Cell-Free DNA and Active Rejection in Kidney Allografts.

Histologic analysis of the allograft biopsy specimen is the standard method used to differentiate rejection from other injury in kidney transplants. Donor-derived cell-free DNA (dd-cfDNA) is a noninvasive test of allograft injury that may enable more frequent, quantitative, and safer assessment of allograft rejection and injury status. To investigate this possibility, we prospectively collected blood specimens at scheduled intervals and at the time of clinically indicated biopsies. In 102 kidney recipients, we measured plasma levels of dd-cfDNA and correlated the levels with allograft rejection status ascertained by histology in 107 biopsy specimens. The dd-cfDNA level discriminated between biopsy specimens showing any rejection (T cell-mediated rejection or antibody-mediated rejection [ABMR]) and controls (no rejection histologically), P<0.001 (receiver operating characteristic area under the curve [AUC], 0.74; 95% confidence interval [95% CI], 0.61 to 0.86). Positive and negative predictive values for active rejection at a cutoff of 1.0% dd-cfDNA were 61% and 84%, respectively. The AUC for discriminating ABMR from samples without ABMR was 0.87 (95% CI, 0.75 to 0.97). Positive and negative predictive values for ABMR at a cutoff of 1.0% dd-cfDNA were 44% and 96%, respectively. Median dd-cfDNA was 2.9% (ABMR), 1.2% (T cell-mediated types ≥IB), 0.2% (T cell-mediated type IA), and 0.3% in controls (P=0.05 for T cell-mediated rejection types ≥IB versus controls). Thus, dd-cfDNA may be used to assess allograft rejection and injury; dd-cfDNA levels <1% reflect the absence of active rejection (T cell-mediated type ≥IB or ABMR) and levels >1% indicate a probability of active rejection.

Long-term outcomes in African American kidney transplant recipients under contemporary immunosuppression: a four-yr analysis of the Mycophenolic acid Observational REnal transplant (MORE) study.

Mycophenolic acid Observational REnal transplant (MORE) was a prospective, observational study of de novo kidney transplant patients receiving mycophenolic acid (MPA). Four-yr data on 904 patients receiving tacrolimus and enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) were analyzed to evaluate immunosuppression and graft outcomes in African American (AA, n = 218) vs. non-AA (n = 686) patients. Mean tacrolimus dose was higher in AA vs. non-AA patients but mean tacrolimus trough concentration was similar. Use of the recommended MPA dose in AA patients decreased from 78.9% at baseline to 33.1% at year 3. More AA patients received the recommended MPA dose with EC-MPS than MMF at month 6 (56.2% vs. 35.7%, p = 0.016) and month 36 (46.6% vs. 16.7%, p = 0.029), with no safety penalty. Significantly, more AA patients received corticosteroids than non-AA patients. Biopsy-proven acute rejection was higher in AA vs. non-AA patients (18.9% vs. 10.7%, p = 0.003), as was graft loss (10.9% vs. 4.4%, p = 0.003); differences were confirmed by Cox regression analysis. Patient survival was similar. Estimated GFR was comparable in AA vs. non-AA patients. Kidney allograft survival remains lower for AA vs. non-AA recipients even under the current standard of care.

Does reduction in mycophenolic acid dose compromise efficacy regardless of tacrolimus exposure level? An analysis of prospective data from the Mycophenolic Renal Transplant (MORE) Registry.

Prospective data are lacking concerning the effect of reduced mycophenolic acid (MPA) dosing on efficacy and the influence of concomitant tacrolimus exposure. The Mycophenolic Renal Transplant (MORE) Registry is a prospective, observational study of de novo kidney transplant patients receiving MPA therapy under routine management. The effect of MPA dose reduction, interruption, or discontinuation (dose changes) was assessed in 870 tacrolimus-treated patients: 375 (43.1%) reduced tacrolimus (≤ 7 ng/mL at baseline) and 495 (56.9%) standard tacrolimus (>7 ng/mL); enteric-coated mycophenolate sodium 589 (67.7%) and mycophenolate mofetil 281 (32.3%). During baseline to month 1, months 1-3, months 3-6, and months 6-12, 9.3% (78/838), 16.6% (132/794), 20.7% (145/701), and 13.1% (70/535) patients, respectively, required MPA dose changes. These patients experienced an increased risk of biopsy-proven acute rejection at one yr with tacrolimus exposure either included in the model (hazard ratio [HR] 2.60, 95% CI 1.28-5.29, p = 0.008) or excluded (HR 2.58, 95% CI 1.28-5.23, p = 0.008). MPA dose changes were significantly associated with one yr graft failure when tacrolimus exposure was included (HR 2.23; 95% CI 1.01-4.89, p = 0.047) but not when tacrolimus exposure was excluded (HR 2.16; 95% CI 0.99-4.79; p = 0.054). These results suggest that reducing or discontinuing MPA can adversely affect graft outcomes regardless of tacrolimus trough levels.

Association of mycophenolic acid dose with efficacy and safety events in kidney transplant patients receiving tacrolimus: an analysis of the Mycophenolic acid Observational REnal transplant registry.

BACKGROUND: Dose-finding studies for mycophenolic acid (MPA) in tacrolimus-treated kidney transplant patients are lacking. METHODS: Data from 901 de novo kidney transplant recipients enrolled in the prospective, non-interventional Mycophenolic acid Observational REnal (MORE) transplant registry were analyzed according to baseline daily MPA dose (<2000, 2000 or >2000 mg). RESULTS: The proportion of patients receiving 2000 and <2000 mg was 77.6% and 19.9% at baseline, 74.5% and 23.3% at month 1, 62.4% and 35.5% at month 3, 48.5% and 50.2% at month 6, and 44.1% and 55.2% at month 12. More patients were maintained on 2000 mg with enteric-coated mycophenolate sodium (EC-MPS) vs. mycophenolate mofetil (month 6, 52.7% vs. 43.0% [p=0.02]; month 12, 47.3% vs. 39.4% [p=0.08]). Multivariate modeling showed no significant effect of baseline MPA dose on 12-month risk of biopsy-proven acute rejection, graft loss or estimated GFR, or on safety events including MPA discontinuation other than a higher rate of gastrointestinal adverse events in patients with an initial MPA dose>2000 mg (p=0.029) vs. 2000 mg. CONCLUSIONS: These findings suggest that an initial MPA dose of <2000 mg does not compromise 12-month efficacy in tacrolimus-treated kidney transplants, but controlled trials are required and the lower threshold for MPA dose remains to be defined.

Thrombotic microangiopathy with multiorgan involvement following COVID-19.

Acute kidney injury is common among hospitalized COVID-19 patients, with the incidence ranging from 0.5% to 80%, due to diverse pathologies including acute tubular injury, collapsing glomerulopathy, and thrombotic microangiopathy (TMA). While macrovascular thrombosis is common in these individuals, the frequent finding of extensive microvascular thromboses in several series and case reports raises the possibility of thrombotic microangiopathy (TMA) being a contributing factor in the thrombotic and multiorgan complications of the disease. TMA has been described as either the primary finding or in concert with other pathologic findings in COVID-19 patients and carries a poor prognosis, with all patients requiring dialysis. We present a case of TMA with retinal injury and bowel perforation in addition to pulmonary and renal manifestations.

Management of Metabolic Acidosis in Chronic Kidney Disease: Past, Present, and Future Direction.

Chronic kidney disease (CKD) is a major global epidemic associated with increased morbidity and mortality. Despite the effectiveness of kidney protection strategies of hypertension, diabetes, and lipid control and use of newer hypoglycemic agents and anti-angiotensin II drugs, the nephropathy in CKD continues unabated toward irreversible kidney failure. Thus, interventions targeting modifiable risk factors in CKD such as metabolic acidosis (MA) are needed. Acid reduction with sodium-based alkali has been shown to be an effective kidney-protection strategy for patients with CKD and reduced glomerular filtration rate (GFR). Small-scale studies reveal diets emphasizing ingestion of plant-sourced over animal-sourced protein reduce dietary acid, improve MA, and slow further nephropathy progression in patients with CKD and reduced GFR. Additionally, veverimer, an investigational, nonabsorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as a novel treatment for MA. As further studies define how to best use these interventions for kidney protection, clinicians must become aware of their potential utility in the management of patients with CKD. The aim of the present review is to explore the various intervention strategies that increase or normalize serum [HCO3-] in patients with CKD-associated MA or low normal serum [HCO3-] that may further slow progression of CKD.

Mercury in natural health products as a cause of membranous nephropathy.

Membranous nephropathy is a glomerular disease characterized by diffuse subepithelial immune complex deposition along the glomerular basement membrane. It can be both primary and secondary to malignancy and various drugs. An emerging area of concern is heavy metal exposure from use of largely unregulated natural health products. Here we present a case of biopsy-proven membranous nephropathy due to natural health products contaminated with mercury.

Immune Dysfunction and Risk of Infection in Chronic Kidney Disease.

Cardiovascular disease and infections are directly or indirectly associated with an altered immune response, which leads to a high incidence of morbidity and mortality, and together, they account for up to 70% of all deaths among patients with chronic kidney dysfunction. Impairment of the normal reaction of the innate and adaptive immune systems in chronic kidney disease predisposes patients to an increased risk of infections, virus-associated cancers, and a diminished vaccine response. On the other hand, an abnormal, exaggerated reaction of the immune systems can also occur in this group of patients, resulting in increased production and decreased clearance of proinflammatory cytokines, which can lead to inflammation and its sequelae (eg, atherosclerotic cardiovascular disease). Epigenetically, modifications in hematopoietic stem cells involving a shift from lymphoid to myeloid cell lineage may underlie uremia-associated immunological senescence, which is not reversed by renal replacement therapy, including kidney transplantation. Measures aimed at attenuating the immune abnormalities in chronic kidney disease/end-stage renal disease should be an area of focused research as this could potentially lead to a better understanding and, thus, development of therapies that could reduce the disastrously high death rate in this patient population. The aim of the present article is to review the characteristics, causes, and mechanisms of the immune dysfunction related to chronic kidney disease.

Strongyloidiasis hyperinfection after renal transplant presenting as diffuse alveolar hemorrhage with respiratory failure.

Strongyloides stercoralis is a helminthic enteric parasite estimated to infect at least 30 to 100 million people globally. It is transmitted via contaminated soil with a unique ability to complete its entire life cycle in the human host. It is common in humid, tropical, and subtropical regions of the world and is endemic in the Southeastern United States. Strongyloidiasis hyperinfection has been described in a variety of conditions that impair host immunity, including immunosuppression after transplantation. The syndrome has a high mortality rate but may initially present with nonspecific symptoms. A high degree of clinical suspicion coupled with early detection and aggressive therapeutic measures is paramount to a successful outcome.

Successful pregnancy in a hemodialysis patient and marked resolution of her nephrogenic systemic fibrosis.

Nephrogenic systemic fibrosis (NSF) is a recently recognized clinicopathologic entity. It is believed to be related to exposure to gadolinium-containing magnetic resonance imaging agents with gadolinium deposition in the tissues, including skin and other organs. It mainly affects patients on dialysis therapy. Pregnancy in dialysis patients is a rare occurrence. We present a case of a dialysis patient who developed NSF after exposure to gadodiamide and went on to have a successful pregnancy while on hemodialysis therapy. The patient had marked clinical and histological improvement in NSF during and after her pregnancy. This also correlated with decreasing gadolinium levels in skin biopsy tissue specimens. We discuss the interplay of factors involved in the successful pregnancy and improvement in NSF lesions in this patient.

Effect of hepatitis C infection on anemia in hemodialysis patients.

Hepatitis C (HCV) infection is commonly seen in dialysis patients, but its long-term deleterious effects in these patients are unknown. We evaluated the effect of HCV infection on anemia in our hemodialysis population. This retrospective case control study was carried out from January 1999 to February 2007. The HCV positive patients were assessed for a 12-month period by quarterly lab results for the prevalence of anemia, iron stores, dialysis adequacy, and alanine aminotranferase levels. Their requirements of erythropoietin (EPO) and intravenous (IV) iron were assessed during these months of clinical stability. A control group of age-matched, race-matched, and gender-matched hemodialysis patients with no history of HCV was similarly assessed for anemia, iron stores, and EPO and IV-iron requirements. Twenty-two HCV-positive patients were included for comparison analysis with 44 control patients for 1:2 matching. The mean EPO requirement for the hepatitis group was 17,307 +/- 14,708 U/month in comparison with the control group, which required 49,134 +/- 49,375 U/month (p value <0.01). The mean dose of IV-iron was 120 +/- 143 mg/month for hepatitis patients and 163 +/- 112 mg/month in the control group (p=0.07). The patients with HCV have lower requirement of exogenous EPO replacement compared with their age-matched, gender-matched, and race-matched dialysis counterparts. The IV-iron requirement was not significantly different between the 2 groups but had a suggestive lower trend in the hepatitis group. This needs to be further studied in larger trials.

Nephrogenic systemic fibrosis: a review of 6 cases temporally related to gadodiamide injection (omniscan).

OBJECTIVES: Nephrogenic systemic fibrosis (NSF) is a rare acquired disorder that was first recognized in 1997. Presented is a retrospective review of 6 cases of NSF diagnosed by skin biopsy in our institution during the past 4 years and their relationship to gadodiamide exposure. METHODS AND RESULTS: Patient age ranged from 23 to 71 years. The onset of symptoms consistent with NSF was between 19 days and 2 months after gadodiamide exposure. Five patients had severe renal impairment and started dialysis around the period of gadodiamide exposure (1 day before the 37 days after contrast administration). The sixth patient had a clotted access at the time of a contrast-enhanced magnetic resonance venogram and was hence not being adequately dialyzed. The dose of gadodiamide ranged from 16 to 40 mL (0.11 to 0.36 mmol/kg). Despite having normal serum bicarbonate, 5 of the 6 patients had an elevated anion gap metabolic acidosis. CONCLUSIONS: In our 6 patients, all had either failing native or transplant kidneys at the time of gadodiamide exposure. The development of NSF was temporally related to gadodiamide injection, suggesting as the etiology dechelation of the agent and thus emphasizing the need for change in clinical practice.

Biological Variation of Donor-Derived Cell-Free DNA in Renal Transplant Recipients: Clinical Implications.

BACKGROUND: Previous studies have demonstrated that donor-derived cell-free DNA (dd-cfDNA) found in circulating blood of transplant recipients may serve as a noninvasive biomarker of allograft rejection. To better interpret the clinical meaning of dd-cfDNA, it is essential to understand the biological variation of this biomarker in stable healthy recipients. This report establishes the biological variation and clinical reference intervals of dd-cfDNA in renal transplant recipients by using an analytically validated assay that has a CV of 6.8%. METHODS: We sampled venous blood at patient surveillance visits (typically at posttransplant months 1-4, 6, 9, and 12) in a 14-center observational study. Patients with stable renal allograft function spanning ≥3 serial visits were selected. We used AlloSure®, a targeted next-generation sequencing-based approach, to measure dd-cfDNA in the plasma and computed the intraindividual CV (CVI) and interindividual CV (CVG), the index of individuality (II), and reference change value (RCV). RESULTS: Of 93 patients, 61% were men, 56% were Caucasian, mean age was 49 years, and 63% were deceased donor kidney recipients. Of 380 blood samples, the dd-cfDNA median value was 0.21% (interquartile range 0.12%-0.39%) and the 97.5th percentile was 1.20%. In 18 patients with an average of 4.1 tests, the CVI was 21%, CVG was 37%, II was 0.57, and RCV was 61%. CONCLUSIONS: In a renal transplant recipient, a dd-cfDNA level above 1.2% is out of range and potentially abnormal. A serial increase of up to 61% in level of dd-cfDNA in a patient may be attributable to biological variation.Clinicaltrials.gov Identifier: NCT02424227.

Disseminated mucormycosis in a patient with recent kidney transplantation: a case report and review of the literature.

Mucormycosis is an invasive fungal infection commonly seen in diabetics and immunocompromised patients. We report a case of disseminated mucormycosis in a 47-year-old diabetic male who underwent deceased donor renal allograft transplantation about 5 weeks prior to presentation. Our patient presented with increasing fatigue, diarrhea and oligoanuria and was found to have significant acute kidney injury. Doppler ultrasound of the allograft revealed segmental decreased renal perfusion in the upper pole of the allograft with moderate hydronephrosis. Nephrostomy tube placement yielded minimal urine output. An allograft biopsy showed diffuse C4d-positive staining and fungal hyphae suggestive of Mucor infection. Computed tomography (CT) imaging revealed a right upper lobe mass, a small hypodensity in the liver and normal findings in the head. Despite prompt management including discontinuation of immunosuppression, amphotericin B and allograft nephrectomy, the patient had a rapid decompensation, developed respiratory failure requiring intubation, hypotension and supraventricular tachycardia with multiple new areas of hypoattenuation on head CT - all of which ultimately resulted in his death. A review of the literature revealed that mucormycosis is a relatively rare disease with a cumulative 12-month incidence rate of 0.07% in solid organ transplant recipients. Disseminated disease was found in about 23% of cases, with a mortality rate of 96%.

Outcomes in African American kidney transplant patients receiving tacrolimus and mycophenolic acid immunosuppression.

BACKGROUND: Prospective data regarding immunosuppression and rejection in African American patients receiving modern immunosuppressive regimens are sparse. METHODS: One-year data were analyzed from 901 tacrolimus-treated de novo kidney transplant patients in the prospective Mycophenolic Acid Observational Renal Transplant registry. RESULTS: Mean tacrolimus dose was significantly higher in African Americans (n=217) versus non-African Americans (n=684), but mean tacrolimus trough concentrations were similar. The proportion of patients receiving mycophenolic acid dose equal to or more than 2000 mg per day (mycophenolate mofetil equivalents) was significantly higher with enteric-coated mycophenolate sodium versus mycophenolate mofetil at month 6 among African Americans and at month 3 in non-African Americans, but rates of acute rejection and adverse events (including gastrointestinal events) were similar. The 1-year incidence of biopsy-proven acute rejection (BPAR) was 14.1% in African Americans versus 7.5% in non-African Americans. On multivariate analysis, African American ethnicity was associated with a higher risk of BPAR (hazard ratio, 1.93; 95% confidence interval, 1.19-3.09; P=0.007). Mean (standard deviation) glomerular filtration rate at month 12 estimated by the Chronic Kidney Disease Epidemiology Collaboration formula was 59.2 (22.2) mL/min/1.73 m in African Americans versus 58.8 (19.9) mL/min/1.73 m in non-African Americans (confidence interval of the difference, -3.4 to 4.3; P=0.83). CONCLUSION: This observational study confirms that African Americans require higher doses of tacrolimus to achieve target trough concentrations and are more likely to experience BPAR during the first year after kidney transplantation despite modern immunosuppression regimens. In our 1-year study, this was not associated with significantly inferior graft survival.

A Rare Case of Subarachnoid Hemorrhage due to Rupture of Isolated Anterior Spinal Artery Aneurysm in a Patient with Polycystic Kidney Disease.

Only a very few cases of subarachnoid hemorrhage due to isolated anterior spinal artery aneurysms have been reported in the literature. We report a case of subarachnoid hemorrhage due to anterior spinal artery aneurysm rupture in a renal transplant patient at our institution. A 47-year-old male had abrupt onset of left lower extremity weakness with bowel and bladder disturbances which prompted emergent surgical evacuation of the clot and hence immediate diagnostic angiography was not performed. However, follow-up serial intracranial arterial ultrasound studies showed only vasospasm of the basilar artery. Repeat MRI of the thoracic spine showed persistence of subarachnoid blood products, but no larger foci compared to previous imaging. When spinal subarachnoid hemorrhage is present in the appropriate clinical setting, isolated anterior spinal artery aneurysm should be considered as a possible, treatable cause.

Surgical correction of nephrogenic ascites in a renal transplant recipient.

The unusual development of massive ascites, 3 years after renal transplant, caused by undefined, innate renal allograft pathology is described. Challenges of surgical correction of this problem, allowing for salvage of the allograft, are reviewed.