Carl H. Cramer

Proliferative Glomerulonephritis Secondary to Dysfunction of the Alternative Pathway of Complement

BACKGROUND AND OBJECTIVES dense deposit disease (DDD) is the prototypical membranoproliferative glomerulonephritis (MPGN), in which fluid-phase dysregulation of the alternative pathway (AP) of complement results in the accumulation of complement debris in the glomeruli, often producing an MPGN pattern of injury in the absence of immune complexes. A recently described entity referred to as GN with C3 deposition (GN-C3) bears many similarities to DDD. The purpose of this study was to evaluate AP function in cases of GN-C3. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Five recent cases of MPGN with extensive C3 deposition were studied. Renal biopsy in one case exhibited the classic findings of DDD. Three cases showed GN-C3 in the absence of significant Ig deposition; however, the classic hallmark of DDD-dense deposits along the glomerular basement membranes and mesangium-was absent. The remaining case exhibited features of both DDD and GN-C3. RESULTS Evidence of AP activation was demonstrable in all cases and included increased levels of soluble membrane attack complex (all cases), positive AP functional assays (four cases), and a positive hemolytic assay (one case). Autoantibodies were found to C3 convertase (two cases) and to factor H (one case). Factor H mutation screening identified the H402 allele (all cases) and a c.C2867T p.T956M missence mutation (one case). Laser microdissection and mass spectrometry of glomeruli of GN-C3 (two cases) showed a proteomic profile very similar to DDD. CONCLUSIONS These studies implicate AP dysregulation in a spectrum of rare renal diseases that includes GN-C3 and DDD.

Immune response to rabies vaccination in pediatric transplant patients

Abstract:  Children have become engaged in a wider variety of activities as the success of solid organ transplantation has improved. These activities can result in exposure to infectious agents for which there are no data documenting the efficacy of standard treatment in children on immunosuppressive therapy. This is a retrospective review of five OLT patients and three RT patients who were potentially exposed to rabies during camp. They completed the immunoprophylaxis treatment for rabies exposure outlined by the CDC in the 2003 Red Book. Rabies titers were followed for six to 12 months post‐immunization. All five OLT patients were on tacrolimus. All three RT patients were on tacrolimus, mycophenolate mofetil, and prednisone. At the time of exposure median age was 10.0 yr (8.4–17.3). None of the subjects developed rabies. A positive rabies titer, indicative of successful immunization, was present by one month in seven subjects and all subjects by six months. Rabies vaccination in pediatric transplant patients is safe and associated with the successful production of antirabies titers.

Thrombotic Microangiopathy Care Pathway: A Consensus Statement for the Mayo Clinic Complement Alternative Pathway-Thrombotic Microangiopathy (CAP-TMA) Disease-Oriented Group

Thrombotic microangiopathies (TMAs) comprise a heterogeneous set of conditions linked by a common histopathologic finding of endothelial damage resulting in microvascular thromboses and potentially serious complications. The typical clinical presentation is microangiopathic hemolytic anemia accompanied by thrombocytopenia with varying degrees of organ ischemia. The differential diagnoses are generally broad, while the workup is frequently complex and can be confusing. This statement represents the joint recommendations from a multidisciplinary team of Mayo Clinic physicians specializing in the management of TMA. It comprises a series of evidence- and consensus-based clinical pathways developed to allow a uniform approach to the spectrum of care including when to suspect TMA, what differential diagnoses to consider, which diagnostic tests to order, and how to provide initial empiric therapy, as well as some guidance on subsequent management.

Empiric switch from calcineurin inhibitor to sirolimus‐based immunosuppression in pediatric heart transplantation recipients

Sirolimus is used in heart transplant patients with CAV and CNI‐induced nephropathy. However, little is known regarding the tolerability, rejection rate, and effect on renal function when used empirically in children. We describe our experience with the empiric use of a sirolimus‐based immunosuppressive regimen in pediatric heart transplantation recipients. We reviewed records of patients in whom conversion was attempted to a CNI‐free sirolimus‐based regimen. Rejection episodes and measures of renal function were recorded. We attempted to convert 20 patients, of which 16 were successful. In total, six of 20 patients (30%) experienced adverse effects. Of the 16 converted, four patients converted to sirolimus due to CNI‐induced disease (three nephropathy, one CAV), while 12 patients (mean age 5.5 yr, range 0.1–21 yr; 33% female; 33% with a history of congenital heart disease) were empirically switched to sirolimus at a mean of 2.3 yr after transplant. Follow‐up was available for a mean of 2.5 yr after conversion (range 0.5–8.3 yr). The rate of rejection while taking CNIs was 0.18 rejection episodes per patient‐year (total of five episodes), compared with 0.03 rejection episodes per patient‐year (total of one episode) while on sirolimus. Renal function, in terms of GFR, significantly improved after sirolimus conversion at latest follow‐up (from 86 ± 37 mL/min to 130 ± 49 mL/min, p = 0.02). Here, we demonstrate the potential benefit of empiric use of sirolimus in pediatric heart transplant patients in a CNI‐free regimen. Larger and longer studies are needed to further clarify risks of rejection and adverse effect profiles.

Correlation of blood pressure readings from 6-hour intervals with the daytime period of 24-hour ambulatory blood pressure monitoring in pediatric patients.

J Clin Hypertens (Greenwich). 2012; 14:396–400. ©2012 Wiley Periodicals, Inc.

Negative Staining for COL4A5 Correlates With Worse Prognosis and More Severe Ultrastructural Alterations in Males With Alport Syndrome

Introduction Alport syndrome (AS) is a genetic disorder characterized by progressive hematuric nephropathy with or without sensorineural hearing loss and ocular lesions. Previous studies on AS included mostly children. Methods To determine the prognostic value of loss of staining for collagen type IV alpha 5 (COL4A5) and its relationship with the ultrastructural glomerular basement membrane alterations, we performed direct immunofluorescence using a mixture of fluorescein isothiocyanate-conjugated and Texas-red conjugated antibodies against COL4A5 and COL4A2, respectively, on renal biopsies of 25 males with AS (including 16 who were diagnosed in adulthood). Results All patients showed normal positive staining of glomerular basement membranes and tubular basement membranes for COL4A2. Of the 25 patients, 10 (40%) patients showed loss of staining for COL4A5 (including 89% of children and 13% of adults) and the remaining 15 (60%) had intact staining for COL4A5. Compared with patients with intact staining for COL4A5, those with loss of staining had more prominent ultrastructural glomerular basement membrane alterations and were younger at the time of biopsy. By Kaplan-Meier survival analysis and Cox regression analysis, loss of staining for COL4A5 predicted earlier progression to overt proteinuria and stage 2 chronic kidney disease or worse. By multivariate Cox regression analysis, loss of staining for COL4A5 was an independent predictor of the development of overt proteinuria and stage 2 chronic kidney disease or worse. Discussion Thus, the COL4A5 expression pattern has an important prognostic value and it correlates with the severity of ultrastructural glomerular basement membrane alterations in males with AS. Loss of COL4A5 staining is uncommon in patients with AS diagnosed in their adulthood.

Technical Aspects of Pediatric Continuous Renal Replacement Therapy

Abstract The challenges that face pediatric or neonatal patients that develop oliguric acute kidney injury are complex. This is particularly true in pediatric/neonatal patients that are hemodynamically unstable thereby rendering acute hemodialysis or peritoneal dialysis non-optimal treatment modalities. While equipment for adult patients is often readily available, pediatric/neonatal patients need special consideration and equipment adaptation in order to provide state of the art continuous renal replacement therapy (CRRT). The following article provides insight on the basic principles governing pediatric/neonatal CRRT, including prescription considerations and complication overview. It also provides key point considerations for effectively introducing CRRT into this complex population group.

Abdominal Pain, Flank Pain, Blurry Vision, and Lower Extremity Weakness in a 16-Year-Old Female

History of the present illness The patient was healthy until 4 weeks prior (mid-July 2012) to her transfer, when she developed sudden-onset abdominal pain, right flank pain, and anorexia (Figure 1). Evaluation at a local emergency department, including an abdominal ultrasound, was reportedly normal. The impression was possible renal colic and constipation. She was discharged with acetaminophen and stool softener. Approximately 3 weeks later, she presented to a local clinic with progressive general and lower extremity weakness, left-eye blurry vision, cough, chest congestion, and palpitations. She was diagnosed with viral syndrome and given eye drops. Three days later, her symptoms worsened. She developed dyspnea and bilateral blurry vision. She was rushed to the emergency department, where she was hypertensive (blood pressure [BP] 180–200/130 mm Hg), tachycardic (150 beats/minute), and diaphoretic. Within hours, she became hypoxic and required intubation. Her chest radiograph showed diffuse bilateral infiltrates. Laboratory studies revealed hemoglobin of 9.2 gm/dl (reference value 12–15.5), leukocytes of 13.7 10/liter (reference value 3.5–10.5), platelet count of 154 10/liter (reference value 150–450), reticulocytes of 4.38% (reference value 0.60–1.83%), prothrombin time of 16.7 seconds (reference value 9.5–13.8), serum creatinine of 4.8 mg/dl (reference value 0.6–1.1), complement C3 of 92 mg/dl (reference value 75–175), and C4 of 8 mg/dl (reference value 14–40). Urinalysis showed red blood cells of 10–20/high-power field and proteinuria of 300 mg/ dl. Human immunodeficiency virus, hepatitis B, and hepatitis C were negative. Transthoracic echocardiogram showed a left ventricular ejection fraction of 30%, and a kidney ultrasound with Doppler study showed normalsized kidneys with nonspecific changes in the renal arteries. She was provisionally diagnosed with renal failure due to rapidly progressive glomerulonephritis. Pulse steroids (intravenous [IV] methylprednisolone 1 gm/day), plasma exchange, and dialysis were initiated. After 2 runs of hemodialysis, she was extubated and transferred to the Mayo Clinic the following day. The evening before transfer, antineutrophil cytoplasmic antibody (ANCA) and anti–glomerular basement membrane (anti-GBM) studies returned negative. A computed tomography (CT) angiogram and renal biopsy were performed; the images and tissue sample were forwarded to our institution for interpretation.

Pseudohypoaldosteronism presenting with thrombocytosis and bilateral pneumothoraces in an infant

Abstract Pseudohypoaldosteronism type 1 (PHA-1) is a rare salt-wasting syndrome caused by a peripheral resistance to aldosterone. Here, we describe an unusual presentation of the autosomal dominant PHA-1 featuring bilateral pneumothoraces at birth, thrombocytosis in infancy, and hypercalcemia in addition to the well-described findings of hyponatremia, hyperkalemia, and failure to thrive. These findings contribute to the limited case descriptions of PHA-1 and may suggest additional diagnostic considerations in a neonate presenting with hyperkalemia, hyponatremia, and failure to thrive.