Pathogenesis of Contrast Induced Nephropathy
Contrast-induced nephropathy has become an important basis of hospital acquired morbidities due to high utility of iodinated contrast agents. The cases are rapidly growing in the area of diagnostic imaging and strategies that involve angiography in patients at risk (1). It is considered as the third important cause of renal failure which is next to surgery and hypotension (1). The administration of CM contributes to immediate renal vasodilatation and a continued vasoconstriction which in turn leads to high intrarenal vascular resistances, a reduction of total renal blood flow (RBF) and a decrease in glomerular filtration rate (GFR) (2). These alterations in the renal circulation may lead to ischaemia which serves as the vital component for nephropathy (2). This also contributes to increasing in the levels of metabolite adenosine which in turn is crucial for hemodynamic renal biphasic reaction (2). Adenosine is a nucleoside and a plays role in ATP hydrolysis by acting as a vasoactive substance (3). It influences renal circulation by exerting its effects on vasoconstriction and vasodilatation through Adenosine receptors (3). The outcome of this effect also leads to high diuresis and natriuresis which in turn is having connection with endothelin (2). Next in CIN pathogenesis, the aberrations in endothelial function cause the generation of free radicals after ischemic reperfusion which leads to medullary vasoconstriction (3). Here, NO undergoes reaction with free radicals to generate peroxynitrite (3). This leads to inactivation of NO causing hemodynamic changes in the outer medulla which further worsens ischemic harm (3). Further, the pathogenesis of CIN is thought to involve hypoxic renal medullary injury (5). Here, nitric oxide, adenosine and prostaglandins participate in the medullary transport activity (5). This process when gets altered would lead to insufficient oxygen demand and thereafter acute tubular necrosis (ATN) (5). CM administration affects renal parenchymal oxygenation leading to medullary hypoxaemia as also revealed from non-invasive blood oxygenation level dependent magnetic resonance imaging (BOLD MRI) (5). Therefore, a fall in renal parenchymal oxygenation causes an alteration in the renal microcirculation (5). The ultimate effect is that there would not be any motility of red blood corpuscles in the blood vessels which results in cellular aggregation (5).
Therefore, human radiocontrast nephrotoxicity is better assessed by several risk contributing agents that affect a hygienic renal circulation (6). A defect in the production of vasoactive substances in renal/vascular diseases increases the risk of radiocontrast nephropathy (6). Substances like prostanoids and nitric oxide provide resistance against the radiocontrast agents (6). This was revealed when rats received pretreatment with indomethacin and N omega-nitro-L-arginine methyl ester (L-NAME) developed acute renal failure (6). As Nitric oxide synthesis gets inhibited by L-NAME, its significance was considered important in minimizing the risk of radiocontrast nephropathy (6). Further, as renal ischemia is associated with nephropathy, as discussed earlier, it may predispose the patients to transient azotemia (7). This occurs because of restricted trauma to the nephron which is similar to complicated forms of acute renal failure (8). Here, parameters like GFR, renal plasma flow, transmembrane hydraulic pressure difference need to be assessed as their levels are important to understand the pathogenesis contrast induced nephrotoxicity (8). However, further studies are required for concrete information. Earlier, Russo and his co workers (9) described the role of several parameters in the pathophysiology of contrast media (CM)-induced nephropathy. These include endothelin-1 (ET-1) levels, urinary sodium concentration, sodium levels and glomerular filtration rate (GFR), and RPF (9). This was revealed when patients who developed chronic renal failure were checked for the levels of above mentioned clinical indicators of CRF (9). A sudden decrease in GFR, tubular functional defect related to the proximal nephron, protection offered with treatment on acute and short-term GFR variations have indicated the influence of CM on CRF patients (9). Therefore, the patients having CRF need to be assessed for clinical markers to assess the severity of CM-induced nephropathy. The other aspects in the pathogenesis are the function of adenosine. It was reported that renal adenosine when gets stimulated and produced in high levels would predispose individuals to acquire CM-ARF (10). Diabetic subjects and those with a history of renal disease serve as good targets for CM-ARF (9).
This could be due to increased sensitivity to adenosine by the renal vasculature as many animal investigations reported high vasoconstriction driven by adenosine in kidneys of diabetic model animals (7). But this adverse event in the pathogenesis could be overcome by the supply of antagonists specific of adenosine receptors, in patients with diabetes and without diabetes (7). Therefore, the metabolite adenosine plays important role in modulating the CM-ARF especially, in patients with diabetes (9). This could indicate that antagonists developed for adenosine receptors may have therapeutic efficacy in lessening the incidence of CM-ARF in susceptible diabetic patients and those with low renal functional defects. It is reasonable to mention that in the present case, the old woman who developed acute renal failure 48 hours may be having Diabetes Mellitus as an underlying complication. Probably, this might have aggravated the problem. This may indicate that the diagnostic evaluation of the patient suspected for CM-ARF could be made feasible by employing markers related to adenosine metabolism. Next, nephropathy is better connected with conventional high-osmolality contrast media (HOM) (11). This condition develops due to intravascular dose of HOM (11).
Research work by Lautin and his group indicated that LOM (lower-osmolality contrast media) is related to decreased risk of nephropathy indicating its reduced nephrotoxic effect (11). The other aspects in the pathogenesis of CIN are that proximal tubular cells are susceptible to cytotoxicity induced by contrast media (3). However, in vitro studies emphasizing on cell cultures and tubular segments are under investigation (3). Mainly, cell vacuolization is the frequent problem indicating cellular injury (3). Loss of proteins like cytochrome C of mitochondria, sodium-potassium ATPase pump, enhanced susceptibility of cell membrane to phospholipase A2(3). These conditions result due to the direct effect of contrast media on tubular cells (3). In addition, cytotoxicity also occurs because of low resistance in the transepithelial region, inulin infiltration and dislocation of membrane proteins after the induction of radio contrast materials (3). Contrast media induces N-acetyl-beta-D-glucosaminidase (NAG) driven enzymuria alanine aminopeptidase (AAP) and microproteinuria where alpha1-and beta2- microglobulin participate (3). Both these conditions contribute to tubular damage (3). Similarly, immunological alterations include complement system activation in contrast to the endothelial cell activation through the alternate pathway. Infiltration of neutrophils and macrophages into the mesangial region causes low GFR and contraction (3). These pathogenic mechanism contributing to CIN are believed to be associated with many hyperosmolar agents like, hypertonic saline and mannitol as they induce related alterations in enzymatic pathways and structural integrity (3). Therefore the pathogenesis of radiocontrast nephropathy may be influenced by several parameters, like vasoactive substances, nonionic low-osmolarity, High or low osmolality, RPF, GFR, renal plasma flow, transmembrane hydraulic pressure, endothelin-1, serum and creatinine etc. To better assess the magnitude of nephrotoxicity, the above mentioned parameters need to be thoroughly evaluated for their diagnostic relevance.
This could be better done by screening programs. It would be an added advantage to select patients especially with ischemia, azotemia, diabetes, obesity and cardiovascular problems.
Gentamycin Nephrotoxicity
The next aspect of the description is on the Nephrotoxic Effect of Gentamicin. This drug was earlier utilized to study toxic events keeping in view of enzyme activities excluding the cellular abnormalities at the gross morphology level (12). The pathogenic changes to note were inhibition of protein synthesis specific to cellular and brush border membrane (BBM) (12). There were high phosphatidylinositol and phosphatidylcholine levels, low levels of sphingomyelin (SPH), in BBM (12). The research group has observed differences in control and treated group of animals (12). It was found that in treated animals the levels of phospholipids in cortical homogenates and BBM were high compared to low amount in control animals (12). Therefore, gentamycin mostly serves to affect phospholipid metabolism by preventing phospholipid degradation (12). The presence of gentamycin was reported to be high on basal structures and cell organelles like lysosomes Golgi complex, and mitochondria (12). Hence, gentamicin-induced nephrotoxicity was reported to involve a kind of long-established trafficking (12). Gentamicin facilitates increased production of plasma creatinine and urea, protein, copper and zinc excretion in the urine, decreased creatinine production and activity of cortical alkaline phosphatase, in diabetic animal models (13). Proximal renal damage was high and further it also contributed to fatal conditions in about one third of the old animals compared to younger ones (13). This may indicate that severity of gentamicin induced nephrotoxicity develops with age. In the present case, the old woman seems to be more likely to have been affected by or susceptible to gentamicin.
Hence, gentamicin effects may be more prominent in old individuals those with diabetes mellitus (13). Therefore, the present case seems to support the literature in this context of nephrotoxicity. Further, gentamicin-induces nephrotoxicity through the aid of platelet-activating factor (PAF) (14). It was revealed that rats when treated with PAF antagonist BN-52021 showed a marked elevation of plasma creatinine level decreased creatinine clearance and high amounts of N-acetyl-beta-D-glucosaminidase (NAG) and alkaline phosphatase (AP) in urine (14). In addition, histopathology indicated necrosis of cortical tubules. The generation of Glomeruli PAF in gentamicin-treated rats was high compared to control groups (14). These findings have indicated the importance of PAF in the nephrotoxicity driven by gentamicin. Gentamicin was reported to exert its effects through reactive oxygen metabolites (15). This was revealed in models of acute renal failure (15). Gentamicin was reported to produce iron from the renal cortical mitochondria (15). The role of iron is central in models of tissue injury, as it able to catalyze the production of free radicals (15). However, certain agents offer protection against gentamicin-induced nephrotoxicity by guarding iron chelators and reactive oxygen metabolites (15). Therefore, acute renal failure in humans could be avoided by better understanding the mechanism of reactive oxygen metabolites. (15).
The association between hydrogen peroxide and superoxide anion in the presence of iron contributes to the formation of hydroxyl radicals (16). This interaction probably emphasizes the role of gentamicin they may exert its effects in a cascade manner starting from generation of superoxide anion, hydrogen peroxide, hydroxyl radical, and water(16). This may indicate decrease of oxygen species along the single pathway which may be vital for Acute renal failure (16). Large number of studies have provided a clearcut description on the gentamicin as nephrotoxicity with regard to the mediators and reduced oxygen metabolites (16). Hence, the role free radicals may also become an important aspect in the pathogenesis of gentamicin induced nephrotoxicity. The role of mitochondria needs to be understood to gain further insights in the pathogenesis of gentamicin induced nephrotoxicity (17). This is because mitochondrial respiration was reported to increase the production of reactive oxygen metabolites (17). Gentamicin could induce changes in mitochondrial respiration by acting stimulating state 4 and inhibiting state 3(17). It was revealed in a fluorescence technique that gentamicin induced formation of hydrogen peroxide was increased in a great amount from 0.17 +/- 0.02 nmol (17). This activity has indicated the important role of mitochondria in the production of hydrogen peroxide (17). This aspect of drug toxicity may need an evaluation. To his end, it was reported that by employing instruments like gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS), nephrotoxicity can be better assessed(18). It was found that polyamines and amino acids were high in urine samples of animals exposed to gentamicin after a single dose (18). This event occurred before the histological examination of kidney damage and clinical manifestations of nephrotoxicity(18). But when the dose level was increased, the variations induced by nephrotoxicity led to more severe loss of amino acids in urine, accompanied with low nucleosides amino acids in kidney tissue (19). This had indicated that depending on the levels of amino acids when present in the branched chain manner in urine, a model was developed for studying and assessing nephrotoxin-treated samples with various proportions of accuracy for several days since the beginning of the experiment to the end (18). Therefore, the degree of acute renal failure which has a damaging effect on kidney could be assessed by range of clinical markers in a noninvasive approach (18).
Further, the biomarkers must get thoroughly verified for their efficacy with regard to the diagnostic application. It is reasonable to describe that the toxic effects of gentamicin have a long cascade system that needs to be deciphered at the molecular, biochemical and cellular level. From the above mentioned literature, it was learnt that the enzymes catalyzing the generation of oxygen metabolites may be controlled by feed back mechanism. Genes acting at this level may need to be studied to determine their downstream or upstream effects. Cell organelles like mitochondria play important role in the generation of energy through a cycle of events that involve oxygen species. The generation of free radicals may be another important source to modify the gentamicin driven nephrotoxicity. As such markers that reflect the activity of free radicals may provide insights on the gentamicin induced pathogenesis. In the present case, it can be assumed the old lady might have received gentamycin therapy before hospitalization. This could have resulted in the development of nephrotoxicity.
IgA Nephropathy
The final aspect to be focused in the description is Pathophysiology and Pathogenesis of IgA Nephropathy. The most frequent cause of glomerulonephritis was considered globally to be of IgA nephropathy (IgAN) (19). This condition is presented by microhematuria and/or proteinuria, recurrent gross hematuria, and diffuse mesangial IgA deposits in glomeruli. Initially, IgAN was thought to be less harmful, but it has potential to contribute to end-stage renal disease as found in nearly in 20-40% of patients who are susceptible to renal disease (19). IgAN occurs in patients diagnosed late after 5 to 25 years (19).
The indicators of this disease are high serum creatinine levels, high systemic blood pressure, and continuous protein excretion (19). The histopathological indicators are extension of immune deposits to the perivascular space and crescent formation, glomerulosclerosis and tubular atrophy/interstitial fibrosis (19).
Rauta and his co workers described that various parameters determine the effect of IgAN (20). These include histopathological findings, proteinuria, serum cholesterol, level of Ccr, and hypertension (20). In addition, certain indicators could assess the disease progression like lack of episodes of macroscopic hematuria, male sex, magnitude of tubular atrophy and serum urate level (20). These factors need to be assessed in combination to gain insights on IgAN. But, several parameters are independently related to the disease progression like the level of glomerular score, presence of hypertension and in histopathology arteriolosclerosis and urinary erythrocytes. (20). These parameters have provided a paradigm for assessing the risk as far as the outcome is concerned. Therefore, IgAN relies on the renal function which is largely influenced by the connection between parameters and outcome (20). As there is an existence of independent parameters that reflect the early and evident form of disease, predicting IgAN at an earlier stage is warranted (20). In view of the growing research importance, there is need to be considered primary IgA nephropathy (IgAN) with regard to its natural history(21). This is because there are concerns in characterizing this disease while considering patients for renal biopsy, in the utility of various classifying criteria for the renal lesions, statistics which lead to misinterpretation (21). It was further described that prolonged progression from 5 to 25 years and remission, geographic fluctuations are well known features that reflect a good natural history of IgAN(21).
Similarly, the random cases that demonstrate severe forms renal damage, high creatinine concentrations, arterial hypertension and nephrotic range proteinuria have been well implicated as predictors. In contrast, the independent predictors are Mean blood pressure value (MAP) and proteinuria during follow-up period (21). Histopathologic observations include severity of interstitial fibrosis and glomerular sclerosis (21). The other risk factors were the connection between crescents and tuft adhesions which occur due to segmental necrosis (21). It was further reported that parameters that serve as independent prognostic markers are age and mean proteinuria during follow-up period (21). Therefore, these factors need to be considered to better assess the severity of progression IgAN. In the present case, there may be a defect in the evaluation of the patient with regard to the IgAN.Although serum creatinine levels and age were measured, certain independent factors could have helped the patient to survive.
It is reasonable to connect this part of description with Henoch-Schoenlein purpura (HSP). HSP is a kind of systemic vasculitis represented by vascular wall deposits of IgA (22). This encompasses arthralgia or arthritis, haematuria, gut and glomeruli and is associated with purpura, colic, small vessels in skin and gut (22). This condition contributes to chronic renal failure mostly in 20 % of pediatric cases and is evident by the manifestation of glomeruli with epithelial crescents (22). HSPN is associated with high generation of aberrant glycosylated IgA, which is not metabolized by the liver (22). This result in the production of IgA macromolecules, that reside in the blood stream with further deposits stored in vessel walls and the glomerular mesangium (22). HSPN is also represented by the clinical signs of skin, and joint disorders (23). Immunofluorescent investigations revealed that HSPN and IgA nephropathy are similar due to the existence of IgA deposits in the glomeruli and the vessel walls (23).
This has indicated the immunologic form of pathologic lesions (23). Therefore, HSPN may play vital role in the overall pathogenesis of contrast induced nephropathy. Relationships and differences do exist between IgAN and HSPN as these disorders could occur in the same patient with the manifestation of more or less similar clinical defects (24). The age could vary from 15 to 30 years as seen in IgAN whereas HSPN was reported to occur in childhood (22). Manifestations specific to Nephritic and/or nephrotic syndromes commonly occur in HSPN (24). On contrary to IgAN, hypersensitivity is associated with HSPN (24). Further, inflammations of extracapillary and endocapillary regions and that of fibrin deposits in the glomerulus are also common in HSP (24). Although, there were no wide differences between the two disorders, the only exemption is for an increased frequency of high plasma IgE levels in HSPN and for a superior mass of circulating IgA-containing complexes (IgA-CC) (24). Leukocytes get largely infiltrated at tissue level in HSPN vasculitis, whereas these cells are activated at a higher degree by HSP induced IgA-CC and/or circulating chemokines (24).
Pankhurst and his associates have reported that vasculitic glomerulonephritis occurs in both IgAN and HSP (25). This was revealed in large group of patients presented with IgAN, HSP (25). The clinical characteristics include median glomerular filtration rate at 45.56 ml/min arterial blood pressure 104.67 mm Hg and proteinuria 1.19 g/24 h. Similarly, biopsy studies revealed a median chronic damage of 10% (25). The immune system of study patients was tuned to a compromised state (25). This has indicated the reliability of the biopsy studies in assessing the extent of chronic damage, renal function and blood pressure at presentation (25). Therefore biopsy studies seem to furnish insights on the pathogenesis of vasculitic IgA nephropathy. In the present case, the old woman may be having a compromised immune system compromised. This probably could have made her susceptible to advanced stages acute renal failure or nephrotoxicity and associated problems. Here, the important point to note is that although HSPN occurs in childhood, it could also develop in adult individuals. A large population study has been carried out in adults having HSP and they were also followed up for nearly 14 years (26). Biopsy investigations were in agreement with mesangial deposits characteristic of HSP and this is connected to abdominal pain, purpura and bowel angina (26). Significant proportion of patients presented palpable purpura, arthritis and gut association (26). Similarly, renal insufficiency related to proteinuria and hematuria were also noted (26). The follow up period also revealed the significant survival of patients (26). Few death cases were attributed to gastric discomfort and few patients were close to end-stage renal failure, serious renal failure and temperate renal insufficiency in various proportions. This was revealed from the levels of CrCl (26). In addition, the degree of altered renal function and proteinuria presented, the extent of interstitial fibrosis, proportion of sclerotic glomeruli and occurrence of glomeruli with fibrinoid necrosis were reported to correlate with reduced weak renal prognosis (24). This reported has strongly indicated that the outcome of HSPN pathogenesis in adult population is serious and weak compared to that found in children (26). Biopsy investigations were in agreement with mesangial deposits characteristic of HSP and this is connected to abdominal pain, purpura and bowel angina. It has further emphasized on the need of biopsy investigations to better understand the pathogenesis with regard to that of renal function and associated symptoms.
Appropriate scientific intervention would enable to understand pathogenesis of IgA and/ or its association with HSPN. This study has strongly favored the present case of old women who is having similar clinical characteristics like abdominal pain, urine dipstick turning out was positive for ketones and proteins etc. She could have been thoroughly evaluated for the mentioned parameters that were covered in the cited literature. This may indicate that there is a need of evidence based approach. The health care professionals must consider the available literature extensively, retrieve the needful information and do best for the betterment of the patient.
References
Tadhg, G. Gleeson and Sudi Bulugahapitiya. AJR. 2004.183
Simian Detrenis, Michele Meschi, Sabrina Musini, Giorgio Savazzi. Lights and shadows on the pathogenesis of contrast-induced nephropathy: state of the art. Nephrol Dial Transplant. 2005 20: 1542–1550.
Efstratiadis, G, Pateinakis, P, Tambakoudis, G, Pantzaki, A, Economidou, P, Memmos, D Contrast media-induced nephropathy: case report and review of the literature focusing on pathogenesis. Hippokratia. 2008; 12(2): 87–93.
Christiane M. Erley, Heyne, N, Rossmeier, S, Vogel, T, Teut Risler, Hartmut Osswald. Adenosine and extracellular volume in radiocontrast media-induced nephropathy. Kidney International 1998 54 (67): S-192–S-194.
Samuel N. Heyman, Christian Rosenberger and Seymour Rosen. Regional alterations in renal haemodynamics and oxygenation: a role in contrast medium-induced nephropathy.Nephrol Dial Transplant.2005 20 (1): i6–i11
Agmon, Y Peleg, H, Greenfeld, Z, Rosen, S, Brezis, M. Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat. J Clin Invest 1994;94(3):1069-75.
Cigarroa, R, G, Lange, R,A, Williams, R,H, Hillis ,L,D. Dosing of contrast material to prevent contrast nephropathy in patients with renal disease. Am J Med. 1989;86(6 Pt 1):649-52.
Myers, B,D, Miller, D,C, Mehigan, J,T, Olcott, C,O, 4th, Golbetz, H, Robertson, C,R, Derby, G, Spencer, R, Friedman ,S. Nature of the renal injury following total renal ischemia in man. J Clin Invest 1984; 73(2):329-41.
Russo, D, Minutolo, R, Cianciaruso, B, Memoli, B, Conte, G, De Nicola, L. Early effects of contrast media on renal hemodynamics and tubular function in chronic renal failure. J Am Soc Nephrol 1995;6(5):1451-8.
Pflueger, A, Larson ,T,S, Nath, K,A, King ,B,F, Gross, J,M, Knox, F,G. Role of adenosine in contrast media-induced acute renal failure in diabetes mellitus. Mayo Clin Proc. 2000;75(12):1275-83
Lautin, E,M, Freeman, N,J, Schoenfeld, A,H, Bakal ,C,W, Haramati, N, Friedman, A,C, Lautin, J,L, Braha ,S, Kadish, E,G, et al. Radiocontrast-associated renal dysfunction: a comparison of lower-osmolality and conventional high-osmolality contrast media. AJR Am J Roentgenol. 1991; 157(1):59-65.
David, P. Sundin, Ruben Sandoval and Bruce A. Molitoris. Gentamicin Inhibits Renal Protein and Phospholipid Metabolism in Rats: Implications Involving Intracellular Trafficking. J Am Soc Nephrol. 2001 12:114-123.
Ali, B, H, Bashir, A, K, Mugamer, I,T, Tanira, M,O. Gentamicin nephrotoxicity in the rat: influence of age and diabetes mellitus. Hum Exp Toxicol. 1996;15(1):51-55.
Rodriguez-Barbero ,A, López-Novoa, J,M, Arévalo, M. Involvement of platelet-activating factor in gentamicin nephrotoxicity in rats. Exp Nephrol. 1997 ;5(1):47-54.
Baliga, R, Ueda, N, Walker, P,D, Shah, S,V. Oxidant mechanisms in toxic acute renal failure. Am J Kidney Dis. 1997; 29(3):465-77.
Walker, P,D, Barri, Y, Shah, S,V. Oxidant mechanisms in gentamicin nephrotoxicity. Ren Fail. 1999; 21(3-4):433-42.
Walker, P,D, Shah, S,V. Gentamicin enhanced production of hydrogen peroxide by renal cortical mitochondria. Am J Physiol. 1987; 253(4 Pt 1):C495-9.
Boudonck ,K,J, Mitchell ,M,W, Német, L, Keresztes, L, Nyska, A, Shinar, D, Rosenstock, M. Discovery of metabolomics biomarkers for early detection of nephrotoxicity. Toxicol Pathol. 2009;37(3):280-92.
Rychlik, I, Andrassy, K, Waldherr, R, Zuna, I, Tesar, V, Jancová, E, Stejskalová ,A, Ritz, E. Clinical features and natural history of IgA nephropathy. Ann Med Interne (Paris). 1999;150(2):117-26.
Rauta, V, Finne, P, Fagerudd, J, Rosenlöf ,K, Törnroth, T, Grönhagen-Riska , C. Factors associated with progression of IgA nephropathy are related to renal function–a model for estimating risk of progression in mild disease. Clin Nephrol 2002;58(2):85-94.
Coppo, R, D’Amico, G. Factors predicting progression of IgA nephropathies. J Nephrol. 2005;18(5):503-12.
Davin, J,C, Weening ,J,J. Henoch-Schönlein purpura nephritis: an update. Eur J Pediatr. 2001; 160(12):689-95.
Ferrario, F, Rastaldi, M,P. Henoch-Schonlein nephritis. J Nephrol. 2005;18(6):637-41.
Davin, J, C, Ten Berge, I, J, Weening ,J,J.. What is the difference between IgA nephropathy and Henoch-Schönlein purpura nephritis? Kidney Int. 2001 Mar;59(3):823-34
Pankhurst, T, Lepenies, J, Nightingale, P, Howie, A,J, Adu, D, Harper, L. Vasculitic IgA nephropathy: prognosis and outcome. Nephron Clin Pract. 2009;112(1):c16-24.
Chacko, B, John, G,T, Neelakantan, N, Korula ,A, Balakrishnan, N, Kirubakaran ,M,G, Jacob, C,K. Presentation, prognosis and outcome of IgA nephropathy in Indian adults. Nephrology (Carlton). 2005;10(5):496-503.