Hernán Trimarchi

FK506-associated thrombotic microangiopathy: report of two cases and review of the literature.

BACKGROUND FK506 is a recently developed immunosuppressant that has been useful in improving the survival of transplanted organs. Among the numerous adverse side effects of FK506, thrombotic microangiopathy (TMA) stands out as an infrequent but severe complication. METHODS We report two cases of FK506-associated TMA and review the 19 previous reported cases. RESULTS From these 21 cases, the reported incidence of FK506-associated TMA is between 1% and 4.7%. It is more frequent in females, and the mean age at presentation is 47 years. Eighty-one percent of the cases occurred in patients with kidney allografts, and the remaining patients had liver, heart, or bone marrow transplants. Clinically, TMA was diagnosed at an average interval of 9.3 months from the time of transplantation. Patients may be asymptomatic or may present with the full-blown picture of hemolytic uremic syndrome. All patients had an elevated serum creatinine level but did not always show signs of hemolysis. Trough levels of FK506 were not predictive for the development of TMA, but generally a reduction of drug dose correlated with kidney function improvement and disappearance of the hemolytic picture. The renal allograft biopsy provided a conclusive diagnosis in all 17 cases in which this procedure was performed. Treatment, which mainly consisted of reduction or discontinuation of FK506, anticoagulation, and/or plasmapheresis with fresh-frozen plasma exchange, resolved TMA in most patients (57%). However, in one of these patients (5%), the graft was subsequently lost due to causes unrelated to TMA, such as acute or chronic rejection. Despite treatment, one patient (5%) lost the graft due to acute rejection and persistent TMA, and three other patients (14%) who had bone marrow, heart, and liver transplants, died of multiple organ failure, probably unrelated to TMA. In the remaining four patients (19%), response to treatment was not reported. CONCLUSIONS TMA must be considered in organ transplant patients treated with FK506 whenever kidney function deteriorates, even in the absence of microangiopathic hemolytic anemia. Although TMA usually responds to treatment, it may, in rare cases, lead to loss of kidney function or even the patients death.

Nationwide and Long-Term Survey of Primary Glomerulonephritis in Japan as Observed in 1,850 Biopsied Cases

Primary chronic glomerulonephritis is the most common cause of end-stage renal failure in Japan. The incidence in dialysis patients in Japan is about four times higher than in the United States for reason which are unclear. We conducted a nationwide survey on the natural history and treatment of primary glomerulonephritis under a program project from the Ministry of Health and Welfare of Japan entitled ‘Progressive Chronic Renal Disease’. We analyzed patient characteristics, disease onset, clinical data, and histological findings in 1,850 patients with primary glomerulonephritis from 53 institutions in 1985 who underwent renal biopsy at least 5 years ago, and the follow-up study was carried out 8 years after registration. The incidence of diffuse-mesangial proliferative glomerulonephritis is 41.9%, that of minor glomerular abnormalities 17.5%, and that of focal-mesangial proliferative glomerulonephritis 13.0%. Of 1,045 biopsy specimens that were examined by immunofluorescence microscopy, 47.4% showed IgA nephropathy. Half of all cases with primary chronic glomerulonephritis were asymptomatic and were detected on routine health examination. The survival rates at 20 years from the apparent onset or earliest known renal abnormality are: focal glomerular sclerosis 49%, membranoproliferative glomerulonephritis 58%, diffuse-mesangial proliferative glomerulonephritis 66%, focal-proliferative glomerulonephritis 81%, membranous nephropathy 82%, minor glomerular abnormalities 94%, and IgA nephropathy 61%. In conclusion, a high incidence of IgA nephropathy and a better renal survival of membranous nephropathy are the features of primary chronic glomerulonephritis in Japan. This high incidence of IgA nephropathy together with its poor prognosis is probably the reason for the increased incidence of primary chronic glomerulonephritis in dialysis patients in Japan. In addition, the importance of routine health examination including urinalysis is demonstrated.

Hyponatremia-Associated Rhabdomyolysis

Background: Hyponatremia is the most frequent electrolyte disorder. However, hyponatremia rarely results from excessive water intake, unless the kidney is unable to excrete free water, such as in patients on thiazide diuretics; in addition, hyponatremia is an uncommon cause of rhabdomyolysis. Methods: We present a 51-year-old hypertensive woman on chronic hydrochlorothiazide therapy who developed acute water intoxication and severe myalgias. Results: The patient developed acute hypotonic hyponatremia and subsequent rhabdomyolysis. We discuss the mechanisms responsible for the development of hyponatremia and its association with rhabdomyolysis. Conclusion: Muscle enzymes should be monitored in patients with acute hyponatremia who develop muscle pain, and hyponatremia-induced rhabdomyolysis must be considered in patients with myalgias receiving thiazide diuretics.

Shared cadaver donor-husband HLA class I mismatches as a risk factor for renal graft rejection in previously pregnant women.

During the last few years, we have observed four cases in which accelerated rejection of a cadaver donor kidney in a previously pregnant woman could be clearly attributed to the rapid emergence of anti-human leukocyte antigen (HLA) antibodies that had been stimulated by mismatched paternal antigens but were completely undetectable at the time of transplantation. In addition to reviewing those cases, we also reviewed data on 19 other women with a history of at least one pregnancy who underwent transplantation with a first cadaveric kidney since 1991 and were followed for at least six months. The HLA antigens of the husbands had to have been determined and all accelerated rejection or early graft losses due to confirmed or presumed immunological causes were considered. Of the 19 additional women meeting these inclusion criteria, three suffered early immunological graft loss. As in our index cases, two of these women had also received kidneys from donors who shared at least one major immunogenic mismatched antigen with the respective husband for a total of six of seven women with early immunological graft loss. Only one of the 16 women without accelerated rejection or early immunological graft loss had a donor who shared a mismatched antigen with her husband. The difference between the two groups is statistically significant (p = 0.0005). These findings, considered with individual cases reported by other groups, indicate that transplantation from a cadaver donor with immunogenic mismatched class I HLA antigen(s) shared with the husband should be avoided in women with a previous history of pregnancy even when anti-HLA antibodies are not currently detected.

Clopidogrel Diminishes Hemodialysis Access Graft Thrombosis

Background: The most common complication of hemodialysis (HD) access graft is thrombosis. Clopidogrel, an inhibitor of platelet aggregation, was assessed to prevent this serious complication. Methods: A prospective study in which 24 patients on chronic HD whose vascular accesses were grafts were divided into two groups: group A (n = 12, 50%) consisted of patients who did not receive antithrombotic therapy after graft creation, and group B (n = 12, 50%) received clopidogrel 75 mg/day from 2 days after surgery onwards. Both groups were not different according to age, gender, cause of renal failure, hematocrit levels, platelet counts and Kt/V. All patients’ thrombotic episodes were followed up from the day of graft surgery until thrombosis was diagnosed. Finally, the patient survival difference between both groups was determined. Results: Eleven thrombotic episodes were diagnosed in group A while one event was reported in group B (p < 0.001). Graft access days of patency were significantly longer in group B compared to group A (380.8 ± 170 vs. 90.1 ± 57.2, p < 0.001). Time that elapsed from dialysis initiation to graft creation was not different (group A 18 ± 12 days, group B 20 ± 10 days). Days on HD were different between both groups (group A 208.9 ± 97.2 vs. group B 583.2 ± 287.0, p < 0.001) and all patients from group A (n = 12, 100%) and 2 patients from group B (16.7%) died (p = 0.001). Major bleeding events were not reported. Conclusions: Clopidogrel significantly decreased thrombotic graft episodes. Patients on clopidogrel had a prolonged vascular access patency, longer time on HD and better survival.

Randomized Trial of Methylcobalamin and Folate Effects on Homocysteine in Hemodialysis Patients

Background: There are no data available on the effects of intravenous (i.v.) methylcobalamin (Me-Cbl), the coenzymatically active form of vitamin B12 that acts as a cofactor for methionine synthase in the conversion of total homocysteine (tHcy) to methionine, with or without oral folic acid (FA) supplementation, on fasting tHcy levels in hemodialysis (HD) patients. Methods: We performed a prospective randomized trial in which 62 chronic HD patients without previous vitamin supplementation were divided into four groups. Group A received Me-Cbl 500 µg twice/week plus FA 10 mg/day; group B received FA 10 mg/day alone; group C received no vitamin supplementation, and group D was on Me-Cbl 500 µg twice/week alone. Fasting tHcy, vitamin B12, serum (s) FA and erythrocytic (e) FA were measured predialysis before and after 4 months of therapy. Results: Final tHcy levels were significantly lower in group A (10.2 ± 3.1 µmol/l) compared to groups C (27.3 ± 9.7 µmol/l, p < 0.001) and group D (24.3 ± 11.8 µmol/l, p < 0.001) and similar to group B (11.2 ± 1.9 µmol/l, p = n.s.). Mean tHcy levels showed a significant decrease in group A from 22.5 ± 15.6 to 10.2 ± 3.1 µmol/l (p = 0.003) and in group B from 19.9 ± 4.0 to 11.2 ± 1.9 µmol/l (p = 0.012), while no significant changes were observed in groups C (25.9 ± 9.3 vs. 27.3 ± 9.7 µmol/l, p = n.s.) and D (26.6 ± 14.3 vs. 24.3 ± 11.8 µmol/l, p = n.s.). Conclusion: Oral FA (10 mg/day) supplementation appears to be an effective approach to normalize plasma tHcy in chronic HD patients; the addition of i.v. Me-Cbl (500 µg twice/week) to this regimen showed no benefit. Separately, FA corrected hyperhomocysteinemia (HtHcy), while Me-Cbl showed no change.

Creatinine- vs. cystatin C-based equations compared with 99mTcDTPA scintigraphy to assess glomerular filtration rate in chronic kidney disease.

BACKGROUND In chronic kidney disease (CKD), accurate estimation of the glomerular filtration rate (GFR) is mandatory. Gold standard methods for its estimation are expensive and time-consuming. We compared creatinine- versus cystatin C-based equations to measure GFR, employing (99m)Tc-DTPA scintigraphy as the gold standard. METHODS This was a prospective cross-sectional observational study including 300 subjects. CKD was defined according to K/DOQI guidelines, and patients were separated into groups: stage 1 (G1), n=26; stage 2 (G2), n=52; stage 3 (G3), n=90; stage 4 (G4), n=37; stage 5 (G5), n=60; and control group, n=35. Creatinine-based estimates were from 24-hour creatinine clearance using the Walser formula, Cockcroft-Gault, MDRD-4 and CKD-EPI; cystatin C equations used were Larsson, Larsson modified equation, Grubb and Hoek. RESULTS Age and body mass index were different among groups; proteinuria, hypertension, diabetes and primary glomerulopathies significantly increased as CKD worsened. In the global assessment, CKD-EPI and Hoek gave the highest correlations with (99m)Tc-DTPA: rho=0.826, p<0.001 and rho=0.704, p<0.001, respectively. Most significant linear regressions obtained: CKD-EPI vs. (99m)Tc-DTPA, Hoek vs. (99m)Tc-DTPA and CKD-EPI vs. Hoek. However, important differences emerged when each group was analyzed separately. Best significant correlations obtained with (99m)Tc-DTPA: control group, creatinine clearance rho=0.421, p=0.012; G1, Crockoft-Gault rho=0.588, p=0.003; G2, CKD-EPI rho=0.462, p<0.05; G3, CKD-EPI rho=0.508, p<0.001; G4, Hoek rho=0.618, p<0.001; G5, CKD-EPI rho=0.604, p<0.001. CONCLUSIONS At GFR <60 ml/min, CKD-EPI and Hoek equations appeared to best correlate with (99m)TcDTPA. In controls and at early stages of CKD, creatinine-based equations correlated better with (99m)Tc-DTPA, with CKD-EPI being the one with the best degree of agreement.

Low initial vitamin B12 levels in Helicobacter pylori--positive patients on chronic hemodialysis.

Background:Helicobacter pylori has been identified as a possible cause of vitamin B12 deficiency in the general population. We assessed any potential relationship between low cyanocobalamin serum levels and Helicobacter pylori status in hemodialysis patients and subsequently correlated these results with the existence of anemia (a common complication in hemodialysis patients), and macrocytosis. Methods: In 29 chronic hemodialysis patients, active H. pylori infection was diagnosed using two different methods regardless of digestive symptoms: by searching for bacterial antigens in stools and by the detection of urea breakdown through breath testing. If these results were non-coincident, gastroscopy was performed and antral biopsies obtained. Patients were subsequently divided into group A (H. pylori-positive, n = 8, 28%) and group B (H. pylori-negative, n = 21, 72%). The corresponding initial values of erythrocytic folic acid, vitamin B12 and homocysteine prior to the first hemodialysis session of each patient were retrospectively collected. Results: Vitamin B12 levels (normal 200– 900 pg/ml) were significantly lower in group A compared to group B (225.4 ± 111.9 vs. 707.9 ± 258.3 pg/ml, p < 0.011). In group A, 5 patients (63%) had vitamin B12 deficiency (154 ± 24.6 pg/ml). Baseline hematocrits, erythrocyte folic acid and serum homocysteine levels were not different between the groups, but mean corpuscular volumes were significantly higher in group A compared to group B (109.7 ±14.1 vs. 91.8 ± 8.8 fl, p = 0.002). Conclusions:H. pylori-positive chronic hemodialysis patients may present with lower vitamin B12 blood levels and macrocytosis. H. pylori infection should be suspected in this population when low or low-normal vitamin B12 levels or macrocytosis exist.

Proteinuria: an ignored marker of inflammation and cardiovascular disease in chronic hemodialysis.

Background Cardiovascular disease is the leading cause of morbidity and mortality in hemodialysis (HD) patients, the main etiologies being diabetes and hypertension. Cardiac and inflammatory biomarkers are usually employed to assess risk or damage, or during follow-up. Proteinuria is considered a strong predictor of morbidity, a cause of inflammation, oxidative stress, hemodynamic alteration, and progression of chronic kidney disease. However, proteinuria is rarely considered in the clinical assessment of HD patients. Methods This was a concurrent, cohort-observational, cross-sectional study in which 52 chronic HD subjects were divided into three groups according to the degree of proteinuria: Group (G) A: <1 g/day, n = 25; GB: 1–3 g/day, n = 13; GC: >3 g/day, n = 14. Baseline hemoglobin, albuminemia, cholesterol, body mass index, Malnutrition-Inflammatory Score, pro-B-type natriuretic peptide, troponin T, C-reactive protein (CRP), and ultrafiltration rates were analyzed. Results There was no difference between groups in terms of baseline age, gender, hypertension, cause of renal failure, hemoglobin, cholesterol, albumin, CRP levels, cardiac biomarkers, adiponectin, body mass index, or Malnutrition-Inflammatory Score. Time on HD: GA, 34.56 ± 23.3 (range [r]: 6–88); GB, 25.15 ± 19.40 (r: 6–58); GC, 18.21 ± 9.58 (r: 6–74) months; P = 0.048. Proteinuria: GA, 0.33 ± 0.30 (r: 0.0–0.88); GB, 1.66 ± 0.54 (r: 1.03–2.75); GC, 7.18 ± 2.80 (r: 3.04–21.5) g/day; P < 0.001. Mean ultrafiltration rates were significantly different: GA, 2.80 ± 0.73; GB: 1.85 ± 0.96 liters/session; P = 0.003. Fourteen diabetic patients were identified (27%): GA, 3 (12%); GB, 3 (23%); GC, 8 (57%); P = 0.009. A positive and significant correlation was observed between diabetes and proteinuria >3 g/day: rho 0.438, P = 0.027. Although troponin T, pro-B-type natriuretic peptide, adiponectin, and CRP were not different among groups, the positive correlation between troponin T and CRP elevated significantly as proteinuria increased: GA, rho 377, P = 0.063; GB, rho 663, P = 0.013; GC, rho 687, P = 0.007. Conclusion In chronic HD, nephrotic-range proteinuria was significantly higher in diabetic nephropathy patients versus other causes. This was associated with inflammation and cardiac stress and was independent of fluid removal. Proteinuria >3 g/day was associated with shorter time on HD. Whether severe proteinuria is associated with shorter survival in HD, independent of diabetes, is to be determined. Proteinuria should be considered in the assessment of cardiovascular and inflammatory states in HD patients.

Immunoglobulin A Nephropathy and Ulcerative Colitis

The immune response has largely been implicated in the pathogenesis of inflammatory bowel disease (ulcerative colitis and Crohn’s disease) and immunoglobulin A nephropathy. We present a 26-year-old woman with a long past history of asymptomatic macroscopic hematuria who later developed several episodes of bloody stools and abdominal pain. A colonic biopsy disclosed ulcerative colitis and a renal biopsy was consistent with immunoglobulin A nephropathy. Immunoglobulin A nephropathy is the most common glomerulonephritis, being end-stage renal disease a rare but the most serious complication. It can be primary or secondary, but the association between both entities is unusually observed. We discuss the possible immunologic mechanisms involved and believe the initial immunologic derangement originates in the bone marrow. We suggest both conditions must be considered when either a patient with ulcerative colitis and micro- or macrohematuria or with renal involvement and a past history of diarrhea or abdominal pain presents.