Background
Chronic kidney disease (CKD) is being diagnosed with increased frequency worldwide [
1‐
3]. Glomerulonephritis (GN) is a major cause of CKD but is estimated to account for only 10% of end-stage renal disease (ESRD) in the West and in the developed countries of Asia where more than 75% of ESRD is attributed to diabetes and hypertension [
4,
5]. Many of the larger countries of the Middle-East are unable to collect comprehensive data on kidney disease, and the incidence of CKD and the extent to which GN or diabetes contributes to ESRD are poorly defined [
6].
The regional frequencies of different types of CKD are mainly determined by the proportions of diagnostic categories in biopsy series. These studies have shown that IgA nephropathy (IGAN) is the predominant form of CKD in many European and Asian populations but is rare among persons of African ancestry and, when compared to Europe, is relatively uncommon in the Middle-East [
7,
8]. An increased frequency in the diagnoses of focal segmental glomerulosclerosis (FSGS) seems to have begun in the early 1980s in the United States (US) and Brazil and in the 1990s in Singapore and India, and FSGS is now the major cause of nephrotic syndrome in many parts of the world [
7,
9‐
12].
In the US and Australia, biopsy registries from well-defined populations have been used to estimate the incidence of specific types of glomerular diseases [
13,
14]. In both countries, GN rates composed largely of IGAN and FSGS increased steadily with age, with the relative risk of GN, diabetes, and hypertension all contributing to a growing population of older ESRD patients.
The Middle-East is often considered a homogeneous region with respect to disease [
15]. We question this assumption. Conflict has been a part of Iraqi life for nearly 30 years, and epidemiologic record keeping on non-communicable diseases other than cancer is only beginning to receive attention. This current study used a renal biopsy registry from the largely Kurdish population of Northern Iraq to investigate the incidence of the common forms of GN that might lead to ESRD. We also applied the proposals by Anand et al., [
15], on the use and initiation of dialysis services as surrogates for prevalence and incidence of ESRD when regional or national data is not available. The findings are compared to Jordan, the adjacent country having a rigorous collection of nationwide data on ESRD, to assess how the findings in Northern Iraq might contribute to a better understanding about the variability of CKD in the region.
Discussion
In 2013, Anand et el. [
15] proposed using estimates of use and initiation of renal replacement therapy as a method of quantitating ESRD in developing countries. They pointed out that renal disease registries are non-existent in most of the world but emphasized the need for data on regional requirements for renal replacement therapy. Northern Iraq has 14 government dialysis centers with no conditions that exclude any person from receiving services. Daily and monthly records include name, age, blood pressures, and diabetes status. Date of entry into or exit from dialysis is rarely available, and data are not collected into a regional repository for formal estimates of incidence or prevalence.
We believe that rates of the initiation and the repeated use of dialysis when sampled at multiple dialysis centers can serve as surrogates for the incidence (initiation) and prevalence (total use, initiated and repeated) of ESRD. Our proportion of patients initiating dialysis in 2017 to the total number of patients using dialysis was 0.39. This is very close to the 0.34 reported by Anand et al. [
15] for the Middle-East and North Africa as a whole and supports the validity of the concept as it is applied to our region. Using this approach, the annual crude incidence of ESRD for Iraqi Kurdistan was estimated at 60 per million. This is similar to an incidence of 64 per million reported in a 2014 review [
21] from Iran that lies just to the East of Iraq but is considerably lower than Jordan that is on the Western Iraqi border [
19].
Nevertheless, before 65 years old, age specific incidence rates for Jordan and Kurdistan were very similar to each other and to the US suggesting that before late middle age, ESRD rates in the Middle East resemble other geographic regions and that the major difference between low and high incidence regions is the accrual of CKD in aging populations. In this regard, it is important to recognize that Kurdistan and Jordan have young populations that contrast with the older population structures of the US and Australia. When standardized to the 2000 US population, the ESRD incidence for Kurdistan was still comparatively low at 124 per million; while the age standardized rate for Jordan was 237 per million, a value close to that for Olmstead County and twice as high as Australia [
13,
22].
In Northern Iraq, FSGS was the most frequently diagnosed type of GN. FSGS had an age adjusted incidence of 1.6 per 100,000 that was close to the incidence of 1.8 per 100,000 seen in Olmstead County and was not markedly lower than the incidence of 2.2 per 100,000 in Victoria [
13,
14]. Nevertheless, FSGS was diagnosed at a younger age in Kurdistan than in Olmstead County or Victoria. The incidence of FSGS and all GN in Kurdistan peaked at approximately age 40 and then began to decline; whereas, in Victoria and Olmstead County there was a continued rise in later years [
13,
14].
The rates of diagnosis and the age of FSGS in a population raise at least two epidemiologic issues. One concerns the variable frequency of FSGS in different populations in which there is little relationship to the population risk for ESRD. This is in part because the major cause of ESRD in high incidence populations is diabetes. The US has the highest national incidence of ESRD in the world at a 2010 unadjusted rate of 369 per million with approximately 44% of new US ESRD patients being diabetic [
4,
5]. In Australia, the rate of ESRD is considerably lower than the US at 101 per million, and just fewer than 35% of patients are diabetic [
13]. IGAN is the most common form of GN in Australia, and contributes to nearly twice the frequency of GN-related ESRD as FSGS (IGAN 44% vs FSGS 23%) [
13]. While these data do not indicate that FSGS or GN overall will add to a large future burden of ESRD in regions where diabetes is prevalent, the impact on lower risk regions is not known, and if FSGS in Iraq begins at an early age, a second issue is whether FSGS will increase in frequency as the young population ages.
In the US, FSGS was not always a commonly recognized disease, but it is currently the leading cause of nephrotic syndrome in both African Americans and whites [
9,
23‐
27]. In the US, the risk of ESRD owing to FSGS is 4-times greater in African Americans, and African Americans are diagnosed with more severe disease at a peak age of 35 to 43 years old compared to 47 to 57 years old among whites [
27,
28]. There is not any indication that age per se has any effect on prognosis, but FSGS has a generally poor out-come, and early versus late age of onset of any CKD results in a significantly increased loss of “kidney life” [
29,
30].
FSGS appears to be increasing in many countries of the Middle-East and replacing SLE as the most common type of GN [
31‐
33]. SLE is well known to have geographic, racial, and ethnic variations [
13,
34,
35]. Some of the geographic differences are undoubtedly due to biopsy practices. The Australian biopsy rate is > 20 per 100,000. The US rate is approximately 17 per 100,000, less than Australia but higher than the 4–8 per 100,000 practiced by nephrologists in most parts of the world and the 7.8 per 100,000 in Kurdistan [
13,
36]. High biopsy rates, particularly for minor abnormalities, will certainly increase rates of IGAN and less active forms of SLE.
The validity of the reported causes of ESRD in the US and other developed countries has been questioned [
37]. A patient with long-standing diabetes will be appropriately considered to have diabetic nephropathy, but hypertension is problematic, as physician biases have been shown to influence the assignment of hypertensive nephropathy to ESRD patients rather than exploring other causes [
37].
With biopsies, a diagnosis of a specific cause of late stage kidney disease can often be made [
38]. End-stage glomerulonephritis is characterized by solidified glomeruli that in the case of immune-complex disease frequently contain immunoglobulin deposits, and in IGAN, IgA deposits usually remain with advanced glomerulosclerosis [
38]. Hypertension progresses by increasingly severe arteriosclerosis and glomerular loss that is primarily the result of ischemic glomerular obsolescence [
39]. A predominance of glomerular solidification with hyalinosis lesions and IgM and C3 deposits favors primary FSGS as a cause of ESRD [
39,
40]. Our analysis of causes of biopsy determined ESRD in Iraqi patients indicates that the proportional contribution of FSGS to non-diabetic ESRD could be as high as 41% and suggests that FSGS could raise ESRD rates if the disease followed the patterns in the US and Australia and became more common in older members of the population.
One hypotheses for the lowered rates of ESRD and FSGS in the elderly of Northern Iraq is that physicians stop looking for disease in older patients, or older persons become oblivious to their illnesses and do not seek medical help. We believe that these are unlikely explanations. The elderly are valued members of Iraqi and Kurdish society, and there is no age discrimination for any form of medical service.
A second hypothesis is an age cohort effect in which older members of the population have not been exposed to the factors causing the disease. This certainly could affect rates of diabetes and ESRD, as older Iraqis have been living in deprived conditions imposed by international trade restrictions since the 1980s. A current 26–30% rate of obesity is reported for Southern Iraq [
41,
42], but this is excessive for Sulaimaniyah, where the all-age obesity rate was less than 10%. The obesity rate of 36% in Jordan [
41] may portend changes that will be seen in the future, but we do not see a large segment of the Kurdish population currently at risk for diabetic kidney disease.
Although both Iraq and Jordan have similarly young populations, the estimated risk of ESRD in Northern Iraq was low; while the Jordanian population when adjusted for age had a risk of ESRD that more resembled the US. These differences highlight the impact of undernutrition and over nutrition on kidney health. Political instability is an unfortunate fact-of-life in many parts of the Middle-East and North Africa. Somalia and Sudan are examples where war and continuous undernutrition have lead to endemically high rates of hypertension and non-diabetic CKD possibly influenced by an intra-uterine derived nephron deficit [
43,
44]. Diabetes as a disease of overnutrition and ageing will almost certainly become more common as economies improve. FSGS appears to be increasing throughout the Middle-East, and we suggest that GN and particularly FSGS are also age-dependent with effects on ESRD that are unlikely to be known for many years.