The Effect of Dialytic Modalities on Clinical Outcomes in ESRD Patients with Familial Mediterranean Fever

Abstract

Background. Familial Mediterranean fever (FMF) is an autosomal recessive disease seen primarily in Sephardic Jews, Turks, and Armenians. The disease manifests as recurrent attacks of fever and serositis. The most important complication of FMF is the development of renal failure due to AA type amyloidosis. There has not been extensive experience with renal replacement therapy in FMF amyloidosis. Nevertheless, there may be a concern about the possibility of higher rates of morbidity and mortality in amyloidotic patients maintained on chronic hemodialysis. Moreover, there is not enough experience regarding patients on chronic peritoneal dialysis. As a result, the best treatment modality of end-stage renal disease (ESRD) in these circumstances still remains unclear. This study aimed to compare the effect of hemodialysis and peritoneal dialysis modalities on clinical outcomes in ESRD patients associated with FMF amyloidosis. Methods. Forty FMF patients with ESRD due to amyloidosis were retrospectively analyzed. All 40 patients were on renal replacement therapy, 20 on hemodialysis (HD), 20 on peritoneal dialysis (PD). Peritoneal solute transport rates, weekly mean creatinine clearance, and daily mean ultrafiltration (UF) of the patients on chronic peritoneal dialysis were evaluated. Weekly dialysis durations, dialysis membrane properties, Kt/V values, interdialytic weight gains, and frequency of hypotension during dialysis were evaluated on hemodialysis patients. All of the patients were examined according to their demographic characteristics, laboratory results, duration time on dialysis, erythropoietin requirements, frequencies of infectious complications requiring hospitalization, and the two renal replacement modalities mentioned above were compared in terms of these parameters. Results. Serum albumin levels of the patients with FMF amyloidosis who were maintained on peritoneal dialysis treatment were lower (2.87 vs 3.45) and the frequency of infections of the same group was higher (4.2 vs 0.5) than the patients with ESRD secondary to other diseases in the CAPD group. Conclusions. This retrospective analysis showed that peritoneal dialysis may have some disadvantages in amyloidotic patients. Due to the high frequency of hypoalbuminemia and infectious complications seen in this group, peritoneal dialysis is widely accepted as an alternative choice of treatment when hemodialysis is not appropriate.

Keywords:

• amyloidosis
• clinical outcome
• Familial Mediterranean Fever
• hemodialysis
• peritoneal dialysis

INTRODUCTION

Familial Mediterranean fever (FMF) is a recurrent inflammatory disease with autosomal recessive inheritance, characterized by acute attacks of fever, peritonitis, and arthritis.[1] The disease is restricted to ethnic groups such as Armenian, Sephardic Jewish, and Turks.[1],[2] Familial Mediterranean fever is not a benign disease. The most serious complication of FMF is systemic amyloidosis of AA type, which is frequently seen in Turkish and Israeli patients.[3] The regular use of colchicine decreases the frequency of acute attacks in FMF and prevents the development of systemic amyloidosis over the long term.[1],[4] The prognosis of patients who are prone to develop end-stage renal disease secondary to amyloidosis is worse.[5],[6] In such patients, all renal replacement modalities have some disadvantages. Vascular access failure and hypotension during dialysis may limit the efficacy of hemodialysis, and attacks of peritonitis can be a major problem of peritoneal dialysis modality. Therefore, the best treatment modality of end-stage renal failure in these patients still remains unclear. From the point of primary underlying disease, higher rates of morbidity and mortality have been reported in amyloidotic patients who were maintained on chronic hemodialysis modality. In terms of kidney transplantation, patient survival rates are lower in amyloid patients when compared to transplant recipients whose ESRD was due to other etiologies.[7],[8] However, there is no comparative study about the outcome of hemodialysis and peritoneal dialysis in such patients.

The aim of this study was to compare the effect of hemodialysis and peritoneal dialysis modalities on clinical outcomes in ESRD patients with FMF amyloidosis.

PATIENTS AND METHODS

In this study, a total of 40 patients with end-stage renal failure due to FMF amyloidosis, 20 on chronic hemodialysis and 20 on chronic peritoneal dialysis, were retrospectively evaluated. Clinical data of hemodialysis patients were obtained from questionnaire forms sent to eight dialysis centers. Peritoneal dialysis patients evaluated in this study were selected from the patients followed at a peritoneal dialysis outpatient clinic at Göztepe Training Hospital, and data about patients were obtained from their follow-up charts. Peritoneal solute transport rates from Peritoneal Equilibration Test (PET), weekly mean creatinine clearance, and daily mean ultrafiltration (UF) of the patients in the chronic peritoneal dialysis program were evaluated. Weekly dialysis durations, dialysis membrane properties, Kt/V values, interdialytic weight gains, and number of hypotensive episodes during dialysis of the patients in chronic hemodialysis program were evaluated. Demographic characteristics and duration time on dialysis, erythropoietin requirements, frequencies of infectious complications requiring hospitalization, serum urea, creatinine, albumin, and Hb and Htc levels of all patients were examined, and the two renal replacement modalities mentioned above were compared in terms of these parameters.

All data were evaluated using a Microsoft Excel 97 spreadsheet, and SPSS 8.0 software was used for statistical analysis. Results were expressed as mean ± SD for each value. Variables were compared using Student's t-test. A p value of <0.05 was regarded to indicate statistical significance.

RESULTS

It was found that 20 of 178 patients (11.2%) followed at our peritoneal dialysis outpatient clinic had end-stage renal failure due to FMF amyloidosis. All patients included in the study had a positive family history of FMF and a diagnosis of AA amyloidosis in the renal or gingival biopsy material. All patients in the peritoneal dialysis and hemodialysis groups were receiving colchicine therapy (12 of 20 patients at a dose of 1.5 mg/day, others at a dose of 1 mg/day). All patients on peritoneal dialysis were previously selected to receive hemodialysis as a first line renal replacement treatment but were obliged to be transferred to peritoneal dialysis for reasons such as vascular access problems and the development of hypotension during hemodialysis.

Patient's characteristics of the peritoneal dialysis group are given in Table 1. The frequency of infections in FMF group was higher than the CAPD population in follow-up (4.2 vs. 0.5).

Table 1 Demographic characteristics of the peritoneal dialysis group

Age (years)	30.2 ± 7.4
Gender	4M/16F
Body weight (kg)	52.6 ± 6.8
Dialysis duration (months)	38.1 ± 40.8
Frequency of infections requiring hospitalization (n/patient year)	4.2 ± 1.3

It was observed that in the peritoneal dialysis group, target values of dialysis efficiency were reached, and there was no ultrafiltration failure (see Table 2). When peritoneal solute transport characteristics of the patients with renal failure due to FMF amyloidosis were analyzed, it was observed that at the beginning of the PD treatment, high average (HA) transporter frequency was markedly higher than peritoneal dialysis population in our follow-up (75% vs. 30%; see Table 2). Protein loss via peritoneum is seen most frequently in PD patients with high (H) or HA peritoneal solute transport characteristics. Demographic characteristics of the hemodialysis group are shown in Table 1.

Table 2 Dialysis characteristics of the peritoneal dialysis group

Kt/V	2.24 ± 0.82
PET score	HA (75%) LA (25%)
D/P creatinine, four hours	0.74 ± 0.32
Ultrafiltration (mL/24 h)	1480 ± 380
Residual renal function (mL/min)	1.55 ± 3.76

*Peritoneal permeability features of our general peritoneal dialysis group are as follows: LA, 32%; HA, 30%; L, 22%, H, 16%.

It was noted that, in spite of large interdialysis weight gain and high frequency of hypotensive episodes during dialysis session, target values of dialysis adequacy were reached in the hemodialysis group (see Table 3). It was observed that in the peritoneal dialysis and hemodialysis groups, target values of dialysis efficiency were reached (Kt/V = 2.24 ± 0.82 and 1.34 ± 0.68 p = 0.01).

Table 3 Demographic characteristics of the hemodialysis group

Age (years)	33.5 ± 12.8
Gender	10M/10F
Body weight (kg)	56.9 ± 5.3
Dialysis duration (months)	32.5 ± 16.6
Frequency of infections requiring hospitalization (n/patient year)	1.3 ± 1.2

Laboratory data of hemodialysis and peritoneal dialysis patients are summarized in Table 4. All of the patients with FMF amyloidosis who were on peritoneal dialysis treatment were suffering from hypoalbuminemia (see Table 5). In the same group, the frequency of infections was higher than the CAPD population in the follow-up (4.2 ± 1.3/0.5 ± 0.8). Ninety-two percent of infections that required hospitalization were peritonitis, and 76% of them were culture-negative peritonitis in FMF amyloidosis patients receiving peritoneal dialysis treatment.

Table 4 Laboratory data of hemodialysis and peritoneal dialysis patients

	CAPD	HD	p
Hb (g/dL)	10.7 ± 1.6	9.1 ± 2.8	0.09
Htc	33.4 ± 5.1	26.9 ± 7.7	0.04
BUN (mg/dL)	60 ± 23	70 ± 35	0.15
Creatinine (mg/dL)	8.9 ± 2.1	9.3 ± 2.1	0.4
Albumin (g/dL)	2.87 ± 1.33	3.45 ± 0.77	0.18

Table 5 Dialysis characteristics of the hemodialysis group

Kt/V	1.34 ± 0.68
Weekly dialysis duration (hours)	12
Dialyzer type	Polysulfon 35%
	Cellulose acetate 65%
Interdialitic weight gain (kg)	3.6 ± 1.8
Intradialitic hypotensive episode (n/month)	6.2 ± 1.3

When infections requiring hospitalization in FMF amyloidosis patients on hemodialysis modality were examined, 72% of them were catheter-related infections (MRSA, MRSE) and 28% were lower respiratory tract infections.

Three of the 20 patients in the peritoneal dialysis group were returned to hemodialysis following removal of PD catheters due to fungal peritonitis, and two patients returned to hemodialysis by removing PD catheter because of recurrent sterile peritonitis attacks. (These attacks were accepted as FMF attacks.)

Two of the remaining 15 patients died because of sepsis following a lower respiratory tract infection. It was noted that among the patients receiving renal replacement treatment because of chronic renal failure due to FMF amyloidosis, those under chronic peritoneal dialysis had serum albumin lower than those under chronic hemodialysis. Recombinant human erythropoietin (rHuEPO) requirements were higher in the peritoneal dialysis group than the hemodialysis group, although the difference was not statistically significant. The rate of clinically manifest infections (especially peritonitis requiring hospitalization) during the observation period was also significantly higher in the FMF amyloidosis patients receiving peritoneal dialysis than the hemodialysis group.

DISCUSSION

Familial Mediterranean fever is an autosomal recessive disorder with a specific ethnic distribution. Turks are among the groups in which the disease is frequently seen. Although there are no official records about its incidence and prevalence in Turkey, a study on 933 children has reported its prevalence as 24%.[10]

Also in Turkey, two retrospective analysis of secondary amyloidosis cases revealed that FMF is the most frequent cause of secondary amyloidosis, with a rate of 64% and 30.5%.[11–13] Colchicine controls the frequency of the attacks and progression of amyloidosis. However, 5–10% of the patients do not respond to therapy. The present study determined that although all of the patients were given colchicine, recurrent sterile peritonitis attacks were frequently seen in the PD group but not the HD group. It could be speculated that alteration in the pharmacokinetics of the drug in PD or peritoneal clearance of the drug may be responsible.

Hemodialysis patients seem to have a low Hb level, but there was no significant differences between two groups (p = 0.09), and the hemodialysis group patients had higher interdialytic gain, which may be the reason of low Hb levels.

When rHuEPO requirements were compared, erythropoietin need in the peritoneal dialysis group was higher than the hemodialysis group, although this was statistically insignificant. It is interesting that despite the expectations, the required higher dosage for rHuEPO in the PD group could be explained with chronic inflammation due to frequent attacks of peritonitis.

It was observed that at the beginning of the PD treatment, high average (HA) transporter frequency was markedly higher and protein loss via peritoneum was seen most frequently especially in PD patients with high (H) or HA peritoneal solute transport characteristics, and that this dialysis modality is less successful in such patients.[9] Protein loss via peritoneum is seen most frequently in especially PD patients with H or HA peritoneal solute transport characteristics, and this dialysis modality is less successful in such patients.[9]

Renal failure due to amyloidosis is the most serious and important complication of FMF. All renal replacement modalities have some disadvantages, and there is no consensus about the choice of the renal replacement treatment when end stage renal failure develops in this group of patients. Gertz et al. have reported the mean survival rate of their 211-case series of primary systemic amyloidosis as 8.2 months from the beginning of dialysis, and in 2/3 of cases, causes of death were complications due to cardiac amyloidosis.[5] Moroni et al. have found the mean survival rate from the beginning of dialysis in 61 patients with AA and AL amyloidosis requiring dialysis as 25 months, and have reported that cardiovascular complications were frequent and that hypotension episodes during dialysis session was a serious problem in this group of patients.[6] The possible cause of large interdialytic weight gain in amyloidotic patients who have a tendency to hypotension is the rapid administration of hypertonic saline solutions during hypotensive episode in the dialysis session. The patients on peritoneal dialysis were previously selected to receive hemodialysis as a first line renal replacement treatment but were obliged to be transferred to peritoneal dialysis for reasons such as vascular access problems and the development of hypotension during hemodialysis sessions. Thus, these patients are already difficult ones.

Interestingly, no fatal cardiac arrhythmia has been seen in these patients. Total recovery after transfer to PD was reported in debilitating hemodialysis hypotension in patients with chronic renal failure due to systemic amyloidosis secondary to rheumatoid arthritis.[14] Accordingly, the incidence of hypotension and cause of death are not different from hemodialysis in CAPD patients. However, the increased frequency of peritonitis in patients with amyloidosis in comparison with the general CAPD population affects the outcome unfavorably.

There is no comparative study about dialysis modalities in end stage renal failure due to amyloidosis. On the other hand, there is little experience about CAPD in end-stage renal failure in amyloidosis. In the Altiparmak et al. study with 40 patients (10 had FMF-amyloidosis, 10 had diabetes mellitus, 10 had chronic glomerulonephritis, and 10 had chronic interstitial nephritis), undergoing CAPD were included.[15] The onset of ESRD and frequency of FMF peritonitis attacks decreased, with fewer attacks occurring during CAPD in FMF-amyloidosis patients. There was no significant difference between the FMF-amyloidosis group and other groups in terms of efficiency of CAPD, peritoneal function, complications, and survival, there was no survival difference between FMF-amyloidosis patients and other groups, and thus the authors concluded that CAPD is an effective and safe renal replacement therapy for FMF-amyloidosis.[15] On the contrary, in the present study's patients, morbidity was higher in the peritoneal dialysis group than the hemodialysis group.

The limited number of patients in this group precludes the possibility of prospective studies. The number of patients on peritoneal dialysis is very small in this patient group in spite of relatively high incidence among secondary amyloidosis causes in Turkey. This retrospective analysis was carried out in order to share the authors' experience with ESRD patients due to FMF amyloidosis, though there was a small number of patients in the peritoneal dialysis group. In addition to an increased tendency to hypoalbuminemia and infections in the peritoneal dialysis group, the difficulties with the differential diagnosis of frequently recurring peritonitis attacks despite colchicine therapy and the disruption of peritoneal dialysis treatment during these attacks have created serious problems.

In conclusion, although these patients are already difficult, it was determined that peritoneal dialysis should not be the first choice in the selection of renal replacement treatment to be conducted in ESRD due to FMF amyloidosis.