirus infections and the introduction of newer immunosuppressive agents that constantly change the risk profiles for opportunistic infections has added layers of complexity to this burgeoning field. Although remarkable progress has been made in these disciplines, comprehensive understanding of the clinical manifestations of infections remains limited, and the standardization of prophylaxis, diagnosis, and treatment of most infections is yet inadequately defined. The long-term goal for optimal care of transplant recipients, with respect to infection, is the prevention and/or early recognition and treatment of infections while avoiding drug-related toxicities.

Outcome of low-dose ganciclovir for cytomegalovirus disease prophylaxis in renal-transplant recipients.

To assess the outcome of low-dose-ganciclovir prophylaxis (500 mg twice a day for 3 months) in renal-transplant recipients, a retrospective analysis of 185 patients transplanted between 1998 and 2001 was performed. There were 29 (15.6%) patients who belonged to the highest risk group, donor cytomegalovirus (CMV) positive, recipient negative (D + R-), and 37 (20%) patients in the lowest risk group, D-R-. Induction immunosuppression consisted of polyclonal antibody or OKT3 (n = 62, 33.5%), interleukin-2 receptor antibody (n = 61, 33%), and no induction (n = 62, 33.5%). CMV disease occurred in 13 (7%) patients. Highest incidence was in D + R- group (17.2%), with no cases in D-R- group (P = 0.03). Tissue-invasive CMV occurred in 4 of these 13 patients. In patients developing CMV disease, there was no evidence of ganciclovir resistance and no mortality over a mean follow-up of 42 months. Low-dose ganciclovir was found to be as effective in decreasing the incidence of clinical CMV disease as high-dose ganciclovir (1 gm three times a day for 3-6 months) in previous studies.

Severe necrotizing adenovirus tubulointerstitial nephritis in a kidney transplant recipient.

Adenoviruses (AdV) are emerging pathogens with a prevalence of 11% viruria and 6.5% viremia in kidney transplant recipients. Although AdV infection is common, interstitial nephritis (ADVIN) is rare with only 13 biopsy proven cases reported in the literature. We report a case of severe ADVIN with characteristic histological features that includes severe necrotizing granulomatous lesion with widespread tubular basement membrane rupture and hyperchromatic smudgy intranuclear inclusions in the tubular epithelial cells. The patient was asymptomatic at presentation, and the high AdV viral load (quantitative PCR>2,000,000 copies/mL in the urine and 646,642 copies/mL in the serum) confirmed the diagnosis. The patient showed excellent response to a combination of immunosuppression reduction, intravenous cidofovir, and immunoglobulin therapy resulting in complete resolution of infection and recovery of allograft function. Awareness of characteristic biopsy findings may help to clinch the diagnosis early which is essential since the disseminated infection is associated with high mortality of 18% in kidney transplant recipients. Cidofovir is considered the agent of choice for AdV infection in immunocompromised despite lack of randomized trials, and the addition of intravenous immunoglobulin may aid in resolution of infection while help prevention of rejection.

Renal Function and NODM in De Novo Renal Transplant Recipients Treated with Standard and Reduced Levels of Tacrolimus in Combination with EC-MPS.

Information is lacking concerning concomitant administration of enteric-coated mycophenolate sodium with tacrolimus (EC-MPS+Tac) in renal transplant recipients (RTxR). In this 6-month, prospective, open-label, multicenter study, de novo RTxR were randomized (1 : 1) to low-dose (LD) or standard-dose (SD) Tac with basiliximab, EC-MPS 720 mg bid, and steroids. Primary objective was to compare renal function at 6-month posttransplantation. Secondary objectives were to compare the incidences of biopsy-proven acute rejection (BPAR), graft loss and death, and new-onset diabetes mellitus (NODM). 292 patients (LD n = 151, SD n = 141) were included. Mean Tac levels were at the low end of the target range in standard-exposure patients (SD, n = 141) and exceeded target range in low-exposure patients (LD = 151) throughout the study. There was no significant difference in mean glomerular filtration rate (GFR) between treatments (ITT-population: 63.6 versus 61.0 mL/min). Incidence of BPAR was similar (10.6% versus 9.9%). NODM was significantly less frequent in LD Tac (17% versus 31%; P = 0.02); other adverse effects (AEs) were comparable. EC-MPS+Tac (LD/SD) was efficacious and well tolerated with well-preserved renal function. No renal function benefits were demonstrated, possibly related to poor adherence to reduced Tac exposure.

Increasing trend in infection-related death-censored graft failure in renal transplantation.

BACKGROUND: Advances in kidney transplantation have significantly improved early outcomes but failed to improve long-term graft survival. Despite many causes, the contribution of infection to death-censored graft failure (DCGF) is unknown. The aim of our study is to assess the impact of infections on DCGF using United Network for Organ Sharing data. METHODS: We analyzed 38,286 DCGFs among 189,110 first kidney transplants performed between January 1, 1990 and December 31, 2006. Information on infection contributing to DCGF was available in 31,326 DCGF recipients. Student's two-sample t test for normally distributed variables, Wilcoxon rank sum test for nonnormally distributed, and Chi-square test for categorical variables were used in univariable comparisons. Multivariable logistic regression analysis was performed to assess the independent contribution of variables to infection-related DCGF. RESULTS: Overall, infection accounted for 7.7% (2397/31,326) of all DCGF. The rate of infection-related DCGF increased from 6.4% in 1990 to 10.1% in 2006 and was significantly higher during 1997 to 2006 when compared with 1990 to 1996 period (9.1% vs. 6.3%, P<0.001). Over these 17 years, the trends in infection-related DCGF and rejection rates showed an inverse relationship with the former exceeding the latter starting in 2005. The risk of infection-related DCGF was higher (14.1%) in recipients older than 65 years and exceeded the rejection rate in those older than 60 years. Urological complications and polyoma infection were the most significant risk factors with odds ratios of 8.77 (confidence interval: 5.15-14.93) and 2.55 (confidence interval: 1.41-4.61), respectively. CONCLUSION: Infection is increasingly contributing to DCGF in recent years and warrant reevaluation of current immunosuppression protocols, especially in older recipients.

Primary nonfunction of renal allograft secondary to acute oxalate nephropathy.

Primary nonfunction (PNF) accounts for 0.6 to 8% of renal allograft failure, and the focus on causes of PNF has changed from rejection to other causes. Calcium oxalate (CaOx) deposition is common in early allograft biopsies, and it contributes in moderate intensity to higher incidence of acute tubular necrosis and poor graft survival. A-49-year old male with ESRD secondary to polycystic kidney disease underwent extended criteria donor kidney transplantation. Posttransplant, patient developed delayed graft function (DGF), and the biopsy showed moderately intense CaOx deposition that persisted on subsequent biopsies for 16 weeks, eventually resulting in PNF. The serum oxalate level was 3 times more than normal at 85 µmol/L (normal <27 µmol/L). Allograft nephrectomy showed massive aggregates of CaOx crystal deposition in renal collecting system. In conclusion, acute oxalate nephropathy should be considered in the differential diagnosis of DGF since optimal management could change the outcome of the allograft.

Updated principles and clinical caveats in the management of infection in renal transplant recipients.

Renal transplantation is now considered the treatment of choice for patients with end-stage renal disease. In transplant recipients, infection and rejection are entwined and are unavoidable tribulations unless clinical tolerance becomes a reality. Although rejection rates have significantly decreased with the introduction of newer immunosuppressive agents, infections remain a major cause of morbidity and mortality, and the magnitude of the problem is on the rise. Newer infections are emerging and patterns of known infections are changing. The continuous evolution of donor and recipient characteristics also alters the landscape of infections. In clinical practice, establishing a definite diagnosis of infection in a timely manner remains a challenge in transplant recipients as compared to immunocompetent individuals. Hence a comprehensive knowledge of the principles of management of infections in renal transplant recipients is very essential. In this review, we would like to provide an overview of some of the key principles that we believe are essential in the management of infectious complications in renal transplant recipients with no focus on any individual infection.

Utility of estimated glomerular filtration rate in live kidney donation.

Live kidney donation is considered safe; nevertheless, data supporting such claims are almost exclusively of white origin with very limited long-term outcomes in ethnic minority donors. This prospective observational study consisted of a total of 103 previous kidney donors (54 black and 49 white) with mean follow-up days of 743.5 +/- 603.9 for white and 845.1 +/- 668.5 for black donors. The black donors had a statistically significant greater loss of estimated GFR (eGFR; 39.8 ml/min per 1.73 m2) in comparison with white donors (30.4 ml/min per 1.73 m2; P = 0.001). In multivariate analysis, predonation eGFR of <100 ml/min and age at the time of donation were the significant predictors for postdonation eGFR <60 ml/min among black donors. Because eGFR using the Modification of Diet in Renal Disease 4 formula is not validated in live kidney donors, the significance of eGFR <60 ml/min per 1.73 m2 in previous kidney donors is unclear. Long-term prospective study with a gold standard method such as iothalamate GFR measurement is needed to define the actual decrease in eGFR after kidney donation.

Mortality risk factors in chronic haemodialysis patients with infective endocarditis.

BACKGROUND: It is well documented that infective endocarditis (IE) is strongly associated with morbidity and mortality in haemodialysis (HD) patients. Less clear are the mortality risk factors for IE, particularly in an urban African-American dialysis population. METHODS: IE patients were identified from the medical records for the period from January 1999 to February 2004 and confirmed by Duke criteria. The patients were classified as 'survivors' and 'non-survivors' depending on in-hospital mortality, and risk factors for IE mortality were determined by comparing the two cohorts. Survivors were followed as out-patients with death as the endpoint. RESULTS: A total of 52 patients with 54 episodes of IE were identified. A catheter was the HD access in 40 patients (74%). Mitral valve (50%) was the commonest valve involved, and Gram-positive infections accounted for 87% of IE. In-hospital mortality was high (37%) and valve replacement was required for 13 IE episodes (24%). On logistic regression analyses, mitral valve disease [P = 0.002; odds ratio (OR) = 15.04; 95% confidence interval (CI) = 2.70-83.61] and septic embolism (P = 0.0099; OR = 9.56; 95% CI = 1.72-53.21) were significantly associated with in-hospital mortality. Using the Cox proportional hazards model, mitral valve involvement (P = 0.0008; hazard ratio 4.05; 95% CI = 1.78-9.21) and IE related to drug-resistant organisms such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus sp. (P = 0.016; hazard ratio 2.43; 95% CI = 1.18-5.00) were associated with poor outcome after hospital discharge. CONCLUSIONS: IE was associated with high mortality in our predominantly African-American dialysis population, when the mitral valve was involved, or septic emboli occurred and if MRSA or VRE were the causal organisms.

Rapid resolution of proteinuria of native kidney origin following live donor renal transplantation.

To assess the contribution of the protein content of urine from the native kidneys to post-transplant proteinuria, we prospectively studied 14 live donor transplant recipients with a pre-transplant random urine protein to creatinine ratio (UPr:Cr) >0.5. Seven patients received preemptive transplants, and seven patients were on dialysis pre-transplant (with residual urine output). Resolution of proteinuria was defined as UPr:Cr < 0.2. Immunosuppression consisted of tacrolimus, mycophenolate mofetil and corticosteroids. Anti-hypertensive drugs that might reduce proteinuria were avoided during the study. The serum creatinine was 8.7 +/- 0.7 mg/dL pre-transplant, and the nadir post-transplant serum creatinine was 1.4 +/- 0.1 mg/dL. The pre-transplant UPr:Cr ranged between 0.5 and 9.2 (mean = 2.9 +/- 0.6). The UPr:Cr decreased to <0.2 in all 14 patients at a mean of 4.5 weeks post-transplant (range 1-10 weeks). In conclusion, in live donor renal transplant recipients with immediate graft function, proteinuria of native kidney origin resolves in the early post-transplant period. After the immediate post-transplant period, proteinuria cannot be attributed to the native kidneys, and work up for proteinuria should focus on the allograft.

Recurrence of Scedosporium apiospermum infection following renal re-transplantation.

Immunosuppression for organ transplantation results in increased susceptibility to opportunistic infections including fungal, such as Scedosporium apiospermum. Even though many reported cases of this infection had both local and systemic manifestations, majority of the systemic infections had a fatal outcome. We report a case of a 50-year-old Caucasian male with lymphocutaneous and presumed pulmonary Scedosporium infection 4 years after renal transplantation that was successfully treated with voriconazole and discontinuation of immunosuppression. He received a second transplant 3 years later in the absence of clinical evidence of S. apiospermum infection. Unfortunately, 4 months after transplantation he developed recurrence of the same infection localizing to the soft tissues. Presently this infection is under control with surgical excision and voriconazole therapy. To our knowledge this is the first reported case of recurrent S. apiospermum infection in a renal transplant recipient. We suggest prophylactic antifungal therapy in all re-transplants with this infection.

Rapid progression of native renal artery fibromuscular dysplasia following kidney donation.

Fibromuscular dysplasia is the second commonest anatomical abnormality apart from multiple renal arteries in the potential live donors. Pretransplant evaluation of the donors may include an angiography to evaluate the renal arteries, and failure to recognize renal arterial stenosis, particularly fibromuscular dysplasia, by noninvasive methods may eventually lead to hypertension and ischemic renal failure. We report a case of fibromuscular dysplasia that was undetected by computed tomographic angiography prior to donation. One year after kidney donation, it rapidly progressed to severe symptomatic stenosis with hypertension and acute renal failure. Following renal artery angioplasty, her blood pressure normalized over a period of 2 weeks without any need for antihypertensive medications and the serum creatinine returned to her baseline. The acceptability of renal donors with fibromuscular dysplasia depends on the age, race and the availability of the other suitable donors. Mild fibromuscular dysplasia in a normotensive potential renal donor cannot be considered a benign condition. Such donors need regular follow-up postdonation for timely detection and treatment.