Acute Renal Failure Due to Intrinsic Renal Diseases: Review of 1122 Cases

Abstract

In this study we have analyzed incidence, causes and clinical course of ARF due to primary intrarenal disease other than acute tubular necrosis. Thousand hundred and twenty two cases of ARF of diverse etiology were studied over a period of 16 years; 07 1984 to Dec, 1999. Surgical ARF 231 (20.6%) were not included in the present study. Intrinsic renal diseases were responsible for ARF in 891 (79.4%) of cases. The most common intrinsic renal diseases 705 (79.4%) causing ARF were ischemic/toxic acute tubular necrosis, but not included in this study. Acute renal failure was related to acute glomerulonephritis (9.3%), acute interstitial nephritis (7%), and renal cortical necrosis in (4.6%) of cases. Therefore intrinsic renal diseases other than ATN were the causative factor for acute renal failure in 186 (20.8%) patients in our study. Crescentic (51.8%) and endocapillary proliferative glomerulonephritis (34.9%), were the main glomerular diseases responsible for ARF and 75.9% of GN was related to infectious etiology. Fifty three percent of acute interstitial nephritis was drug induced and in 25 (40%) patients it was related to an infectious etiology. Renal cortical necrosis due to HUS was observed in 16 (39%) children and majority (76.47%) of the cases had a diarrhoeal prodrome. Obstetrical complications were the main causes (61%) of cortical necrosis in adults with acute renal failure. Thus, intrinsic renal diseases other than ATN were responsible for ARF in 186 (20.8%) cases. Post-infectious glomerulonephritis, acute interstitial nephritis and renal cortical necrosis (complicating HUS in children and obstetrical complications in adult) are the main causes of acute renal failure in our study. Both acute GN and interstitial nephritis had excellent prognosis, however renal cortical necrosis was associated with a very high mortality.

• Acute renal failure
• Intrinsic renal disease
• Glomerulonephritis
• Interstitial nephritis
• Renal cortical necrosis

Introduction

Acute renal failure (ARF) is characterized by deterioration of renal function over a period of hours to days, resulting in retention of nitrogenous waste products and failure to maintain fluid and electrolyte homeostasis. Prerenal and intrinsic renal failure due to ischemia and nephrotoxins are responsible for most episodes of acute renal failure. Acute renal failure due to primary intra-renal disease is called as intrinsic renal failure and accounts for 35–40% of all patients with acute renal failure. Intrinsic renal diseases that result in ARF are categorized according to the primary site of injury: tubules, interstitium, vessels, and glomerulus. Ischemic or toxic acute tubular necrosis (ATN) accounts for 80–90% of acute intrinsic ARF in most series and the remaining 10–20% of intrinsic ARF are caused by acute glomerulonephritis, acute interstitial nephritis, and renal vasculitis. The purpose of the present study is to document incidence, etiology, clinical course and outcome of ARF due to glomerular, interstitial and vascular diseases of the kidney in a tertiary referral center over a period of 16 years.

Material and Methods

A total of 1122 cases of acute renal failure due to various causes were studied over a period of 16 years (July 1984 to Dec. 1999), at the Department of Nephrology, University Hospital, Banaras Hindu University, Varanasi. The age of the patients (male—626, female—496) ranged between 1–85 years with a mean ± SD (33.2 ± 19.0) years. Patients with acute on chronic renal failure and surgical ARF were excluded. Acute renal failure was diagnosed using standard clinical criteria. Data pertaining to the etiology of acute renal failure was analyzed. All patients were investigated to determine the cause and severity of renal failure. Urinalysis and microscopic examination of urinary sediments were done meticulously in every patient. Biochemical and hematological profile, ultrasonic examination of kidneys and serologic assay (complements, ASO titer, HBsAg) were carried out in each patient. Coagulation profile, platelet count, LDH, serum FDP, fibrinogen, and bilirubin were done in selected cases. Antinuclear antibody (ANA), anti dsDNA, ANCA, and anti HCV was done as and when required. Renal biopsy was done in 286 cases using Tru-Cut biopsy needle. The indications of biopsy were strong clinical suspicion of lesions other than acute tubular necrosis, presence of systemic disease and clinical features favoring glomerular, vascular, and interstitial disease of kidneys. The diagnosis of cortical necrosis, various glomerulonephritis and interstitial nephritis were confirmed on histological examination of renal tissue. All patients were followed for 4–16 weeks. The clinical course, outcome and mortality were recorded in each patient.

Result

Of the 1122 patients with ARF studied over a period of 16 years (July 1984 to Dec. 1999), at the Department of Nephrology, University Hospital, Banaras Hindu University, Varanasi: 891 (79.4%) patients had ARF due to intrinsic renal diseases. Surgical ARF 231 (20.6) was excluded. Ischemic/toxic ATN was responsible for ARF in 705 (79%) cases and were not included in this study. The intrinsic renal diseases other than ATN were noted in 186 (20.8%) patients. Of the 186 patients with intrinsic ARF, acute glomerulonephritis, acute interstitial nephritis and renal cortical necrosis were seen in 83, 62, and 41 cases respectively (Table 1).

Table 1. Demographic data

Duration of study	:	July 1984 to Dec. 1999
Total no. of ARF	:	1122
Age range (years)	:	1–85
Mean age (years)	:	mean ± SD (33.2 ± 19.2)
Total intrinsic ARF	:	891 (79.4%)
Acute tubular necrosis	:	705 (79.4%)
Intrinsic ARF other than ATN	:	186 (20.8%)
Acute glomerulonephritis	:	83 (9.3%)
Acute interstitial nephritis	:	62 (7%)
Cortical necrosis	:	41 (4.6%)

Glomerulonephritis

Of the 83 patients with acute glomerulonephritis 63 (75.9%) cases had post-infectious GN. Idiopathic GN, SLE, and systemic necrotizing vasculitis were seen in 15, 3, and 2 cases respectively. Crescentic (51.8%) and endocapillary proliferative glomerulonephritis (34.9%) was the major glomerular disease in our patients with acute renal failure. Lupus nephritis (WHO class IV) and necrotizing glomerulonephritis were seen in 2 cases each. Endocapillary proliferative GN had good prognosis; 24 (82.75%) patients improved and 5 (17.25%) cases progressed to chronic renal failure with no mortality. Patients with crescentic GN had poor prognosis with mortality of 18.6%. 24 (55.8%) cases progressed to chronic renal failure and only 11 (25.5%) patients had recovery of renal function (Table 2). Thus, acute glomerulonephritis associated with vasculitis, SLE and anti GBM disease are uncommon cause of intrinsic ARF in our study.

Table 2. Prognosis of glomerulonephritis (n = 83): follow-up for 4–16 weeks

	Improved		Progressed to ESRD		Death
Type of GN	No.	%	No.	%	No.	%
Crescentic GN (n = 43)	11	25.58	24	55.80	8	18.60
Endocapillary proliferative GN (n = 29)	24	82.75	5	17.25	—	—
Mesangial proliferative GN (n = 4)	3	75.00	1	25	—	—
Mesangiocapillary GN (n = 3)	1	33.33	1	33.33	1	33.33
Lupus nephritis (n = 2)	1	50.00	1	50.00	—	—
Necrotizing GN (n = 2)	1	50.00	1	50.00	—	—
Total	41	49.4	33	39.8	9	10.8

Acute Interstitial Nephritis

Acute renal failure due to acute interstitial nephritis was noted in 62 (7%) cases. Drug was the cause of acute TIN in 33 (53%) of patients, while it was related to infection in 25 (40%) of patients. Thus, incidence of drug induced and infection related acute interstitial nephritis were almost similar in our study. Acute interstitial nephritis had a very good prognosis: 57 (92%) patients had improved and 4 (6.4%) cases died and only one patient progressed to chronic renal failure and became dialysis dependent (Table 3).

Table 3. Prognosis of interstitial nephritis (n = 62): follow-up period 4–16 weeks

		Prognosis
Etiological type	No. of patients (n)	Improved		Progressed to ESRD		Death
		No.	%	No.	%	No.	%
Infection related	25	21	84	1	4	3	12
Drug induced	33	33	100	—	—	—	—
Miscellaneous	4	3	75	—	—	1	25
Total	62	57	92	1	1.6	4	6.4

Renal Cortical Necrosis

Renal cortical necrosis (RCN) was responsible for intrinsic ARF in 41 (4.6%) patients. Obstetrical complications were the dominant 25 (61%) cases of renal cortical necrosis. It was related to hemolytic uremic syndrome in 16 (39%) cases. Diarrhea associated HUS was noted in 81.25% cases. Renal function improved in 10 (24.3%) cases with s. creatinine ranging between 1.6–2.8 mg%. The disease had a progressive course leading to chronic renal failure in 8 (19.5%) patients. Mortality was noted in 23 (56%) patients. They died during the acute phase of illness on account of uremic complications and sepsis (Table 4).

Table 4. Prognosis and outcome of cortical necrosis (n = 41): follow-up period 4–16 weeks

	Outcome {no. (%)}
Lesion type	Improved	Progressed to CRF	Death
HUS (n = 16)	6 (37.5)	4 (25)	6 (37.5)
Obstetrical (n = 25)	4 (16)	4 (16)	17 (68)
Total (n = 41)	10 (24.3)	8 (19.5)	23 (56)

Discussion

Acute renal failure due to a primary intrarenal cause can be called intrinsic renal failure or renal azotemia. From a clinic-pathologic viewpoint all components of renal parenchyma namely glomeruli, tubules, interstitium, and vessels may be affected by different diseases leading to intrinsic ARF. Intrinsic acute renal failure constitutes about 35–40% of total ARF cases.[[1]] Most acute intrinsic renal azotemia is caused by ischemia or nephrotoxins and is clinically associated with acute tubular necrosis (ATN) which accounts for about 90% of acute intrinsic renal failure.[[2]], [[3]], [[4]] Of the 891 patients with intrinsic ARF, acute tubular necrosis was noted in 705 (79%) cases in our study, which is the single most common parenchymal lesion responsible for intrinsic ARF. Intrinsic renal disease other than ATN had been detected in 186 (20.8%) patients. This group consists of patients with acute glomerulonephritis, interstitial nephritis, and renal cortical necrosis. We have given particular emphasis on the renal lesions other than ATN contributing to intrinsic ARF in the present study. Therefore most of the discussion will be centering on the group of patients having glomerular, interstitial and vascular disease of the kidney.

Glomerulonephritis is relatively uncommon cause of acute renal failure and accounts for about 10% of cases of ARF.[[5]], [[6]] Review of 250 cases of ARF between 1981–1984 from UK revealed that intrinsic renal disease contributed to ARF in 24% of cases and 17.5% were due to acute glomerulonephritis.[[7]] Acute glomerulonephritis was responsible for ARF in 10% of cases in a north Indian study comprising of 1862 cases of ARF studied between 1965–1986.[[8]] We have noted intrinsic renal diseases other than ATN in 20.8% of cases of ARF and acute glomerulonephritis was the cause of ARF in 9.3% of patients. Thus, incidence of acute glomerulonephritis in developing countries is similar to Europe and North America.[[8]], [[9]] Acute renal failure with glomerulonephritis is common in small vessel vasculitis, systemic lupus erythematosus and anti-GBM disease in Europe and North America, but infection-associated glomerulonephritis is probably the most common cause worldwide. Acute renal failure in the context of proliferative glomerulonephritis is usually associated with crescents and focal necrotizing glomerulonephritis.[[10]], [[11]] Post infectious glomerulonephritis is still a common entity in tropical and developing countries, and may result in acute renal failure. The incidence is low in Europe and North America but still accounts for up to 10–20% of cases of acute renal failure due to glomerulonephritis in adult and possibly more in children.[[12]], [[13]] In our study among the different histologic type of acute GN contributing to ARF, crescentic GN was the most common (51.8%) followed by endocapillary proliferative glomerulonephritis (34.93%). Both endocapillary PGN and crescentic GN were related to post infectious/post streptococcal etiology. Endocapillary PGN had excellent prognosis with recovery of renal function in 82.75% cases; only 5 (17.25%) patients progressed to chronic renal failure. There was no mortality in this group. In contrast, post infectious crescentic GN had poor prognosis, 55.8% progressed to chronic renal failure with mortality of 18.6%. Renal function returned to normal only in 11 (25.6%). From etiologic standpoint majority (75.9%) of our patients had acute GN of post infectious etiology. Idiopathic GN was seen in 15 (18%) of cases. The glomerulonephritis related to systemic lupus erythematosus and small vessel vasculitis was seen in only 3 and 2 patients respectively. Thus, acute glomerulonephritis in association with small vessel vasculitis, SLE, and anti-GBM disease is rare in our study, which are common in Europe and North America. The outcome of our patients of ARF with glomerulonephritis revealed that, renal function improved in 41 (49.4%) cases, 33 (39.8%) progressed to CRF and became dialysis dependent and 9 (10.8%) patients died. Uncontrolled uremia, pulmonary oedema, hyperkalemia, and sepsis were causes of mortality. The survival in patients with acute glomerulonephritis was 75% and only 50% patients recovered renal function.[[7]] Our result was similar to this study except a low mortality of 10.8%.

Sixty two (7%) cases had acute interstitial nephritis (AIN) leading to intrinsic ARF. Acute interstitial nephritis is one of the common causes of ARF. The incidence of AIN was 8–14% in different series where biopsy was done because of unexplained acute renal failure, and in most the diagnosis was not suspected before biopsy.[[14]], [[15]], [[16]] We have observed ARF in association with acute interstitial nephritis in 7% of cases. Acute interstitial nephritis however can frequently be seen in the setting of systemic infection[[17]], [[18]] and having exposure to different drugs.[[19]], [[20]], [[21]], [[22]] Acute interstitial nephritis has been reported to occur in association with various infectious diseases.[[23]], [[24]], [[25]], [[26]] Renal failure from infection related AIN generally resolves with the treatment of the underlying infection and steroid therapy is usually not recommended or needed. Of the 62 patients with AIN: 33 (53%) cases had drug induced AIN and 25 (40%) patients developed it in association with infections in our study. Thus, infection associated and drug induced acute interstitial were seen in almost equal number of cases in our study. Miscellaneous causes are responsible for AIN in 4 (6.45%) cases such as insect bite. The common offending drugs were ampicillin, co-trimoxazole, NSAIDS, and rifampicin. Acute interstitial nephritis was related to drug in 40–60% of cases.[[27]], [[28]] We had similar observation. Drug induced AIN had excellent prognosis. Renal function returned to normal in all patients after withdrawal of the offending drugs. Schwarz et al. in a recent study noted the infection induced and idiopathic type of acute interstitial nephritis was always reversible. However, today acute interstitial nephritis is mainly drug induced and transition to chronicity occurs only in such cases.[[29]] The incidence of infection induced AIN is decreasing in Europe, and drug induced AIN is becoming the major cause. In a recent study acute interstitial nephritis was found in 6.5% of all biopsies: it was infection induced in 10%, idiopathic in 4% and drug induced in 85% of the cases.[[29]] In contrast infection related AIN was observed in 40% of cases in our study. Renal function improved in 84% of cases and mortality was 12%. As a group acute renal failure patients due to AIN had excellent prognosis; 52 (92%) patients recovered, 4 (6.4%) died and only one patient progressed to chronic renal failure.

Renal cortical necrosis is a rare entity that accounts for only 2% of all cases of acute renal failure in developed countries.[[30]] However it is an important cause of ARF in developing countries with incidence ranging between 3.8–7.1% in patients dialyzed for ARF.[[31]], [[32]] We have reported RCN in 23 (6.3%) patients with acute renal failure in our previous study.[[33]] Obstetric complications were the commonest cause of renal cortical necrosis[[34]], [[35]] and non-obstetric causes account for 20–30% of all cases of cortical necrosis and in these circumstances the incidence is higher in men than in women.[[36]] In the present study 4.6% of intrinsic ARF was due to renal cortical necrosis. In a large series reported from India obstetrical causes account for ACN in 56% of patients. Other causes included snakebites (14.2%), hemolytic uremic syndrome (11.5%), and gastroenteritis (4.4%).[[31]] Of the 41 patients with RCN, obstetrical causes were responsible in 25 (61%) cases and hemolytic uremic syndrome in 16 (39%) patients. The incidence of renal cortical necrosis due to HUS was very high (39%) in our study. Hemolytic uremic syndrome had typical diarrheal prodrome (D + HUS) in 12 (75%) cases and remaining 4 (25%) patients did not have diarrheal disease (D − HUS). Of the 16 patients with HUS; 6 (37.5%) died during acute phase, 4 (25%) progressed to ESRD and renal function improved in 6 (37.5%) patients. Higher mortality in HUS was reported earlier but in recent years mortality rate has decreased.[[37]], [[38]] In our series mortality rate was higher (37.5%) compared to other recent studies. The possible explanation were; all patients had severe ARF at presentation with several uremic complications and most of the patients did not receive plasma exchange. Some of them even could not afford dialysis on account of financial constraints. For similar reasons high mortality (56%) was also noted in the group of patients who had cortical necrosis in association with obstetrical complications.

Thus, overall frequency (20.8%) of intrinsic renal diseases causing ARF in Indian patients is similar to the developed nations. However, spectrum of intrinsic ARF is different in our patients. Post infectious glomerulonephritis, infectious related acute interstitial nephritis, and renal cortical necrosis (complicating HUS in children and obstetric complications in adult) are the major intrinsic renal disease causing acute renal failure. In contrast, post infectious GN and renal cortical necrosis are the rare causes of ARF in Europe and America. Similarly acute glomerulonephritis in association with small vessel vasculitis, SLE, anti-GBM disease are rare in our study, which are common in Europe and North America.