You are on page 1of 6

Nephrol Dial Transplant (2006) 21: 419424 doi:10.

1093/ndt/gfi207 Advance Access publication 25 October 2005

Original Article

Epidemiology of renal disease in Romania: a 10 year review of two regional renal biopsy databases
Adrian Covic1, Adalbert Schiller2, Carmen Volovat1, Gheorghe Gluhovschi2, Paul Gusbeth-Tatomir1, Ligia Petrica2, Irina-Draga Caruntu1, Gheorghe Bozdog2, Silvia Velciov2, Virginia Trandarescu2, Flaviu Bob2 and Cristina Gluhovschi2
Dialysis and Transplantation Center, C.I. Parhon University Hospital, Ias i and 2Dialysis and Transplantation Center, Timisoara, Romania
1

Abstract Background. Epidemiological data of renal disease are available from large national renal biopsy registries from Central and Western European countries; in contrast, detailed epidemiological data from Eastern European countries are missing. This report is the rst review of histological data, over a period of 10 years (19952004), covering a population of over 6 million inhabitants and two distinct regions from an East European country Romania. Methods. 635 eco-guided kidney biopsies from the Moldova (North-Eastern Romania, 8 counties, 4 754 048 inhabitants) and Banat (Western Romania, 3 counties, 1 454 747 inhabitants) regions were analysed. Data on serum creatinine concentration (sCr), 24 h proteinuria, haematuria, clinical diagnosis, histological diagnosis and complications after renal biopsy were collected. Results. The number of biopsies performed varied between 10.9 p.m.p./year in 1995 and 11.3 p.m.p./year in 2004. The most common clinical syndromes as indication for performing the renal biopsy were: nephrotic syndrome (52.3%), followed by nephritic syndrome (21.9%), acute renal failure (ARF) (12.4%), chronic kidney disease (CKD) (10.2%) and asymptomatic urinary abnormalities (AUA) (3.3% of the cases). The major histological groups identied were: primary glomerulonephritis (GN) (66.2%), secondary GN (26.4%), vascular nephropathies (2.3%), and tubulointerstitial nephropathies (TIN) (1.5%) of the cases. Among primary GNs, the most frequent diagnoses were: membranoproliferative GN (MPGN) (29.4%, incidence in 2004 9.3 p.m.p./year), mesangioproliferative GN (MesGN) (28.9%, incidence 10 p.m.p./year), membranous GN (MGN) (11.2%,
Correspondence and offprint requests to: Adrian Covic, MD PhD, Professor of Nephrology, C.I. Parhon University Hospital, Blvd. Carol 1st No. 50, Iasi 6600, Romania. Email: acovic@xnet.ro

incidence 5.3 p.m.p./year), minimal change disease (MCD) (8.5%, incidence 7.3 p.m.p./year), focal and segmental glomerulosclerosis (FSGS) (11.5%, incidence 3.3 p.m.p./year) and crescentic GN (CGN) (7.9%, incidence 3.3 p.m.p./year). The prevalence of membranoproliferative GN signicantly decreased from 1995 to 2004. The prevalence of different types of secondary GN was similar to Western and Central European countries, with the particular difference of higher infectious diseases associated GN. Conclusion. The present data are an important contribution to the epidemiology of renal diseases in Europe, highlighting not only numerous similarities but also signicant epidemiological differences in Western and Central European countries, particularly a higher, albeit declining, incidence and prevalence of membranoproliferative GN. This report represents the basis for the future of Romanian Registry of Renal Biopsies and is intended to serve as a source of information for nephrologists concerned with East European renal pathology. Keywords: chronic kidney disease; parenchymal diseases; renal biopsy; renal biopsy registry

Introduction
Knowledge of the epidemiology of renal disease along with clinico-pathological correlations provides important information in clinical practice. Current epidemiological data of renal disease in Western Europe are available from large national renal biopsy registries from Italy [1,2], Denmark [3,4] and Spain [5]. Information derived from local regional registries of renal biopsy has also been reported from other Western European countries France, Holland [6,7] showing comparable trends in incidence and prevalence of

The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

420 Table 1. Distribution of clinical syndromes according to age and gender Clinical syndrome Whole population N 635 (%) <60 years N 526 (82.8%) Overall N 526 (%) 54.9a 23 3.2 9.2a 9.7 Male N 270 (%) 50.8 22.2 2.6 9.6 14.8 Female N 256 (%) 58.9b 23.9 4 8.9 4.3b

A. Covic et al.

60 years N 109 (17.2%) Overall N 109 (%) 40.4 16.5 3.7 26.6 12.8 Male N 57 (%) 40.4 17.5 3.5 26.3 12.3 Female N 52 (%) 40.4 15.4 3.8 26.9 13.5

Nephrotic Nephritic AUA ARF CKD

52.3 21.9 3.3 12.4 10.1

AUA, asymptomatic urinary abnormalities; ARF, acute renal failure; CKD, chronic kidney disease. a Signicant difference age 60 vs age <60. b Signicant difference males vs females, P<0.05.

primary glomerular diseases. In contrast, only one large report [8] provides detailed epidemiological data for renal disease in Central Europe. Moreover, there is a complete lack of systematic data from Eastern Europe, over a long period of time. There are two main reasons to suspect signicant epidemiological differences for this region: a higher prevalence of infectious diseases (hepatitis B and C, streptococcal infections, etc.) [www.who.int] and differences in social and economic status that may translate into differences in the epidemiological pattern, as recently suggested by the concept of transitional epidemiology [9]. The aim of this study was to report long-term, detailed epidemiology of renal disease, based on histological diagnosis, in a large representative sample from an Eastern European Country, to identify clinicopathological correlations and to provide the embryo for the national Romanian Registry for Renal Biopsies.

of renal disease from Western Europe and from the single Central and Eastern European national registry available the Czech Registry of Renal Biopsies (CRRB), and for the histological classication of renal diseases, we used the scheme described by Gesualdo et al. in the Italian Registry of Renal Biopsies (IRRB) [1], and subsequently also followed by Rychlik et al. [8] in their registry reports see Methods section of [1], [2] and [8].

Data analysis
Data were stored on a standard EXCEL database; an SPSS 13.0 statistics package was used. The annual incidence was dened as the number of new cases per year related to the mean total population, expressed as per million populations (p.m.p.) per year.

Results Methods
We evaluated all renal biopsies performed during the 19952004 period in patients >18 years old; data were provided by two large regional referral centres Iasi and Timisoara. These centers were selected for the following reasons: (1) each unit performed all the renal biopsies for a homogenous (historical, geographical, social, cultural) but different area from Romania: Moldova (North-eastern Romania, 8 counties, 4 754 048 inhabitants), and Banat (Western Romania, 3 counties, 1 454 747 inhabitants); (2) comparable technical expertise, previously reported in the literature [10], (3) similar indications for performing the renal biopsy, (4) for the reported study period, this sample represents more than 50% of all renal biopsies performed in Romania. The following data were collected for each case: clinical and histological diagnosis, serum creatinine concentration (sCr), 24 h proteinuria, presence of haematuria, presence of arterial hypertension dened as a blood pressure >140/90 mmHg and/or antihypertensive medication, clinical complications after renal biopsy (with serious complications dened as: clinically symptomatic subcapsular or perirenal haematoma, gross haematuria, presence of hypovolaemic shock and/or need for blood transfusion). In order to enable comparisons of the biopsy and clinical results from our database with current epidemiological data

The total population of the two regions reported, for the 19952004 period was 6.4 (1995) to 6.2 (2004) million inhabitants, with a male/female ratio of 0.97 and an urbanrural distribution ratio of 2 : 1. Median age increased from 69.2 years in 1995 to 71.4 years in 2004. Over the 10-year study, a total of 635 renal biopsies were performed (all native kidneys, 51.5% males, mean age 38.515.2, range 1880 years). The number of renal biopsies performed was stable year by year, being 10.9 p.m.p./year in 1995 and 11.3 p.m.p./year in 2004 (compared with 44.1 p.m.p./year in 1994 and 69.3 p.m.p./year in 2000 for the CRRB [8]). The distribution of clinical syndromes according to age and gender is presented in Table 1. Nephrotic syndrome was more frequently recorded as an indication for performing a renal biopsy in the age group 18 to 60 years (compared with the 60 years age-group), while ARF was signicantly more frequent in the older (60 years) age group. There were no differences for other indications between the two age groups. The only gender-related differences were seen in the 18 to 60 years age group, again for the nephrotic syndrome (more frequent in males), and also for CKD (more frequent in females).

Epidemiology of renal diseases in Romania Table 2. Distribution of major histological groups of renal disease Romania, Moldova and Banat regions 2005 N 606 (%) Primary GN Secondary GN TIN Vascular nephropathies Miscellaneous/unclassiable 66.2 26.4 1.5 2.3 3.6 IRRB, Gesualdo et al. [1] N 14 607 (%) 70.8 23.7 2.3 3.2 N/A

421

CRRB, Rychlik et al. [8] N 4 004 (%) 59.8 25.4 4.4 3.4 2.4

IRRB, Italian Registry of Renal Biopsy; CRRB, Czech Registry of Renal Biopsy; GN, glomerulonephritis; TIN, tubulointerstitial nephropathy.

Table 3. Incidence of various histological forms in 2004 Incidence (p.m.p.) Romania, Moldova and Banat regions CRRBa Western Franceb MPGN 9.3 4.6 2 MGN 5.3 9.3 6 to 17* MesGN 10 11.3 25 MCD 7.3 12.5 N/A FSGS 3.3 10.8 N/A TIN 6 N/A N/A CGN 3.3 3.2 4 to 27**

MPGN, membranoproliferative glomerulonephritis; MGN, membranous glomerulonephritis; MesGN, mesangioproliferative glomerulonephritis; MCD, minimal change disease; FSGS, focal segmental glomerulosclerosis; TIN, tubulointerstitial nephropathy; CGN, crescentic glomerulonephritis. a CRRB, The Czech Registry of Renal Biopsies [8]. b Western France, period 19962002, 412 375 inhabitants [6]. *6 for the 2059 years range and 17 for the 6079 years range. **4 for the 2059 years range and 27 for the 6079 years range.

Table 4. Prevalence of different forms of primary glomerulonephritis Romania, Moldova and Banat regions 2005 N 401 MPGN (%) MesGN (including IgA) (%) FSGS (%) MGN (%) MCD (%) CGN (%) Non classiable/other (%) 29.4 28.9 11.5 11.2 8.5 7.9 2.5 IRRB, Gesualdo et al. [1] N 6990 6.6 43.5 13.1 23.4 9.2 2.3 1.9 CRRB, Rychlik et al. [8] N 2333 4.6 45.8 10.8 9.3 12.5 3.2 13.8

IRRB, Italian Registry of Renal Biopsy; CRRB, Czech Registry of Renal Biopsy; MPGN, membranoproliferative glomerulonephritis; MesGN, mesangioproliferative glomerulonephritis; FSGS, focal segmental glomerulosclerosis; MGN, membranous glomerulonephritis; MCD, minimal change disease; CGN, crescentic glomerulonephritis.

An adequate renal fragment was obtained in 606 cases (95.4%). The mean number of glomeruli/ fragment was 9.14.9. These 606 cases were included in the analysis. The distribution of major histological groups of renal disease is shown in Table 2, comparatively with data from the largest Western European registry (the Italian Registry of Renal Biopsies IRRB) and with data from a Central European country (CRRB). Of all diseases, primary GN was the most frequent 66.2%; but overall, the relative distribution of the major groups was similar between the three registries. The incidence (number/per million) of various histologic forms in 2004, is presented in Table 3. The overall incidence of primary GN was 38.5 p.m.p./year.

Table 4 shows the frequency of different forms of primary GN, again in comparison with similar data from IRRB and CRRB. Clearly, membranoproliferative and crescentic GN were more frequently encountered in Romania; mesangial GN was less frequent, while FSGS, minimal change disease and membranous GN had a similar prevalence with IRRB and particularly with CRRB. The prevalence of MPGN signicantly decreased from 1995 to 2004 (Figure 1). Correlations between the histologic diagnosis and the clinical presentation are presented in Table 5. Nephropathies which most frequently presented as a nephrotic syndrome were: membranoproliferative GN (35.1%) and MesGN (19.8%) (compared with MGN (44.1%) and FSGS (16.9%) in Italy).

422

A. Covic et al.

Table 6 shows the frequency of different types of secondary GN, also in comparison with similar data from IRRB and CRRB. Immune-mediated GN and dysgammaglobulinaemia associated GN had similar prevalences in all three registries. More infectious disease associated GN were present in both Romanian regions, while metabolic and hereditary associated GN were less frequent. Among secondary GN, dysgammaglobulinaemia associated GN (39.7%) were the type of nephropathies which most frequently presented as a nephrotic syndrome, very similar to the Italian Registry: 30.4%. Ultrasound needle guidance and the biopsy gun were used for all biopsies. Fifty-seven clinically serious complications were recorded (8.9% of all biopsies) (Table 7), a rate similar to Ref. [11]. Serious complications were observed most frequently when a large fragment was harvested (>20 glomeruli, data not shown); 14/15 patients with hypotension following biopsy had concomitant severe renal insufciency and were on antihypertensive therapy.
40 35 30 25 20 15 10 5 0 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
Fig. 1. The prevalence of MPGN decreased from 1995 to 2004.

Discussion
This report provides information about the occurrence of renal diseases diagnosed by renal biopsy, during a period of 10 years, in a population of over 6 million, from two distinct regions from Romania: Moldova (North-eastern Romania) and Banat (Western Romania). To our knowledge, this is the rst systematic review of histological data from Eastern Europe and the Balkan area. The main ndings of this large regional database are: (a) similar incidence of primary and secondary GN, and a similar distribution of major histological groups of renal disease to Western and Central European countries, (b) a higher incidence and prevalence of MPGN, although this form of primary GN is steadily declining over the 10 years interval and, (c) similar prevalence of different types of secondary GN to Western and Central European countries, with the particular difference of a higher infectious diseases associated GN (including hepatitis B and C). Nephrotic and nephritic syndromes were the most frequent clinical presentations, accounting for approximately 75% of all cases, at the time of the biopsy. The incidence of GN (38.5 p.m.p./year) was comparable with that seen in other European countries: 34, 47, 39 p.m.p./year [4,8,12]. The distribution pattern of major histological groups of renal disease also corresponded to other European series. Furthermore, a very similar proportion of nephrotic patients with FSGS, MGN and MCD were seen in the Czech Registry of Renal Biopsies (10.3%, 12.7% and 9.4% respectively), compared with our series (12.1%, 14.5% and 10.9% respectively). However, there are also signicant differences compared with other registries. First, both in Italy [1] and in Spain [5] MCD and specially MGN, in nephrotic cases, are observed with a higher frequency. Second, both MPGN (35.1%) as a primary GN and

Table 5. Frequency of histologic diagnosis on the basis of clinical presentation of nephropathy Nephrotic syndrome (%) Primary GN MPGN MesGN (including IgA) FSGS MGN MCD CGN Glomerulosclerosis Total (N) Secondary GN Immune-mediated Dysgammaglobulinaemia associated GN Infectious disease associated GN Others (metabolic, hereditary, etc.) Total (N) Nephritic syndrome (%) AUA (%)

35.1a 19.8 12.1 14.5 10.9 5.2 2.4 248 (100%) 39.7 24.4 30.8 5.1 78 (100%)

16.9 46.7b 12.2 6.5 6.5 7.5 3.7 107 (100%) 55.2 0b 44.8 0 29 (100%)

11.1 83.3c 0 5.6 0 0 0 18 (100%) 50 50 0c 0 2 (100%)

MPGN, membranoproliferative glomerulonephritis; MesGN, mesangioproliferative glomerulonephritis; FSGS, focal segmental glomerulosclerosis; MGN, membranous glomerulonephritis; MCD, minimal change disease; CGN, crescentic glomerulonephritis. Signicantly different from nephritic syndrome and AUA. b Signicantly different from nephrotic syndrome and AUA. c Signicantly different from nephrotic and nephritic syndrome.
a

Epidemiology of renal diseases in Romania

423

infectious diseases associated GN (30.8%) as a secondary GN are the most frequent causes of nephrotic syndrome in Romania, in sharp contrast with published European series [1,5,6]. The issue of MPGN deserves special attention. It is interesting to point out that the annual prevalence has constantly decreased in our study from 1995 to 2004. In fact, in 2004 MPGN we report close gures to the Italian registry (Figure 1). Such a trend can hardly be exclusively explained by improvements in technique [13], and has been reported elsewhere for example in France, where a decline in rheumatic fever was associated with a parallel decline in MPGN and post-streptococcal GN [6]. We hypothesize that the epidemiology of MPGN is strongly related to socioeconomic conditions. Improvement in income, sanitation, social and medical infrastructure are followed by a decrease in MPGN. These improvements were evident in Romania following 1989, as in all Eastern European countries [14]. Further arguments to support our hypothesis are epidemiology gradients seen in Europe (see above) and in Romania (higher prevalence in Moldova, region with a lower income per capita and infrastructure than the Banat region). Finally, it is important to underline the high prevalence of streptococcal and hepatitis infections in the general population in Romania [www.who.int]. What we describe is probably another excellent example of the concept of transitional epidemiology described by La Porte [9]. IgAN is the most frequent disease among patients with primary GN, ranging from 7.9 p.m.p./year in Spain [5] to 8.4 p.m.p./year in Italy [1], to the very high 2531 p.m.p./year in France [6] (11.2 p.m.p./year in the
Table 6. Prevalence of different types of secondary GN

CRRB [8]). In reality, the true incidence of IgAN is unknown, but probably higher since an important proportion of primary GN, diagnosed as MesGN, is not always evaluated by immunouorescence [3,15]. In our study MesGN, including IgA was the second most frequent cause of nephrotic syndrome and the rst cause of nephritic syndrome/AUA. In this (morphologic) series, ARF was mainly due to vasculitis and crescentic GN; furthermore, there was a high prevalence of CGN (8%) among primary GN. Overall, one-third of the cases presenting with ARF had crescentic GN (data not shown) similar to a recent Italian survey [2] and to large series from Spain and Baltimore [12,16]. This report shares clear limitations common to all disease registries based on diagnostic manoeuvres. Analysis is based on retrospective data collected from different centres with different referral patterns, local expertise and changing indications. However, this report represents the embrion for the Romanian Registry of Renal Biopsies (RRRB), which will include prospective collected data from Transylvania, Bucuresti and Southern Romania, providing the basis for the design of regional protocols for preventive medicine. In conclusion, we show that while primary and secondary GN have a similar incidence and a similar distribution of major histological groups to other European countries, a higher (but declining) incidence and prevalence of MPGN is recorded in Romania. Present data represent an important contribution to the epidemiology of renal diseases in Europe, providing a valuable comparison with other renal biopsy registries worldwide, as a basis for nephrologists

Romania, Moldova and Banat regions 2005 N 160 Immune mediated GN (%) Necrotizing vasculitides LES Others (Goodpasture, Henoch-Schonlein, etc.) Dysgammaglobulinaemia associated GN (%) Renal amyloidosis Others (essential mixed cryoglobulinaemia) Infectious diseases associated GN (%) Others (metabolic, hereditary, etc.) (%) 55.6 20.6 29.4 5.6 14.4 11.9 2.5 25 5

IRRB, Gesualdo et al. [1] N 2348 57.6

CRRB, Rychlik et al. [8] N 990 48.6 15.6 23 6.9 14.9 9.9 5 N/A 36.5

15.9 3 23.5

IRRB, Italian Registry of Renal Biopsy; CRRB, Czech Registry of Renal Biopsy. Table 7. Clinical signicant complications after renal biopsy No. cases N 635 Concomitant co-morbidity Renal insufciency S-Cr. >2 mg/dl Gross haematuria Haemorrhage and hypotension Haematoma and hypotension 52 (8.1%) 15 (2.4%) 6 (0.9%) 17 (2.6%) 1 (0.2%) 0 Hypertension Both

10 (1.6%) 0 0

25 (3.9%) 14 (2.2%) 6 (0.9%)

424

A. Covic et al. 8. Rychlik I, Jancova E, Tesar V et al. The Czech registry of renal biopsies. Occurrence of renal diseases in the years 19942000. Nephrol Dial Transplant 2004; 19: 30403049 9. La Porte RE. Global epidemiology and public health: The years of epidemiologic transition. Plenary Lecture, ERA/EDTA Congress, Istanbul 2005 10. Covic A, Caruntu I, Marian D et al. Renal pathology in Moldova territory in the period 19951998: clinico-histological study. Nefrologia 1998; 9: 303311 11. Ponticelli C, Mihatsch MJ, Imbasciati E. Renal biopsy: performance and interpretation. In: Davison AM et al. eds. Oxford Textbook of Clinical Nephrology, 2nd ed. Oxford: Oxford University Press, 1999; 158159 12. Rivera F, Lopez-Gomez Jm, Perez-Garcia R, In Representation of the Spanish Registry of Glomerulonephritis: Frequency of renal pathology in Spain for 19941999. Nephrol Dial Transplant 2002; 17: 15941602 13. Simon P, Ramee MP. Interet de la biopsie renale dans letude epidemiologique des maladies renales. In: Droz D, Lantz B, eds. La biopsie renale. France: Inserm Paris, 1996; 579586. 14. Mircescu G, Capsa D, Covic M et al. Nephrology and renal replacement therapy in Romaniatransition still continues (Cinderella story revisited). Nephrol Dial Transplant 2004; 19: 29712980 15. Research Group on Progressive Chronic Renal Disease. Nationwide and long-term survey of primary glomerulonephritis in Japan as observed in 1850 biopsied cases. Nephron 1999; 82: 205213 16. Haas M, Spargo BH, Wit EJC, Meehan SM. Etiologies and outcome of acute renal insufciency in older adults: A renal biopsy study of 259 cases. Am J Kidney Dis 2000; 35: 433447

and health care providers to stimulate new analysis and improve treatment of renal diseases.
Conict of interest. None declared.

References
1. Gesualdo L, Di Palma AM, Morrone LF et al. The Italian experience of the national registry of renal biopsies, Kidney Int 2004; 66: 890894 2. Schena FP. Survey of the Italian Registry of Renal Biopsies. Frequency of the renal diseases for 7 consecutive years. Nephrol Dial Transplant 1997; 12: 418426 3. Heaf J. The Danish renal biopsies register. Kidney Int 2004; 66: 895897 4. Heaf JG, Lkkegaard H, Larsen S. The epidemiology and prognosis of glomerulonephritis in Denmark 198597. Nephrol Dial Transplant 1999; 14: 18891897 5. Rivera F, Gomez JML, Garcia RP et al. Clinicopathologic correlations of renal pathology in Spain. Kidney Int 2004; 66: 898904 6. Simon P, Ramee MP, Boulahrouz R et al. Epidemiologic data of primary glomerular diseases in western France. Kidney Int 2004; 66: 905908 7. van Paassen P, van Breda Vriesman PJC, van Rie H, Tervaert JWC. Signs and symptoms of thin basement membrane nephropathy: A prospective regional study on primary glomerular disease The Limburg Renal Registry. Kidney Int 2004; 66: 909913

Received for publication: 18.7.05 Accepted in revised form: 12.9.05