Abstract
There are few studies that examine, prospectively, the epidemiological profile of glomerulopathy (GP) and its clinicopathological correlation. All patients referred to Al-Amiri renal center in Kuwait from 01 1st, 1995 to 12 31st, 2001 were screened for GP. Detailed clinical data were collected and serological markers were done. Renal biopsy was performed whenever indicated. During those 7 years, a total of 584 patients were diagnosed, on histological basis, to have GP, 315 of whom were Kuwaiti nationals. During the same period of the study, 26 patients presented with bilateral small kidneys, history of proteinuria >2 g/day and lacked systemic manifestations of autoimmune disease. Furthermore, 164 patients with clinical manifestations of diabetic glomerulosclerosis were not subjected to kidney biopsy. Hence, the calculated annual incidence rate of GP in Kuwaiti nationals was 34.5 per 100,000 population (PTP). The calculated rate of diabetic glomerulosclerosis was 13.4 PTP and that of non-diabetic 21.1 PTP. The calculated incidence rates of GP increased with age and were twice as high in males compared to females. Vasculitis was more common in elderly males while SLE nephritis was a disease of adults, 88.7% of whom were females. In the subgroup of primary GP, focal segmental glomerulosclerosis was the most common histological lesion accounting for 18.0% of the total biopsies in Kuwaiti patients, yet only 36.8% of those who fulfilled the criteria of primary type. Minimal change disease was the second primary GP (13.0%), followed by immunoglobulin A deposition disease (7.9%) and membranous glomerulonephritis (5%). Autoimmune diseases such as systemic lupus erythematosus (SLE) and vasculitis were common. Interestingly, only 44 of 72 (61.1%) of patients with SLE and 11 of the 62 (17.7%) of patients with vasculitis presented with rapidly progressive glomerulonephritis. On the other hand, 10 of 58 (17.2%) patients with nephroangiosclerosis presented with renal failure and protein excretion >2 g/day simulating primary GP. Furthermore, only 21 of 40 (52.5%) patients with IgA nephropathy presented with “benign disease”. Prospective studies are essential to ascertain the actual incidence and etiology of GP. The loose clinicopathological correlation in GP dictates an aggressive diagnostic approach in its study and management.
Introduction
Glomerulopathy (GP) is heterogeneous collection of disorders in which the glomerulus function or structure is impaired. This disorder can manifest as a renal limited lesion (primary GP) or as a part of multisystem disease (secondary GP). The introduction and wide application of percutaneous kidney biopsy, presented exploration of the hitherto hidden facets of GP and presented two important observations. First, the immunologically mediated disorders affecting the glomerulus viz. glomerulonephritis (GN) are no more accepted as the sole etiology of disease and factors such as hereditary predisposition, direct trauma, hyperfiltration, substance deposition, etc., are increasingly recognized causes of GP.Citation[[1]] Second, non-invasive testing such as clinical manifestations of autoimmune disease as well as surrogate and serological markers of systemic diseases have limited role in diagnosis of GP.Citation[[2]], Citation[[3]] Data on GP is emerging, yet most of the available information is limited to dialysis or transplantation registriesCitation[[4]], Citation[[5]], Citation[[6]] with their inherent limitations on definite histological diagnosis and/or affected by their retrospective nature of data harvestingCitation[[7]], Citation[[8]], Citation[[9]] or admixture of different races.Citation[[5]] In Kuwait, retrospective studies, have shown that GP is the possible underlying etiology for 24% of the 72 patient per million Kuwaiti nationals accepted on renal replacement therapy every yearCitation[[10]] and 44% of the 18 per million Kuwaiti children.Citation[[11]] To examine the spectrum of GP in Kuwait, we conducted our study in a prospective manner, for a period of seven years, using the mature diagnostic facilities at Al-Amiri renal center, which covers nearly 1/2 of the care of patients with renal diseases in the state of Kuwait.
Methods
In Kuwait, management of patients with renal diseases is the responsibility of two centers based in the two teaching hospitals of Kuwait University, viz. Al-Amiri and Mubarak centers. Each center has a specific geographical area of patient referral designated by the ministry of health. Al-Amiri center is responsible for patients referred from the three hospitals located in the capital and Al-Jahra health areas. Each hospital has a renal clinic and consultation service conducted by Al-Amiri renal team. In mid-1998, Kuwait had a population of 1.72 million of which 0.72 million (41%) were Kuwaiti nationals.Citation[[12]] In the latter group, 209108 were residents in the capital and Al-Jahra governments. In those areas children (age ≤14 years old) were 85734 and elderly (≥60 years old) were 8364. Among Kuwaiti nationals and at all age groups, the male:female ratio was 1:1.
Study Design
At Al-Amiri center, all patients referred, from January 1st, 1995 to December 31st, 2001, were screened for GP. All patients were considered for kidney biopsy if they manifested one of the following features: (a) nephrotic syndrome (persistent proteinuria >40 mg/h/m2 in children) which failed to respond to 8-week course of prednisone (≥2 mg/kg/alternate day) or any adult with proteinuria ≥2.5 g/24 h (b) persistent proteinuria of any degree (>150 mg/24 h) with hematuria (c) isolated hematuria unexplained by hematological, renovascular, or urinary tract disease (d) rapidly progressive renal failure (i.e., rapid decline in creatinine clearance over 3–6 weeks) (e) unexplained renal failure with normal-sized kidneys.
Clinical and Laboratory Data
The data collected included: age of the patient at diagnosis of GP, sex, and nationality as well as the clinical manifestations of GP. Laboratory investigations included: urinalysis, 24 h urinary protein excretion, and creatinine clearance as well as serum cholesterol, complements (C3 and C4), immunoglobulins, ANA, antids-DNA, ANCA, HBsAg, hepatitis C-virus antibodies, ASOT, and Rheumatoid factor. Histological diagnosis of GP was made based on the results of: (a) light microscopic examination of 2-micron thick sections of renal tissues which were stained with hematoxylin and eosin, periodic acid-schiff, Mason's trichrome, and periodic acid-silver methenamine (b) immunofluorescence using antisera against C3, fibrinogen, and immunoglobulins (IgA, IgM, and IgG) (c) electron-microscopy in selected patients.
Results
During the study period, a total of 584 patients were diagnosed to have biopsy-proven GP, 315 of whom were Kuwaiti nationals (). During the same period, 26 Kuwaiti patients were suspected to have primary chronic GN (on clinical basis) but were not biopsied since their kidneys were small at their initial presentation, 21 of who had ESRD while 5 are still being followed on outpatient basis. Moreover, 164 diabetic Kuwaiti patients were not subjected to kidney biopsy for ethical reasons or due to a co-morbid condition/s. The latter group were considered to have diabetic glomerulosclerosis, on clinical grounds, since they had long-standing history of diabetes mellitus, proliferative retinopathy, normal-sized kidneys, nephrotic range proteinuria (without hematuria), and lacked signs of chronic illness (other than diabetes), manifestations or serological markers of autoimmune disease.
Table 1. Histological lesions in patients with glomerulopathy in Kuwait (1995–2001)
Incidence Rates
Since the expatriate population consisted of a heterogeneous group of manual laborers, mostly from Egypt and the Indian subcontinent, only rates based on Kuwaiti nationals are expected to represent meaningful findings.
As seen in , the calculated annual incidence rate of GP in Kuwaiti nationals was 34.5 per 100,000 population (PTP). The calculated annual incidence rate of diabetic glomerulosclerosis was 13.4 PTP and that of non-diabetic GP 21.1 PTP. As seen in , the calculated incidence rates of GP increased with age and were twice as high in males compared to females. Vasculitis was more common in elderly males while SLE nephritis was a disease of adults with female predominance (4 times than that in males). Since kidney biopsy was limited to steroid refractory GP in children, the incidence rate of the latter was 0.7 PTP and 2.3 PTP in males and females. In general, congenital nephrotic syndrome and membranoproliferative GN were not seen in the Kuwaiti children and nephrotic syndrome secondary to IgA glomerulopathy was diagnosed in one child only.
Table 2. Calculated incidence rates of glomerulopathy in Kuwaiti nationals (1995–2001)
Table 3. Incidence rates of the most common non-diabetic glomerulopathy in Kuwaiti nationals subjected to kidney biopsy between 1995–2001
Etiology of GP
On histological examination, focal segmental glomerulosclerosis (FSGS) was the most common histological lesion in primary GP in Kuwaiti nationals accounting for 18% of the total biopsies. However, only 36.8% of those fulfilled the criteria of primary type viz. (a) hyalinosis (b) IgM and C3 deposition (c) mesangial deposits on electron microscopic examination.Citation[[13]] Minimal change disease was the second primary GP (13.0%) followed by immunoglobulin A deposition disease (7.9%) and membranous glomerulonephritis (5%). The histological distribution of GP was similar among Kuwaiti nationals and the expatriates except for a slightly higher prevalence of IgA nephropathy among Kuwaiti nationals and membranous GN in the expatriates, but none of those differences reached statistical significance.
Aggressive autoimmune diseases such as systemic lupus erythematosus (SLE) and vasculitis were common. Seventy-two (12.3%) patients had SLE, 37 of whom were Kuwaiti nationals and 62 (10.6%) had vasculitis, 34 of which were Kuwaiti.
Associated Diseases
In our study, parasitic infestations and microbial infections such as malaria, leishmaniasis, schistosomiasis, brucellosis, hepatitis B or C and were not seen in our Kuwaiti patients with mesangioproliferative GN or amyloidosis. Only one patient with secondary form of amyloidosis had long-standing history of partially treated tuberculosis. None of the 40 adult and elderly patients with membranous GN had or developed lymphoproliferative disease or carcinoma.
Clinicopathological Correlation
The spectrum of renal disease associated with the seven most common causes of GP is summarized in (). Nephrotic syndrome was the presenting feature in all patients with minimal change disease and most those with membranous GN (90%) compared to only 39 (37.9%) in those FSGS. In the latter disease, chronic renal failure with proteinuria >2 g/day was the most common presentation and accounted for 59 of the 103 patients studied (57.3%). Even in its “primary type”, the nephrotic presentation of FSGS was 71.8%. Hypertension and hematuria were rarely encountered in patients with minimal change disease and membranous GN contrary to that seen in patients with FSGS and nonbenign IgA disease (95% and 40%, respectively). Interestingly, only 44 of 72 (61.1%) of patients with SLE and 11 of the 62 (17.7%) patients with vasculitis presented with rapidly progressive GN. On the other hand, 13 patients with nephroangiosclerosis presented with renal failure with protein excretion >2 g/day and 3 with rapidly progressive renal failure. In our study, only 21 of 40 (52.5%) patients diagnosed to have IgA disease had asymptomatic hematuria without evidence of progressive renal disease.
Table 4. The spectrum of renal disease in patients with major glomerulopathy in Kuwait (1995–2001)
Discussion
Our study represents the first attempt to establish, prospectively, the epidemiological profile of GP in our area. The high incidence rates of most GP in Kuwaiti nationals, being nearly 10 times those reported from Europe,Citation[[8]] is alarming but should be more realistic. The long-duration of our study, its prospective design, semi nation-wide population, free access to all strata of health service which is fully financed by the Kuwaiti government, close collaboration with our colleagues in different disciplines of medicine as well as the aggressive approach of investigating all those referred for renal disorder with kidney biopsy, has helped to obtain near factual rates on GP in this Arab population. In our study, we concentrated our epidemiological analysis on Kuwaiti nationals and it is not surprising the low incidence of certain GP associated with endemic infections or disorders viz. (a) membranoproliferative GN associated with schistosomiasis and hepatitis C in native Egyptians,Citation[[14]] (b) secondary forms of amyloidosis due to tuberculosis and membranous GN due to malaria in patients from the Indian subcontinentCitation[[15]] and (c) amyloidosis due to familial Mediterranean fever (FMF) in patients from Mediterranean countries.Citation[[16]] Our study revealed a high incidence rate of diabetic glomerulosclerosis. This disease with its relentless progression to ESRD, contrary to primary GP, confirms our previous observation that it is the most common cause of ESRD in Kuwait.Citation[[10]] This is a distressing observation since diabetic patients generally form a high-risk group on dialysis, having an overall mortality rate of 53% and a 50-month survival rate of only 20%.Citation[[10]] They also have a poor chance for optimal rehabilitation.Citation[[17]] Despite, excluding children with minimal change disease from actual rates, since biopsy was limited to those who manifested steroid-refractoriness, our data indicates that the latter character of minimal change disease is not rare. Interestingly, the incidence rate of minimal change disease in adults is moderate (3.2–4.2 PTP) and this encouraging finding, with a disease amenable to corticosteroids, cyclophosphamide, cyclosporin, or FK-506 therapy, should be taken in consideration in the management of GP in our area. Unfortunately, when compared to FSGS, the latter disease is the most commonly encountered primary GP in Kuwaiti nationals. This observation is consistent with recent data reported from a tertiary referral hospital from Saudi Arabia,Citation[[9]] our previous reports on patients accepted to RRT in KuwaitCitation[[10]] and USRD system.Citation[[4]] Contrary to previous reports from the US,Citation[[18]], Citation[[19]] only two patients were black and none had history of intravenous drug abuse or HIV infection, which indicate that it is not race-dependent or a secondary phenomenon to the latter two disorders.
Analysis of the clinicopathological correlation of GP in our area is interesting. Chronic renal failure with proteinuria >2 g/day was the most common presentation of FSGS and accounted for 59 of the 103 patients studied (57.3%). Even in its “primary type”, the nephrotic presentation of FSGS was 71.8%. This important observation underestimates the role of clinical features in diagnosis of GP and in fact may have contributed to underestimating the true prevalence of this disease in the 3 major ESRD registries i.e., USRD, EDTA, and ANZDATA since only 37, 53, and 32% in the respective registries of their had histological diagnosis.Citation[[6]] Despite the aggressive methodology in our prospective study and good referral facilities from all strata of health providers in Kuwait, we are still hesitant to report the exact incidence rate of IgA nephropathy. Asymptomatic patients with isolated minimal hematuria may have escaped referral and resulted in underestimation of the true incidence of the “benign form” of this disease especially in children. Despite that, IgA was noted to be the third cause of primary GP after FSGS and MCD. Moreover, it is distressing to report that nearly 1/2 of the cases subjected to kidney biopsy showed variable degree of aggressive renal disease. At this stage, and despite our aggressive methodology, we are not sure that our incidence of IgA nephropathy is “just” better than studying the tip of the “ice berg” of this disease or the high incidence of “aggressive IgA disease” in our area is not a “biopsy bias” rather than an actual racial phenomenon.Citation[[20]]
Contrary to reports from the western countries,Citation[[6]] the incidence of membranous GN is relatively low and none of our patients including the elderly population had evidence of malignant disease despite our long period of follow-up.
Analysis of the clinicopathological spectrum of secondary forms of GP in native Kuwaitis revealed three interesting observations. (a) Nephroangiosclerosis, even its benign form, can present with nephrotic range proteinuria. (b) Secondary amyloidosis is a rare disease. The latter may have been due to an early and aggressive management of tuberculosis and multiple myeloma and also the low incidence of FMF in our population. (c) SLE and vasculitis are very common. Contrary to North America and Europe,Citation[[6]] SLE is the most common form of secondary GP in our area and may reflect an ethnic predisposition to such disease. However, our finding of a high incidence of patients with renal-limited lupus and vasculitis, which lacked clinicopathological correlation, is worrisome. Our study emphasizes the role of better surveillance in diagnosis of GP in our area and provides a cogent argument in favor of adopting aggressive diagnostic approaches in its management.
Related Research Data
References
- Couser W.G. Glomerulonephritis. Lancet 1999; 353(9163)1509–1515
- El-Reshaid K., Kapoor M.M., El-Reshaid W., Madda J.P., Varro J. The spectrum of renal disease associated with microscopic polyangiitis and classic polyarteritis nodosa in Kuwait. Nephrol. Dial. Transplant. 1997; 12(9)1874–1882
- El-Reshaid K, Kapoor M.M., Nampoory M.R.N., Madda J.P., Jaffar N.H., Johny K.V. Glomerulonephritis in children: experience from the Kuwaiti renal centers. Med. Principles and Practice 1999; 8(4)328–333
- U.S. Renal Data System, USRDS 1998 Annual Data Report. National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases: Bethesda, MD, April 1998
- Tognoni G. A conceptual-methodological framework for a participatory use of the EDTA registry. Nephrol. Dial. Transplant. 1997; 12(2)251–253
- Disny A.P.S., Collins J., Russ G.R., Herberrt K., Walker R., Kerr P. ANZDATA Registry Report 1998. Adelide, South Australia, Australia and New Zeland Dialysis and Transplant Registry, 1998
- Nationwide and long-term survey of primary glomerulnephritis in Japan as observed in 1,850 biopsied cases. Nephron 1999; 82(3)205–213
- Schena FP and the Italian group of renal immunopathology. Survey of the Italian registry of renal biopsies. Frequency of the renal diseases for 7 consecutive years. Nephrol. Dial. Transplant. 1997; 12(3)418–426
- Mitwalli A.H., Al Wakeel J.S., Al Mohaya S.S., Malik H.G., Abu-Aisha H., Hassan O.S., Akhtar M. Pattern of glomerular disease in Saudi Arabia. Am. J. Kidney Dis. 1996; 27(6)797–802
- El-Reshaid K., Johny K.V., Sugathan T.N., Hakim A., Georgous M., Nampoory M.R.N. End-stage renal disease and renal replacement therapy in Kuwait-epidemiological profile over the past four and half years. Nephrol. Dial. Transplant. 1994; 9: 532–538
- El-Reshaid K., Kapoor M., Nampoory M.R., El-Reshaid W., Johny K.V. Pediatric dialysis and renal transplantation in Kuwait over the past 11 years. Pediatr. Nephrol. 1999; 13(3)259–264
- Central Statistical Organization. Annual Statistical Abstract. Ministry of Planning, Kuwait 1998
- Rennke H., Klein P. Pathogensis and significance of nonprimary focal and segmental glomerulosclerosis. Am. J. Kidney Dis. 1989; 13(6)443–456
- Barsoum R., Francis MR. Spectrum of glomerulonephritis in Egypt. Saudi J. Kidney Dis. Transplant. 2000; 11: 421–429
- Adler S.G., Cohen A.H., Glassock R.J. Secondary glomerular diseases. Brenner and Rector's The Kidney B. Saunders, B.M. Brenner, 1996; 1498–1596
- Said R., Hamzeh Y., Tarawneh M. The spectrum of glomerulopathy in Jordan. Saudi J. Kidney Dis. Transplant. 2000; 11: 430–433
- Paganini E.P. The future of end-stage renal disease program. Am. J. Kidney Dis. 1992; 59(suppl 1)12–15
- Korbert S.M., Genchi R.M., Borok R., Schwartz M.M. The racial prevalence of glomerular diseases in nephrotic adults. Am. J. Kidney Dis. 1996; 27(5)647–651
- Barisoni L.D., Agatti V. The changing epidemiology of focal segmental glomerulosclerosis in New York city. Mod. Pathol. 1994; 7: 156A
- Schmidt S., Ritz E. Genetic factors of IgA nephropathy. Ann. Med. Interne. (Paris) 1999; 150: 86–90