Fifteen percent of myocardial infarctions and coronary revascularizations explained by family history unrelated to conventional risk factors. The Reykjavik Cohort Study.

Aims To examine the relationship between history of myocardial infarction in first-degree relatives and the risk of developing coronary heart disease (myocardial infarction or coronary revascularization). Methods and Results A total of 9328 males and 10062 females, randomly selected residents of the Reykjavik area, aged 33-81 years, were examined in the period from 1967 to 1996 in a prospective cohort study. Cardiovascular risk assessment was based on characteristics at baseline. Information on history of myocardial infarction in first-degree relatives was obtained from a health questionnaire. Mean follow-up was 18 and 19 years for men and women, respectively. During follow-up 2700 men and 1070 women developed coronary heart disease. Compared with subjects without a family history, the hazard ratio of coronary heart disease was 1.75 (95% confidence interval, CI, 1.59-1.92) for men and 1.83 (95% CI, 1.60-2.11) for women, with one or more first-degree relatives with myocardial infarction. The risk factor profile was significantly worse in individuals with a positive family history. After allowance for these risk factors, the hazard ratio was still highly significant, 1.66 (CI, 1.51-1.82) and 1.64 (CI, 1.43-1.89) for men and women, respectively. Family history of myocardial infarction was attributed to 15.1% of all cases of coronary heart disease in men and 16.6% in women, independent of other known risk factors. Conclusion Family history of myocardial infarction increases the risk of developing coronary heart disease in both men and women and is largely independent of other classic risk factors. Approximately 15% of all myocardial infarctions can be attributed to familial factors that have not been measured in the study or remain to be elucidated.

Favorable outcome of renal transplantation in patients with IgA nephropathy.

BACKGROUND: The outcome of renal transplantation in patients with IgA nephropathy (IgAN) may be affected by recurrence of the original disease. Despite this risk of recurrent glomerulonephritis, graft survival in patients with IgAN is considered good although formal comparisons with graft survival in patients with other renal diseases have given conflicting results. METHODS: We have studied both recurrence rate and outcome after renal transplantation in 79 adult patients with IgAN, all of whom received a first renal graft (55 cadaveric, 24 living-related donor) in our center in the period between 1969 and 1997. Graft survival in patients with IgAN was compared with the outcome in patients with pyelonephritis and adult polycystic kidney disease (group 2) and patients with non-IgA primary glomerulonephritis (group 3). RESULTS: Follow-up averaged 5.6 +/- 4.5 years. Histological evidence of mesangial IgA deposits was present in 17 of 32 available biopsies (53%). Clinically recurrent IgAN was diagnosed only in 7 patients (9% of all recipients), with a higher incidence in recipients of a living-related donor graft (5/24 (20%) vs 2/55 (4%)). These recurrences were diagnosed in biopsies taken 13-145 months after transplantation; and all were characterized by significant proteinuria (> 1 g/day). In only one patient the graft was lost due to the recurrence. For recipients of a cadaveric graft, the 5-year graft survival was significantly better in IgAN patients than in both reference groups (86% vs 67% in group 2; p = 0.012, and 60% in group 3; p = 0.007). This difference remained significant after censoring for death. There was no statistically significant difference in the patient survival between the groups. The rejection rate in the first 3 months was numerically lower in the IgAN patients (37% vs 43% and 49%, respectively). and total immunological failure rate was also lower in the IgAN patients compared to the control groups (13% vs 21% and 23%, respectively); although the differences were not statistically significant. The 5- and 10-year graft survival in recipients of living-related donor grafts was significantly better in IgAN patients than in group 3 (96% and 84% vs 64% and 21%, respectively; p = 0.02), but similar to graft survival in group 2 (87% and 75%). CONCLUSION: A clinical recurrence of IgAN occurred in 4% of patients with a cadaveric donor graft and 20% of patients with a living-related donor graft. The recurrence had negligible influence on 5- and 10-year graft survival. Graft survival after cadaveric transplantation was better in the IgAN patients compared to control groups; possibly due to the lower immunological failure rate in IgAN.

Type I membranoproliferative glomerulonephritis in a renal allograft: A recurrence induced by a cytomegalovirus infection?

A 40-year-old white woman with end-stage renal disease from idiopathic type I membranoproliferative glomerulonephritis (MPGN) developed proteinuria and renal dysfunction 7 weeks after cadaveric donor renal transplantation. At the same time, a primary cytomegalovirus (CMV) infection was diagnosed. Complement levels were low. A renal biopsy disclosed an acute exudative proliferative glomerulonephritis with influx of polymorphonuclear granulocytes (PMNs), with granular deposits of C3, C1q, IgG, and IgM. The immunofluorescence (IF) and electron microscopy (EM) findings were compatible with an early stage of a type I MPGN. CMV could not be detected in the glomeruli nor elsewhere in the kidney by IF or EM. The patient was treated with ganciclovir. In a renal biopsy 3 weeks later, the exudative lesions had disappeared, and some glomeruli now showed the characteristic lesions of a type I MPGN with an increase of mesangial cells and matrix, and reduplication of the glomerular basement membrane. Over the following period, repeated biopsies were performed. The activity of the glomerular inflammation and immune complex deposits paralleled the waxing and waning of the CMV viral load. After 10.5 months, the graft was removed because of a life-threatening systemic fungal infection. At that time, the CMV infection had cleared, and in the transplantectomy material, the membranoproliferative pattern of injury had disappeared, and in the glomeruli hardly any deposits were found. These data strongly suggest that a primary CMV virus infection can induce an apparent recurrence of type I MPGN.

[Renal transplantation.].

Renal transplantation is the treatment of choice for most patients with end-stage renal disease. The improved success of this treatment modality over the past four decades can large part be attributed to advances in immunosuppressive therapy. However, while the demand for renal transplantation has been steadily growing due to the rising incidence of end-stage renal disease, shortage of organ donors is a major limitation. The shortage of kidneys for transplantation has been met with an increase in the use of living donors. Renal allograft survival has improved over the years, although late graft loss is still a significant problem. One and five-year survival of living donor grafts is approximately 94% and 72%, and 88% and 60% for cadaveric donor grafts, respectively. The main causes of late graft loss are death of the patient and chronic allograft nephropathy. Risk factors for chronic allograft nephropathy are complex and include both immunlogic and non-immunologic mechanisms. Finally, the results of renal transplantation in Icelandic recipients are discussed.

Ankle edema formation during treatment with the calcium channel blockers lacidipine and amlodipine: a single-centre study.

All studies suggesting a lower incidence of edema on lacidipine than on amlodipine are based on subjective scoring. Therefore, we have compared edema formation on two dihydropyridine calcium channel blockers, using an accurate method for quantitative assessment of foot volume. In a randomized study, we treated 62 patients with essential hypertension for 12 weeks starting with either lacidipine 4 mg o.d. (n = 30) or amlodipine 5 mg o.d. (n = 32). At 6 weeks, the doses were increased to that maximally allowed (lacidipine 6 mg, n = 18; amlodipine 10 mg, n = 12) if trough diastolic blood pressure response was insufficient (>90 mmHg and decrease < 10 mmHg). Edema, scored visually, occurred more frequently (p = 0.02) on amlodipine (15/32) than on lacidipine (6/30); this was confirmed by an increase of foot volume above the 95% upper limit of normal variation in 15 patients on amlodipine and in only five patients on lacidipine (p = 0.01). In the whole group of patients, both the increases of foot volume and the decreases of blood pressure just failed to be significantly different between amlodipine and ]acidipine (foot volume, +3.3+/-1.0% on amlodipine and +1.2+/-0.5% on lacidipine, p = 0.08; mean arterial pressure, -11+/-1% on amlodipine and -8+/-1% on lacidipine, p = 0.052). In patients requiring dose increase, the increase of foot volume on amlodipine was more pronounced (p < 0.05), and the antihypertensive effect was larger (p < 0.05) than on lacidipine. In conclusion, our data show a higher incidence of edema on amlodipine than on lacidipine, which has to be explained at least partly by a comparably higher dose c.q. a larger antihypertensive effect of amlodipine. Other mechanisms might have contributed to these differences and need to be explored.

The impact of recurrent glomerulonephritis on graft survival in recipients of human histocompatibility leucocyte antigen-identical living related donor grafts.

BACKGROUND: Graft loss due to rejection is uncommon after human histocompatibility leukocyte antigen-identical living related donor (LRD) transplantation, resulting in an excellent long-term graft survival. Data on the impact of recurrence of the original disease on graft survival after LRD transplantation are scarce. METHODS: We have studied the influence of recurrent glomerulonephritis in adult recipients of a human histocompatibility leukocyte antigen-identical LRD graft transplanted in our center in the period from 1968 to 1996. To that end, the data of 33 patients with proven or suspected primary glomerulonephritis and 27 patients with nonglomerular diseases were analyzed. RESULTS: The patient survival was similar in both groups at 5, 10, and 20 years. The functional graft survival, i.e., graft survival after censoring for death, was, however, significantly worse for patients with glomerulonephritis as underlying disease (P<0.01). At 5 years graft survival was 100% vs. 88%, at 10 years 100% vs. 70%, and at 20 years 100% vs. 63%, respectively. Thus none of the patients with nonglomerular diseases lost a graft, whereas eight grafts were lost in the group of patients with glomerulonephritis. The main cause of graft loss in this patient group was recurrent glomerulonephritis (n=5), whereas chronic vascular rejection caused graft loss in two patients and occlusion of a transplant artery was the cause in one. A clinically significant proteinuria was detected in six more patients in the glomerulonephritis group: a recurrent glomerulonephritis was diagnosed in four patients and in two patients there was no biopsy. The cumulative incidence of recurrence was as high as 45% at 12 years after transplantation. CONCLUSION: Recipients of a human histocompatibility leukocyte antigen-identical LRD kidney have a good prognosis with respect to graft survival. After censoring for death, recurrent glomerulonephritis is the main cause of graft failure in these patients and the impact of recurrent disease on graft survival will become even more prominent with longer follow-up.

Recurrent focal glomerulosclerosis: natural course and treatment with plasma exchange.

BACKGROUND: Focal glomerulosclerosis (FGS) can recur after renal transplantation and prognosis is poor in untreated patients. A circulating plasma factor has been implicated in the pathogenesis of a recurrent FGS and treatment with plasma exchange has proven effective in decreasing proteinuria in some patients. METHODS: We retrospectively studied the course of disease in patients with recurrent FGS, transplanted in our centre. Seven patients transplanted between 1991 and 1997, received treatment with plasma exchange, whereas 10 patients, transplanted between 1973 and 1991, were left untreated and served as historical controls. RESULTS: The time of onset of proteinuria (>3.5 g/day) was comparable in the untreated and treated patients (9 and 10 days respectively), as was the average proteinuria at that time (5.5 and 5.8 g/day respectively). In the untreated patients, proteinuria persisted and eventually all grafts were lost, on average 43 months after the diagnosis of a recurrence. In five cases (50%) the recurrence was the single cause of graft loss. The clinical course was different in the seven patients who were treated with plasma exchange. In five of these patients, the recurrence occurred within 3 weeks after transplantation. Plasma exchange was started 1-14 days after onset of proteinuria in these patients. Two lost their grafts after 0.7 and 1.0 months because of untreatable rejection. In the remaining three patients the plasma exchange resulted in abrupt disappearance of the proteinuria, and the response has been lasting for 2-3.2 years. In these patients the only histological abnormality was foot effacement on electron-microscopy. In two patients the recurrence became manifest at 9 weeks and 5.8 years after transplantation respectively. These two patients relapsed after the initial course of plasma exchange, but responded to repeated session, and are currently being treated once a month. They have been followed for 1. 7 and 1.4 years after the onset of proteinuria and their urinary protein levels are 0.23 and 1.2 g/10 mmol creatinine. CONCLUSIONS: The prognosis of untreated recurrent FGS is poor. Treatment with plasma exchange can lead to complete remission of proteinuria and relapsing patients may respond to repeated sessions. Best results are obtained when plasma exchange is started early, when there are no visible lesions on light-microscopy.

Renal transplantation in patients with dense deposit disease: morphological characteristics of recurrent disease and clinical outcome.

BACKGROUND: Dense deposit disease (DDD) is an uncommon cause of end-stage renal disease (ESRD). As a consequence, information on the outcome of renal transplantation in patients with DDD comes from series with a limited number of patients. METHODS: We present the histological and clinical data of 13 adult patients with DDD, who received their first allograft in our centre in the period between 1983 and 1994. RESULTS: Renal transplant biopsies were performed in 11 patients, at 2.9 months after transplantation (median; range 0.4-13.8 months). The indication for taking the biopsy was in all instances a raised serum creatinine level. Five patients also had a significant proteinuria. In only one patient, light microscopy showed alterations in the capillary walls suggestive of a recurrence of DDD. However, by immunofluorescence or electron microscopy, we found glomerular deposits compatible with a recurrence of DDD in all 11 patients. Three patterns of glomerular C3 deposition were found: globular depositions only in the mesangium; mesangial accumulation with linear deposits in the capillary wall; and prominent linear presence in the capillary wall with only a few mesangial granules. The findings by electron microscopy matched the immunofluorescence results. The linear C3 accumulation in the capillary wall was visible ultrastructurally as electron-dense ribbon-like transformation of the glomerular basement membrane. Mesangial C3 deposits were seen ultrastructurally as local electron-dense deposits in the mesangium. Four patients showed a pronounced glomerular influx of neutrophils, accompanied by crescents in three patients. In these three latter patients, the recurrence of DDD was the only histological lesion. In the other patients, the recurrence was merely a coincidence, the biopsy demonstrating an additional histological lesion (three chronic vascular rejection, two acute rejection, one ischaemic necrosis and two cyclosporin A toxicity). Eight patients with a recurrence of DDD have progressed to ESRD at an average of 14 months (range 0.2-38 months) after transplantation. The recurrence was the sole cause of graft loss in the three patients with crescents. The patients in whom the C3 deposits were confined to the mesangium appeared to have a better prognosis. CONCLUSIONS: The histological recurrence rate of DDD is high. The histological picture is quite diverse, and in most patients abnormalities are only found by immunofluorescence and electron microscopy. Up to one-quarter of the patients with DDD lost their grafts because of a recurrence.

Immunohistological and ultrastructural differences between recurrent type I membranoproliferative glomerulonephritis and chronic transplant glomerulopathy.

In renal transplant recipients with type I membranoproliferative glomerulonephritis (MPGN), the posttransplantation course can be complicated by a recurrence of the original disease. However, it is well known that a recurrence of type I MPGN and chronic transplant glomerulopathy (CTG) cannot easily be distinguished. It has been suggested that the two entities can be differentiated by using electron microscopy (EM) and immunofluorescence (IF) techniques. However, studies are lacking that compare biopsy specimens from patients with either a recurrence of type I MPGN or CTG. We have studied renal biopsy specimens from 10 patients with CTG and compared the ultrastructural and IF findings with biopsy specimens from 12 patients with a possible recurrence of type I MPGN. All the patients with CTG showed an electron-lucent zone of finely flocculent material in the subendothelial space, whereas all patients with a recurrence of type I MPGN showed subendothelial electron-dense deposits on EM. On IF, all patients with CTG showed Immunoglobulin M (IgM) with greater intensity than C3. For the patients with recurrent type I MPGN, the opposite was true. Eleven specimens showed C3 deposits with greater intensity than IgM, and in one patient, C3 and IgM were found in equal intensity. In conclusion, when IF and EM studies are available, CTG and recurrence of type I MPGN can reliably be distinguished.

[Glomerulonephritis caused by acute serum sickness]. / Glomerulonefritis door acute serumziekte.

A 51-year-old male patient was treated for a rejection episode after kidney transplantation with horse antithymocyte globulin (ATG). Twelve days after the start of the ATG treatment he developed fever, arthralgia, purpura and acute renal failure. This clinical picture is characteristic of serum sickness, resulting from formation of antibodies to a foreign protein and development of immune complexes. Kidney biopsy revealed an endocapillary glomerulonephritis. Immune complexes probably develop in the mesangium and along the glomerular basal membrane through local formation and precipitation from the circulation. Spontaneous recovery is the rule.

Recurrence of type I membranoproliferative glomerulonephritis after renal transplantation: analysis of the incidence, risk factors, and impact on graft survival.

BACKGROUND: The information in the medical literature on the incidence of recurrence of type I membranoproliferative glomerulonephritis (MPGN) after renal transplantation and its impact on graft survival is limited because most data are derived from case reports or from studies involving a small number of patients. METHODS: We analyzed the data from our transplant center. Among 1097 adult patients receiving their first allograft between 1977 and 1994, we identified 32 patients with type I MPGN. RESULTS: A recurrence was detected in 9 of the 27 recipients of a first cadaveric graft (33%). The cumulative incidence reached 48% at 4 years after transplantation when patients with graft failure from other causes were censored. All patients with recurrent MPGN had clinically significant proteinuria (>1 g/24 hr) that was first observed at a median time of 20 months (range, 1.5-42 months) after transplantation. Graft survival was significantly worse in patients with recurrence as compared with patients without recurrence. Mean duration of graft survival after the diagnosis of recurrence was 40 months. We could not detect any clinical characteristics of patients or donors that were associated with recurrent disease. However, an increased risk of recurrence was observed in patients with the HLA haplotype B8DR3. Four patients received an HLA-identical graft from a living related donor. Recurrence occurred in three patients (75%), with ensuing graft loss in two. The only patient with a haploidentical living related graft did not have a recurrence. Five patients with a recurrence in the first graft received a second transplant. Recurrence was observed in four of these patients (80%). CONCLUSIONS: Type I MPGN recurred after renal transplantation in half of the patients. The incidence may be even higher in recipients of an identical living related donor graft and in patients receiving a second transplant after having experienced a recurrence in their first graft. Recurrence of type I MPGN has a detrimental effect on graft survival.

Polyarteritis nodosa in a young man, a ten-year delay in diagnosis.

We present a case history of a patient with polyarteritis nodosa (PAN). The first disease symptoms started when the patient was 6 years old and concerned mainly musculoskeletal complaints. The disease persisted into adulthood when, 10 years later, the diagnosis of PAN could be confirmed by histopathological examination.