|Year : 2011 | Volume
| Issue : 4 | Page : 651-661
|Can we improve the diagnosis of renal failure? A revised coding system for the Middle East and North Africa
Guy H Neild1, D Deren Oygar2, Mohamed Ben Hmida3
1 UCL Centre for Nephrology, Royal Free Campus, London, United Kingdom
2 Nicosia State Hospital, Burhan Nalbantoglu General Hospital, North Cyprus
3 Department of Nephrology, H Chaker Hospital, 3029 Sfax, Tunisia
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|Date of Web Publication||9-Jul-2011|
| Abstract|| |
We reviewed the regional data on primary renal disease (PRD) causing end-stage renal failure (ESRF) during the decade 2000-2009. Reporting was generally inconsistent and diagnostic groups were poorly defined. We propose a system in which all diagnoses fall into one of eight broad groups: ESRF of uncertain etiology, congenital abnormalities of the kidney and urinary tract (CAKUT) and acquired uropathy, glomerular diseases, tubulo-interstitial disease (TID), other congenital and familial diseases, diabetes, renovascular disease and other specified diagnoses. Each group has sub-headings; for instance, primary glomerulonephritis, secondary glomerulonephritis, and hereditary glomerular disease. For each sub-heading, there is a list of specific diagnoses similar to that used by the European Dialysis and Transplant Association (EDTA) and United States Renal Data System (USRDS) coding systems. We also recommend that "etiology unknown" group should be reported in more detail as either "glomerular phenotype" or "tubular phenotype" and careful attention be paid to evidence for a family history of renal disease. To improve reporting, all patients who are diabetic, and all who have evidence of familial inheritance, should be recorded and a diagnostic category should be chosen. Thus, a diabetic patient is designated as "diabetic nephropathy" only if he/she fulfils the case definition for that diagnosis. We believe that the collection can be done much better as exemplified by the pediatric community, where data collection is very consistent, and there is a low rate of "unknown disease".
|How to cite this article:|
Neild GH, Oygar D D, Hmida MB. Can we improve the diagnosis of renal failure? A revised coding system for the Middle East and North Africa. Saudi J Kidney Dis Transpl 2011;22:651-61
|How to cite this URL:|
Neild GH, Oygar D D, Hmida MB. Can we improve the diagnosis of renal failure? A revised coding system for the Middle East and North Africa. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2019 Jul 19];22:651-61. Available from: http://www.sjkdt.org/text.asp?2011/22/4/651/82640
(This review has been simultaneously published in the Arab Journal of Nephrology and Transplantation)
| Introduction|| |
Before we treat patients, we should know what is wrong with them. Yet, in adult registry data, "etiology unknown" is often the most common diagnosis mentioned.  There may be many reasons for this, and poor quality reporting and late presentation account for some. But results are so consistent that it would seem that many patients defy diagnosis.
The objective of this study is: a) to review the published literature from this part of the world, b) report the similarities and differences, and c) recommend a system for reporting primary renal disease (PRD) that can be used by all. This will allow direct comparisons of national data sets.
Apart from patients who are actually designated as "etiology unknown", there are many others in whom the diagnosis assigned is no more than an informed guess. This is not necessarily a problem as long as terms are used precisely, consistently and above all are clearly defined. For instance, we must know what percentage of those categorized as "glomerulonephritis" have had a renal biopsy. Currently, common diagnostic categories such as hypertension and renovascular disease are undefined.
We report the regional data published during the decade 2000-2009, and highlight the current problems and issues to be addressed. We propose a system in which all specific diagnoses can be summarized into one of eight broad groups. We recommend that the unknown group should be reported in more detail as either "glomerular phenotype" or "tubular phenotype" and careful attention be paid to evidence for a family history of renal disease.
| Methodology|| |
We identified all papers published from the regions that include Eastern Mediterranean, Middle East, Arabia and North Africa and that are reflected in the membership of the Arab Society of Nephrology and Transplantation. We used PubMed, Google, and the following cited references to find papers that report data on PRD in patients reaching end-stage renal failure (ESRF) in this region.
| Lessons from Pediatric Nephrology|| |
Since 1976, pediatric registries have reduced the number of children with "no specific diagnosis" from 39%  to less than 5%. Registry data from around the world, recording the PRD resulting in ESRF in children, show that around 50% of cases are caused by "congenital abnormalities of the kidney and urinary tract" (CAKUT) and a further 20% by "other congenital and inherited diseases".  Data from the Middle East are consistent with this worldwide view [Table 1].
|Table 1: Review of pediatric literature from the Middle East and North Africa.|
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Since 2008, the British Association for Pediatric Nephrology (BAPN) has taken the view, "renal dysplasia, with or without vesicoureteric reflux (VUR), is the most common cause of ESRF in the pediatric population. On the basis that the clinical overlap between reflux nephropathy and renal dysplasia is so great and that clinical distinction between these two groups is quite arbitrary, these two categories have been united". 
In our review, we use the term CAKUT for all forms of congenital malformations and they can be broadly divided into obstructive and non-obstructive causes. The latter group includes the synonyms: reflux nephropathy, renal dysplasia, renal hypo-dysplasia and chronic pyelonephritis.
| Review of Adult Literature from the Middle East and North Africa|| |
In 2003, Professor Barsoum published a review of this topic, from the literature and his personal experience, and concluded that the principal causes of ESRF in North Africa were interstitial nephritis (14-32%), glomerulonephritis (11-24%), diabetes (5-20%), nephrosclerosis (5-21%), polycystic and other hereditary diseases (<5%).  His paper also makes helpful comments about geographical and historical differences in schistosomiasis, amyloid, sickle cell disease, tuberculosis, renal stones, and Takayasu's disease.
The literature published from this region in the past 10 years that we reviewed is summarized in [Table 2]. Several problems emerge when the data are analyzed. None of the papers uses a methodology similar to another. All papers are characterized by lack of case definitions, by lack of details of whether diagnoses are supported by biopsies and whether biopsies are supported by immuno-peroxidase (IP)/immuno-fluorescence (IF), or electron microscopy (EM). Three papers specifically recognize tubulointerstitial disease (TID) as a significant diagnostic group, while others mention it as a minor sub-group and the remainder make no mention of TID. We noticed that the sum of "unknown" plus "hypertension" is usually 45-50%.
|Table 2: Review of published renal data in adults from the Middle East and North Africa.|
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| Specific Comments from Individual Papers|| |
The PRD data are presented as the whole group and subdivided in ages <40, 40-60 and >60 years. They found that in the <40 years age-group, the commonest cause of PRD was unknown (25%) followed by hypertension (21%) [Table 2]. 
Data on PRD were expressed as incident rates. They highlighted the fact that idiopathic chronic TID was common and varied from region to region. Geographical variation of data is shown in both tables and map. 
Patients had "CRF" that was not defined, but two thirds required dialysis. About 58% were described as "unknown", none had a diagnosis of glomerulonephritis (so presumably none had renal biopsies) and 25% were classified as post-renal, which included bilateral renal stones (7%), ureteral stones (4%), bladder stone (4%), bilateral hydronephrosis (4%), schistosomiasis (4%), enlarged prostate 2% and bladder carcinoma (1%). 
| Definitions|| |
In our proposal for a regional classification, we define some of the terms that are commonly used.
Not all renal failure in diabetic patients is caused by diabetic nephropathy (DN). The term should be used for patients with significant proteinuria and evidence of other complications of diabetes (e.g. retinopathy) consistent with the likely duration of the diabetes. The other criteria used are as follows:
- long duration of diabetes before the onset of CRF (usually more than 10 years).
- normal sized kidneys on ultrasound.
- presence of diabetic retinopathy on fundus examination.
- absence of hematuria or red blood cell casts in urine.
- presence of proteinuria even after the patient has begun dialysis. 
Familial (inherited, family history)
Any patient with a known member of the family, however remote, who has had renal disease, should be considered as having a positive family history.
Glomerulonephritis can present in various ways but not as asymptomatic ESRF. All forms of primary glomerulonephritis will present either with macroscopic hematuria, nephritic syndrome, nephrotic syndrome, fluid retention, malignant hypertension, or some will be diagnosed based on routine investigations. Glomerular phenotype is defined by the presence of clinical history consistent with glomerulonephritis, without performing a renal biopsy.
Hypertensive nephropathy (HN)
This is (probably) a rare condition, except in patients who have sub-Saharan African ethnicity. Patients can be classified as HN if a renal biopsy shows that the primary pathology is nephro-angiosclerosis. , Without a biopsy, they should be classified as unknown etiology (glomerular or tubular phenotype).
The nephrotic syndrome
This is defined as patients with the triad of nephrotic range proteinuria (>3 g/day, >300 mg/mmol), hypoalbuminemia (albumin below the laboratory normal, <35 g/L), and peripheral (dependent) edema. This must be differentiated from the patient who has only nephroticrange proteinuria (see below).
Nephrotic-range proteinuria (alone)
This is defined as proteinuria (>3 g/day or >300 mg/mmol) occurring in a patient with normal plasma albumin and no peripheral edema.
Primary focal and segmental glomerulosclerosis (FSGS) with the nephrotic syndrome
Renal biopsy showing features of FSGS in a patient with the nephrotic syndrome.
IgA nephropathy (proven by IP or IF)
Renal biopsy showing mesangioproliferative glomerulonephritis with mesangial deposits of IgA.
Renal histology showing thickening of the peripheral glomerular basement membrane, presence of "spikes" on silver stain, with IF showing C3 and IgG deposits around the glomerular basement membrane (GBM).
Membranoproliferative (mesangiocapillary) GN
Renal histology characterized by thickening of the peripheral basement membrane of the glomeruli, with demonstration of double contours on silver stain (reduplication of the GBM). Also, IF should demonstrate variable degrees of C3 and IgG deposits.
Crescentic (extracapillary) glomerulonephritis (idiopathic)
Renal histology showing the presence of crescentic and necrotizing glomerulonephritis, without evidence of systemic disease.
Secondary FSGS (without the nephrotic syndrome)
Patients with biopsy proven FSGS without history of the nephrotic syndrome (may have nephrotic-range proteinuria).
Mesangioproliferative (other, unspecified)
Mesangioproliferative glomerulonephritis without mesangial deposits of IgA.
Idiopathic endocapillary GN (including post-infectious)
Characterized by enlarged and hypercellular glomeruli due to swelling and proliferation of glomerular cells (endocapillary proliferation), with neutrophil exudation and IF showing granular deposits of IgG and complement in the GBM and mesangium and EM showing large sub-epithelial deposits (humps).
Renal stones, with or without nephrocalcinosis, rarely cause renal failure in the absence of obstruction and infection. Co-existence of renal stones and renal failure suggests hyperoxaluria (code 48), magnesium-losing nephropathy (code 40) or Dent's disease (code 36). In patients with recurrent stones causing obstruction, one must exclude cystinuria (code 50) and hyperoxaluria (code 48). Staghorn calculi are caused by triple phosphate (struvite) stones growing in the presence of infection (code 64) [Table 3].
Diagnosis is suspected in patients with evidence of atheroma and asymmetric kidneys. The EDTA reports the broad group of renovascular disease from two non-specific codes: "Renal vascular disease - type unspecified (code 70)", and "Renal vascular disease - due to other cause (not given above) (code 79)".
This entity is defined by patients who reach ESRF with minimal symptoms, minimal proteinuria (urine dipstick 1+ or less), in the absence of peripheral edema and malignant hypertension.
| Proposal|| |
The proposed classification is shown in [Table 3]. We propose a system in which all diagnoses fall into one of eight groups:
Each group has sub-headings, for instance, primary glomerulonephritis, secondary glomerulonephritis, and hereditary glomerular disease (see column 2 of [Table 3]). For each sub-heading, there is a list of specific diagnoses similar to that used by EDTA and USRDS coding systems.
- ESRF of uncertain etiology,
- CAKUT and acquired uropathy,
- glomerular diseases,
- tubulo-interstitial disease,
- other congenital and familial diseases,
- renovascular disease, and
- other specified diagnoses.
We also recommend that "etiology unknown" group should be reported in more detail as either "glomerular phenotype" (code 1) or "tubular phenotype" (code 2) and careful attention should be paid to evidence for a family history of renal disease.
To improve reporting, all patients who are diabetic as well as those with evidence of familial inheritance should be recorded separately, following which a diagnostic category should be chosen. Consequently, a diabetic patient is designated as "diabetic nephropathy" only if he fulfils the case definition as the most likely diagnosis.
| Discussion|| |
The motivation behind these proposals is to improve the knowledge of how much we know, or more specifically how much we currently do not know. This information will direct future research. There are a number of key clinical issues that need to be resolved which relate to clinical terminology.
The nephrotic syndrome is something very specific. It should not be confused with nephrotic-range proteinuria (>3 g/day or >300 mg/ mmol) occurring in a patient with normal plasma albumin and no peripheral edema.
FSGS : Primary FSGS is a cause of the nephrotic syndrome commonly leading to renal failure in children and sometimes adults (EDTA codes 11, 17). Many patients with slowly progressive renal disease, such as reflux nephropathy/renal dysplasia, develop secondary FSGS. This is commonly associated with heavy proteinuria (nephrotic-range) but normal plasma albumin. This has important clinical implications because patients with true nephrotic syndrome will respond poorly to ACE inhibitors (ACEI) while patients with secondary FSGS should have a prompt reduction in proteinuria when blood pressure is reduced with ACEI. The EDTA has no code for secondary FSGS. The USRDS has only a catch all "focal glomerulosclerosis, focal sclerosing -code 5" (with no clinical conditions attached).
Essential hypertension in young white patients does not cause renal failure.  The underlying renal disease can lead to malignant or accelerated hypertension, which can result in rapid loss of the remaining renal function. This is not true in those of West African ethnicity, who do develop renal failure with hypertension and renal biopsy shows a conspicuous nephroangiosclerosis.  In 2008, the association of renal failure was reported in this ethnic group with polymorphisms of MYH9 gene encoding the non-muscle myosin (NMM) heavy chain IIA (NMMHC-IIA), which is present on chromosome 22q11-13. , In fact, the region responsible also includes the gene APOL1 which codes for apolipoprotein L1.  It remains to be investigated whether "hypertensive nephropathy" is a common cause of renal failure in the Middle East and North Africa, as is currently believed.
Hereditary glomerular disease . Although Alport's disease is a type of glomerulonephritis, it is more appropriate to have it listed with other congenital forms of glomerulonephritis because it is not an acquired, immunological disease that might be treated with immunosuppressive drugs.
Diabetes . Over the age of 50 years, approximately one in five patients with non-diabetic renal disease will also be diabetic.  More effort is therefore required to classify patients who are diabetic and have renal failure as having either "diabetic nephropathy" (see definitions) or some other non-diabetic form of disease.
The next major issue is the problem of patients with "no known diagnosis". We have found that even in the West, when renal registries are examined carefully and all uncertain diagnoses are added together ("etiology unknown", "glomerulonephritis; histologically examined but unspecified", "hypertension: unspecified with renal failure") in young adults, rates of unknown diagnosis range from 26 to 36%.  Two main issues will probably account for most genuine cases of "etiology unknown". Firstly, in patients who present late when biopsy may be difficult, and secondly, in diseases that are still uncharacterized and therefore unknown in this part of the world. It is beyond doubt that novel renal diseases, hitherto unrecognized in the West, occur commonly in some countries. ,,
We have previously argued that late presentation with ESRF is not a feature of glomerulonephritis (at least in the West).  Late presentation without earlier symptoms is suggestive of "a tubular phenotype". In the West, there has been traditionally reluctance to biopsy such people, probably with the opinion that it would not change management. We believe that uncharacterized tubular disease is much more common than is recognized.
Data from a large biopsy series in Egypt, described by Barsoum and Francis,  reported that 21% of all renal biopsies (n = 1234) were performed because of unexplained CRF, of which 33% had chronic interstitial nephritis (IN), 8% had FSGS, 5% had nephroangiosclerosis and 11% had ESRF. These diagnoses would all be compatible with primary tubular disease (such as medullary cystic kidney disease) and together represent 57% of all their CRF biopsies.
With late presentation of renal failure, renal imaging is often unrewarding. Imaging patients with advanced renal failure was virtually impossible until the advent of routine ultrasound (circa 1980). It is difficult to obtain accurate information on the shape of small contracted kidneys. Computerized tomography (CT) scan and magnetic resonance imaging (MRI) scanning should give useful information, but there is very little published data on renal imaging in uremia with the exception of analgesic nephropathy. ,
Similarly, renal biopsy is often not an option. One good reason not to biopsy patients with ESRF is that the sample is unlikely to show enough viable tissue to make a specific diagnosis. The majority of glomeruli will show global sclerosis. The only EDTA code for this would be "glomerulonephritis; histologically examined, not given above" (EDTA code 19). We propose that this small group be reported as "etiology unknown, glomerular phenotype".
In conclusion, we hope that a simple and unified system of reporting ESRF will allow our colleagues around the Middle East and North Africa to pool and share data and that this will lead to regional registries that will help direct our future clinical activities and research.
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Guy H Neild
UCL Centre for Nephrology, Royal Free Campus, London NW3 2QG
[Table 1], [Table 2], [Table 3]
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