Pattern of glomerular disease in Saudi Arabia

Pattern of Glomerular Disease in Saudi Arabia Ahmed H. Mitwalli, MD, FACP, FRCPE, Jamal S. AI Wakeel, MD, FRCP, S.S. AI Mohaya, MD, FACP, H.G. Malik, MD, MRCP, Hassan Abu-Aisha, MD, FRCP, Omer S. Hassan, MD, DTMH, CTM, and M. Akhtar, MD, FRCPA • Clinical data and renal biopsy study of 186 adult paUenta found to have nephropathy and seen at the Security Forces Hospital, Rlyadh, over a 5-year period (1989 to 1994) were reviewed. Primary glomerular disease accounted for more than three fourths of all patients (79%), and the most common histological lesion was focal segmental glomerulosclerosis (40.8%) associated with a high incidence of hypertension (86.7%), nephrotic syndrome (61.7%), hemsturia (48.8%), and renal impairment (33.3%). Mssangioproliferative glomeruIonephri'ds was the second most common lesion (21.1%), followed by membreous glomerulonephrltis (13.6%), immunoglobulin A nephropathy (IgAN) (13.6%), membranoproliferative glomerulonephritis (9.5%), and minimal change disease (1.4%). Although not as common as in most other developed countries, IgAN is being increasingly recognized in Seudis. Lupus nephritis remained the commonest cause of secondary glomeruIonephriUs (48.5%), whereas amyloidosis was conspicuously absent. There is no evidence, at least in this series, that chronic infection such as hepat~is B virus infection has a major role in the development of glomerulonephrltis. © 1998 by the National Kidney Foundation, Inc. INDEX WORDS: Glomerular disease; focal segmental glomerulosclerosis; Saudi Arabia.

LOMERULAR disease is one of the commonest causes of end-stage renal failure in many countries, including Saudi Arabia.~-3 Its pattern, however, is not uniform in all countries. It is more frequent in the tropics and reflects the consequences of exposure to infective agents. 4 Conversely, immunoglobulin A nephropathy (IgAN) has emerged as the commonest primary glomerular disease in the Far East and Europe.5-7 Although several studies have been published from Saudi Arabia, 8-~2the pattern of nephrophathy is still ill defined. In a series of 147 renal biopsies, Qunibi et al reported focal segmental glomerosclerosis as the commonest disease. 8 In Huraib et al's study, membranoproliferative glomerulonephritis and membranous nephropathy predominated. ~ From the southern part of Saudi Arabia, mesangioproliferative glomerulonephritis was reported to be the most common lesion.9 In this study, we report the pattern of nephropathy as seen in a major referral hospital in Saudi Arabia.

light microscopy at the time of biopsy. The tissues obtained were processed for light microscopy, immunofluorescence, and electron microscopy studies. All biopsy specimens were then examined by a renal histopathologist, and interpreted according to World Health Organization (WHO) classification. ~3 Generally, biopsy specimens containing two or more giomeruli were considered adequate; however, in some cases in which diagnosis was obvious (for example, membranous nephritis), fewer glomeruli were considered sufficient. In all cases, a minimum of 20 sections were obtained and stained for hematoxylin-eosin, periodic acid-Schiff (PAS), trichrome, and Jone's stain. Immunofluorescent microscopy panel included IgA, lgM, IgG, C3, C~q, and fibrinogen. For electron microscopy, attempt was made to study at least two glomeruli in each case. The available medical charts were reviewed, and the following information was collected: age, sex, nationality, complete urinalysis and microscopy; 24-hour urine protein excretion and creatinine clearance; serum creatinine, urea and electrolytes; serological markers for hepatitis B and C, including HbsAg, HbsAb, HbeAg, HbeAb, HbcAb, and HCV Ab; and human immunodeficiency virus (HIV) status. All patients had ultrasound and retrograde pyelography to rule out obstruction, reflux, and other pathological conditions. The distribution of histopathological lesions as shown by renal biopsy was such that 147 patients were considered to have primary giomerular disease, 33 secondary glomerulonephritis (GN),

MATERIALS AND METHODS

From the Department of Medicine and the College of Medicine Research Centre, King Khalid University Hospital, Riyadh; Pathology Department, King Faisal Specialist Hospital, Riyadh; and the Department of Medicine, Security Forces Hospital, Riyadh, Saudi Arabia. Received August 3, 1995; accepted in revisedform February 2, 1996. Address reprint requests to Ahmed H. Mitwalli, MD, FACP, FRCPE, Department of Medicine (38), King Khalid University Hospital, PO Box 2925, Riyadh 11461, Saudi Arabia. © 1996 by the National Kidney Foundation, Inc. 0272-6386/96/2706-000553.00/0

G

The medical charts of 186 adult patients who underwent renal biopsies at the Security Forces Hospital, Riyadh, Saudi Arabia, between October 1989 and December 1994, were retrospectively reviewed. There were 104 men and 82 women, with a mean age of 32.4 years. The indications for renal biopsy included nephrotic syndrome; unexplained microscopic or macroscopic hematuria with or without active urine sediments; systemic disease with clinical evidence of renal involvement; and unexplained renal impairment. All renal tissues were obtained by percutaneous biopsy (using a Tru-cut needle) under ultrasound guidance. Another core was taken if the obtained tissue was found inadequate under the

American Journal of Kidney Diseases, Vol 27, No 6 (June), 1996:797-802

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MITWALLI ET AL

and six patients had tubulointerstitial disease. The criteria for classifying glomerular lesions as primary (or idiopathic) was based on the lack of evidence of systemic disease or other underlying abnormalities. Statistical analysis was performed using the statistical package for social sciences.

RESULTS

With a mean age of 32.3 years and a male-tofemale ratio of 1.3:1, 95% of the patients were Saudi nationals, indicating the homogeinity of the patient population (Table 1). Patients younger than 20 years of age represented 20.4% of the sample; 21 to 40 years, 53.8%; 41 to 60 years, 22.6%; and older than 60 years, 3.2%.

Primary Glomerular Disease Primary glomerular disease (GD) constituted 79% of all renal biopsy specimens, and the commonest lesion was focal segmental glomerulosclerosis (40.8%); it accounted for 32.3% of all renal biopsy specimens. Mesangioproliferative GN was the second most common diagnosis (21.1%) of the primary GD and represented 16.7% of all the cases. Membranous GN (MGN) and IgAN occurred with similar frequency (13.9%) and accounted for 10.8% of all renal biopsy specimens. Membranoproliferative GN (MPGN) was found in 14 cases (9.5%) of the primary GD, constituting 7.5% of all renal biopsy specimens (9 patients with type I, 5 patients with type II). Minimal change disease (MCD) was diagnosed only in 2 patients (1.1%).

Secondary Glomerular Disease Secondary GD was diagnosed in 17.8% of all the cases, and the most common cause was sys-

Table 1. Patient Characteristics No. of Patients (N = 186)

Sex Male Female

Mean age (Y0 Nationality Saudi Non-Saudi Primary glomerular disease Secondary glomerular disease Miscellaneous

104 82

%

55.9 44.1

32.4 178 8 147 33 6

95.7 4.3 79.1 17.7 3.2

temic lupus erythematosus (SLE) (48.5%), which accounted for 8.6% of the study population. Using the WHO classification for SLE, six cases (37.5%) were in class HI, four cases (25%) in class II, three cases (18.8%) in class IV, two cases (12.2%) in class I, and one case (6.25%) in class V. Hypertensive nephrosclerosis was the second most common cause of secondary GD (24.2%) and represented 4.3% of all cases. There were six (18.2%) patients with diabetic nephropathy, representing 3.2% of all renal biopsy specimens. All of them had biopsies to exclude other underlying renal pathology. Henoch-Schtnlein purpura was implicated in three cases (9.1%). Tubulointerstitial diseases were relatively less frequent and included four cases of interstitial disease (one case was due to tuberculosis), and two cases were due to chronic pyelonephritis. Table 2 shows the age distribution of histopathological lesions as shown by renal biopsy. Primary focal segmental glomerulosclerosis (FSGS) appeared to be the major pattern in all age-groups, and its age-specific incidence increased with age, reaching its maximum (peak) in patients older than 60 years (50%). IgAN and diabetes mellitus (DM) also showed similar trends. In contrast, the age-specific peak incidence of mesangioproliferative GN (23.7%), MPGN (15.8%), MCD (2.6%) and HenochSchtnlein purpura (2.6%) occurred among adolescents and young adults (ie, <40 years), and decreased with increasing age. MGN, SLE, and interstitial disease were more common in young adults (21 to 40-years age-group) than in other age-groups. It appears, therefore, that distinct histopathological patterns predominated within each age category. Table 3 shows the sex distribution of the various disease entities as shown by renal biopsy. Primary GD affected men more often (82.7%) than the women (74.4%), and this was manifested primarily in FSGS (37.5% v 25.6%), MGN (13.5% v 7.3%), and IgAN (12.5% v 8.5%). Women, however, were affected by secondary GD more often than men (25.6% v 11.5%), particularly with respect to SLE (15.9% v 2.9%) and Henoch-Schtnlein purpura (all three cases were female). The clinicopathological features of the primary GD are presented in Table 4. At the time of renal biopsy, 90 (61.2%) patients had nephrotic

GLOMERULAR DISEASE IN SAUDI ARABIA

799

Table 2. Age Distribution of Histopathological Lesions in 186 Renal Biopsy Specimens Age-Group (yr) <20 (n = 38) Diagnosis Primary GD FSGS Mesangioproliferative GN MGN IgAN MPGN MCD Secondary GD SLE Essential hypertension (nephrosclerosis) DM Henoch Schonlein purpura Tubulointerstitial disease Interstitial disease Pyelonephritis

21-40 (n = 100)

41-60 (n = 42)

>60 (n = 6)

No.

%

No.

%

No.

%

No.

%

11 9 3 2 6 1

28.9 23.7 7.9 5.3 15.8 2.6

27 18 12 12 7 1

27 18 12 12 7 1

19 4 5 5 1 0

45.2 9.5 11.9 11.9 2.4 0.0

3 0 0 1 0 0

50.0 0.0 0.0 16.7 0.0 0.0

3 2 0 1

7.9 5.3 0.0 2.6

11 5 1 2

11 5 1 2

2 1 4 0

4.8 2.4 9.5 0.0

0 0 1 0

0.0 0.0 16.7 0.0

0 0

0.0 0.0

4 0

4 0

0 1

0.0 2.4

0 1

0.0 16.7

ics. IgAN was always associated with hematuria (100%), which was also common among patients with MGN (77.4%) and MPGN (71.4%). There was a significant hypertension (86.7%) in FSGS. Renal insufficiency was diagnosed more frequently in IgAN (35%), membranous (35%) and FSGS (33.3%). Among the secondary GD, essential hypertension and DM were the leading

syndrome, 87 (59.2%) patients presented with hematuria, 74 (50.3%) patients with hypertension, and 40 (27.2%) patients had renal impairment. With the exception of MCD (diagnosed only in two patients), nephrotic syndrome was an important manifestation of MGN (90%) and FSGS (61.7%), although FSGS accounted for 41.1% and MGN for only 12.5% of all nephrot-

Table 3. Sex DislnbuUon of Histopathological Lesions in 186 Renal Biopsy Specimens Male Diagnosis Primary GN FGS Mesangioproliferative GN MGN IgAN MPGN MCD Secondary GN SLE Essential hypertension (nephrosclerosis) DM Henoch Schonlein purpura Tubulointerstitial Interstitial disease* Pyelonephritis * One case is tuberculosis.

Female

Total

No.

%

No.

%

No.

%

39 11 14 13 7 2

37.5 10.6 13.5 12.5 6.7 1.9

21 20 6 7 7 0

25.6 24.4 7.3 8.5 8.5 0.0

60 31 20 20 14 2

32.3 16.7 10.8 10.8 7.5 1.1

3 5 4 0

2.9 4.8 3.8 0.0

13 3 2 3

15.9 3.7 2.4 3.7

16 8 6 3

8.6 4.3 3.2 1.6

4 2

3.8 1.9

0 0

0.0 0.0

4 2

2.1 1.1

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MITWALLI ET AL

Table 4. Clinicopathological Features of Primary Glomerular Disease Nephrotic Syndrome

Hematuria

Hypertension

Renal Impairment

Diagnosis

No.

%

No.

%

No.

%

No.

%

FSGS (n = 60) Mesangioproliferative Glomerular Nephritis (GN) (n = 31) MGN (n = 20) IgA nephropathy (n = 20) MP GN (n = 14) MCD (n = 2) Total

37

61.7

29

48.3

52

86.7

20

33.3

17 18 8 8 2

54.8 90 40 57.1 100

24 4 20 10 0

77.4 20 100 71.4 0

7 7 4 4 0

22.6 35 20 28.6 0

2 7 7 4 0

6.5 35 35 28.6 0

90

causes of impaired renal function (42.9% and 35.7%, respectively). Hepatitis B surface antigen (HBsAg) was detected in 14 of 173 patients tested (8%), and 8 of 162 (4.9%) patients had positive serology for hepatitis C. All patients (80) tested for HIV infection were negative, and none of the patients had a history of drug abuse. DISCUSSION

As reported earlier, ~4glomerular disease (GD) remained the predominant form of renal diseases in this study. Distinct features, however, were observed with respect to its pattern. It was interesting to observe that primary GD accounted for more than three quarters (79%) of all nephropathies in our series, a higher rate than earlier reported. 8,t~ The infrequency with which renal biopsy is performed on patients known to have secondary causes probably explains the excess rate of the primary GD in our series. The diagnosis of primary GD was based on the lack of evidence of systemic disease or other abnormalities, such as obstruction reflux, tumors, etc., which could be implicated in the cause and pathogenesis of nephropathy. Despite the high rate of seropositivity for hepatitis B and C in our patients, there was no clinical or histopathological evidence for a causal relationship with nephropathy. Another important observation was the high frequency of primary FSGS. It constituted 32.3% of all renal biopsy specimens and accounted for 40.8% of the primary GD. The reported frequency of primary FSGS in local series varies widely from less than 4% In Gizan, Southern Saudi Arabia, 9 to approximately 35% in Riyadh. ~2However, only in two series was primary

87

74

40

FSGS reported as the major pattern of renal disease in adults. 7.~t Qunibi et al 8 reported that primary FSGS represented 15.6% of all renal biopsies and accounted for 30.7% of the primary glomerular disease. This finding was replicated by Akhtar et all2 in a relatively larger series, who found that primary FSGS constituted 30.4% of the primary GD. The reported frequency of primary FSGS in other countries ranges between 7% and 15% in patients evaluated for proteinuria. 15,16 FSGS is a condition of unknown origin and pathogenesis. In recent years, it has been suggested that FSGS is not a single clinicopathological entity but represents a heterogenous group of disease in which focal and segmented glomerular sclerosis is the common denominator. Some authors have attempted to subdivide FSGS into specific subgroups based on such features as size of the glomernlus and location of the segmented sclerosis within the glomeruli. ~7 For example, cases of FSGS with sclerosis limited to the tubular pole of the glomerulus (tip lesion) are thought to belong to a specific entity with excellent prognosis. Another lesion is characterized by enlarged glomerular size and lesions of sclerosis primarily limited to the vascular pole. This is typically associated with reduced renal mass and has been suggested as a specific subgroup of FSGS. Others, however, have argued that these features are not sufficiently consistent and reproducible to warrant specific subcategorization of FSGS lesions. J8 In the current study, no attempt was made to distinguish between various subgroups of FSGS. The diagnosis of FSGS in our cases was based

GLOMERULAR DISEASE IN SAUDI ARABIA

on the demonstration of classical lesions characterized by collapse of capillaries with sclerosis and capsular synenchae. None of our biopsy specimens showed features of collapsing glomerulopathy as described by Weiss et al. f9 Why the frequency of primary FSGS should be so high in this series is not very clear. Histologically, the distinction between MCD and FSGS in its early stage is not easy, and FSGS could be misdiagnosed as minimal change disease (MCD). 2°'2~ This may explain in part the relatively high frequency of MCD that has been reported in some local series, because some cases of FSGS might have been classified as MCD. Furthermore, the time at which the renal biopsy is performed is also said to be critical for the histological classification of glomerular disease, with minimal changes occurring more frequently in areas where the renal biopsy policy is performed early and vice versa. 6 Therefore, the discrepancy between local centers in the reported frequencies of FSGS might have been influenced by the referral pattern and renal biopsy policy. Until further studies are carried out and methods are standardized, it is not possible to determine whether the disease pattern seen in this study is truly representative of that seen in the population. Clinically, FSGS was the leading cause of nephrotic syndrome among adult patients in this series (41%). Comparable figures have been reported from Saudi Arabia (35.8%) and Ghana (36%). 22FSGS has also been reported as the most common cause of nephrotic syndrome in black adults. 23'24FSGS has been recognized as an ominous sign with a tendency to progress rapidly to end-stage renal failureY This is reflected in our series by the high incidence at the time of renal biopsy of such poor prognostic factors as hypertension (86.7%), 26 nephrotic syndrome (61.7%), and renal insufficiency (33.3%). 27 IgAN was fairly common in this series, because 13.6% of all adult patients with primary glomerular disease fell in this category. This is higher than the 6% earlier reported by Akhtar et al, ~2but lower than in Europe and the Far EastY where IgAN has emerged as the major pattern of primary glomerulonephritis. In common with most studies, IgAN was more common in men than in women (2:1), with peak incidence in young adults, and it remained an important cause of hematuria. The absence of amyloidosis in our patients was also

801

astriking, despite the high prevalence in the population served of tuberculosis, rheumatoid arthritis, and other chronic conditions that have been linked to it. 8'9 In conclusion, glomerular disease, in this series, is characterized by a high frequency of primary FSGS, which is a leading cause of nephrotic syndrome. It differs from many other tropical and subtropical countries by the low prevalence of infection-associated glomerulonephritis. As a significant percentage of patients with primary FSGS progress to ESRD, which represents a heavy burden on health services because of the large number of patients for whom dialysis and transplantation facilities will be required, it is mandatory that the cause, pathogenesis, and the natural history of FSGS be pursued. REFERENCES 1. VoUmer WM, Wahl PW, Balagg CR: Survival with dialysis and transplantation in patients with end-stage renal failure. N Engl J Med 308:1553-1558, 1983 2. Disney APS, Correll R: Report of the Australian and New Zealand Combined Dialysis and Transplantation Registry. Med J Aust 1:117-122, 1981 3. Nielson GN, Nielson B: On the prevalence of kidney diseases in Southern Arabia. Kidney Int 26:487, 1984 4. Chugh KS, Sakhyja V: Glomernlar diseases in the tropics. Am J Nephrol 10:437-450, 1990 5. Levy M, Berger J: Worldwide perspective of IgA nephropathy. Am J Kidney Dis 12:340-347, 1988 6. Schena FP: A retrospective analysis of the natural history of primary IgA nephrotpathy worldwide. Am J Med 89:209-215, 1990 7. Bailey RR, Lynn KL, Robson RA, Smith AH, Wells JE: Long-term follow-up of patients with IgA nephropathy: The leading cause of glomerulonephritis in New Zealand. Kidney Int 46:921, 1994 8. Qunibi WY, AI-Sibai MB, Taher S, Akhtar M: Renal disease in Saudi Arabia: A study of 147 renal biopsies. King Faisal Specialist Hospital Journal 4:317-323, 1984 9. Jorgensen HE, Malik SH, Paul "IT, Whorra PC: Renal disease in Saudi Arabia. Ann Saudi Med 5:195, 1985 10. Abdulrahman MB, El-ldrissy ATH: Childhood disorders in Saudi Arabia. Pediatr Nephrol 2:368-372, 1988 11. Huraib SO, Abu-Aisha H, Mitwalli A, Mahmood K, Momon NA, Sulimani F: The spectrum of renal disease found by kidney biopsies at King Khalid University Hospital. Saudi Kidney Dis Transplant Bull 1:15-19, 1990 12. Akhtar M, Qunibi W, Taher S, Ginn E, Furayh O, Sanjad S, A1-Sabban E: Spectrum of renal disease in Saudi Arabia. Ann Saudi Med 10:37-44, 1990 13. Churg J, Sobin LH: Renal disease: Classification and atlas of glomerular diseases. Tokyo, Igaku-Shoin, 1995 14. Cameroon JS: Glomerulonephritis: Current problem and understanding. J Lab Clin Med 99:755-787, 1982

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15. Habib R, Kieinknecht C: The primary nephrotic syndrome of childhood, in Pathology Annual. New York, NY, Appleton-Century-Crofts, 1971, pp 427-434 16. Lewis EJ: Management of nephrotic syndrome in adults, in Cameroon JS, Glassock RJ (eds): The Nephrotic Syndrome. New York, NY, Dekker, 1986, pp 461-521 17. Howie AJ: Segmented sclerosing glomerular lesions. Pediatr Nephrol 7:370-374, 1993 18. Schwartz MM, Korbet SM: Primary focal segmented glomurulosclerosis: Pathology, histological variants and pathogenesis. Am J Kidney Dis 22:874-883, 1993 19. Weiss MA, Daquioag F, Morgolin EG, Pollak VE: Nephrotic syndrome, progressive irreversible renal failure and glomerular collapse: A new clinicopathologic entity. Am J Kidney Dis 7:20-28, 1986 20. Kashgarin M, Hayslett JP, Siegal NJ: Lipoid nephrosis and focal sclerosis: Distinct entities or spectrum of disease. Nephron 13:105, 1974 (editorial) 21. Lichtiz C, Ben-lzhak O, Avi ON, Levy J, Allon U: Childhood minimal change disease and focal segmental glomerulonephritis: A continuous spectrum of disease? Am J Nephrol 11:325-331, 1991 22. Adu D, Anim-Addo Y, Foli AK, Blankson TM, Anno-

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bil SH, Reindorf CA, Christian EC: The nephrotic syndrome in Ghana: Clinical and pathological aspects. Q J Med 50:297306, 1981 23. Bakir AH, Bazilinski NG, Rhee HL, Ainis H, Dunca G: Focal segmental glomerulosclerosis: A common entity in nephrotic black adults. Arch Intern Med 149:1802-1804, 1989 24. Pontier PJ, Patel TG: Racial differences in the prevalence and presentation of glomerular disease in adults. Clin Nephrol 42:79-84, 1994 25. Korbet SM, Schwartz MM, Lewis FJ: The prognosis of focal segmental glomerulosclerosis of adulthood. Medicine 65:304-311, 1986 26. Ritz E, Rambausek M, Hasslacher C, Mann J: Pathogenesis of hypertension glomerular disease. Am J Nephrol 9:85-90, 1989 (suppl) 27. Rydel JJ, Korbet SM, Borok RZ, Schwarts MM: Focal segmental glomerular sclerosis in adults: Presentation, course, and response to treatment. Am J Kidney Dis 25:534542, 1995 28. Lai FM, Lai KN, Chan KW, Au TC, Tong KL, Vallance-Owen J: Pattern of glomerulonephritis in Hong Kong. Pathology 19:247-252, 1987