Human granulocytic ehrlichiosis presenting with acute renal failure and mimicking thrombotic thrombocytopenic purpura. A case report and review.

We present the case of an elderly female patient presenting with recurrent acute renal failure, fever, altered mental status, abdominal pain, thrombocytopenia and a small number of fragmented red cells on peripheral smear mimicking recurrent thrombotic thrombocytopenic purpura (TTP). Eventually, however, she was diagnosed to have human granulocytic ehrlichiosis (HGE), and after treatment for HGE her clinical and laboratory abnormalities resolved. Ehrlichiosis mimicking TTP, diagnosed at postmortem examination, has been described in a single prior case. As illustrated in this case, there are potential difficulties in diagnosing HGE after plasma exchange, blood transfusion and immunosuppressive therapy. Ehrlichiosis, a potentially curable disease, should be considered in the differential diagnosis of thrombotic microangiopathic disorders.

A randomized trial comparing cyclosporine induction with sequential therapy in renal transplant recipients.

Calcium antagonists may reduce the nephrotoxicity of cyclosporine (CsA), allowing CsA to be introduced immediately after renal transplantation and thereby obviating the need for sequential induction therapy with a monoclonal or polyclonal antibody. To test this hypothesis, in a pilot feasibility trial 100 cadaveric or one-haplotype-mismatched living-related renal transplant recipients were randomized to either (1) sequential therapy with anti-thymocyte globulin (ATG) (ATGAM; Upjohn, Kalamazoo, MI) 20 mg/kg/d for 7 to 14 days until renal function was established and CsA (Sandimmune; Sandoz, East Hanover, NJ) was started, or (2) CsA 8 mg/kg/d begun immediately before surgery with diltiazem (Cardizem; Marion Merrell Dow, Kansas City, MO) 60 mg sustained release twice daily. Acute rejection episodes during the first 90 days were not different with ATG versus CsA induction (42% v 28%; P = 0.142 by chi-square analysis). Graft failures (10% v 16%; P = 0.372) and the incidence of delayed graft function (28% v 34%; P = 0.516) were also similar with ATG compared with CsA. ATG caused lower platelet counts (138 +/- 59 x 10(3) v 197 +/- 75 x 10(3) at 7 days; P < 0.001) and lower white blood cell counts (9.6 +/- 4.6 x 10(3) v 12.3 +/- 4.9 x 10(3) at 7 days; P = 0.003). Diltiazem reduced the dose of CsA required to maintain target blood levels (479 +/- 189 mg/d v 576 +/- 178 mg/d at 14 days; P = 0.015). There were no statistically significant differences between the groups in serum creatinine levels at days 1, 3, 5, 7, 14, 28, 60, or 90. The results of this pilot feasibility trial suggest that prophylactic treatment with CsA and diltiazem may be equally effective and less toxic than ATG induction after renal transplantation.

Triton-soluble phosphovariants of the heavy neurofilament subunit in developing and mature mouse central nervous system.

The low abundance of soluble neurofilament (NF) subunits in mature axons has suggested that newly synthesized NF proteins rapidly assemble into highly stable polymers and associate with the Triton X-100-insoluble cytoskeleton. The dynamic nature of these subunit associations in vivo remains unresolved, and the applicability of this assembly model to NFs in other neuronal compartments or to developing neurons is unknown. Here, we report that a unique pool of Triton X-100-soluble, extensively phosphorylated, high molecular weight NF subunits (NF-H, or H-200) are abundantly expressed in the mouse CNS during early postnatal development and persist in the perikaryal compartment of some mature neurons. Triton-soluble H-200 subunits appeared at postnatal day 14 (P14) and remained high through P60, beyond which the percentage declined to marginal levels by P120. Medium and low molecular weight NF (NF-M and NF-L, respectively) were at all times only detectable within the cytoskeleton. Comparison of soluble and cytoskeleton-associated H-200 immunoreactivity indicated that certain phosphorylation-dependent epitopes were confined to the cytoskeleton. Pulse-chase radiolabeling analyses in optic pathway demonstrated that some Triton-soluble NF-H subunits are extensively phosphorylated within retinal perikarya before they are incorporated into Triton-insoluble structures. These findings indicate that the assembly behaviors of NF-H differ substantially from those of NF-M and NF-L, and that the interaction of NF-H with NFs may be more dynamic than is generally recognized, especially during brain development and within specific compartments of mature neurons.

Long-term results and complications of renal transplantation: the Hennepin experience.

Approximately one sixth of patients receiving renal transplants have a functioning kidney beyond 20 years. Chronic rejection is the predominant cause of late allograft loss. Malignancy, cardiovascular disease, hepatic failure, and infections are the major causes of late death. Early detection and control of the risk factors that contribute to patient death should favorably influence the long-term success of renal transplantation.

Risk factors for nephropathy and cardiovascular disease in diabetic Northern Minnesota American Indians.

Although complications of diabetes are common among Southwest American Indians, little is known about diabetes and associated risk factors for nephropathy and cardiovascular disease in other genetically distinct tribes. We conducted a retrospective analysis of 665 diabetic patients at two Chippewa Indian reservations in northern Minnesota to evaluate the prevalence of risk factors for diabetic nephropathy and cardiovascular disease. In 79 patients, a more detailed study was carried out, including an assessment of renal function and urinary albumin excretion (UAE). The overall prevalences of proteinuria and hypertension were 47.9% and 62.6%, respectively. Proteinuria was observed more often in hypertensive than in non-hypertensive patients (55.2% vs 44.4%, p < 0.05), and in patients with diabetes for longer than 10 years (57% vs 40% for diabetes less than 10 years, p < 0.05). Although hypercholesterolemia (total cholesterol > or = 200 mg/dl) was observed in 54% of patients, there was no relationship between hypercholesterolemia and proteinuria. In the 79 patients studied in more detail, UAE was greater in hypertensive patients compared to non-hypertensive patients (606 +/- 15600 mg/24h vs 101 +/- 157 mg/24 h, p < 0.05), and in patients with diabetes for 10 years or longer compared to patients in the first decade of disease (748 +/- 1732 mg/24 h vs 96 +/- 171 mg/24 h, p < 0.05). Hypercholesterolemia and elevated LDL-cholesterol (> 130 mg/dl) were observed in 56% and 49% of patients, respectively, but were not associated with increased UAE. In contrast, hypertriglyceridemia (> 250 mg/dl) was associated with an elevated UAE (932 +/- 2150 mg/24 h vs 245 +/- 735 mg/24h, p < 0.05). Increased lipoprotein(a) was found in patients with overt albuminuria. In summary, the prevalence of risk factors for diabetic nephropathy and associated cardiovascular disease is high in Chippewa American Indians in northern Minnesota. Although detecting abnormal UAE may be useful in identifying high-risk patients who may benefit from early intervention, traditional risk factors such as hypercholesterolemia may not explain the risk associated with increased UAE.

Value of liver biopsy in the evaluation and management of chronic liver disease in renal transplant recipients.

PURPOSE: Liver disease is a frequent complication in renal transplant recipients. To understand the nature and progression of hepatic disease in these patients, we performed percutaneous biopsies in 77 subjects who had chronic liver dysfunction in the posttransplant period. The purpose of the present investigation is to delineate the morphologic spectrum of chronic liver disease in the renal allograft recipients and to characterize the clinical and histologic progression of each of the different morphologic forms. PATIENTS AND METHODS: Between 1971 and 1990, 915 patients received renal transplants at the Hennepin County Medical Center, Minneapolis, Minnesota. One hundred nineteen (13%) of them had abnormal liver function that persisted for longer than 6 months. Percutaneous liver biopsies were performed in 77 of these patients, but adequate tissue for histologic evaluation was available in only 72. After the biopsy, the clinical and histologic course of each subject was monitored in relation to the baseline hepatic morphology. To assess the predictive value of serum enzymes in diagnosing the histologic lesions, the level of serum enzymes at the time of the biopsy was correlated with the morphologic diagnosis. In addition, several clinical, biochemical, etiologic, and histologic variables were screened for their association with histologic progression to liver cirrhosis. RESULTS: The morphologic diagnosis in the 72 specimens evaluated at baseline was as follows: fat metamorphosis in 8 (11%), chronic persistent hepatitis in 20 (28%), early chronic active hepatitis in 20 (28%), advanced chronic active hepatitis in 15 (21%), and hemosiderosis in 9 (12%). There was no statistical correlation between the serum enzyme levels and the histologic diagnosis. During a mean follow-up of 5.7 +/- 3.9 years, clinical progression to hepatic failure and death occurred in 35% of patients with early chronic active hepatitis, 55% with hemosiderosis, and 60% with advanced chronic active hepatitis. None of the patients with the morphologic diagnosis of fat metamorphosis or chronic persistent hepatitis died as a consequence of hepatic failure. Follow-up liver specimens were obtained in 34 (47%) of the original 72 subjects after a mean interval of 4.5 +/- 4.3 years. Of the 15 patients with the initial diagnosis of early chronic active hepatitis, 9 (60%) showed morphologic transition to advanced chronic active hepatitis, and in 1 of the 5 patients with hemosiderosis (20%), the lesion had resolved after successive phlebotomies. During the follow-up, 60% with early chronic active hepatitis (9 of 14), 66% with hemosiderosis (2 of 3), and 100% with advanced chronic active hepatitis (4 of 4) showed histologic progression to liver cirrhosis. On the contrary, no morphologic alterations were observed in the follow-up specimens of patients with fat metamorphosis or chronic persistent hepatitis. Of the different variables screened for their association with histologic progression, older age at transplant, female sex, and morphologic diagnosis of advanced chronic active hepatitis were found to be significant. CONCLUSION: Histologic diagnosis can be a useful marker in predicting the course of chronic liver disease after renal transplantation. Liver biopsy should be incorporated into the evaluation and management of chronic liver disease in renal transplant recipients.

Ammonium chloride increases kidney cell protein content.

Augmented renal ammoniagenesis and renal hypertrophy often occur together. Ammonia may increase cell protein content by modulating protein synthesis, protein degradation, or both. We conducted experiments to examine the effect of ammonium chloride on the synthesis and degradation of protein in cultured kidney cells. Quiescent opossum kidney cells were exposed to 20 mM NH4Cl for two days. Monolayers were then analyzed for cell number, protein content, protein synthesis ([14C]valine incorporation), protein degradation ([14C]valine release) and DNA synthesis ([3H]thymidine incorporation). Cell protein content was increased by 18% in NH4Cl-treated cells (190 +/- 6 pg/cell control vs. 225 +/- 7 pg/cell NH4Cl, p < 0.001). NH4Cl suppressed protein degradation (1.36 +/- 0.02%/h control vs. 1.12 +/- 0.04%/h NH4Cl, p < 0.001) but did not change protein synthesis, DNA synthesis, or cell number. Thus, reduced protein degradation accounts entirely for enhanced protein accumulation at 2 days in this in vitro model of kidney cell hypertrophy.

Effect of bacitracin on retroendocytosis and degradation of insulin in cultured kidney epithelial cell line.

In an earlier study, we described the presence of a retroendocytotic pathway for insulin in a cultured kidney epithelial cell line. Derived from the opossum kidney (OK), these cells possess many features of proximal tubule epithelium, which is the major site of kidney insulin metabolism. We studied the interaction between the retroendocytotic and the degradative pathways with bacitracin as a pharmacological probe. Monolayers of OK cells were loaded with 125I-labeled insulin over 30 min, acid washed to remove membrane-bound insulin, then incubated in fresh medium for 60 min while the release of intracellular radioactivity was monitored. In experiments carried out in the presence of bacitracin (2 mM), there was a two-thirds increase in intracellular radioactivity at the end of the loading phase. Measurements made during the subsequent release phase showed that bacitracin reduced the release of degradation products. Thus, although controls released 72.1 +/- 8.1% of the internalized radioactivity as trichloroacetic acid (TCA)-soluble products, bacitracin-treated cells released 59.2 +/- 9.4% (P less than 0.02). In contrast, release of TCA-precipitable insulin increased from 15.2 +/- 4.6% in controls to 25.8 +/- 3.7% in bacitracin-treated cells (P less than 0.01). In separate experiments analyzed by gel-exclusion chromatography, 6.4 +/- 0.6% of radioactivity released from preloaded control cells into medium over 60 min was insulin sized compared to 29.7 +/- 1.4% in bacitracin-treated cells. High-performance liquid chromatography revealed that 61.5 +/- 3.5% of this insulin-sized material released from control cells preloaded with A14-insulin eluted as intact insulin and the remainder as unidentified intermediate degradation products.(ABSTRACT TRUNCATED AT 250 WORDS)

Retroendocytosis of insulin in a cultured kidney epithelial cell line.

It has been generally accepted that in renal tubular epithelium endocytosed proteohormones are transported to lysosomes where they undergo complete hydrolysis. En route, as endosomal pH falls, the proteohormone uncouples from the endocytosed membrane binding site, which recycles to the cell surface. However, studies in other tissues have uncovered alternate intracellular pathways for proteins. One such pathway is retroendocytosis (endocytosis then exocytosis). To determine whether a retroendocytotic pathway exists for insulin in renal epithelium, a study was carried out with confluent monolayers of a proximal-like opossum kidney cell line that exhibits receptor-mediated endocytosis of insulin. Cells were preloaded with 125I-labeled insulin (4 X 10(-10) M) for 30 min, surface-bound insulin was then removed by acid washing, and over the next 60 min the release of intracellular radioactivity into the medium was monitored. At 37 degrees C, control cells released on average 7-15% of the intracellular radioactivity as intact insulin [trichloroacetic acid (TCA)-precipitable radioactivity] and approximately 62% as TCA-soluble degradation products. In the presence of 0.1 mM chloroquine (an acidotropic agent) the release of intact insulin increased approximately twofold while degradation fell by nearly one-half. With Sephadex G-50 chromatography we found that the released radioactivity included insulin-size material that increased in the presence of chloroquine. High-performance liquid chromatography revealed that 53 (controls) and 81% (chloroquine treatment) of this latter material consisted of intact insulin. We conclude that, in addition to a major degradative pathway, cultured kidney epithelial cells exhibit a retroendocytotic pathway for insulin. Chloroquine inhibits degradation and appears to divert insulin from the degradative into the retroendocytotic pathway.(ABSTRACT TRUNCATED AT 250 WORDS)