Chronic Glomerulonephritis: Practice Essentials, Pathophysiology, Etiology (original) (raw)

Practice Essentials

Nearly all forms of acute glomerulonephritis have a tendency to progress to chronic glomerulonephritis. The condition is characterized by irreversible and progressive glomerular and tubulointerstitial fibrosis, ultimately leading to a reduction in the glomerular filtration rate (GFR) and retention of uremic toxins. If disease progression is not halted with therapy, the net results are chronic kidney disease (CKD), end-stage renal disease (ESRD), and cardiovascular disease. Chronic glomerulonephritis is the third leading cause of CKD, and accounting for about 10% of all patients on dialysis.

The exact cause of CKD in patients with chronic glomerulonephritis may never be known in some patients. Therefore, it has generally been accepted that the diagnosis of CKD can be made without knowledge of the specific cause. [1]

The National Kidney Foundation (NKF) defines CKD on the basis of either of the following:

Evidence of kidney damage based on abnormal urinalysis results (eg, proteinuria or hematuria) or structural abnormalities observed on ultrasound images
A GFR of less than 60 mL/min for 3 or more months

In accordance with this definition, the NKF developed guidelines that classify the progression of renal disease into five stages, from kidney disease with a preserved GFR to end-stage kidney failure. This classification includes treatment strategies for each progressive level, as follows:

Stage 1 – This stage is characterized by kidney damage with a normal GFR (≥ 90 mL/min); the action plan consists of diagnosis and treatment, treatment of comorbid conditions, slowing of the progressing of kidney disease, and reduction of cardiovascular disease risks
Stage 2 – This stage is characterized by kidney damage with a mild decrease in the GFR (60-90 mL/min); the action plan is estimation of the progression of kidney disease
Stage 3 – This stage is characterized by a moderately decreased GFR (to 30-59 mL/min); the action plan consists of evaluation and treatment of complications
Stage 4 – This stage is characterized by a severe decrease in the GFR (to 15-29 mL/min); the action plan is preparation for renal replacement therapy
Stage 5 – This stage is characterized by kidney failure; the action plan is kidney replacement if the patient is uremic

At the later stages of glomerular injury, the kidneys are small and contracted and biopsy results cannot help distinguish the primary disease. Histology and clues to the etiology are often derived from other systemic diseases (if present). Considerable cause-specific variability is observed in the rate at which acute glomerulonephritis progresses to chronic glomerulonephritis.

The prognosis depends on the type of chronic glomerulonephritis (see Etiology). ESRD and death are common outcomes unless renal replacement therapy is instituted.

Pathophysiology

Reduction in nephron mass from the initial injury reduces the GFR. This reduction leads to hypertrophy and hyperfiltration of the remaining nephrons and to the initiation of intraglomerular hypertension. These changes occur in order to increase the GFR of the remaining nephrons, thus minimizing the functional consequences of nephron loss. The changes, however, are ultimately detrimental because they lead to glomerulosclerosis and further nephron loss.

In early renal disease (stages 1-3), a substantial decline in the GFR may lead to only slight increases in serum creatinine levels. Azotemia (ie, a rise in blood urea nitrogen [BUN] and serum creatinine levels) is apparent when the GFR decreases to less than 60-70 mL/min. In addition to a rise in BUN and creatinine levels, the substantial reduction in the GFR results in the following:

Decreased production of erythropoietin, thus resulting in anemia
Decreased production of vitamin D, resulting in hypocalcemia, secondary hyperparathyroidism, hyperphosphatemia, and renal osteodystrophy
Reduction in acid, potassium, salt, and water excretion, resulting in acidosis, hyperkalemia, hypertension, and edema
Platelet dysfunction, leading to increased bleeding tendencies

Accumulation of toxic waste products (uremic toxins) affects virtually all organ systems. Azotemia occurring with the signs and symptoms listed above is known as uremia. Uremia occurs at a GFR of approximately 10 mL/min. Some of these toxins (eg, BUN, creatinine, phenols, and guanidines) have been identified, but none has been found to be responsible for all the symptoms.

Etiology

The progression from acute glomerulonephritis to chronic glomerulonephritis is variable, depending to a considerable extent on the cause of the condition. Whereas complete recovery of renal function is the rule for patients with poststreptococcal glomerulonephritis, several other glomerulonephritides, such as immunoglobulin A (IgA) nephropathy, often have a relatively benign course, and many do not progress to ESRD. Progression patterns may be summarized as follows:

Focal segmental glomerulosclerosis – About 80% of patients progress to ESRD in 10 years; patients with the collapsing variant (malignant focal segmental glomerulosclerosis) have a more rapid progression; this form may be idiopathic or related to HIV infection
Membranous nephropathy – About 20-30% of patients with membranous nephropathy progress to chronic renal failure (CRF) and ESRD in 10 years
IgA nephropathy – About 10% of patients with IgA nephropathy progress to CRF and ESRD in 10 years [3, 4]
Poststreptococcal glomerulonephritis – About 1-2% of patients with poststreptococcal glomerulonephritis progress to CRF and ESRD; older children who present with crescentic glomerulonephritis are at greatest risk
Lupus nephritis – Overall, about 20% of patients with lupus nephritis progress to CRF and ESRD in 10 years; however, patients with certain histologic variants (eg, class IV) may have a more rapid decline. [5] The presence of antineutrophil cytoplasmic antibody (ANCA) is also an independent risk factor for poor renal outcomes. [6]

Epidemiology

In the United States, chronic glomerulonephritis is the third leading cause of ESRD and accounts for 10% of patients on dialysis.

In Japan and some Asian countries, chronic glomerulonephritis has accounted for as many as 40% of patients on dialysis; however, subsequent data suggest that in Japan, for instance, the rate of chronic glomerulonephritis in patients on dialysis is 28%. [7, 8] The cause of this declining rate is not known. Concurrent with the decline in chronic glomerulonephritis in these countries is an increase in diabetic nephropathy in up to 40% of patients on dialysis.

Patient Education

Dietary education is paramount in managing patients with CKD. The typical dietary restriction is to 2 g of sodium, 2 g of potassium, and 40-60 g of protein a day. Additional restrictions may apply for diabetes, hyperlipidemia, and fluid overload.

Patients should be educated regarding the types of ESRD therapy. The specific choices of ESRD therapy include hemodialysis, peritoneal dialysis, and renal transplantation. For further information, see Mayo Clinic - Kidney Transplant Information.

Patients opting for hemodialysis should be educated on home hemodialysis (in which patients are trained to do their dialysis at home) and center hemodialysis (in which patients come to a center 3 times a week for 3.5- to 4-hour dialysis sessions). They should also be educated on the types of vascular access. Arteriovenous fistulae should be created when the GFR falls below 25 mL/min or the serum creatinine level is greater than 4 mg/dL to allow maturation of the access before the initiation of dialysis.

In the United States and most developed countries, patients on dialysis can travel. In fact, there are even dialysis cruises. However, patients should inform their social workers to make the necessary arrangements beforehand to ensure that the destination has the right resources to continue dialysis.

Sexual dysfunction and loss of libido are common in patients with kidney disease, especially men. Patients should be instructed to seek medical therapy if they experience these symptoms.

Renal failure and hypertension worsen during pregnancy in patients with CKD, particularly when the serum creatinine level exceeds 2 mg/dL, and this leads to decreased fetal viability and increased maternal morbidity in pregnant women with CKD. Therefore, women with CKD should consult their doctors before becoming pregnant. [9, 10]

Kawasaki Y. Mechanism of onset and exacerbation of chronic glomerulonephritis and its treatment. Pediatr Int. 2011 Dec. 53(6):795-806. [QxMD MEDLINE Link].
Sethi S, Nester CM, Smith RJ. Membranoproliferative glomerulonephritis and C3 glomerulopathy: resolving the confusion. Kidney Int. 2011 Dec 7. [QxMD MEDLINE Link].
Goto M, Wakai K, Kawamura T, et al. A scoring system to predict renal outcome in IgA nephropathy: a nationwide 10-year prospective cohort study. Nephrol Dial Transplant. 2009 Oct. 24(10):3068-74. [QxMD MEDLINE Link]. [Full Text].
Schöll U, Wastl U, Risler T, Braun N, Grabensee B, Heering P, et al. The "point of no return" and the rate of progression in the natural history of IgA nephritis. Clin Nephrol. 1999 Nov. 52(5):285-92. [QxMD MEDLINE Link].
Fernandes das Neves M, Irlapati RV, Isenberg D. Assessment of long-term remission in lupus nephritis patients: a retrospective analysis over 30 years. Rheumatology (Oxford). 2015 Aug. 54 (8):1403-7. [QxMD MEDLINE Link].
Wang Y, Huang X, Cai J, Xie L, Wang W, Tang S, et al. Clinicopathologic Characteristics and Outcomes of Lupus Nephritis With Antineutrophil Cytoplasmic Antibody: A Retrospective Study. Medicine (Baltimore). 2016 Jan. 95 (4):e2580. [QxMD MEDLINE Link].
Nakai S, Wada A, et al. An overview of regular dialysis treatment in Japan (as of 31 December 2004). Ther Apher Dial. 2006. 10:476-97. [QxMD MEDLINE Link]. [Full Text].
Research Group on Progressive Chronic Renal Disease. Nationwide and long-term survey of primary glomerulonephritis in Japan as observed in 1,850 biopsied cases. Nephron. 1999. 82(3):205-13. [QxMD MEDLINE Link].
Blowey DL, Warady BA. Outcome of infants born to women with chronic kidney disease. Adv Chronic Kidney Dis. 2007. 14:199-205. [QxMD MEDLINE Link].
Imbasciati E, Gregorini G, Cabiddu G, Gammaro L, Ambroso G, Del Giudice A, et al. Pregnancy in CKD stages 3 to 5: fetal and maternal outcomes. Am J Kidney Dis. 2007. 49:753-62. [QxMD MEDLINE Link].
Idasiak-Piechocka I, Oko A, Pawliczak E, Kaczmarek E, Czekalski S. Urinary excretion of soluble tumour necrosis factor receptor 1 as a marker of increased risk of progressive kidney function deterioration in patients with primary chronic glomerulonephritis. Nephrol Dial Transplant. 2010 Dec. 25(12):3948-56. [QxMD MEDLINE Link].
Hindricks J, Ebert T, Bachmann A, Kralisch S, Lössner U, Kratzsch J, et al. Serum levels of fibroblast growth factor-21 are increased in chronic and acute renal dysfunction. Clin Endocrinol (Oxf). 2014 Jun. 80 (6):918-24. [QxMD MEDLINE Link].
Abou-Mrad RM, Abu-Alfa AK, Ziyadeh FN. Effects of weight reduction regimens and bariatric surgery on chronic kidney disease in obese patients. Am J Physiol Renal Physiol. 2013 Sep 1. 305(5):F613-7. [QxMD MEDLINE Link].
Wolf G. Antiproteinuric response to dual blockade of the renin-angiotensin system in primary glomerulonephritis. Nat Clin Pract Nephrol. 2008 Sep. 4(9):474-5. [QxMD MEDLINE Link].
Tsuruoka S, Kai H, Usui J, Morito N, Saito C, Yoh K, et al. Effects of irbesartan on inflammatory cytokine concentrations in patients with chronic glomerulonephritis. Intern Med. 2013. 52(3):303-8. [QxMD MEDLINE Link].
Wolf G, Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Kidney Int. 2005. 67:799-812. [QxMD MEDLINE Link].
Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008 Apr 10. 358(15):1547-59. [QxMD MEDLINE Link].
Omae K, Ogawa T, Nitta K. Influence of T-calcium channel blocker treatment on deterioration of renal function in chronic kidney disease. Heart Vessels. 2009 Jul. 24(4):301-7. [QxMD MEDLINE Link].
Cho ME, Smith DC, Branton MH, et al. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2007 Sep. 2(5):906-13. [QxMD MEDLINE Link].
de Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM. Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol. 2009 Sep. 20(9):2075-84. [QxMD MEDLINE Link]. [Full Text].
Mahajan A, Simoni J, Sheather SJ, Broglio KR, Rajab MH, Wesson DE. Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy. Kidney Int. 2010 Aug. 78(3):303-9. [QxMD MEDLINE Link].
Goraya N, Simoni J, Jo CH, Wesson DE. A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate. Clin J Am Soc Nephrol. 2013 Mar. 8(3):371-81. [QxMD MEDLINE Link]. [Full Text].
Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008 Jun 5. 358(23):2433-46. [QxMD MEDLINE Link].
Naguib MT. Kidney disease in the obese patient. South Med J. 2014 Aug. 107(8):481-5. [QxMD MEDLINE Link].
Cameron JS. The Long-Term Outcome of Glomerular Diseases. Schrier RW, Gottschalk CW, ed. Diseases of the Kidney. 6th ed. Little, Brown & Company: Boston, Mass; 1997. 1919.
[Guideline] K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002 Feb. 39(2 Suppl 1):S1-266. [QxMD MEDLINE Link].
Murray SL, Dorman A, Benson KA, Connaughton DM, Stapleton CP, Fennelly NK, et al. Utility of Genomic Testing after Renal Biopsy. Am J Nephrol. 2020. 51 (1):43-53. [QxMD MEDLINE Link].
Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG. Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease. Ann Intern Med. 2004 Dec 21. 141 (12):929-37. [QxMD MEDLINE Link].
Hsu CY, Yang W, Parikh RV, Anderson AH, Chen TK, Cohen DL, et al. Race, Genetic Ancestry, and Estimating Kidney Function in CKD. N Engl J Med. 2021 Nov 04. 385 (19):1750-1760. [QxMD MEDLINE Link]. [Full Text].
Andrew S. Levey, Silvia M. Titan, Neil R. Powe, Josef Coresh and Lesley A. Inker. Kidney Disease, Race, and GFR Estimation. CJASN. Aug 2020. 15(8):1203-1212. [QxMD MEDLINE Link]. [Full Text].
L.A. Inker, N.D. Eneanya, J. Coresh, H. Tighiouart, D. Wang, Y. Sang, et al. New Creatinine- and Cystatin C–Based Equations to Estimate GFR without Race. N Engl J Med. 2021 Nov 4. 385(18):1737-1749. [QxMD MEDLINE Link]. [Full Text].
van der Aart-van der Beek AB, de Boer RA, Heerspink HJL. Kidney and heart failure outcomes associated with SGLT2 inhibitor use. Nat Rev Nephrol. 2022 May. 18(5):294-306. [QxMD MEDLINE Link]. [Full Text].
DeFronzo RA, Bakris GL. Modifying chronic kidney disease progression with the mineralocorticoid receptor antagonist finerenone in patients with type 2 diabetes. Diabetes Obes Metab. 2022 July 24. Vol 24 Issue 7:1197-1205. [QxMD MEDLINE Link]. [Full Text].
de Zeeuw D, et al; BEACON Trial Investigators. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013 Dec 26. 369 (26):2492-503. [QxMD MEDLINE Link]. [Full Text].
Nangaku M, Takama H, Ichikawa T, Mukai K, Kojima M, Suzuki Y, et al. Randomized, double-blind, placebo-controlled phase 3 study of bardoxolone methyl in patients with diabetic kidney disease: Design and baseline characteristics of AYAME study. Nephrol Dial Transplant. 2022 Aug 24. [QxMD MEDLINE Link]. [Full Text].

Author

Moro O Salifu, MD, MPH, MBA, MACP Associate Professor, Department of Internal Medicine, Chief, Division of Nephrology, Director of Nephrology Fellowship Program and Transplant Nephrology, State University of New York Downstate Medical Center

Moro O Salifu, MD, MPH, MBA, MACP is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society for Artificial Internal Organs, American Society of Diagnostic and Interventional Nephrology, American Society of Nephrology, American Society of Transplantation, National Kidney Foundation