Myeloma Nephropathy

What is Myeloma Nephropathy?

As for the pathogenesis of myeloma nephropathy, it consists primarily in damage to the renal nephrons by pathological (abnormal) proteins – paraproteins. Given this, myeloma nephropathy in its origin is considered as a classic example of “nephrosis of discharge” (G. A. Alexeev, 1970). Specific to true myeloma kidney is considered to be the deposition of precipitates of pathological myeloma proteins in the distal tubules with blockage and damage to the latter. At the same time, the Bens-Jones micromolecular proteins synthesized by myeloma cells enter the blood flow, reach the kidneys and easily pass through an intact glomerular filter. In the lumen of the tubules, where the liquid has an acid reaction, the protein masses filtered in the glomeruli coagulate, forming a large number of cylinders, leading to obstruction of the lumen of the distal tubules. As a result, the intratubular pressure increases in the overlying (proximal) sections of the tubules with the expansion of their lumen and the development of the so-called intrarenal hydronephrosis (nephrogidrosis). In addition, pathological proteins partially reabsorbed by the tubular epithelium penetrate the interstitial tissue, causing swelling of the renal stroma, lymph stagnation with the appearance of lymphocytic infiltrates, i.e., an inflammatory process in the interstitial tissue (interstitial nephritis). Subsequently, hyalinosis and interstitial sclerosis develop, followed by the death of the glomeruli, nephrons, and nephrotic shrinkage of the kidneys. Damage to the tubules can cause the development of nephrotic syndrome.

All other lesions of the nights detected in multiple myeloma are non-specific. Thus, pyelonephritis may occur as a result of an infection. Approximately 5-25% of patients develop kidney amyloidosis. Metabolic disorders often lead to the development of not only interstitial nephritis, but also nephrocalcinosis and urolithiasis.

Pathogenesis during Myeloma Nephropathy

Macroscopically, the kidneys with myeloma nephropathy are enlarged, of a dense consistency, of an intense red color. On the incision, an edematous medulla protrudes. In some cases, the kidneys can be reduced in size and shriveled.

Histologically, the main changes are found in the distal tubules. Most characteristic of the myeloma kidney is an abundance of cylinders in the extended lumen of the tubules, in some areas – with the deposition of calcium (calcareous cylinders). The appearance of these cylinders is associated with the precipitation of the Bens-Jones protein. In some cases, most of the tubules are filled with homogeneous protein masses. Occasionally, cylinders of characteristic flaky shape are surrounded on the periphery by giant cells such as resorption cells of foreign bodies. The tubular epithelium undergoes significant changes in the form of hyaline-vacuole, vacuole and granular dystrophy, and is easily exfoliated. These changes in the epithelium develop predominantly in the proximal sections of the tubules, where reabsorption of the Bens-Jones protein occurs, which is believed to have a direct damaging effect on epithelial cells. In some cases, deposits of paraproteins are found in the glomeruli, interstitial tissue and around the vessels.

However, it should be noted that the renal glomeruli with myeloma nephropathy almost do not undergo pathological changes, except in those cases that are accompanied by the development of amyloidosis. Fibrosis and cellular infiltrates are detected in the interstitial tissue (at least 50% of cases). Kidney vessels, like the glomeruli, with true myeloma kidney remain practically intact. In severe and prolonged hypercalcemia, nephrocalcinosis and the formation of stones develop (approximately 10% of cases). Since myeloma develops predominantly in elderly people, atherosclerosis of the renal vessels is often found, and the possibility of kidney ischemia is associated with this. Disturbances of lymph circulation and blood circulation noted in the future lead to the death of nephrons and the development of nephrosclerosis with the clinical picture of chronic renal failure. It should be noted that in individual patients, regardless of the severity of clinical and laboratory manifestations of myeloma nephropathy in the kidneys, no significant changes are found.

Symptoms of Myeloma Nephropathy

The clinical picture of myeloma nephropathy is characterized by significant diversity. It depends on the nature of the pathological changes in the kidneys, and on the symptoms of damage to other organs and systems, mainly the skeletal system. The earliest and most persistent sign of myeloma kidney is proteinuria, which is found in 65-100% of patients. Its expression varies widely – from traces of protein to 3.3-10 g / l, and sometimes it reaches 33 g / l and even 66 g / l. There have been cases where persistent, persistent proteinuria has been the only symptom of myeloma for many years. Sometimes proteinuria may well precede the appearance of other symptoms of this disease. In such cases, the disease takes a long time under the guise of chronic glomerulonephritis with isolated urinary syndrome. Using electrophoresis of urine proteins (from its daily volume) on paper or in a starch gel, as well as immunoelectrophoresis, it is possible to establish the micromolecular (Bens-Jones protein) nature of myeloma uroprotein in the form of a monoclonal peak (“M” gradient), similar to the peak on electrophoregram serum proteins. Bens-Jones uroprotein is detected electrophoretically in the urine of 95% of myeloma patients (GA A. Alekseev, 1970). Therefore, in each case, proteinuria of unclear etiology, especially in the elderly, as a rule, it is necessary to carry out electrophoresis of urine proteins, that is, to investigate the uroproteinogram. For uroproteinograms of patients with myeloma nephropathy, in contrast to proteinuria of other origin, globulins prevail over albumin with a “peak of globulinuria”. Considering the above, the qualitative characterization of urine proteins with the help of the methods mentioned above has only an important diagnostic value.

For myeloma nephropathy, the detection of Bens-Jones protein in urine is characteristic. However, in a typical study by heating urine to 50-60 ° C, Bens-Jones protein is detected only in 30-40% of patients. Meanwhile, finding it has not only diagnostic, but also prognostic significance, since the persistent presence of this protein in the urine may indicate the imminent development of irreversible renal failure. The Bens-Jones protein makes up the bulk of urine proteins and its daily excretion can reach 20 g or more (I. Ye. Tareeva, N. A. Mukhin, 1986). Hyaline cylinders are constantly detected in the urine sediment, less often granular and epithelial cylinders, and in the case of pyelonephritis leukocyturia is detected. Hematuria is not characteristic of the myeloma kidney, and only in rare cases there is a slight erythrocyturia (3-10 erythrocytes in sight). Approximately 1/3 of patients observed phosphaturia and alkaline urine.

Edema, arterial hypertension and changes in the fundus vessels are not characteristic of myeloma nephropathy and are usually absent, even with the development of renal failure. Blood pressure, as a rule, does not increase and tends to decrease as the disease progresses. Edema is possible only in those rare cases when myeloma nephropathy manifests itself in the form of renal amyloidosis with nephrotic syndrome.

Clinically, myeloma nephropathy occurs as a kind of “nephrosis of discharge” with relatively quickly (subacute) developing renal failure, which manifests itself as polyuria, decreased glomerular filtration, hyperazotemia, and results in a lethal outcome due to azotemic uremia. Renal failure in multiple myeloma occurs in 20-40% of patients and is regarded as the second most common cause of death for these patients (after infectious complications). The development of renal failure is usually preceded by more or less prolonged proteinuria with the presence of Bens-Jones protein in about 1/3 of the patients. It is interesting to note that in the absence of this protein in the urine, renal failure does not develop even with pronounced and prolonged proteinuria. In addition to the Bens-Jones protein, which has a nephrotoxic effect on the tubular epithelium, the mechanism of development of renal failure, the obstruction of the tubule lumen (tubular obstruction), as well as such factors as hypercalcemia, hyperuricemia, increased blood plasma viscosity, nephrocalcinosis and development individual cases of plasmacytic infiltrates.

Proteinuria and chronic renal failure are the most common and characteristic manifestations of myeloma nephropathy. Other renal syndromes and symptoms are less common (acute renal failure, nephrotic syndrome, Fanconi syndrome).

In some cases, as the initial manifestation of myeloma nephropathy, an arrester may develop. The causes of its occurrence are various: most often as a result of blocking the tubules with protein precipitates or calcium crystallization (nephrocalcinosis). For example, cases of the development of acute renal failure in patients with myeloma disease immediately after intravenous (excretory) urography, which was carried out to clarify the cause of proteinuria of unclear genesis, are described. ARF in such cases is very difficult and mostly fatal. Therefore, if you suspect a multiple myeloma, and even more so if the diagnosis of this disease is already established, excretory urography is contraindicated in such patients.

Nephrotic syndrome, as already noted, with myeloma is rare and usually results from the addition of amyloidosis.

In some cases, when myeloma nephropathy occurs with severe lesions of the tubules, pronounced dysfunction of the latter develops with a violation of their partial functions. As a result, glucosuria, aminoaciduria, phosphaturia, hypokalemia, and hypostenuria, i.e., signs characteristic of Fanconi syndrome, which often complicates myeloma, may appear.

Treatment of myeloma nephropathy, as well as the myeloma disease itself, is chronic, steadily progressive, with the development of chronic renal failure, which in about 1/3 of cases is the direct cause of death. In diffuse forms of myeloma with a total lesion of the bone marrow, severe anemia and hemorrhagic diathesis are the cause of death. In other cases, death occurs with symptoms of general cachexia or due to complications associated with multiple bone fractures, such as pneumonia with rib fractures, urosepsis due to vertebral compression fractures.

The average duration of the disease from the beginning of its first clinical and laboratory manifestations is 2-5 years and only in some uncomplicated cases reaches 6-10 years.

Diagnosis of Myeloma Nephropathy

It is very difficult to diagnose myeloma nephropathy, especially in cases where it is the first or main syndrome of myeloma. Kidney damage, accompanied by isolated and persistent proteinuria, often occurs under the guise of glomerulonephritis, amyloidosis, or pyelonephritis. The lifetime clinical diagnosis of such variants of myeloma is very difficult, and diagnostic errors reach 30-50% (A. P. Peleshchuk, 1983). The presence of anemia and an increase in ESR at first do not find a proper explanation, and only in the late stage of the disease is it given a retrospective correct assessment.

It is necessary to think about the possibility of a myeloma kidney even in cases when proteinuria arises as if “unreasonably” (without preceding sore throat, if there is no indication in the history of acute glomerulonephritis, chronic suppurative diseases, etc.) in combination with anemia, high ESR, especially if such a combination is observed in persons older than 40-45 years, in the absence of edema, hypertension, hematuria, and in the presence of hyperproteinemia and hypercalcemia. The diagnosis is more convincing if the mentioned symptoms develop against the background of bone pathology, that is, against the background of bone pain.

To clarify the diagnosis, it is necessary to examine the urine for Bens-Jones protein, conduct an x-ray of the bones (skull, ribs, iliac, vertebrae), electrophoresis of blood and urine proteins (in order to detect the myeloma-specific M-fraction or M-gradient) and finally a sternal puncture. As for the puncture biopsy of the kidney, the diagnostic value of this method is controversial, since the morphological changes in the kidneys with myeloma disease are characterized by great diversity, and it is not always possible to establish the specific signs of myeloma kidney. At the same time, needle biopsy of the kidney eliminates amyloidosis and glomerulonephritis.

Chronic renal failure caused by myeloma kidney, unlike CRF of a different etiology (in particular, glomerulonephritis), is not accompanied by the development of arterial hypertension and hypocalcemia. The level of calcium in the blood of such patients is always elevated, including in the stage of chronic renal failure. With the development of canalicular acidosis in the blood, the level of sodium and chlorine increases and the content of potassium decreases, whereas with urine the daily excretion of sodium, chlorine, calcium, phosphorus decreases and the excretion of potassium increases.

Treatment of Myeloma Nephropathy

To date, there are no reliable methods and. treatment of myeloma. Nevertheless, the use of complex therapy with the use of cytostatics (sarkolysin, cyclophosphamide, etc.) in combination with glucocorticoids and anabolic hormones allows in many cases to achieve a long (up to 2-4 years) clinical remission and, consequently, an increase in the patient’s life expectancy, temporary recovery his physical activity and even work capacity (for people not engaged in physical labor).

However, cytostatics and glucocorticoids can be prescribed only in the absence of signs of renal failure. In patients with myeloma nephropathy in the stage of chronic renal failure, the use of these drugs is contraindicated. In such cases, symptomatic therapy is carried out (as in the case of CRF of a different etiology). Peritoneal dialysis and hemodialysis are not recommended. In some cases, using plasmapheresis. Not shown so sick and kidney transplantation.

For the correction of hypercalcemia observed in myeloma kidney, corticosteroids, diuretics, calcitonin are prescribed; recommend abundant fluid intake (in order to combat dehydration and increase diuresis). With the development of hyperuricemia, allopurinol is indicated. The use of detoxification solutions, blood transfusions and red blood cells are also used.