Thrombotic Microangiopathy, an Unusual Form of Monoclonal Gammopathy of Renal Significance: Report of 3 Cases and Literature Review.

Monoclonal gammopathies result from neoplastic clones of the B-cell lineage and may cause kidney disease by various mechanisms. When the underlying clone does not meet criteria for a malignancy requiring treatment, the paraprotein is called a monoclonal gammopathy of renal significance (MGRS). One rarely reported kidney lesion associated with benign paraproteins is thrombotic microangiopathy (TMA), provisionally considered as a combination signifying MGRS. Such cases may lack systemic features of TMA, such as a microangiopathic hemolytic anemia, and the disease may be kidney limited. There is no direct deposition of the paraprotein in the kidney, and the presumed mechanism is disordered complement regulation. We report three cases of kidney limited TMA associated with benign paraproteins that had no other detectable cause for the TMA, representing cases of MGRS. Two of the cases are receiving clone directed therapy, and none are receiving eculizumab. We discuss in detail the pathophysiological basis for this possible association. Our approach to therapy involves first ruling out other causes of TMA as well as an underlying B-cell malignancy that would necessitate direct treatment. Otherwise, clone directed therapy should be considered. If refractory to such therapy or the disease is severe and multisystemic, C5 inhibition (eculizumab or ravulizumab) may be indicated as well.

Noninvasive Assessment of the Alloimmune Response in Kidney Transplantation.

Transplantation remains the optimal mode of kidney replacement therapy, but unfortunately long-term graft survival after 1 year remains suboptimal. The main mechanism of chronic allograft injury is alloimmune, and current clinical monitoring of kidney transplants includes measuring serum creatinine, proteinuria, and immunosuppressive drug levels. The most important biomarker routinely monitored is human leukocyte antigen (HLA) donor-specific antibodies (DSAs) with the frequency based on underlying immunologic risk. HLA-DSA should be measured if there is graft dysfunction, immunosuppression minimization, or nonadherence. Antibody strength is semiquantitatively estimated as mean fluorescence intensity, with titration studies for equivocal cases and for following response to treatment. Determination of in vitro C1q or C3d positivity or HLA-DSA IgG subclass analysis remains of uncertain significance, but we do not recommend these for routine use. Current evidence does not support routine monitoring of non-HLA antibodies except anti-angiotensin II type 1 receptor antibodies when the phenotype is appropriate. The monitoring of both donor-derived cell-free DNA in blood or gene expression profiling of serum and/or urine may detect subclinical rejection, although mainly as a supplement and not as a replacement for biopsy. The optimal frequency and cost-effectiveness of using these noninvasive assays remain to be determined. We review the available literature and make recommendations.

Bilateral Renal Hypoperfusion Following Motor Vehicle Accident.

Renal hypoperfusion noted on abdominal computed tomography (CT) scan without any underlying comorbid condition is a rare finding. Most reported cases of renal hypoperfusion have an association with an underlying cardioembolic problem, such as atrial fibrillation, endocarditis, cardiomyopathies, or artificial valve thrombi. We present a case of transient renal hypoperfusion evident on abdominal CT scan following blunt trauma. An 18-year-old male without any significant past medical history presented to the emergency department with the complaint of abdominal pain. The patient reported history of motor vehicle accident 1 week prior to his presentation. He was a front seat passenger wearing a seatbelt when the car went into a ditch. Airbags were deployed and the patient briefly lost consciousness. He presented 1 week later with complaints of generalized abdominal pain, more on the left side that started a few days after his accident, nonradiating, constant, 4/10 intensity. He denied dysuria, hematuria, groin pain, fever, chills, nausea, vomiting, abdominal pain, diarrhea, constipation, decreased oral intake, joint pain, leg swelling, or redness. He denied any medication use or any history of intravenous drug abuse. There was no reported family history of kidney disease or blood clots. Initial laboratory tests, including complete blood count, basic metabolic panel, erythrocyte sedimentation rate, and urinalysis were unremarkable except trace protein on the urinalysis. Contrast-enhanced CT of the abdomen showed multiple, confluent, focal areas of hypoperfusion of the renal parenchyma bilaterally. Given the CT findings of bilateral renal hypoperfusion, the patient was admitted to the hospital and an extensive workup was performed to rule out cardioembolic etiology. Echocardiogram, renal ultrasound, magnetic resonance angiogram of the abdomen, vasculitis panel, and hypercoagulable workup was unremarkable. The CT findings of renal hypoperfusion were considered secondary to transient hypoperfusion from blunt trauma. Abdominal pain resolved with nonsteroidal anti-inflammatory drugs and he was discharged to home. Follow-up abdominal CT scan with contrast obtained a few months later showed normal kidneys with resolution of previously noted renal hypoperfusion. Our case highlights a benign incidental finding of bilateral renal hypoperfusion following motor vehicle accident (with airbag injury), which resolved on follow-up imaging. On literature search, such CT scan findings of transient renal hypoperfusion of unclear significance have not been previously reported. Even though our patient underwent extensive workup to rule out cardioembolic etiology, it may be reasonable to forego such workup following blunt abdominal trauma.

Complement inhibition with eculizumab for thrombotic microangiopathy rescues a living-donor kidney transplant in a patient with antiphospholipid antibody syndrome.

Antiphospholipid antibody syndrome (APS) is an enigmatic heterogeneous disorder despite several revelations in its pathobiology. Renal transplantation in patients with APS has been notoriously difficult due to the high risk of development of thrombotic microangiopathy (TMA), which is often refractory to conventional treatment modalities such as aggressive anticoagulation and plasmapheresis. We describe a case of a 58-year-old male with secondary APS undergoing living unrelated renal transplantation for end-stage renal disease from lupus nephritis. Shortly after transplantation, he developed graft dysfunction from APS related TMA that was refractory to systemic anticoagulation and plasmapheresis. After becoming hemodialysis dependent, the patient was started on eculizumab, a humanized monoclonal antibody against complement factor 5, as salvage therapy. We show that this intervention successfully rescued his renal allograft and that the patient has remained dialysis free for over 20 months. Our experience adds to the limited body of literature suggesting the role of complement inhibition in facilitating renal transplantation in patients with APS spectrum of disorders, thus adding a new tool to the therapeutic armamentarium for this difficult disease. The optimal treatment schedule and long term safety data for eculizumab in complement mediated TMA is still unclear. The search for an optimal biomarker to help guide treatment duration is an area of active research.

Sensitization, pathologic, and imaging findings comparing symptomatic and quiescent failed renal allografts.

Late allograft failure (LAF) is a common cause of end stage renal disease. These patients face interrelated challenges regarding immunosuppression management, risk of graft intolerance syndrome (GIS), and sensitization. This retrospective study analyzes sensitization, pathology, imaging, and transfusion requirements in 33 LAFs presenting either with GIS (22) or grafts remaining quiescent (11). All patients underwent immunosuppression weaning to discontinuation at LAF. Profound increases in sensitization were noted for all groups and occurred in the GIS group prior to transplant nephrectomy (TxN). Patients with GIS experienced a major upswing in sensitization at, or before the time of their symptomatic presentation. For both GIS and quiescent grafts, sensitization appeared to be closely linked to immunosuppression withdrawal. Most transfusion naïve patients became highly sensitized. Fourteen patients in the GIS group underwent TxN which revealed grade II acute cellular rejection or worse, with grade 3 chronic active T-cell-mediated rejection. Blinded comparisons of computed tomography scan of GIS group revealed swollen allografts with fluid collections compared with the quiescent allografts (QAs), which were shrunken and atrophic. The renal volume on imaging and weight of explants nearly matched. Future studies should focus on interventions to avoid sensitization and GIS.

De Novo Fibrillary Glomerulonephritis (FGN) in a Renal Transplant with Chronic Hepatitis C.

Chronic hepatitis C viremia (HepC) has been associated with numerous renal manifestations both in native kidneys and in the setting of renal transplantation. Glomerulonephritis (GN) of the renal allograft in the setting of HepC most commonly manifests as type 1 membranoproliferative GN (MPGN), either representing recurrence of the original disease or arising de novo. Other GNs were reported after transplantation in the patient with HepC including membranous nephropathy and thrombotic microangiopathy, as well as an enhanced susceptibility to transplant glomerulopathy. We describe the first case of de novo fibrillary GN in a renal transplant patient with HepC where the primary renal disease was biopsy proven type 1 MPGN. We discuss this relationship in detail.

Peritransplant kidney biopsies: comparison of pathologic interpretations and practice patterns of organ procurement organizations.

The preimplantation kidney biopsy affects utilization by diagnosing glomerulosclerosis, interstitial fibrosis (IF), arteriosclerosis, and arteriolar hyalinosis. Organ procurement organizations (OPOs) determine whether a donor warrants this biopsy and the donor hospital pathologists (DHPs) report on an OPO-specific pathology interpretation form. Biopsy slides from 40 deceased donor kidneys transplanted at our institution were used to compare interpretations between our transplant pathologist and the DHPs. Thirty-three of these kidneys also had post-perfusion biopsies (PPB). All 58 OPOs were queried for criteria used to request a preimplantation biopsy, and their pathology interpretation forms were also analyzed. The transplant and DHPs had substantial agreement for percent glomerulosclerosis with 75% of biopsies being interpreted within five percentage points. Concordance for IF was poor. The DHP rarely reported arterial pathology. Seventy percent of preimplantation and PPB were read similarly for glomerulosclerosis; concordance for other lesions was weaker. There were no cues for arterial disease on our OPO's pathology interpretation form. Criteria for obtaining a preimplantation biopsy lacked uniformity for the 21 OPOs with a self-generated policy. The pathology interpretation forms varied widely among the OPOs. Current OPO practices with regard to the preimplantation biopsy should be improved.

ANTHEM: anatomically tailored hexagonal MRI.

PURPOSE: This study aimed to investigate the use of anatomically tailored hexagonal sampling for scan-time and error reduction in MRI. MATERIALS AND METHODS: Anatomically tailored hexagonal MRI (ANTHEM), a method that combines hexagonal sampling with specific symmetry in anatomical geometry, is proposed. By using hexagonal sampling, aliasing artifacts are moved to regions where, due to the nature of the anatomy, aliasing is inconsequential. This can be used to either reduce scan time while maintaining spatial resolution or reduce residual errors in speedup techniques like UNFOLD and k-t BLAST/SENSE, which undersample k-space and unwrap fold-over artifacts during reconstruction. Computer simulations as well as phantom and volunteer studies were used to validate the theory. A simplified reconstruction algorithm for hexagonally sampled and subsampled k-space data was also used. RESULTS: A reduction in sampling density of 13.4% and 25% in each hexagonally sampled dimension was achieved for spherical and conical geometries without aliasing or reduction in spatial resolution. Optimal subsampling schemes that can be utilized by UNFOLD and k-t BLAST/SENSE were derived using hexagonal subsampling, which resulted in maximal, isotropic dispersal of the aliases. In combination with UNFOLD, ANTHEM was shown to move residual aliasing artifacts to the corners of the field of view, yielding reduced artifacts in CINE reconstructions. CONCLUSIONS: ANTHEM was successful in reducing acquisition time in conventional MRI and in reducing errors in UNFOLD imaging.

Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation.

Experience in the field of pregnancy after transplantation has been gained through continued case reports, center reports, and registry data. The NTPR maintains an ongoing active database to study the safety of pregnancy and includes the outcomes of female transplant recipients as well as male recipients who father pregnancies. Analyses are ongoing and include long-term follow-up of recipients' graft status and of their offspring. For the most part, guidelines proposed in 1976 for counseling recipients remain applicable. While these counseling guidelines were formulated for kidney recipients, they may be extrapolated for other organ recipients as well. Organ-specific issues should also be considered in managing and counseling female transplant recipients. Recipients should be in general good health and graft function should be stable and ideally rejection free. They should have optimal control of comorbid conditions such as hypertension and diabetes prior to conception. While the shortest safe interval from transplant to conception has not been established, one year is a reasonable milestone, given the prerequisites of stable, adequate graft function and maintenance level immunosupression. During pregnancy, stable medication regimens should be changed as little as possible, and close maternal and fetal surveillance are required. These pregnancies are high-risk and require coordinated care among maternal fetal medicine specialists and transplant personnel. The pregnancy issues that face recipients and caretakers with the current adjunctive therapies and differing combinations of immunosuppressive regimens continue to require further study. The most pressing issue is the question of whether fetal exposure to mycophenolate mofetil or sirolimus confers additional risk, relative to the potential improvement in maternal survival and maternal graft function/survival conferred by these drugs. Given the multiplicity of immunosuppressive regimens, only broad-based registry participation can provide the data needed to analyze such complex questions. Future analyses are directed at potential effects of these newer immunosuppressive regimens, not only from immediate exposure, but also from potential long-term exposures such as may occur from breastfeeding. As the registry study design allows for continuing contact between registry staff and recipients and their health care providers, efforts are in progress to analyze long-term outcomes of parent and child. Continued close collaboration among specialists will help to better identify potential pregnancy risks in these populations, especially as new immunosuppressive agents are developed.