Kidney disease caused by multiple myeloma

　　The etiology of multiple myeloma (MM) has not been fully elucidated and may be related to genetic factors, viral infection, ionizing radiation, chronic antigenic stimulation, and other factors. Recent research has found that C-myc gene rearrangement, some with high levels of H-ras gene protein products, and abnormal regulation of lymphokines, especially interleukin-6 secretion, are related to the occurrence of MM. The related factors causing renal damage in MM include:

　　1. Large amounts of light chain protein cause renal tubular damage. Myeloma cells produce a large amount of abnormal monoclonal immunoglobulin, of which the immunoglobulin light chain, due to its large molecular weight, can be filtered through the glomerulus and enter the renal tubules in large quantities, far exceeding the maximum reabsorption rate of the renal tubules. The excessive light chain protein excreted in the urine is called overflow proteinuria. The maximum feature of MMN is the presence of a large amount of light chain immunoglobulin in the renal tubules, forming special casts, causing obstruction of casts in the renal tubules, and can also cause damage to renal tubules.

　　2. In addition to secreting monoclonal immunoglobulin, osteoclast activation factors are also secreted by osteolytic tumor cells, which stimulate osteoclasts to produce localized bone resorption, causing an increase in calcium entering the blood. In addition, osteoblast activation is suppressed at the site of the myeloma lesion. These factors can all lead to hypercalcemia, hypercalciuria, and cause renal tissue and renal function damage. Hypercalcemia and hypercalciuria promote the deposition of calcium salts in the renal tubules and interstitium, causing renal calcium deposition disease. Widespread calcium deposition leads to a decrease in renal concentrating function. High concentrations of calcium salts in the renal tubules can polymerize with BJP to form casts or form calculi, further damaging renal tubular function. Therefore, hypercalcemia and light chain protein are considered to be the main pathogenic factors of MMN.

　　3. In patients with uric acid nephropathy in multiple myeloma, due to the destruction of tumor cells or chemotherapy, the enhanced nucleic acid decomposition metabolism leads to excessive production of blood uric acid, resulting in secondary hyperuricemia. Long-term hyperuricemia can easily cause uric acid deposition in the renal medulla under low oxygen and low pH conditions, damaging the tubular interstitium. In addition, uric acid crystals not only damage renal tubular epithelial cells but also block renal tubular lumens, forming renal internal obstruction and causing obstructive nephropathy.

　　4. The bone marrow is the main organ for the production of plasma cells, so the primary site of MM is mainly in the bone marrow. In addition to the bone marrow, lymph nodes, spleen, gastrointestinal tract, and submucosal lymphatic tissue of the upper respiratory tract can also produce plasma cells, becoming primary lesions. In addition to the primary lesion site, tumor cells can also widely infiltrate other tissues and organs, such as the kidney, lung, gastrointestinal tract, heart, thyroid, testis, ovary, uterus, adrenal glands, and subcutaneous tissue. The infiltration of tumor cells into the renal parenchyma can cause damage to renal tissue. It is generally believed that direct infiltration of tumor cells into renal tissue is less common. Once affected, the renal volume can increase significantly.

　　5. In multiple myeloma with renal amyloidosis, the complex of monoclonal immunoglobulin light chains and polysaccharides deposits in tissue and organs, causing amyloidosis and leading to corresponding clinical manifestations such as tongue hypertrophy, liver and spleen enlargement, cardiac dilation, peripheral neuropathy, and renal dysfunction. It can lead to renal amyloidosis, with amyloid fibers mainly deposited in the glomerular basement membrane, mesangium, renal tubular basement membrane, and interstitium, eventually leading to renal failure.

　　6. Hyper viscosity syndrome Myeloma cells secrete a large amount of monoclonal immunoglobulins, which increase blood viscosity, causing renal hemodynamics and microcirculatory disorders.

　　7. Cryoglobulinemia Abnormal immunoglobulins have the characteristic of cold precipitation, which is prone to aggregate in the glomerular capillaries, leading to renal damage.

　　8. Urinary tract infection MM patients have low systemic resistance and are prone to associated urinary tract infections. The reasons for the decreased systemic resistance are: first, immune deficiency, myeloma cells secrete certain substances that inhibit the function of macrophages, causing the normal synthesis of immunoglobulins mediated by them to be suppressed; second, the abnormal light chain protein secreted by myeloma cells damages the phagocytic and opsonic effects of granulocytes in the blood circulation. In addition, local factors leading to urinary tract infection include urinary casts and uric acid crystal blockage of the renal tubules, obstruction caused by urinary tract stones, and decreased local resistance of the urinary tract mucosa.

　　The common complications of multiple myeloma kidney disease mainly include pneumonia, sepsis, urinary tract infection, renal amyloidosis, renal failure, and tubular acidosis. Pathological fractures may also occur. Patients with renal function damage in this disease may develop chronic renal failure, hyperphosphatemia, hypercalcemia, and uric acid stones may form when hyperuricemia occurs.

　　Multiple myeloma kidney disease is generally caused by multiple myeloma disease, multiple myeloma diseasePatients will eventually show clinical manifestations of renal damage throughout the course of the disease, among whom about half of the patients present with proteinuria or renal insufficiency as the first complaint, followed by symptoms such as bone marrow damage and anemia. Clinically, it is easy to misdiagnose or miss the diagnosis. These patients are often misdiagnosed as chronic glomerulonephritis. The main clinical characteristics of this disease are summarized as follows:.

　　1. Pure proteinuria type:Proteinuria is an early manifestation of myeloma kidney disease, and some patients may only present with proteinuria, with other symptoms of myeloma or renal insufficiency appearing several years later, hence it is prone to be misdiagnosed as glomerulonephritis, asymptomatic proteinuria, or latent nephritis. Some believe that myeloma often has a symptom-free period of about 20 years, known as the premalignant stage of myeloma, with only persistent proteinuria. These cases are likely to have evolved from primary benign monoclonal immunoglobulin disease. The main component of urinary protein is light chain protein, also known as Bence-Jones protein. A distinct low molecular weight protein band [at a molecular weight of (2.2～4.4)×10^4D] can be seen in the disc electrophoresis of urinary protein. When light chain protein damages the proximal tubule, in addition to light chain protein, β2 microglobulin, lysozyme, and albumin also appear in the urine. As more middle molecular weight proteins and high molecular weight proteins appear, it indicates that the lesion has involved the glomerulus. The amount of urinary protein can vary greatly, from a few grams to more than ten grams per 24 hours, occasionally reaching 20g, and the highest reported abroad can reach 70g.

　　2. Nephrotic syndrome type:This clinical type is relatively rare. If it appears with typical nephrotic syndrome, most cases are accompanied by renal amyloidosis, immune-mediated glomerulonephritis, or light chain-induced nodular glomerulosclerosis. It should be noted that these patients excrete a large amount of monoclonal light chain protein in their urine, over 3.5g/d, poor nutrition leads to decreased serum albumin, and misdiagnosis as primary nephrotic syndrome. However, the urine of these patients often shows negative results in urine protein dipstick test, while urine protein qualitative test by acetic acid heating method or Coomassie brilliant blue method shows 3+ to 4+, and the electrophoresis of urine protein shows less albumin and significantly increased globulin.

　　3. Tubular dysfunction type:Renal damage in MM patients is mainly in the renal tubules, which is the earliest and most common. Renal damage caused by the obstruction of the distal renal tubules by light chain protein casts is called myeloma cast nephropathy. Light chain protein-induced toxic damage in the proximal tubular epithelial cells is also known as light chain nephropathy. The light chain protein in the urine is mainly κ-type. During the course of MM, secondary hyperuricemia, hypercalcemia, and amyloidosis can all lead to tubular dysfunction. Clinically, it often presents as Fanconi syndrome, which may occur several years before the symptoms of myeloma appear. The clinical characteristics are aminoaciduria, glucosuria, phosphaturia, bicarbonateuria, and proteinuria below 50kD molecular weight, accompanied by tubular acidosis and diuretic hormone-resistant polyuria. In addition, renal osteodystrophy, osteoporosis, and hypokalemia may also occur, and some may appear alone in the form of type I tubular acidosis.

　　4. Acute renal function failure:About half of the patients with MM suddenly develop acute renal failure during the course of the disease. The pathogenesis is comprehensive, and it is usually not caused by a single factor. Chronic tubular damage is the basis, and light chain protein plays an important role. However, half of the acute renal failure is reversible, and the main诱发factors areDehydration and insufficient blood volume caused by various reasons, such as vomiting, diarrhea, or diuresis, etc.;. Patients with hyperuricemia may experience a sudden increase in blood uric acid after chemotherapy, leading to acute uric acid nephropathy;. Severe infection;. Use of nephrotoxic drugs, such as aminoglycoside antibiotics, antipyretic analgesics, and contrast agents, etc..

　　5. Chronic renal function failure:Late-stage myeloma patients will develop chronic renal failure, with myeloma cells directly infiltrating the renal parenchyma. Long-term damage to the renal tissue caused by light chain protein-induced tubular and glomerular damage, renal amyloidosis, hyperuricemia, hypercalcemia, and hypercoagulability, etc., can ultimately lead to tubular and glomerular dysfunction, resulting in severe anemia, nausea, vomiting, anorexia, polyuria, nocturia, and other chronic uremic syndromes. Renal damage in this disease is mainly manifested in the interstitial space of the renal tubules, so there is often no hypertension in chronic renal failure, and even if there is, it is usually not severe.

　　Multiple myeloma and kidney disease is caused by multiple myeloma, which is a malignant tumor. When the myeloma cells infiltrate and cause renal lesions, the condition is often irreversible. The purpose of prevention is to delay the progression of the disease and prolong the survival time of patients. The main preventive measures are active anti-infection treatment, strengthening the treatment of the primary disease and symptomatic treatment. For patients with acute renal failure, in addition to active chemotherapy and dialysis, plasma exchange therapy should be performed at the same time.

　　Multiple myeloma and kidney disease should be examined by blood examination, renal function examination, urine examination, and bone marrow examination, etc., as follows:

　　1, Blood examination

　　Blood examination, such as peripheral blood count and determination of abnormal globulins.

　　2, Renal function examination

　　Abnormal renal function, BUN > 10.71 mmol/L (30 mg/dl), serum Cr > 176.8 μmol/L (2 mg/dl).

　　3, Urine examination

　　Urine examination shows significant hyperuricemia, aminoaciduria, glucosuria, phosphaturia, bicarbonate uria, and proteinuria below 50kD molecular weight. The patient excretes a large amount of monoclonal light chain protein, more than 3.5g/d. Poor nutrition reduces serum albumin, and misdiagnosis as primary nephrotic syndrome. Urine protein dipstick test is often negative, while urine protein qualitative test using acetic acid heating method or Coomassie brilliant blue method is 3+ to 4+. The albumin is less on urine protein electrophoresis, while the globulin is significantly increased.

　　4, Bone marrow examination

　　Bone marrow examination has a significant diagnostic meaning. In the early stage of the disease, bone marrow lesions can present as focal or nodular distribution. A single negative examination cannot exclude the disease, and it is advisable to perform multiple punctures. The nucleated cells in the bone marrow are usually hyperplastic or significantly hyperplastic. When plasma cells are above 10%, accompanied by morphological abnormalities, the possibility of multiple myeloma should be considered.

　　5, X-ray examination

　　X-ray examination shows diffuse osteoporosis, bone destruction, and pathological fractures.

　　Patients with multiple myeloma and kidney disease, in addition to general treatment, should also pay attention to dietary regulation.

　　1, Eel bone marrow soup:One eel (intestines removed), 150 grams of pork spinal cord, 3 slices of ginger, add water together and cook until tender, season with salt and eat. Suitable for yin deficiency and physical fatigue.

　　2, Panax ginseng stewed black chicken:Panax ginseng 12-15 grams, 250 grams of black chicken (skin and bones removed), 3 slices of ginger, put into a steaming pot and add an appropriate amount of clear water, steam for 2 hours, season with salt and eat. Suitable for qi deficiency and physical fatigue.

　　3, Angelica sinensis ginger mutton soup:Angelica sinensis 30 grams, mutton 250 grams, 15 grams of ginger, and add an appropriate amount of water to cook until the mutton is tender, season with salt and eat the meat and drink the soup. Suitable for blood deficiency and physical fatigue.

　　4, Stewed dog meat with shu fuzi and ginger:Shu fuzi 15-20 grams, dog meat 500-1000 grams (cut into pieces), 15 grams of ginger, and appropriate amount of garlic. First, use garlic, ginger, and peanut oil to heat the pot, then add water and shu fuzi, and cook for 2 hours until the dog meat is tender, season and eat in multiple meals. Suitable for yang deficiency and physical fatigue.

　　The treatment principle for multiple myeloma kidney disease should be to prevent and treat infections and to carry out reasonable treatment for factors related to renal damage.

　　1. Maintain sufficient urine volume:This disease often exists with light chain proteinuria, hypercoagulability, hypercalcemia, and hyperuricemia. These are the main factors causing renal damage. Adequate water intake, maintaining sufficient urine volume, is conducive to the excretion of light chain protein, uric acid, and calcium salts, preventing the formation of casts in the renal tubules and collecting ducts. More water should be drunk when mild dehydration occurs, and intravenous fluid replacement may be necessary if needed. More water should be supplemented during and after chemotherapy or radiotherapy.

　　2. Prevention and treatment of uric acid nephropathy:It is particularly valuable to take it during hyperuricemia, especially in the first few months after chemotherapy, as alkalinization of urine can reduce the deposition of uric acid and light chain protein in the kidneys and the formation of casts.

　　3. Prevention and treatment of hypercalcemia:Hypercalcemia itself can cause renal damage, and the nephrotoxicity is enhanced when it coexists with light chain protein. The risk of hypercalcemia crisis may occur when the blood calcium level acutely increases beyond 3.2mmol/L (13mg/dl), at which time the patient may suddenly experience extreme fatigue, abdominal colic, drowsiness, convulsions, and coma, even cardiac arrest. Therefore, it is of great importance to correct the blood calcium level in a timely manner.

　　Sufficiently replenishing normal saline can achieve expansion of blood volume and promote calcium excretion. Rapid intravenous infusion of isotonic saline (5-10L/d) can be administered, while furosemide (Lasix) 100-200mg is injected every hour, which can effectively reduce the serum calcium level. It is noteworthy that at this time, potassium and magnesium are also excreted from the urine in large quantities, which may lead to hypokalemia and hypomagnesemia, and should be supplemented in a timely manner, usually by adding 20-40mmol/L potassium and 0.6-1.2mmol/L magnesium to isotonic saline.

　　Oral prednisone 60-100mg/d can reduce the absorption of calcium in the intestines, increase urinary calcium excretion, and significantly reduce the serum calcium level after several days. Phosphate salts are effective for hypercalcemia caused by various reasons, and a 0.1mol phosphate salt mixture (containing 0.08mol disodium phosphate and 0.02mol sodium dihydrogen phosphate) of 500ml is commonly administered intravenously. For mild cases, oral phosphate 3-6g/d can be taken. Caution should be exercised for those with blood phosphorus levels exceeding 1.6mmol/L (5mg/dl).

　　When the serum calcium level exceeds 3.2mmol/L, Mithramycin (25μg/kg) can be administered intravenously to reduce the serum calcium level to normal within one day and maintain it for several days; Calcitonin (50-100 MRC units) can be administered intravenously or intramuscularly every 6 hours, which can quickly reduce the serum calcium level, but hypercalcemia may reappear a few hours after discontinuation of the drug. In addition, prostaglandin synthase inhibitors such as indomethacin (anti-inflammatory) or aspirin are often used for hypercalcemia associated with various malignant tumors, but caution should be exercised when severe renal insufficiency is present.

　　4. Antimicrobial Therapy:MM patients are prone to various infections, especially within the first two months after the initial chemotherapy, where the infection rate increases fourfold. Common infection sites are the respiratory tract (pneumonia) and urinary tract (pyelonephritis), which are prone to develop into sepsis and cause death. The use of multivalent pneumonia vaccines and human blood gamma globulin as preventive measures is often ineffective. Therefore, these patients should be closely monitored, and hidden infections or early infection signs should be detected, and effective antibiotics should be used for active treatment. It should be avoided to use nephrotoxic antibiotics, and it should also be noted that the use of antibiotics for preventive infection is often not beneficial.

　　5. Hemodialysis Treatment:More than half of MM patients will develop acute renal failure, and some patients may have concurrent refractory hypercalcemia (or crisis). These complications should all be treated with dialysis therapy. Whether hemodialysis or peritoneal dialysis, both can quickly turn the patient's critical condition around, gain time, and undergo chemotherapy. Peritoneal dialysis is more effective in clearing free light chain proteins than hemodialysis, so some scholars believe that performing peritoneal dialysis before hemodialysis is better. However, peritoneal dialysis is prone to infection, and hemodialysis has more cardiovascular problems, especially in elderly patients. In addition, MM patients with acute renal failure all have a large amount of monoclonal Ig and its fragments (i.e., light chain proteins) in their blood. Dialysis therapy can only remove part of the light chains. Therefore, to extend the patient's life, in addition to active chemotherapy and dialysis, plasma exchange therapy should also be performed. Whether MM patients with irreversible renal failure can undergo kidney transplantation mainly depends on whether the patient's choice is appropriate. The patient's MM condition must be completely stationary before transplantation. If the lesions are active, the transplanted kidney will quickly develop renal insufficiency. The main cause of death after transplantation is still infection. Most transplanted kidneys can maintain renal function, and a few transplanted kidneys also have light chain protein deposition.